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PROG: 1 UNIQUE IDENTIFIER DRG-0347 NAME OF SUBSTANCE Varicella-Zoster Immune Globulin [USPD 2000; p 753] MANUFACTURERS 0000005210: American Red Cross National Headquarters Biomedical Services Arlington, VA 222093100 Contact: Unspecified (800)446-8883 ENTRY MONTH 200105 LAST REVISION DATE 20010523 2 UNIQUE IDENTIFIER DRG-0346 NAME OF SUBSTANCE Sirolimus [USPD 2000; p 651] SYNONYMS Rapamune [USPD 2000; p 651] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 ENTRY MONTH 200105 LAST REVISION DATE 20010523 3 UNIQUE IDENTIFIER DRG-0345 NAME OF SUBSTANCE Mycophenolate mofetil [USPD 2000; p 481] PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5105 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 ENTRY MONTH 200105 LAST REVISION DATE 20010523 4 UNIQUE IDENTIFIER DRG-0344 NAME OF SUBSTANCE Tacrolimus [USPD 2000; p 682] MANUFACTURERS 0000003335: Fujisawa Healthcare Inc Parkway Center North / 3 Parkway North Deerfield, IL 600152548 Contact: Medical Information (800)727-7003 ENTRY MONTH 200105 LAST REVISION DATE 20010523 5 UNIQUE IDENTIFIER DRG-0343 NAME OF SUBSTANCE Carbopol polymer [Protocol ID: HPTN 032 ] SYNONYMS BufferGel [Protocol ID: HPTN 032 ] PROTOCOL ID NUMBERS Not yet recruiting NIAID HPTN 032 MANUFACTURERS 0000005547: ReProtect LLC 703 Stags Head Road Baltimore, MD 21286 MANUFACTURERS 0000005547: ReProtect LLC 703 Stags Head Road Baltimore, MD 21286 REFERENCES MED/11170957. Mayer K, Peipert J, Fleming T, Fullem A, Moench T, Cu-Uvin S, Bentley M, Chesney M, Rosenberg Z. Safety and tolerability of Buffergel, a novel vaginal microbicide, in women in the United States. Clin Infect Dis. 2001 Feb 1;32(3):476-82. MED/11176265. Van De Wijgert J, Fullem A, Kelly C, Mehendale S, Rugpao S, Kumwenda N, Chirenje Z, Joshi S, Taha T, Padian N, Bollinger R, Nelson K. Phase 1 trial of the topical microbicide BufferGel: safety results from four international sites. J Acquir Immune Defic Syndr. 2001 Jan 1;26(1):21-7. GWAIDS/0004337. Van de Wijgert J, Fullem A, Kelly C, Mehendale S, Kumwenda N, Rugpao S, Joshi S, Taha T, Nelson K, Padian N. Phase 1 trial of the topical microbicide bufferGel: safety results from four international sites. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. ThPeC5291. GWAIDS/0001753. Bentley M, Fullem A, Srirak N, Jogelkar N, Khumalo-Sakutukwa G, Mwafulirwa L, Celentano D, Kelly C, Rosenberg Z, Nelson K. Acceptability of a novel microbicide, BufferGel, during a phase I safety trial in four international sites. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. TuPpC1170. GWAIDS/0004268. Srirak N, Sirirojn B-O, Rugpao S, Srisomboon J, Celentano D, Wongthanee A, Wichajarn M, Nelson K, Khamboonruang C. Side-effects of application of Buffergel, a candidate vaginal microbicide: experiences from Thailand. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. ThOrC662. Boskey E, Jansen A, Merski M, Whaley K, Moench T, Cone R. Buffergel favors in vitro growth of lactobacilli while inhibiting BV-associated organisms. Microbicides Conf. 2000 March 13-6;1: abstract no. A07. Co-Uvin S, Chapman S, Mayer K, Rodriguez I, Moench T. Treatment of bacterial vaginosis with an acidic buffering gel (Buffergel): pilot study. Microbicides Conf. 2000 March 13-6;1: abstract no. B08. AIDS/20710150. Mayer KH. The safety and acceptability of BufferGel, a new vaginal microbicide. Natl HIV Prev Conf. 1999 Aug 29-Sep 1;:(abstract no. 219). AIDS/20712025. Jansen AM, Moench TR, Whaley KJ, Cone RA. Bacteria associated with bacterial vaginosis are killed in vitro by mild acidity (pH 4) and by BufferGel, a spermicidal microbicide. Abstr Gen Meet Am Soc Microbiol. 1999 May 30-Jun 3;99:26 (abstract no. A-124). ENTRY MONTH 200105 LAST REVISION DATE 20010511 6 UNIQUE IDENTIFIER DRG-0342 NAME OF SUBSTANCE Z-100 [Protocol ID: 85D10104 ] REGISTRY NUMBER 64060-36-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed April 17, 2001.] SYNONYMS Ancer 20 [Protocol ID: 85D10104 ] PROTOCOL ID NUMBERS Recruiting FDA B014 DISEASES STUDIED/TREATED Z-100 is included in an HIV clinical trial to determine whether it can decrease the amount of HIV-1 and whether it can increase the number of CD4 lymphocytes in HIV-infected patients. [Communication. Email from representative at Quintiles, the organization submitting FDA protocol.] CLASSIFICATION CODE Immunomodulator [Communication. Email from representative at Quintiles, the organization submitting FDA protocol.] OTHER MAJOR USES Z-100 was developed and is marketed in Japan as an immunomodulator in patients undergoing radiation treatments. [Communication. Email from representative at Quintiles, the organization submitting FDA protocol.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Z-100 is an immunotherapeutic anticancer agent prepared from the extract of Mycobacterium tuberculosis strain of Aoyama B. [NLM. Medical Subject Headings (MeSH) Browser. Available at: http://www.nlm.nih.gov/mesh/MBrowser.html. Accessed April 17, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection. [Protocol ID: 85D10104 ] MANUFACTURERS 0000005539: Zeria Pharmaceutical Co Ltd 10-11, Nihonbashi Kobuna-Cho Chuo-Ku, MANUFACTURERS 0000005539: Zeria Pharmaceutical Co Ltd 10-11, Nihonbashi Kobuna-Cho Chuo-Ku, REFERENCES GWAIDS/0002668. Sasaki H, Kobayashi M, Nomoto K, Nokta MA, Pallard RB, Suzuki F. Z-100 a Mycobacterium tuberculosis-derived arabinomannan, induces MIP-1a and inhibits the replication of M-tropic HIV in macrophage cultures. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. WePeA4000. AIDS/20712318. Suzuki F, Kobayashi M, Curry J, Sasaki H, Kobayashi H, Furukawa K, Weirich K, Schuenke K, Nomoto K, Nokta MA, Pollard RB. The induction of macrophage inflammatory protein (MIP)-alpha by Z-100, a M. tuberculosis-derived arabinomannan, in cultures of peripheral blood mononuclear cells (PBMC) from patients with HIV infection. Abstr Gen Meet Am Soc Microbiol. 1999 May 30-Jun 3;99:662 (abstract no. V-30). AIDS/20710823. Sasaki H, Nomoto K, Pollard RB, Suzuki F. M. tuberculosis-derived arabinomannan (Z-100) enhances the anti-HIV activity of zidovudine (AZT) in cultures of human peripheral blood mononuclear cells. Intersci Conf Antimicrob Agents Chemother. 1998 Sep 24-27;38:368 (abstract no. I-18). ENTRY MONTH 200104 LAST REVISION DATE 20010420 7 UNIQUE IDENTIFIER DRG-0341 NAME OF SUBSTANCE Rosiglitazone maleate [USPD 2000; p 633] REGISTRY NUMBER 155141-29-0 [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 19, 2001.] REGISTRY NUMBER 122320-73-4 (rosiglitazone) [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 19, 2001.] STANDARD CHEMICAL NAME 2,4-Thiazolidinedione, 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phen- yl]methyl]-, (2Z)-2-butenedioate (1:1) [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 19, 2001.] SYNONYMS Avandia [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 04/09/01.] PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5082 PHARMACOLOGICAL ACTION Rosiglitazone improves glycemic control by improving insulin sensitivity and therefore is used to treat insulin resistance, which is a common characteristic of type 2 diabetes and the HIV lipodystrophy syndrome. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor gamma (PPAR-gamma). PPAR receptors are found in key target tissues for insulin action (adipose tissue, skeletal muscle, and liver) and regulate the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. PPAR-gamma-responsive genes also participate in the regulation of fatty acid metabolism. The absolute bioavailability of rosiglitazone is 99 percent. Maximum plasma concentration (Cmax) and area under the concentration versus time curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range. Peak plasma levels occur approximately 1 hour after oral dosing. Administration of rosiglitazone with food does not affect overall exposure but has been shown to reduce and delay Cmax; these effects do not appear to be clinically significant. The volume of distribution is approximately 17 liters; protein binding is approximately 99.8 percent (primarily to albumin). The elimination half-life is 3 to 4 hours and is independent of dose. Rosiglitazone is extensively metabolized, predominantly by cytochrome P450 (CYP) isoenzyme 2C8, with no unchanged drug excreted in the urine. Circulating metabolites are less potent than the parent compound and do not contribute significantly to rosiglitazone's insulin-sensitizing activity. Approximately 64 percent and 23 percent of a radio-labeled rosiglitazone dose were excreted in the urine and in the feces, respectively. Pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or alcohol consumption. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response; however, in monotherapy studies, a greater therapeutic response was observed in females. In more obese patients, gender differences were less evident. In patients with moderate to severe liver disease, unbound Cmax and AUC were increased 2- and 3-fold, respectively; elimination half-life was increased by about 2 hours. Therapy with rosiglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at baseline. There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared to individuals with normal renal function. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] DISEASES STUDIED/TREATED Rosiglitazone is included in HIV clinical trials to assess its efficacy in the treatment of the metabolic disturbances (fat redistribution, insulin resistance, and hyperinsulinemia) associated with HIV lipodystrophy syndrome. [Protocol ID: ACTG A5082 ] CLASSIFICATION CODE Antidiabetic [USP DI 2000; p 3210] OTHER MAJOR USES Rosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). Rosiglitazone is indicated as monotherapy or for use in combination with a sulfonylurea or metformin when diet, exercise, and a single agent do not result in adequate glycemic control. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] SUBSTANCE INTERACTIONS Rosiglitazone does not inhibit any of the major CYP enzymes at clinically relevant concentrations and is therefore not expected to interact with drugs metabolized by these enzymes. Rosiglitazone is predominantly metabolized by CYP 2C8 and, to a lesser extent, CYP 2C9. Because rosiglitazone does not affect CYP 3A4, pharmacokinetic interactions are unlikely with drugs metabolized mainly via this isoenzyme (e.g., most antiretrovirals, with the exception of nelfinavir and ritonavir, and estrogen-progestin combination contraceptives). Rosiglitazone also does not appear to have a clinically relevant effect on the pharmacokinetics of drugs metabolized via CYP 2C9 (e.g., warfarin enantiomers). Rosiglitazone used in combination with metformin appears to result in synergistic glycemic control. In a study of NIDDM patients, addition of rosiglitazone to metformin resulted in a substantial added benefit on insulin sensitivity without any related toxicity. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.; Protocol ID: ACTG A5082 ; Protocol ID: ACTG A5082 ] ADVERSE EFFECTS Adverse effects of rosiglitazone reported in 2 percent or more of patients in clinical trials include headache, back pain, upper respiratory tract infection, injury, hyperglycemia, fatigue, sinusitis, and diarrhea. Anemia and edema also occurred. Adverse effects generally did not require discontinuation of the drug. Incidence of these effects was similar between rosiglitazone monotherapy and combined therapy with metformin. In postmarketing experience, adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported. No evidence of hepatotoxicity has been observed in clinical studies to date. However, rosiglitazone is structurally and pharmacologically similar to troglitazone, which has been associated with severe hepatotoxicity. Therefore, liver function tests are recommended prior to initiation of therapy and periodically thereafter. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.; AHFS Drug Information 2000; p 2876-7] CONTRAINDICATIONS Rosiglitazone is contraindicated in patients with known hypersensitivity to the product or any of its components. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA Molecular Formula: C18-H19-N3-O3-S.C4-H4-O4 [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA Molecular Weight: 473.52 [U.S. FDA. CDER. Avandia label. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed 06/19/01] CHEMICAL/PHYSICAL DATA Melting Point: 122-123 C [U.S. FDA. CDER. Avandia label. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed 06/19/01] CHEMICAL/PHYSICAL DATA Elemental Comp: C55.80%, H4.90%, N8.88%, O23.65%, S6.77% [Calculation. ] CHEMICAL/PHYSICAL DATA Solubility: Readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white solid. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (2 mg, 4 mg, and 8 mg). [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 25 C (77 F); excursions are permitted to 15-30 C (59-86 F). Tablets should be dispensed in a tight, light-resistant container. [U.S. FDA. CDER. Avandia monograph. Available at http://www.fda.gov/cder/foi/label/2001/21071s- 6lbl.pdf. Accessed June 19, 2001.] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 REFERENCES MED/21131955. Lebovitz HE, Banerji MA. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res 2001;56:265-94. MED/20560178. Malinowski JM, Bolesta S. Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. Clin Ther 2000 Oct;22(10):1151-68; discussion 1149-50. MED/20452543. Lenhard JM, Furfine ES, Jain RG, Ittoop O, Orband-Miller LA, Blanchard SG, Paulik MA, Weiel JE. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res 2000 Aug;47(2):121-9. AIDS/20711907. Walli RK, Michl GM, Bogner JR, Goebel FD. Effects of the PPAR-gamma activator troglitazone on protease inhibitor associated peripheral insulin resistance. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:194 (abstract no. 673). MED/20273176. Walli R, Michl GM, Muhlbayer D, Brinkmann L, Goebel FD. Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus. Res Exp Med (Berl) 2000 Apr;199(5):253-62. MED/99325992. Balfour JA, Plosker GL. Rosiglitazone. Drugs 1999 Jun;57(6):921-30; discussion 931-2. MED/97146693. Forman BM, Chen J, Evans RM. The peroxisome proliferator-activated receptors: ligands and activators. Ann N Y Acad Sci 1996 Dec 27;804:266-75. ENTRY MONTH 200104 LAST REVISION DATE 20010625 8 UNIQUE IDENTIFIER DRG-0340 NAME OF SUBSTANCE Metformin hydrochloride [USPD 2000; p 449] REGISTRY NUMBER 1115-70-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/cmplxq- ry.html. Accessed June 19, 2001.] REGISTRY NUMBER 657-24-9 (metformin) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/cmplxq- ry.html. Accessed June 19, 2001.] STANDARD CHEMICAL NAME Imidodicarbonimidic diamide, N,N-dimethyl-, monohydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 19,2001.] SYNONYMS Glucophage [USP DI 2000; p 2091] SYNONYMS Glucophage XR [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 04/09/01.] SYNONYMS (component of) Glucovance [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 04/09/01.] PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5082 PHARMACOLOGICAL ACTION Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Unlike sulfonylureas, metformin does not alter insulin secretions, and generally does not produce hypoglycemia or cause hyperinsulinemia. Instead, metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. As insulin resistance is attributable largely to increased hepatic glucose production, metformin may be useful in the treatment of insulin resistance associated with HIV lipodystrophy syndrome. Other metformin effects that may be beneficial to HIV-infected patients with lipodystrophy syndrome include weight loss (mainly due to loss of adipose tissue) and possible favorable effects on serum of lipids. Metformin pharmacokinetics do not appear to be affected by gender, race, or the presence of diabetes mellitus. The absolute bioavailability of metformin under fasting conditions is approximately 50 to 60 percent. Gastrointestinal absorption, mainly from the small intestine, is slow (taking as long as 6 hours) and incomplete because some of the drug binds to the intestinal wall. There is a lack of dose proportionality with increasing doses due to incomplete absorption. Food decreases and slightly delays the absorption of metformin; however, the clinical relevance of these effects is unknown. The extended release (XR) formulation results in a mean peak plasma level (Cmax) that is approximately 20 percent lower than that achieved with the same dose of regular metformin; the extent of absorption (as measured by area under the plasma concentration versus time curve [AUC]) is similar. After repeated administration of metformin XR, metformin did not accumulate in plasma. Metformin is negligibly bound to plasma proteins. Following administration at usual doses, peak plasma drug concentrations are usually attained within 2 to 4 hours and steady-state plasma concentrations are reached within 24 to 48 hours. Metformin is not metabolized in the liver or GI tract and is not excreted in the bile. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Up to 90 percent of a dose is eliminated unchanged via the renal route and up to 30 percent is removed via fecal elimination. The mean plasma elimination half-life is about 6.2 hours. In patients with decreased renal function (based on measured creatinine clearance), the half-life is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.; Protocol ID: ACTG A5082 ; AHFS Drug Information 2000; p 2866-74; U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.; AHFS Drug Information 2000; p 2866-74; U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.; USP DI 2000; p 2086-90; U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] DISEASES STUDIED/TREATED Metformin is included in HIV clinical trials to assess its efficacy in the treatment of the metabolic disturbances (fat redistribution, insulin resistance, and hyperinsulinemia) associated with HIV lipodystrophy syndrome. [Protocol ID: ACTG A5082 ] CLASSIFICATION CODE Antihyperglycemic [USP DI 2000; p 2086] OTHER MAJOR USES Metformin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 (non-insulin-dependent) diabetes mellitus. Metformin is indicated in patients 10 years of age or older, and the extended-release formulation is indicated in patients 17 years of age or older. Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age or older). [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] SUBSTANCE INTERACTIONS Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in drug interaction studies, where coadministration resulted in a 60 percent increase in peak metformin plasma and whole blood concentrations and a 40 percent increase in plasma and whole blood metformin AUC. Also, metformin has the potential to cause lactic acidosis. Since recent data suggest that nucleoside reverse transcriptase inhibitors (NRTIs) may promote mitochondrial toxicity and increased lactate production, lactate levels in patients taking metformin and NRTIs should be carefully monitored. Given that alcohol decreases lactate clearance, combined use of metformin and excessive alcohol also can increase the risk of lactic acidosis. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.; Protocol ID: ACTG A5082 ; AHFS Drug Information 2000; p 2866-74] ADVERSE EFFECTS Lactic acidosis is a rare, but serious, metabolic complication that can occur as a result of metformin accumulation. In general, lactic acidosis is fatal in approximately 50 percent of cases. While the reported incidence of this condition in patients taking metformin is very low, the risk of metformin accumulation and lactic acidosis increases with the degree of renal function impairment and the patient's age. Concerns about lactic acidosis are particularly relevant in patients with HIV infection, given the potential for increased lactate levels with the use of NRTIs. Gastrointestinal disturbances, which are usually transient and dose-related, are commonly reported with metformin therapy. Dose reduction and/or administration with meals may improve these conditions. Gastrointestinal adverse effects, including diarrhea, abnormal stools, nausea, vomiting, abdominal bloating or cramping, flatulence, and taste disorder, were severe enough to require drug discontinuation in about 4 percent of study participants. Additionally, the following adverse reactions were reported by study patients: hypoglycemia (more common in patients on other antidiabetic drugs or insulin), myalgia, lightheadedness, headache, dyspnea, nail disorder, rash, increased sweating, chest discomfort, chills, flu syndrome, flushing, and palpitation. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.; Protocol ID: ACTG A5082 ; AHFS Drug Information 2000; p 2866-74; U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] CONTRAINDICATIONS Metformin is contraindicated in patients with severe renal disease or dysfunction, congestive heart failure requiring pharmacologic treatment, known hypersensitivity to metformin hydrochloride or product excipients, or acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Metformin is an antihyperglycemic agent that is not chemically or pharmacologically related to any other classes of oral antihyperglycemics. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA Molecular Formula: C4-H11-N5.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA Molecular Weight: 165.62 [USPD 2000; p 449] CHEMICAL/PHYSICAL DATA Melting Point: 232 C [Merck Index 1996; p 1014] CHEMICAL/PHYSICAL DATA Elemental Comp: C29.00%, H7.31%, N42.29%, Cl21.40% [Calculation. ] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water and practically insoluble in acetone, ether, and chloroform. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline compound. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (500 mg, 850 mg, 1000 mg) and extended-release tablets (500 mg). [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 20-25 C (68-77 F); excursions are permitted to 15-30 C (59-86 F). Tablets should be kept in light-resistant containers. [U.S. FDA. CDER. Glucophage monograph. Available at http://www.fda.gov/cder/foi/label/2001/20357s- 22lbl.pdf. Accessed June 19, 2001.] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/21102306. Hadigan C, Meigs JB, Rabe J, D'Agostino RB, Wilson PW, Lipinska I, Tofler GH, Grinspoon SS; Framingham Heart Study. Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2001 Feb;86(2):939-43. MED/20366362. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000 Jul 26;284(4):472-7. AIDS/20711906. Saint-Marc T, Touraine JL. Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor (PI) therapy. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:194 (abstract no. 672). ENTRY MONTH 200104 LAST REVISION DATE 20010625 9 UNIQUE IDENTIFIER DRG-0339 NAME OF SUBSTANCE Testosterone [Protocol ID: ACTG A5079 ] REGISTRY NUMBER 58-22-0 [USPD 2000; p 700] STANDARD CHEMICAL NAME Androst-4-en-3-one, 17-hydroxy-, (17beta)- [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus/. Accessed June 25, 2001.] SYNONYMS Androgel [U.S. FDA. Electronic Orange Book. Available at http://www.fda.gov/cder/ob/default.htm. Accessed June 25, 2001.] SYNONYMS Testoderm [U.S. FDA. Electronic Orange Book. Available at http://www.fda.gov/cder/ob/default.htm. Accessed June 25, 2001.] SYNONYMS Androderm [U.S. FDA. Electronic Orange Book. Available at http://www.fda.gov/cder/ob/default.htm. Accessed June 25, 2001.] PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5079 PHARMACOLOGICAL ACTION Testosterone is the principal endogenous androgen. Endogenous androgens are essential hormones that are responsible for a number of physical conditions, including alterations in body musculature and fat distribution. It is estimated that 25 to 60 percent of HIV-infected men have low serum testosterone levels (in the hypogonadal range). Studies have shown that testosterone replacement in middle-aged men with mid-segment obesity decreases visceral fat, plasma glucose, and insulin levels, and also decreases blood pressure. Other studies have shown that testosterone replacement in androgen-deficient HIV-infected men decreases fat mass and augments lean body mass. While the pathophysiology of visceral obesity syndrome (visceral fat accumulation, insulin resistance, and hyperlipidemia) common to HIV-infection is multifactorial, it is possible that testosterone replacement in androgen-deficient men will impact favorably on this syndrome. Testosterone transdermal products deliver physiologic amounts of testosterone through the skin, in a sustained-release fashion, over a 24-hour dosing period. Patients vary in their ability to absorb testosterone transdermally, but proper administration of marketed products at recommended doses usually results in testosterone levels within the range for normal men during the first day of dosing; there is no accumulation of testosterone following repeated applications of these products. Approximately 40 percent of circulating plasma testosterone binds to sex hormone-binding globulin (SHBG), 2 percent remains unbound (free), and the remainder binds to albumin and other proteins. The fraction bound to albumin dissociates easily and is presumed to be biologically active, whereas the SHBG fraction is not. Generally, the amount of SHBG in plasma, which varies significantly with age, determines the distribution of testosterone between free and bound forms, and free testosterone concentrations determine the drug's half-life. Testosterone half-life, however, is highly variable, with values of 10 to 100 minutes being reported in the literature. Testosterone is metabolized principally in the liver to various 17-ketosteroid metabolites, the most active of which are estradiol and dihydrotestosterone (DHT). Both testosterone and its metabolites are excreted in urine and feces (approximately 90 and 6 percent, respectively, of an intramuscular dose). [AHFS Drug Information 2000; p 2772-6; J Clin Endocrinol Metab 2000 Jan;85(1):60-5; Protocol ID: ACTG A5079 ; PDR 2000; p 3170-2; PDR 2000; p 515-8; Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; AHFS Drug Information 2000; p 2772-6] DISEASES STUDIED/TREATED Testosterone is included in HIV clinical trials to assess its efficacy in reducing adverse symptoms (e.g., decreased muscle mass and increased visceral fat) reported by androgen-deficient, HIV-positive men. [Protocol ID: ACTG A5079 ] CLASSIFICATION CODE Androgen [USP DI 2000; p 141] OTHER MAJOR USES Testosterone is indicated as replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone (congenital or acquired). [AHFS Drug Information 2000; p 2772-6] SUBSTANCE INTERACTIONS Concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; these drugs should be combined with caution, particularly in patients with cardiac or hepatic disease. The use of testosterone by diabetic patients may result in decreased blood glucose levels and reduced insulin requirements; testosterone also may reduce anticoagulant requirements of patients taking oral anticoagulants. Patients should be monitored for excessive hypoglycemic or hypoprothrombinemic responses, respectively. [Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; AHFS Drug Information 2000; p 2772-6] ADVERSE EFFECTS Application site skin reactions are frequently reported with the use of transdermal testosterone products. Reactions range from pruritus, erythema, induration, or burning to allergic contact dermatitis to burn-like blister reactions. The skin tolerability of the gel product is reportedly better than that of the testosterone transdermal system (patch); in one study 4 percent of men treated with the gel versus 67 percent of men treated with a marketed patch experienced local skin reaction. The application of a topical corticosteroid cream per manufacturer guidelines, either before application of a patch or after its removal, may improve skin side effects associated with these products. Skin reactions generally tend to decrease with duration of use, however, some reactions are severe enough to warrant discontinuation of treatment. General adverse events associated with androgen replacement therapy also have been reported with transdermal testosterone. Adverse events include: hirsutism, male pattern baldness, seborrhea, and acne; gynecomastia, breast pain or tenderness, excessive frequency and duration of penile erections, abnormal ejaculation, oligospermia, prostate disorder (enlarged prostate, BPH, or elevated PSA results), testis disorder, dysuria, and urinary tract infection; retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates; nausea, diarrhea, cholestatic jaundice, and alterations in liver function tests; suppression of clotting factors II, V, VII, and X, leukopenia, and polycythemia; increased or decreased libido, headache, dizziness, asthenia, generalized paresthesia, and insomnia; anxiety, depression, personality disorder, and CNS stimulation; increased serum cholesterol; and abdominal or back pain, myalgia, and arthralgia. [PDR 2000; p 3170-2; PDR 2000; p 515-8; Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; Protocol ID: ACTG A5079 ; PDR 2000; p 3170-2; PDR 2000; p 515-8; Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.] CONTRAINDICATIONS Testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate. Testosterone is contraindicated in pregnant or lactating women. Testosterone transdermal products should not be used in patients with known hypersensitivity to any of their ingredients. [AHFS Drug Information 2000; p 2772-6] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Testosterone transdermal products deliver physiologic amounts of testosterone through the skin. The skin acts as a reservoir for the sustained release of testosterone into the systemic circulation, allowing for the once-daily application of transdermal products. [PDR 2000; p 3170-2] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H28-O2 [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA Molecular Weight: 288.43 [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA Melting Point: 155 C [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA Elemental Comp: C79.12%, H9.78%, O11.09% [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water; soluble in alcohol, ether, and other organic solvents. [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Testosterone is a white or slightly creamy white, odorless crystalline powder or crystals. [AHFS Drug Information 2000; p 2772-6] SUBSTANCE DELIVERY DATA DOSAGE FORM: Gel (5, 7.5, or 10 grams delivering 50, 75, or 100 mg of testosterone, respectively, per day); [Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; PDR 2000; p 515-8; PDR 2000; p 3170-2; Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; PDR 2000; p 515-8; PDR 2000; p 3170-2] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical, for transdermal absorption. [Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; PDR 2000; p 3170-2; PDR 2000; p 515-8] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Testosterone gel should be stored at controlled room temperature 20-25 C (68-77 F). [Unimed Pharmaceuticals. Marketed Products. Androgel. Available at http://www.androgel.com/pdfs/ANDROGEL.PDF. Accessed June 25, 2001.; PDR 2000; p 3170-2; PDR 2000; p 515-8] MANUFACTURERS 0000003497: Unimed Pharmaceuticals Inc 4 Parkway North 2nd floor Deerfield, IL 60015 Contact: Lauren Boswell (800)864-6330 MANUFACTURERS 0000003497: Unimed Pharmaceuticals Inc 4 Parkway North 2nd floor Deerfield, IL 60015 Contact: Sandy Faulkner (800)864-6330 MANUFACTURERS 0000005209: ALZA Corporation 1900 Charleston Road / PO Box 7210 Mountain View, CA 940397210 Contact: Unspecified (800)227-9953 MANUFACTURERS 0000005404: Watson Laboratories Inc 311 Bonnie Circle Corona, CA 928802882 Contact: Unspecified (800)227-9953 MANUFACTURERS 0000005209: ALZA Corporation 1900 Charleston Road / PO Box 7210 Mountain View, CA 940397210 MANUFACTURERS 0000005404: Watson Laboratories Inc 311 Bonnie Circle Corona, CA 928802882 REFERENCES MED/20358590. Javanbakht M, Singh AB, Mazer NA, Beall G, Sinha-Hikim I, Shen R, Bhasin S. Pharmacokinetics of a novel testosterone matrix transdermal system in healthy, premenopausal women and women infected with the human immunodeficiency virus. J Clin Endocrinol Metab 2000 Jul;85(7):2395-401. MED/20127382. Rabkin JG, Wagner GJ, Rabkin R. A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry 2000 Feb;57(2):141-7; discussion 155-6. MED/20097826. Hadigan C, Corcoran C, Stanley T, Piecuch S, Klibanski A, Grinspoon S. Fasting hyperinsulinemia in human immunodeficiency virus-infected men: relationship to body composition, gonadal function, and protease inhibitor use. J Clin Endocrinol Metab 2000 Jan;85(1):35-41. MED/20097830. Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, Klibanski A. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab 2000 Jan;85(1):60-5. MED/20102603. Kopicko JJ, Momodu I, Adedokun A, Hoffman M, Clark RA, Kissinger P. Characteristics of HIV-infected men with low serum testosterone levels. Int J STD AIDS 1999 Dec;10(12):817-20. MED/20300548. Ferrando SJ, Rabkin JG, Poretsky L. Dehydroepiandrosterone sulfate (DHEAS) and testosterone: relation to HIV illness stage and progression over one year. J Acquir Immune Defic Syndr 1999 Oct 1;22(2):146-54. MED/99174788. Kotler DP, Rosenbaum K, Wang J, Pierson RN. Studies of body composition and fat distribution in HIV-infected and control subjects. J Acquir Immune Defic Syndr Hum Retrovirol 1999 Mar 1;20(3):228-37. MED/98417941. Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I, Shen R, Arver S, Beall G. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998 Sep;83(9):3155-62. MED/98373711. Miller K, Corcoran C, Armstrong C, Caramelli K, Anderson E, Cotton D, Basgoz N, Hirschhorn L, Tuomala R, Schoenfeld D, Daugherty C, Mazer N, Grinspoon S. Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab 1998 Aug;83(8):2717-25. MED/98314795. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998 Jun 20;351(9119):1881-3. MED/97437808. Rabkin JG, Rabkin R, Wagner GJ. Testosterone treatment of clinical hypogonadism in patients with HIV/AIDS. Int J STD AIDS 1997 Sep;8(9):537-45. MED/96235899. Marin P. Testosterone and regional fat distribution. Obes Res 1995 Nov;3 Suppl 4:609S-612S. ENTRY MONTH 200101 LAST REVISION DATE 20010626 10 UNIQUE IDENTIFIER DRG-0338 NAME OF SUBSTANCE Peginterferon alfa-2b [Schering Plough. Available at: http://www.sgp.com/news/research/2000/1-5-00.- html. Accessed 01/05/01.] REGISTRY NUMBER 99210-65-8 (interferon alfa-2b) [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus. Accessed June 15, 2001.] SYNONYMS PEG-Intron [Schering Plough. Available at: http://www.sgp.com/news/research/2000/1-5-00.- html. Accessed 01/05/01.] PROTOCOL ID NUMBERS No longer recruiting FDA B010 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5088 PROTOCOL ID NUMBERS Suspended NIAID ACTG P1017 PHARMACOLOGICAL ACTION The biological activity of peginterferon is derived from its interferon alfa-2b moiety. The mechanism of action of interferon alfa-2b is unknown, but the effects include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells. Interferon alfa must be administered parenterally to avoid degradation by gastrointestinal proteolytic enzymes. Following subcutaneous administration of peginterferon alfa-2b, maximal serum concentration (Cmax) occurs between 15-44 hours post-dose and is sustained for up to 48-72 hours. Cmax and AUC values increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability. Week 48 mean trough concentrations are approximately 3 times higher than Week 4 mean trough concentrations. The mean peginterferon alfa-2b elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. Renal elimination accounts for 30 percent of the clearance, and impaired renal function (creatinine clearance less than 50 ml/minute) leads to a significant reduction in drug clearance. Pegylation of interferon alfa-2b produces a product whose clearance is lower than that of the non-pegylated drug. When compared to non-pegylated interferon alfa-2b, peginterferon alfa-2b has approximately a seven-fold lower mean apparent clearance and a five-fold greater mean half-life. These factors permit a longer dosing interval for peginterferon alfa-2b (once-weekly versus three-times-weekly dosing). At effective therapeutic doses, peginterferon alfa-2b has approximately ten-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b. Pharmacokinetic data from geriatric patients treated with a single dose of peginterferon alfa-2b show no remarkable differences in Cmax, AUC, clearance, or elimination half-life from those obtained in younger patients; pharmacokinetic profiles of patients with chronic hepatitis C infection reveal no gender differences. [AHFS Drug Information 2000; p 958; U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.; Protocol ID: ACTG A5088 ; U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] DISEASES STUDIED/TREATED Peginterferon alfa-2b is studied as an adjunct in the treatment of hepatitis C infection in patients with HIV co-infection. In addition, peginterferon alfa-2b is included in HIV clinical trials to examine its antiproliferative and antiviral effects. [Protocol ID: ACTG A5088 ; Protocol ID: PACTG P1017 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1810] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 1810] OTHER MAJOR USES Peginterferon alfa-2b is indicated for the treatment of chronic hepatitis C in patients not previously treated with interferon alfa who have compensated liver disease and are at least 18 years of age. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] SUBSTANCE INTERACTIONS Alfa interferons may inhibit the activity of hepatic cytochrome P450 isoenzymes. It is not known whether peginterferon alfa-2b therapy causes clinically significant drug-drug interactions with drugs metabolized by the liver in patients with hepatitis C. [AHFS Drug Information 2000; p 980; U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] ADVERSE EFFECTS In clinical trials, patients receiving peginterferon alfa-2b appeared to experience a greater number of adverse events than those receiving regular interferon alfa-2b, and the number of adverse events increased with dose. Nearly all study patients experienced one or more adverse effects, which usually resolved with reduction of dose or discontinuation of therapy; however, some patients continued to experience adverse events for several months after discontinuation. The most common adverse effect associated with peginterferon alfa-2b is a flu-like syndrome (fever, fatigue, myalgia/arthralgia, chills, and headache), which occurs in approximately 50 percent of patients and may decrease in severity as treatment continues. Pre-medication with acetaminophen or a non-steroidal anti-inflammatory drug 30 to 60 minutes prior to and after peginterferon alfa-2b dosing may reduce these effects. Application site disorders, including injection site pain, inflammation, and reaction (i.e., bruise, itchiness, irritation), are frequently reported. Depression, suicidal behavior (ideation, attempts, and suicides), anxiety, irritability, insomnia, and varied CNS reactions are common. GI disturbances, skin rash, and alopecia also occur. Peginterferon alfa-2b may cause neutropenia, thrombocytopenia, and thyroid function abnormalities; it is recommended that patients have hematology and blood chemistry testing before, and regularly while on, peginterferon alfa-2b therapy. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.; Protocol ID: ACTG A5088 ; U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] CONTRAINDICATIONS Peginterferon alfa-2b is contraindicated in patients who are allergic to peginterferon alfa or any component of the product. It also is contraindicated in patients with autoimmune hepatitis or decompensated liver disease. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Peginterferon alfa-2b is a covalent conjugate of recombinant alfa interferon with monomethoxy polyethylene glycol (PEG). The molecular weight of the PEG portion of the molecule is 12,000 daltons. Interferon alfa-2b, the starting material used to manufacture peginterferon alfa-2b, is a water-soluble protein with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon gene from human leukocytes. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] CHEMICAL/PHYSICAL DATA Molecular Weight: Approximately 31,000 daltons. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Peginterferon alfa-2b is available as a white to off-white lyophilized powder. The reconstituted solution is clear and colorless. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Peginterferon alfa-2b is supplied as 2 ml vials containing either 74 mcg, 118.4 mcg, 177.6 mcg, or 222 mcg of drug. Following reconstitution with 0.7 ml of the supplied diluent (Sterile Water for Injection), each vial contains peginterferon alfa-2b at strengths of either 100 mcg/ml, 160 mcg/ml, 240 mcg/ml, or 300 mcg/ml. Product excipients include dibasic sodium phosphate anhydrous, monobasic sodium phosphate dihydrate, sucrose, and polysorbate 80. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Peginterferon alfa-2b vials should be stored at 25 C (77 F). After reconstitution with supplied diluent, the solution should be used immediately but may be stored up to 24 hours at 2 to 8 C (36 to 46 F). [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/label/pegsche011901LB- .pdf. Accessed June 15, 2001.] MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Dr Janice Albrecht (908)298-7985 MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Unspecified (800)526-4099 REFERENCES GWAIDS/0005921. Reynes J, Rouzier-Panis R, Laughlin M, Baillat V, Kanouni T, Garaud JJ. Antiretroviral activity and tolerability of PEG-interferon alpha-2b in patients on stable background therapy: results of a phase I/II study. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7:177 (abstract no. 542). MED/21286405. Kozlowski A, Milton Harris J. Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C. J Control Release 2001 May 14;72(1-3):217-24. MED/21114288. Shiffman ML. Pegylated interferons: what role will they play in the treatment of chronic hepatitis C? Curr Gastroenterol Rep 2001 Feb;3(1):30-7. MED/20552121. Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, Jacobs S. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000 Nov;68(5):556-67. MED/20435237. Wang YS, Youngster S, Bausch J, Zhang R, McNemar C, Wyss DF. Identification of the major positional isomer of pegylated interferon alpha-2b. Biochemistry 2000 Sep 5;39(35):10634-40. ENTRY MONTH 200101 LAST REVISION DATE 20010625 11 UNIQUE IDENTIFIER DRG-0337 NAME OF SUBSTANCE GW433908 [Protocol ID: 316A ] STANDARD CHEMICAL NAME (3S)-tetrahydrofuran-3yl (1S,2R)-(((4-aminophenyl)sulphonyl)(isobutyl)- amino)-1-benzyl-2-(phos phonooxy) propylcarbamate monocalcium salt [Protocol ID: 316A ] PROTOCOL ID NUMBERS No longer recruiting FDA 316A PROTOCOL ID NUMBERS Recruiting FDA 316B PHARMACOLOGICAL ACTION GW433908 represents a simplification of amprenavir therapy, reducing the number of tablets taken daily from 16 to 6 or 8 (depending on dose). GW433908 is designed to be minimally absorbed and quickly hydrolyzed to its active ingredient by intestinal enzymes at or near the point of absorption in the gut wall. In a clinical study, GW433908 was shown to have comparable efficacy, safety, and pharmacokinetics to amprenavir. Although the maximum serum concentration (Cmax) of GW433908 was lower than that of amprenavir, overall drug exposure as measured by area under the concentration time curve (AUC) was similar. [Conf Retroviruses Opportunistic Infect 2001 Feb 4-8;8 (abstract no. 333); Conf Retroviruses Opportunistic Infect 2000 Jan 30-Feb 2;7:171 (abstract no. 505); Conf Retroviruses Opportunistic Infect 2001 Feb 4-8;8 (abstract no. 333)] DISEASES STUDIED/TREATED GW433908 is an investigational protease inhibitor currently being studied for combination therapy in the treatment of acute and chronic HIV infection. A phase III study also is investigating its potential for once-daily administration. [GlaxoSmithKline. Research and Development. Available at http://corp.gsk.com/tomorrow/product_pipeline- .htm#anti_virals. Accessed June 12, 2001.; Vertex Pharmaceuticals. Corporate Information. Available at http://www.vpharm.com/NonEnhanced/Pressreleas- es2000/pr112700.html. Accessed June 12, 2001.] CLASSIFICATION CODE Investigational - Protease inhibitor [GlaxoSmithKline. Research and Development. Available at: http://corp.gsk.com/tomorrow/product_pipeline- .htm#anti_virals. Accessed April 13, 2001.] SUBSTANCE INTERACTIONS Because GW433908 is converted to amprenavir, drug interactions expected for GW433908 may be similar to those associated with amprenavir. Clinical trials have excluded the following medications: amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, flecainide, lovastatin, midazolam, pimozide, propefenone, quinidine, rifabutin, rifampin, sildenafil, simvastatin, terfenadine, and triazolam (excluded for safety reasons); phenobarbital, phenytoin, carbamazepine, dexamethasone, troglitazone, primidone, ethosuximide, and St. John's wort (excluded because of the potential to decrease plasma protease inhibitor concentrations); and erythromycin, clarithromycin, ketoconazole, itraconazole, and cimetidine (excluded because of the potential to increase plasma protease inhibitor concentrations). Concurrent use of GW433908 and oral contraceptives may result in decreased levels and possible decreased efficacy of the contraceptive. [Protocol ID: 316A ] ADVERSE EFFECTS In a clinical study comparing GW433908 to amprenavir, a lower incidence of nausea (5 versus 17 percent) and abdominal pain (2 versus 17 percent) of at least moderate intensity was observed in patients taking GW433908 compared to the amprenavir. Headache (5 versus 0 percent) and sleep disorders (7 versus 0 percent) of at least moderate intensity, which were transient and not treatment limiting, were noted more frequently in patients taking GW433908 compared to the amprenavir. [Vertex Pharmaceuticals. Corporate Information. Available at http://www.vpharm.com/NonEnhanced/Pressreleas- es2001/pr020601.html. Accessed June12, 2001.] CONTRAINDICATIONS Individuals allergic to sulfonamides may be cross-sensitive to amprenavir (therefore GW433908). [USP DI 2000; p 120] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: GW433908 is an amprenavir prodrug. Due to its low aqueous solubility, amprenavir requires a considerable amount of excipients to achieve satisfactory oral bioavailability. GW433908 is more water soluble than amprenavir and allows for a reduction in size and number of tablets required for daily administration. [Conf Retroviruses Opportunistic Infect 2000 Jan 30-Feb 2;7:171 (abstract no. 505)] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (available as 700 mg in clinical trials). [Vertex Pharmaceuticals. Corporate Information. Available at http://www.vpharm.com/NonEnhanced/Pressreleas- es2001/pr042401.html. Accessed June 12, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Vertex Pharmaceuticals. Corporate Information. Available at http://www.vpharm.com/NonEnhanced/Pressreleas- es2001/pr042401.html. Accessed June 12, 2001.] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000003873: Vertex Pharmaceuticals Inc 130 Waverly Street Cambridge, MA 021394242 Contact: Debbie Thomas (919)483-9959 REFERENCES Wood R, Arasteh K, Pollard R, Kaur P, Nadarer O, Wire MB. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no. 333). GW433908, a novel prodrug of the HIV protease inhibitor (PI) amprenavir (APV): safety, efficacy, and pharmacokinetics (PK) (APV20001). GWAIDS/0005886. Spaltenstein A, Baker C, Gray-Nunez Y, Kaldor I, Kazmierski W, Reynolds D, Tung R, Wheelan P, Furfine E. 7th Conf Retro and Opportun Infect. 2000 Jan 30-Feb 2 (abstract no. 505). Highly polar, water-soluble prodrugs of amprenavir: a new approach toward a more compact dosing regimen. ENTRY MONTH 200101 LAST REVISION DATE 20010629 12 UNIQUE IDENTIFIER DRG-0336 NAME OF SUBSTANCE Peginterferon alfa-2a [Protocol ID: B010 ] REGISTRY NUMBER 76543-88-9 (interferon alfa-2a) [ChemIDplus. Available at:http://chem.sis.nlm.nih.gov/chemidplus/. Accessed April 16, 2001.] STANDARD CHEMICAL NAME Interferon alfa-2a [ChemIDplus. Available at:http://chem.sis.nlm.nih.gov/chemidplus/. Accessed April 16, 2001.] SYNONYMS PEGASYS [U.S. FDA. List of Orphan Designations and Approvals. Available at: http://www.fda.gov/orphan/designat/list.htm. Accessed 01/04/01.] PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5071 PHARMACOLOGICAL ACTION Peginterferon alfa-2a has a decreased systemic clearance and an approximately 10-fold increase in serum half-life compared with standard interferon alfa-2a. The biological activity of peginterferon alfa-2a is similarly prolonged, resulting in a significantly improved pharmacodynamic response of peginterferon alfa-2a compared with standard interferon alfa-2a. Pharmacokinetic and pharmacodynamic data obtained from animals and healthy male volunteers suggested that peginterferon alfa-2a injected weekly has the potential for equal or superior efficacy as compared with standard interferon alfa-2a injected 3 times per week. On the basis of ongoing trials involving over 1500 subjects, the safety and tolerability of peginterferon alfa-2a and interferon alfa-2a appear to be similar. For peginterferon alfa-2a, an effective dose (135 mcg) is reached before clearly toxic doses (350 mcg). Data from a recent trial of peginterferon alfa-2a dosed at 180 mcg weekly demonstrated an acceptable sustained virologic response rate with an excellent safety profile. [Protocol ID: ACTG A5071 ] DISEASES STUDIED/TREATED Peginterferon alfa-2a is included in HIV clinical trials due to its antiproliferative and antiviral effects. It is studied in combination with ribavirin for the treatment of chronic hepatitis C virus infection in individuals coinfected with HIV-1. [Protocol ID: ACTG A5071 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1810] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 1810] OTHER MAJOR USES Peginterferon alfa-2a is currently designated an orphan drug for 2 indications: the treatment of chronic myelogenous leukemia and the treatment of renal cell carcinoma. [U.S. FDA. List of Orphan Designations and Approvals. Available at: http://www.fda.gov/orphan/designat/list.htm. Accessed April 16, 2001.; ] SUBSTANCE INTERACTIONS Since the 2 drugs are metabolized by the same mechanisms, drug interactions with peginterferon alfa-2a probably would be similar to those encountered with interferon alfa-2a. Interferon alfa-2a has been reported to reduce the clearance of theophylline. Also, alfa interferons may inhibit the activity of hepatic cytochrome P450 isoenzymes. Although the clinical relevance of this effect is unknown, the potential for interactions between interferon alfa-2a and other similarly metabolized drugs should be considered. The concomitant use of interferon alfa with interleukin-2 (aldesleukin) may increase the risk of renal failure; exacerbation of autoimmune and inflammatory disorders also has occurred. The combination of interferon alfa and zidovudine or acyclovir, while causing synergistic antiviral effects, can increase the risk of hematologic and hepatic toxicity. Interferon alfa-2a should be used with caution in patients receiving other potentially myelosuppressive drugs. In addition, the neurotoxic, hematoxic, hepatotoxic, and cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. [AHFS Drug Information 2000; p 980; Roche U.S. Pharmaceuticals. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed April 17, 2001.] ADVERSE EFFECTS Peginterferon alfa-2a and interferon alfa-2a are similarly tolerated and the frequency and severity of adverse effects are typical of those associated with interferon alfa. Decreases in neutrophil counts and, to a lesser degree, platelet counts, are more common with the pegylated compound than with unmodified interferon alfa-2a. The most common serious adverse events reported in clinical studies to date were infections, psychiatric disorders, and gastrointestinal disorders. The most common adverse events include fatigue, headache, myalgia/arthralgia, flu-like symptoms, nausea/vomiting, injection site reactions, fever, chills, diarrhea, partial alopecia, abdominal pain, depression, irritability, insomnia, dizziness, and anorexia. [Protocol ID: ACTG A5071 ; Roche U.S. Pharmaceuticals. Available at: http://www.rocheusa.com/newsroom/current/2000- /pr2000120701.html. Accessed April 17, 2001.] CONTRAINDICATIONS Peginterferon alfa-2a is contraindicated in patients allergic to alfa interferon or any component of the product (excipients in the investigational product include benzyl alcohol, sodium chloride, sodium acetate trihydrate, acetic acid, and polysorbate 80). [Protocol ID: ACTG A5071 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Pegylation is the attachment of 1 or more chains of polyethelene glycol (also known as PEG) to another molecule. In peginterferon alfa-2a, a 40 kilodalton (40-kD) branched, mobile PEG is covalently bound to the interferon alfa-2a molecule and provides a selectively protective barrier, without significantly reducing binding site receptivity. The barrier shields the interferon alfa-2a molecule from being rapidly degraded by proteases in the body. Pharmacokinetic behavior of a pegylated molecule depends on the size of the PEG and the structure of the link between the PEG moiety and the protein. Clinical trials have demonstrated that the high molecular weight 40-kD PEG helps provide sustained pegylated interferon alfa-2a exposure at clinically significant levels over a one-week dosing period. In contrast, according to earlier studies using smaller PEGs developed by the manufacturer, interferons with smaller PEGs are degraded quickly, requiring more frequent dosing. [Roche U.S. Pharmaceuticals. Available at: http://www.rocheusa.com/newsroom/current/2000- /pr2000120701.html. Accessed April 17, 2001.] SUBSTANCE DELIVERY DATA DOSAGE FORM: The investigational product is supplied as solution in single-use vials for injection (180 mcg/ml). [Protocol ID: ACTG A5071 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection. [Protocol ID: ACTG A5071 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The injectable solution should be stored at 2 to 8 C (36 to 46 F). [Protocol ID: ACTG A5071 ] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES MED/21286405. Kozlowski A, Milton Harris J. Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C. J Control Release 2001 May 14;72(1-3):217-24. MED/21213855. Zeuzem S, Herrmann E, Lee JH, Fricke J, Neumann AU, Modi M, Colucci G, Roth WK. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology 2001 May;120(6):1438-47. MED/21114288. Shiffman ML. Pegylated interferons: what role will they play in the treatment of chronic hepatitis C? Curr Gastroenterol Rep 2001 Feb;3(1):30-7. MED/21100809. Reddy KR, Wright TL, Pockros PJ, Shiffman M, Everson G, Reindollar R, Fried MW, Purdum PP 3rd, Jensen D, Smith C, Lee WM, Boyer TD, Lin A, Pedder S, DePamphilis J. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 2001 Feb;33(2):433-8. MED/20537433. Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, Reindollar R, Reddy RK, Wright TL, Lin A, Hoffman J, De Pamphilis J. N Engl J Med 2000 Dec 7;343(23):1673-80. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. MED/20537432. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, O'Grady J, Reichen J, Diago M, Lin A, Hoffman J, Brunda MJ. N Engl J Med 2000 Dec 7;343(23):1666-72. Peginterferon alfa-2a in patients with chronic hepatitis C. ENTRY MONTH 200101 LAST REVISION DATE 20010625 13 UNIQUE IDENTIFIER DRG-0335 NAME OF SUBSTANCE DPC 083 [Protocol ID: 314A ] PROTOCOL ID NUMBERS Recruiting FDA 314A PHARMACOLOGICAL ACTION DPC 083 demonstrates in vitro potency against wild-type HIV-1 equivalent to efavirenz. DPC 083 also is potent against HIV-1 strains containing resistance mutations (e.g., K103N, L1001, K103N/V108I, K103N/P225H, and K103N/Y181C), which are observed in some patients failing treatment with currently available NNRTIs. DPC 083 is less highly bound to plasma proteins than efavirenz, which results in higher levels of free drug at equivalent total plasma concentrations and a significant (10- to 20-fold) improvement in antiviral activity relative to efavirenz. Phase I pharmacokinetic studies have reported a mean terminal half-life greater than 100 hours after multiple-dose administration, supporting once-daily administration. [Protocol ID: 314A ] DISEASES STUDIED/TREATED DPC 083 is currently being studied for combination therapy in the treatment of acute and chronic HIV infection. A phase II study also is investigating its potential for once-daily administration. [Protocol ID: 314A ] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [Protocol ID: 314A ] SUBSTANCE INTERACTIONS Because DPC 083 is metabolized by the cytochrome P450 (CYP) hepatic enzymes, specifically CYP 2B6 and CYP 3A4, drug interactions are possible when DPC 083 is administered concurrently with potential inducers and/or inhibitors of these enzymes. In addition, DPC 083 is a CYP 3A4 inducer and may interact with drugs metabolized by this enzyme. A barrier method of birth control should be used by patients taking DPC 083, as reduction of hormonal contraceptive plasma levels and impairment of contraceptive effect is possible. Clinical trials with DPC 083 have excluded the following medications: carbamazepine, St. John's wort, and phenytoin, which are CYP 3A4 inducers. [Protocol ID: 314A ] ADVERSE EFFECTS The most frequently reported adverse effects attributable to DPC 083 in Phase I clinical studies include dizziness, skin rashes, paresthesia, euphoric mood, feeling abnormal, feeling drunk, abdominal pain, fatigue, lethargy, and vomiting. Reversible elevations in liver enzymes and increased total cholesterol and triglyceride levels were reported. [Protocol ID: 314A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: DPC 083 is an investigational nonnucleoside reverse transcriptase inhibitor that is structurally related to efavirenz. [Protocol ID: 314A ] SUBSTANCE DELIVERY DATA DOSAGE FORM: In clinical trials, available as 50 mg tablets. [Protocol ID: 314A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 314A ] MANUFACTURERS 0000004866: DuPont Pharmaceuticals Co Chestnut Run Plaza / 974 Centre Rd Wilmington, DE 19805 Contact: Unspecified REFERENCES MED/20408577. Bacheler LT, Anton ED, Kudish P, Baker D, Bunville J, Krakowski K, Bolling L, Aujay M, Wang XV, Ellis D, Becker MF, Lasut AL, George HJ, Spalding DR, Hollis G, Abremski K. Antimicrob Agents Chemother 2000 Sep;44(9):2475-84. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. GWAIDS/0001305. Rayner MM, Garber S, Logue K, Corbett J, Baker D, Lukac S, Powell D, Bacheler L, Erickson-Viitanen S. Second generation NNRTIs require multiple mutations for selection of highly resistant HIV in vitro. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. TuOrA347. GWAIDS/0001322. Jeffrey S, Logue K, Garber S, Cordova B, Wallace L, Baker D, Erickson-Viitanen S, Bacheler L. New second generation NNRTIs: improved resistance and cross resistance profiles. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. TuPpA1145. GWAIDS/0002613. Bacheler L, Jeffrey S, Verbiest W, Hertogs K, Larder B. Potent antiviral activity of second generation NNRTIs DPC 961 and DPC 083 against Group M and Group O strains of HIV-1. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. WeOrA536. GWAIDS/0005480. Fiske WD, Brennan JM, Harrison RR, Jobes JL, Volpato ML, Griffith SG. Pharmacokinetics of a second-generation NNRTI, DPC 083, after multiple oral doses in healthy volunteers. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7:93 (abstract no. 99). MED/20281734. Corbett JW, Ko SS, Rodgers JD, Gearhart LA, Magnus NA, Bacheler LT, Diamond S, Jeffrey S, Klabe RM, Cordova BC, Garber S, Logue K, Trainor GL, Anderson PS, Erickson-Viitanen SK. J Med Chem 2000 May 18;43(10):2019-30. Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. MED/20049914. Corbett JW, Ko SS, Rodgers JD, Jeffrey S, Bacheler LT, Klabe RM, Diamond S, Lai CM, Rabel SR, Saye JA, Adams SP, Trainor GL, Anderson PS, Erickson-Viitanen SK. Antimicrob Agents Chemother 1999 Dec;43(12):2893-7. Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1. ENTRY MONTH 200012 LAST REVISION DATE 20010105 14 UNIQUE IDENTIFIER DRG-0334 NAME OF SUBSTANCE Vaccinia Immune Globulin (Human) [Protocol ID: AVEG 801 ] PROTOCOL ID NUMBERS Not yet recruiting NIAID AVEG 801 DISEASES STUDIED/TREATED Vaccinia immune globulin is an investigational agent used for the prevention and treatment of complications of vaccinia vaccination. Vaccinia is a virus that is employed as a vector in some investigational HIV vaccines. [Protocol ID: AVEG 801 ] CLASSIFICATION CODE Immunizing agent, passive [USPD 2000; p 750] OTHER MAJOR USES Vaccinia immune globulin is released from the Centers for Disease Control and Prevention (CDC) when indicated for the treatment of eczema vaccinatum, vaccinia necrosum, ocular vaccinia, or severe generalized vaccinia in persons who receive the smallpox vaccine. Since the eradication of smallpox in 1980, administration of the vaccine is indicated only in certain laboratory workers and military personnel. [CDC. Drug Service. Immunobiologics Distributed by The Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/ncidod/srp/drugservice/imm- uodrugs.htm#Vaccinia I. Accessed 11/03/00.] SUBSTANCE INTERACTIONS There are no restrictions on the use of concomitant medications during a course of treatment with vaccinia immune globulin. [Protocol ID: AVEG 801 ] ADVERSE EFFECTS The administration of human immune globulin preparations occasionally has been associated with the development of allergic or anaphylactoid systemic reactions. Common side effects include pain, soreness, redness, swelling, and stiffness at the injection site that can persist up to 2 days following injection. [Protocol ID: AVEG 801 ] CONTRAINDICATIONS Vaccinia immune globulin is contraindicated in individuals with vaccinal keratitis. [Protocol ID: AVEG 801 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The manufacturer first received FDA approval to market its vaccinia immune globulin product in 1978. The current lot of vaccinia immune globulin product (0448A101A) also passed all safety and efficacy tests prior to its release in 1995. However, in 1998 the FDA placed a hold on the release of the current lot due to a discoloration of the solution. It is the only remaining lot of this product. As this material is now in short supply and there is a decreasing number of hyperimmune individuals who could serve as plasma donors for future vaccinia immune globulin preparations, this lot continues to be used but is treated as an investigational agent. [Protocol ID: AVEG 801 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Vaccinia immune globulin is an isotonic sterile solution of the immunoglobulin fraction of plasma from individuals vaccinated with vaccinia virus vaccine. [CDC. Morbidity and Mortality Weekly Report. Recommendations and Reports. December 13, 1991/40(RR14);1-10. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/0004- 2032.htm. Accessed 11/03/00.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vaccinia immune globulin is supplied as 5 ml vials of a sterile, 16.5% (range 15 to 18%) solution of the immunoglobulin fraction of plasma from individuals vaccinated with vaccinia virus vaccine. The solution is isotonic and contains 0.3M glycine as a stabilizer, 0.1% sodium chloride, and 0.01% thimerosal as a preservative. The product can only be obtained through the CDC. [Protocol ID: AVEG 801 ; CDC. Morbidity and Mortality Weekly Report. Recommendations and Reports. December 13, 1991/40(RR14);1-10. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/0004- 2032.htm. Accessed 11/03/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The recommended dosage for treatment of complications following vaccinia virus vaccination is 0.6 ml per kg of body weight. The dosage is not adjusted in immunocompromised recipients. The product should be administered as early as possible after the onset of symptoms. Vaccinia immune globulin is administered intramuscularly in the buttock or anterolateral aspect of the thigh. Doses greater than 10 ml should be divided and injected at 2 or more sites to reduce local pain and discomfort. The product can be given in divided doses over a 24- to 36-hour period, and doses may be repeated at intervals of 2 to 3 days until recovery begins (i.e., no new lesions appear). [CDC. Morbidity and Mortality Weekly Report. Recommendations and Reports. December 13, 1991/40(RR14);1-10. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/0004- 2032.htm. Accessed 11/03/00.; CDC. Morbidity and Mortality Weekly Report. Recommendations and Reports. April 09, 1993/42(RR-04). Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/0002- 3141.htm. Accessed 11/03/00.; Protocol ID: AVEG 801 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The product should be refrigerated at 2-8 C (36-46 F). [Protocol ID: AVEG 801 ] MANUFACTURERS 0000005211: Baxter Healthcare Corporation Hyland Immuno Division / 550 North Brand Blvd Glendale, CA 91203 Contact: Unspecified (800)423-2090 REFERENCES MED/99141628. Stienlauf S, Shoresh M, Solomon A, Lublin-Tennenbaum T, Atsmon Y, Meirovich Y, Katz E. Kinetics of formation of neutralizing antibodies against vaccinia virus following re-vaccination. Vaccine. 1999 Jan 21;17(3):201-4. MED/77083115. Feery BJ. The efficacy of vaccinial immune globulin. A 15-year study. Vox Sang. 1976;31(1 SUPPL):68-76. MED/75195667. Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis, and therapy of complications. Pediatrics. 1975 Mar;55(3):342-7. Review. ENTRY MONTH 200011 LAST REVISION DATE 20001201 15 UNIQUE IDENTIFIER DRG-0333 NAME OF SUBSTANCE Fenofibrate [USPD 2000; p 297] REGISTRY NUMBER 49562-28-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 10/05/00.] STANDARD CHEMICAL NAME Isopropyl 2-(p-(p-chlorobenzoyl)phenoxy)-2-methylpropio- nate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 10/05/00.] SYNONYMS Tricor [USP DI 2000; p 1509] PROTOCOL ID NUMBERS Suspended NIAID ACTG A5087 PHARMACOLOGICAL ACTION The exact mechanism of action of fenofibrate in unknown. In vitro, fenofibrate is shown to increase lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles to large, buoyant particles that have a greater affinity for cholesterol receptors and are catabolized rapidly. Fenofibrate is well absorbed from the gastrointestinal tract. Absorption is increased by approximately 35% in comparison to that observed in fasting conditions when administered with food. Serum protein binding is extensive (approximately 99%). Fenofibrate is rapidly hydrolyzed to fenofibric acid, the active metabolite. Peak plasma levels of the metabolite occur within 6 to 8 hours after administration and steady-state levels are achieved within 5 days. Fenofibrate is excreted mainly in the urine in the form of fenofibric acid and fenofibric acid glucuronide metabolites. Renal and fecal eliminations account for 60% and 25% of a given dose, respectively. Fenofibric acid is eliminated with a half-life of 20 hours, which allows for once-daily administration of the drug. [Abbott Laboratories. Tricor. Available at: http://www.rxabbott.com/hr/hr00321.htm. Accessed 10/05/00.; USP DI 2000; p 1506-7] DISEASES STUDIED/TREATED Lipid disorders associated with HIV infection and antiretroviral therapy are of growing concern. Persistently elevated cholesterol and triglyceride levels may represent a significant risk factor in the development of coronary artery disease. Lipid-lowering agents, such as fenofibrate, are studied to determine their safety and efficacy in the treatment of HIV patients with lipid disorders. [Protocol ID: ACTG A5087 ] CLASSIFICATION CODE Antihyperlipidemic [USP DI 2000; p 1509] OTHER MAJOR USES Fenofibrate is approved by the FDA as an adjunct to diet for treatment of adult patients with primary hypercholesterolemia or mixed dyslipidemia (Frederickson Types IIa and IIb). Fenofibrate is also approved as an adjunct to diet for treatment of adult patients with very high elevations of serum triglyceride levels who are at risk of pancreatitis (triglycerides typically over 2000 mg/dl) and who do not respond adequately to dietary interventions (Frederickson Types IV and V). [U.S. FDA. CDER. Drug Approvals. Available at: http://www.fda.gov/cder/approval/index.htm. Accessed 10/05/00.] SUBSTANCE INTERACTIONS Administration of fenofibrate with food increases the bioavailability of the drug. In vivo data indicate that neither fenofibrate nor its active metabolite undergoes metabolism by cytochrome (CYP) P450 to a significant extent. In addition, neither agent is shown to significantly inhibit most CYP 450 isoenzymes; however, fenofibrate and fenofibric acid are mild-to-moderate inhibitors of CYP2C9. The concomitant administration of fenofibrate and warfarin is associated with increased levels of the anticoagulant resulting in prolongation of prothrombin time/INR. The combined use of fenofibrate and HMG-CoA reductase inhibitors is occasionally associated with rhabdomyolysis, markedly elevated creatinine kinase (CK) levels, and myoglobinuria, leading to possible acute renal failure. Since bile acid sequestrants may bind concurrently administered drugs, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after the sequestrant. The concomitant use of fenofibrate and nephrotoxic drugs such as cyclosporine should be monitored. [Abbott Laboratories. Tricor. Available at: http://www.rxabbott.com/hr/hr00321.htm. Accessed 10/05/00.; Abbott Laboratories. Tricor. Available at: http://www.rxabbott.com/hr/hr00321.htm. Accessed 10/05/00.; PDR 2000; p 478] ADVERSE EFFECTS Administration of fenofibrate at therapeutic doses occasionally is associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. Liver enzymes usually return to normal upon discontinuation of the drug; however, hepatocellular, chronic active, or cholestatic hepatitis has been reported. Similar to other fibrate drugs, fenofibrate may cause pancreatitis or cholelithiasis. Fenofibrate occasionally is associated with myositis, myopathy, and rhabdomyolysis. Acute hypersensitivity reactions, including severe skin reactions, and significant hematologic changes are rare. Other adverse effects associated with fenofibrate use include abdominal pain, back pain, headache, skin rash, nausea, constipation, infections, and flu-like symptoms. [PDR 2000; p 478] CONTRAINDICATIONS Fenofibrate is contraindicated in patients with hepatic dysfunction, severe renal dysfunction, and preexisting gall bladder disease. [PDR 2000; p 477] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fenofibrate is a lipid-regulating agent that has a chemical, pharmacologic, and clinical profile similar to the other fibrate drugs clofibrate and gemfibrozil. Fenofibrate produces the following effects in treated patients: decreases in total cholesterol (total-C), including reductions in low-density lipoprotein (LDL) cholesterol and apolipoprotein B; decreases in total triglycerides (TG), including reduction in triglyceride-rich lipoprotein (VLDL); increases in high-density lipoprotein (HDL); increases in apoprotein AI and apoprotein AII; and decreases in serum uric acid concentrations. [USP DI 2000; p 1506; Abbott Laboratories. Tricor. Available at: http://www.rxabbott.com/hr/hr00321.htm. Accessed 10/05/00.] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H21-Cl-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 10/05/00.] CHEMICAL/PHYSICAL DATA Molecular Weight: 360.83 [USPD 2000; p 297] CHEMICAL/PHYSICAL DATA Melting Point: 79-82 C [PDR 2000; p 476] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.57%, H5.87%, Cl9.83%, O17.74% [Calculation. ] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water; slightly soluble in methanol and ethanol; soluble in acetone, ether, benzene, and chloroform [MERCK Index 1996; p 675] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White solid [PDR 2000; p 476] SUBSTANCE DELIVERY DATA DOSAGE FORM: Micronized fenofibrate is available as 67 mg yellow, 134 mg white, and 200 mg orange hard gelatin capsules. [Abbott Laboratories. Tricor. Available at: http://www.rxabbott.com/hr/hr00321.htm. Accessed 10/05/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [PDR 2000; p 478] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Capsules should be stored at room temperature, 15-30 C (59-86 F), and protected from moisture. [Abbott Laboratories. Tricor. Available at: http://www.rxabbott.com/hr/hr00321.htm. Accessed 10/05/00.] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/20318451. Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis. 2000 Jun;30 Suppl 2:S135-42. Review. MED/20310676. Thomas JC, Lopes-Virella MF, Del Bene VE, Cerveny JD, Taylor KB, McWhorter LS, Bultemeier NC. Use of fenofibrate in the management of protease inhibitor-associated lipid abnormalities. Pharmacotherapy. 2000 Jun;20(6):727-34. MED/20285170. Penzak SR, Chuck SK. Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. Scand J Infect Dis. 2000;32(2):111-23. Review. MED/20173938. Pan WJ, Gustavson LE, Achari R, Rieser MJ, Ye X, Gutterman C, Wallin BA. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000 Mar;40(3):316-23. MED/20001789. Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother. 1999 Oct;33(10):1083-103. Review. MED/99380066. Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond MJ, Marcovina SM, Glauser MP, Nicod P, Darioli R, Mooser V. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation. 1999 Aug 17;100(7):700-5. MED/99281337. Bairaktari ET, Tzallas CS, Tsimihodimos VK, Liberopoulos EN, Miltiadous GA, Elisaf MS. Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia. J Cardiovasc Risk. 1999 Apr;6(2):113-6. MED/99048813. Gholami K, Tavakoli N, Maleki M, Shafiee A. Comparison of the efficacy and safety of fenofibrate and lovastatin in patients with primary type IIa or IIb hyperlipidaemia. J Clin Pharm Ther. 1998 Jun;23(3):213-21. MED/99041322. Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. Drug Saf. 1998 Nov;19(5):355-71. Review. MED/97479883. Adkins JC, Faulds D. Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs. 1997 Oct;54(4):615-33. Review. MED/96258948. Steinmetz A, Schwartz T, Hehnke U, Kaffarnik H. Multicenter comparison of micronized fenofibrate and simvastatin in patients with primary type IIA or IIB hyperlipoproteinemia. J Cardiovasc Pharmacol. 1996 Apr;27(4):563-70. ENTRY MONTH 200010 LAST REVISION DATE 20010517 16 UNIQUE IDENTIFIER DRG-0332 NAME OF SUBSTANCE Medroxyprogesterone acetate [USPD 2000; p 435] REGISTRY NUMBER 71-58-9 [USPD 2000; p 435] STANDARD CHEMICAL NAME Pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6-alpha)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 09/28/00.] SYNONYMS Depo-Provera [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SYNONYMS Provera [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5093 PROTOCOL ID NUMBERS Recruiting NIAID HIVNET 021 PHARMACOLOGICAL ACTION Medroxyprogesterone acetate administered to women with adequate endogenous estrogen transforms proliferative endometrium into secretory endometrium. Androgenic and anabolic effects are noted, but the drug lacks estrogenic activity. After adequate contraceptive doses, secretion of pituitary gonadotropin is inhibited thereby preventing follicular maturation and ovulation. Following either oral or intramuscular administration, medroxyprogesterone is well absorbed. The drug is approximately 90% protein bound, primarily to albumin. For the oral tablet, the time to peak concentration is 2 to 4 hours and the apparent elimination half-life is 30 hours. Intramuscular injections achieve a much slower time to peak concentration (3 weeks) and a much longer duration of efficacy in the body (elimination half-life of 50 days). Medroxyprogesterone is extensively metabolized by the liver. Elimination of the metabolites occurs via both the renal (15-22%) and fecal (45-80%) routes. [PDR 2000; p 2438; USP DI 2000; p 2578] DISEASES STUDIED/TREATED Medroxyprogesterone acetate, in a special parenteral formulation, is approved by the FDA for the prevention of pregnancy. Medroxyprogesterone acetate does not protect against HIV infection and AIDS. Studies are being conducted to determine whether there is an increased risk of HIV acquisition in patients using hormonal contraception. [USP DI 2000; p 2575; Protocol ID: HIVNET 021 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 2566] CLASSIFICATION CODE Contraceptive [USP DI 2000; p 2566] CLASSIFICATION CODE Hormone (progestin) [USP DI 2000; p 2566] OTHER MAJOR USES Medroxyprogesterone acetate, in a special parenteral formulation, is approved by the FDA for the prevention of pregnancy. Parenteral medroxyprogesterone acetate also is approved for adjunctive therapy and palliative treatment of advanced endometrial or renal carcinoma. Oral medroxyprogesterone is indicated for secondary amenorrhea, dysfunctional uterine bleeding, and induction of menses. Off-label uses of the oral product include the treatment of breast or endometrial carcinoma and endometriosis. Oral medroxyprogesterone also is used as a diagnostic agent in testing for endogenous estrogen production. [USP DI 2000; p 2575] SUBSTANCE INTERACTIONS Administration of oral medroxyprogesterone acetate with food enhances the drug's bioavailability. Aminoglutethimide may significantly lower the serum concentrations of oral and parenteral medroxyprogesterone. Concurrent administration of medroxyprogesterone acetate and agents known to significantly induce hepatic enzymes (carbamazepine, phenobarbital, phenytoin, rifabutin, or rifampin) may result in decreased serum concentrations of medroxyprogesterone. [PDR 2000; p 2481; USP DI 2000; p 2570] ADVERSE EFFECTS Thromboembolic disorders or thrombophlebitis has occasionally been associated with high doses of medroxyprogesterone acetate. Depending on the indication and dose of the drug, side effects can include skin sensitivity reactions, acne, alopecia, hirsutism, menstrual irregularities, breast tenderness, abdominal pain, weight changes, edema, headache, dizziness, asthenia, nervousness, and depression. [PDR 2000; p 2438; USP DI 2000; p 2575] CONTRAINDICATIONS Medroxyprogesterone acetate use is contraindicated in the following conditions: pregnancy, undiagnosed vaginal bleeding, known or suspected breast malignancy, thromboembolic disorder history, or liver dysfunction or disease. [PDR 2000; p 2438] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Medroxyprogesterone acetate is a 17-hydroxy derivative of progesterone with progestogenic, androgenic, and glucocorticoid effects. [USP DI 2000; p 2575] CHEMICAL/PHYSICAL DATA Molecular Formula: C24-H34-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 09/28/00.] CHEMICAL/PHYSICAL DATA Molecular Weight: 386.52 [USPD 2000; p 435] CHEMICAL/PHYSICAL DATA Melting Point: 207-209 C [Merck Index 1996; p 988] CHEMICAL/PHYSICAL DATA Elemental Comp: C74.58%, H8.87%, O16.56% CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in chloroform; soluble in acetone and in dioxane; sparingly soluble in alcohol and in methanol; slightly soluble in ether; insoluble in water [PDR 2000; p 2438] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white, odorless crystalline powder [PDR 2000; p 2438] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (2.5 mg, 5 mg, 10 mg strengths); injectable suspension (150 mg/ml contraceptive and 400 mg/ml noncontraceptive) [USP DI 2000; p 2575] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intramuscular [USP DI 2000; p 2575] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Both forms should be stored at 15-30 C (59-86 F) and protected from freezing. [USP DI 2000; p 2575] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 REFERENCES MED/20086998. Mostad SB, Kreiss JK, Ryncarz AJ, Mandaliya K, Chohan B, Ndinya-Achola J, Bwayo JJ, Corey L. Cervical shedding of herpes simplex virus in human immunodeficiency virus-infected women: effects of hormonal contraception, pregnancy, and vitamin A deficiency. J Infect Dis. 2000 Jan;181(1):58-63. MED/99454047. Cromer BA. Recent clinical issues related to the use of depot medroxyprogesterone acetate (Depo-Provera). Curr Opin Obstet Gynecol. 1999 Oct;11(5):467-71. Review. MED/99022981. Martin HL Jr, Nyange PM, Richardson BA, Lavreys L, Mandaliya K, Jackson DJ, Ndinya-Achola JO, Kreiss J. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. J Infect Dis. 1998 Oct;178(4):1053-9. MED/98242895. Stephenson JM. Systematic review of hormonal contraception and risk of HIV transmission: when to resist meta-analysis. AIDS. 1998 Apr 16;12(6):545-53. Review. MED/97460489. Mostad SB, Overbaugh J, DeVange DM, Welch MJ, Chohan B, Mandaliya K, Nyange P, Martin HL Jr, Ndinya-Achola J, Bwayo JJ, Kreiss JK. Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet. 1997 Sep 27;350(9082):922-7. MED/96354242. Mishell DR Jr. Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med. 1996 May;41(5 Suppl):381-90. Review. MED/94266271. Daly CC, Helling-Giese GE, Mati JK, Hunter DJ. Contraceptive methods and the transmission of HIV: implications for family planning. Genitourin Med. 1994 Apr;70(2):110-7. Review. ENTRY MONTH 200009 LAST REVISION DATE 20001024 17 UNIQUE IDENTIFIER DRG-0331 NAME OF SUBSTANCE Ethinyl estradiol/levonorgestrel [Protocol ID: HIVNET 021 ] REGISTRY NUMBER 57-63-6 (ethinyl estradiol) and 797-63-7 (levonorgestrel) [USPD 2000; p 281, 409] STANDARD CHEMICAL NAME 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol- , (17-alpha)- (ethinyl estradiol) and 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17-alpha)-(-)- (levonorgestrel) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 09/28/00.] SYNONYMS Nordette [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SYNONYMS Levora [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SYNONYMS Alesse [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SYNONYMS Levlite [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SYNONYMS Triphasil [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SYNONYMS Trivora [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] PROTOCOL ID NUMBERS Recruiting NIAID HIVNET 021 PHARMACOLOGICAL ACTION Combination oral contraceptives act via the inhibition of gonadotropins. The primary result of this action is inhibition of follicular maturation and ovulation. Other results include increased cervical mucus viscosity, which reduces sperm entry into the uterus, and delayed maturation of the endometrium, which impairs ovum implantation. Both estrogen and progestin components are readily absorbed. Bioavailability of ethinyl estradiol is reduced due to a first-pass effect and enterohepatic recirculation. Bioavailability of levonorgestrel is complete due to the lack of a first-pass effect. A significant proportion (28%) of ethinyl estradiol is distributed into adipose tissue. Protein binding is high; the proportion of binding to albumin relative to sex hormone-binding globulin varies by strength and phasic relationship of the components. Metabolism of the estrogen component is primarily hepatic. The plasma elimination half-life of levonorgestrel administered with ethinyl estradiol is 8 to 13 hours. Elimination of ethinyl estradiol is via the renal (22-58%), fecal (30-53%), and biliary (26-43%) routes. Elimination of levonorgestrel is in the form of inactive metabolites via the renal route. [PDR 2000; p 3275; USP DI 2000; p 1445, 1460] DISEASES STUDIED/TREATED The ethinyl estradiol/levonorgestrel combination is approved by the FDA for the prevention of pregnancy. Hormonal contraceptives do not protect against HIV infection and AIDS. Studies are being conducted to determine whether there is an increased risk of HIV acquisition in patients using hormonal contraception. [USP DI 2000; p 1458; Protocol ID: HIVNET 021 ] CLASSIFICATION CODE Contraceptive [USP DI 2000; p 1458] CLASSIFICATION CODE Hormone (estrogen-progestin) [USP DI 2000; p 1458] OTHER MAJOR USES The ethinyl estradiol/levonorgestrel combination is approved by the FDA for the prevention of pregnancy. [USP DI 2000; p 1458] SUBSTANCE INTERACTIONS There are no reported food interactions with ethinyl estradiol/levonorgestrel. Drug interactions between ethinyl estradiol/levonorgestrel and agents known to significantly induce hepatic enzymes are possible. Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities are associated with concomitant use of rifampin, barbiturates, phenylbutazone, phenytoin sodium, griseofulvin, and troglitazone. Ampicillin, amoxicillin, penicillin, and some tetracyclines are associated with reduced efficacy of the contraceptive. This reduced efficacy is thought to be the result of a reduction in enterohepatic circulation of the estrogen component. Ritonavir decreases the bioavailability of the estrogen component by 40%; therefore, concomitant administration of ritonavir necessitates an increase in estrogen component dose or the use of another form of birth control. Concurrent use with oral contraceptives may increase the plasma concentrations of glucocorticoids, cyclosporine, theophylline, and certain benzodiazepines and tricyclic antidepressants. [PDR 2000; p 3276; USP DI 2000; p 1460] ADVERSE EFFECTS Oral contraceptive use is associated with an increased risk of certain conditions, including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease. The incidence and severity of these conditions increases in the presence of underlying risk factors such as hypertension, hyperlipidemias, obesity, diabetes, and smoking. Ocular lesions, contact lens intolerance, jaundice, fluid retention, and depression also can occur. Side effects that are more commonly reported include nausea, vomiting, gastrointestinal symptoms, menstrual flow changes, edema, breast tenderness, weight changes, headache, and allergic rash. [PDR 2000; p 3277] CONTRAINDICATIONS Combination oral contraceptive use is contraindicated in the following conditions: pregnancy, undiagnosed vaginal bleeding, known or suspected breast malignancy, other known or suspected estrogen-dependent neoplasia, hepatic adenomas or carcinomas, thromboembolic disorder history, or prior cholestatic jaundice due to pregnancy or pill use. [PDR 2000; p 3275] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Ethinyl estradiol/levonorgestrel is a combination oral contraceptive (COC). Ethinyl estradiol, the estrogen component, suppresses the follicle-stimulating hormone. Levonorgestrel, the progestin, suppresses luteinizing hormone release and surge. Together the hormones work synergistically to suppress ovulation. Individually, in the strength used in the combination, the hormones do not prevent contraception. [Protocol ID: HIVNET 021 ; USP DI 2000; p 1459] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H24-O2 (ethinyl estradiol) and C21-H28-O2 (levonorgestrel) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus. Accessed 09/28/00.] CHEMICAL/PHYSICAL DATA Molecular Weight: 296.40 (ethinyl estradiol) and 312.45 (levonorgestrel) [USPD 2000; p 280, 409] CHEMICAL/PHYSICAL DATA Melting Point: 141-146 C (ethinyl estradiol) and 205-207 C (levonorgestrel) [Merck Index 1996; p 637, 1151] CHEMICAL/PHYSICAL DATA Solubility: Ethinyl estradiol: practically insoluble in water; 1 part soluble in 6 parts ethanol, 4 parts ether, 5 parts acetone, 4 parts dioxane, 20 parts chloroform; soluble in vegetable oils; soluble in solutions of fixed alkali hydroxides [Merck Index 1996; p 637] SUBSTANCE DELIVERY DATA DOSAGE FORM: Combination tablet containing ethinyl estradiol and levonorgestrel in various strengths [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 09/28/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [PDR 2000; p 3275] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The product should be stored at room temperature (approximately 25 C or 77 F). [PDR 2000; p 3277] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 MANUFACTURERS 0000005404: Watson Laboratories Inc 311 Bonnie Circle Corona, CA 928802882 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 MANUFACTURERS 0000001214: Berlex Laboratories 300 Fairfield Rd Wayne, NJ 074707358 Contact: Unspecified (888)237-5394 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000005404: Watson Laboratories Inc 311 Bonnie Circle Corona, CA 928802882 Contact: Unspecified (800)934-5556 REFERENCES MED/20279616. Jacobson DL, Peralta L, Graham NM, Zenilman J. Histologic development of cervical ectopy: relationship to reproductive hormones. Sex Transm Dis. 2000 May;27(5):252-8. Review. MED/20086998. Mostad SB, Kreiss JK, Ryncarz AJ, Mandaliya K, Chohan B, Ndinya-Achola J, Bwayo JJ, Corey L. Cervical shedding of herpes simplex virus in human immunodeficiency virus-infected women: effects of hormonal contraception, pregnancy, and vitamin A deficiency. J Infect Dis. 2000 Jan;181(1):58-63. MED/99249593. Wang CC, Reilly M, Kreiss JK. Risk of HIV infection in oral contraceptive pill users: a meta-analysis. J Acquir Immune Defic Syndr. 1999 May 1;21(1):51-8. MED/98389211. Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, Leonard JM, Granneman GR. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol. 1998 Aug;46(2):111-6. MED/98242895. Stephenson JM. Systematic review of hormonal contraception and risk of HIV transmission: when to resist meta-analysis. AIDS. 1998 Apr 16;12(6):545-53. Review. MED/97460489. Mostad SB, Overbaugh J, DeVange DM, Welch MJ, Chohan B, Mandaliya K, Nyange P, Martin HL Jr, Ndinya-Achola J, Bwayo JJ, Kreiss JK. Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet. 1997 Sep 27;350(9082):922-7. MED/97066346. Piscitelli SC, Flexner C, Minor JR, Polis MA, Masur H. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis. 1996 Oct;23(4):685-93. MED/95151177. Grange JM, Winstanley PA, Davies PD. Clinically significant drug interactions with antituberculosis agents. Drug Saf. 1994 Oct;11(4):242-51. Review. MED/94266271. Daly CC, Helling-Giese GE, Mati JK, Hunter DJ. Contraceptive methods and the transmission of HIV: implications for family planning. Genitourin Med. 1994 Apr;70(2):110-7. Review. ENTRY MONTH 200009 LAST REVISION DATE 20001024 18 UNIQUE IDENTIFIER DRG-0330 NAME OF SUBSTANCE Naphthalene 2-sulfonate polymer [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] STANDARD CHEMICAL NAME Naphthalene 2-sulfonate polymer (sites of methylene attachments vary) [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] SYNONYMS PRO 2000 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] SYNONYMS PRO 2000/5 [Protocol ID: HPTN 032 ] PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 020 PROTOCOL ID NUMBERS Not yet recruiting NIAID HPTN 032 PHARMACOLOGICAL ACTION Naphthalene 2-sulfonate polymer is active against a wide range of HIV-1 isolates in vitro, including isolates from the United States, Africa, and Thailand. It appears to act by disrupting the initial binding and membrane fusion steps of HIV-1 infection. The compound is also active against herpesviruses and Chlamydia trachomatis. These pathogens often cause infections and genital lesions that are believed to increase the likelihood of HIV transmission. Following topical administration of naphthalene 2-sulfonate polymer to animals and intravaginal application in humans, no systemic absorption was detected. [Protocol ID: HIVNET 020 ] DISEASES STUDIED/TREATED Naphthalene 2-sulfonate polymer is included in clinical trials to determine its effectiveness in preventing the sexual transmission of HIV. [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] CLASSIFICATION CODE Microbicide [Protocol ID: HIVNET 020 ] CLASSIFICATION CODE Virion-receptor binding antagonist [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] CLASSIFICATION CODE Virucidal agent [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] SUBSTANCE INTERACTIONS No drug or food interactions are reported with naphthalene 2-sulfonate polymer vaginal gel. In addition, the product is shown to be compatible with latex condoms. [Protocol ID: HIVNET 020 ] ADVERSE EFFECTS In animal studies, naphthalene 2-sulfonate polymer vaginal gel products are reported to be well tolerated, nonmutagenic, and nonteratogenic. In human subjects, intravaginal application of various concentrations of the gel formulation is found to be safe and well tolerated, and no serious or life-threatening adverse events are reported. The drug is not detectable in the plasma following vaginal administration, indicating low systemic absorption. Side effects are generally mild and infrequent and include vulvovaginal ulceration, irritation, itching, burning, and bleeding. Pain on passing urine also is reported. These symptoms occur more frequently and are more severe in individuals using higher-strength formulations. The incidence of epithelial erosion is lower than that observed with nonoxynol-9. [Protocol ID: HIVNET 020 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Sulfonated polymers have the potential to inhibit HIV by binding to the V3 loop of gp120. A member of this group, naphthalene 2-sulfonate polymer, also binds to CD4 and interferes with gp120/CD4 binding; therefore, naphthalene 2-sulfonate polymer may exhibit a wider range of activity, inhibiting both T-cell and macrophage tropic strains of HIV. [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] CHEMICAL/PHYSICAL DATA Molecular Weight: Approximately 5000 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/032942.h- tm. Accessed 08/17/00.] CHEMICAL/PHYSICAL DATA Solubility: Highly water-soluble (approximately 1gm/5ml). [Protocol ID: HIVNET 020 ] CHEMICAL/PHYSICAL DATA Stability: The manufacturer of naphthalene 2-sulfonate polymer vaginal gel products has data indicating stability of the gel at 40 C and 75% relative humidity for 12 months. [Protocol ID: HIVNET 020 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Light brown solid. [Protocol ID: HIVNET 020 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: This investigational product is an aqueous gel formulation containing 2 or 4% naphthalene 2-sulfonate polymer. [Protocol ID: HIVNET 020 ; Protocol ID: HPTN 032 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravaginal [Protocol ID: HIVNET 020 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The product should be stored at 15-30 C (59-86 F) and protected from light. [Protocol ID: HIVNET 020 ] MANUFACTURERS 0000005381: Interneuron Pharmaceuticals Inc One Ledgemont Center / 99 Hayden Avenue Lexington, MA 02421 Contact: Unspecified (617)491-1100 MANUFACTURERS 0000005381: Interneuron Pharmaceuticals Inc One Ledgemont Center / 99 Hayden Avenue Lexington, MA 02421 MANUFACTURERS 0000005241: Procept Inc 840 Memorial Drive Cambridge, MA 02139 MANUFACTURERS 0000005381: Interneuron Pharmaceuticals Inc One Ledgemont Center / 99 Hayden Avenue Lexington, MA 02421 REFERENCES AIDS/20710568. Darbyshire JH, Manson KH, Miller CJ, Nunn AJ, Profy AT, Stone AB, Stott J, Weber JN. PRO 2000 gel, a candidate topical microbicide, can inhibit vaginal simian/human immunodeficiency virus infection in rhesus macaques. Natl HIV Prev Conf. 1999 Aug 29-Sep 1;(abstract no. 650). MED/20316519. Van Damme L, Wright A, Depraetere K, Rosenstein I, Vandersmissen V, Poulter L, McKinlay M, Van Dyck E, Weber J, Profy A, Laga M, Kitchen V. A phase I study of a novel potential intravaginal microbicide, PRO 2000, in healthy sexually inactive women. Sex Transm Infect. 2000 Apr;76(2):126-30. MED/20283817. Greenhead P, Hayes P, Watts PS, Laing KG, Griffin GE, Shattock RJ. Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol. 2000 Jun;74(12):5577-86. MED/99282607. Bourne N, Bernstein DI, Ireland J, Sonderfan AJ, Profy AT, Stanberry LR. The topical microbicide PRO 2000 protects against genital herpes infection in a mouse model. J Infect Dis. 1999 Jul;180(1):203-5. AIDS/98929154. Wright A, Rosenstein I, Poulter L, McKinlay M, Weber J, Profy A, Kitchen V. Safety and tolerability of PRO 2000 gel: a potential vaginal virucide. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:121 (abstract no. 227). ICA12/98398789. Profy AT, Sonderfan AJ, Bernstein DI, Chancellor T, Kern ER, Stanberry LR. PRO 2000 gel, a potential topical microbicide for HIV prevention, can block infection by other sexually transmitted disease pathogens. Int Conf AIDS. 1998;12:620-1 (abstract no. 33146). AIDS/97927407. Sonderfan AJ, Stump DG, Chancellor T, McKinlay MS, Jenson JC, Profy AT. Contraceptive properties of a new topical microbicide for HIV prevention. Natl Conf Women HIV. 1997 May 4-7;154 (abstract no. 304.8). AIDS/97926360. Sonderfan AJ, Chancellor T, Buckheit RW Jr, Tyms AS, Jenson JC, Profy AT. Safety and in vitro efficacy of a topical microbicide gel for the prevention of HIV-1 transmission. Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:161 (abstract no. 522). MED/96379900. Rusconi S, Moonis M, Merrill DP, Pallai PV, Neidhardt EA, Singh SK, Willis KJ, Osburne MS, Profy AT, Jenson JC, Hirsch MS. Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities. Antimicrob Agents Chemother. 1996 Jan;40(1):234-6. MED/93124455. Tan GT, Wickramasinghe A, Verma S, Singh R, Hughes SH, Pezzuto JM, Baba M, Mohan P. Potential anti-AIDS naphthalenesulfonic acid derivatives. Synthesis and inhibition of HIV-1 induced cytopathogenesis and HIV-1 and HIV-2 reverse transcriptase activities. J Med Chem. 1992 Dec 25;35(26):4846-53. ENTRY MONTH 200008 LAST REVISION DATE 20001025 19 UNIQUE IDENTIFIER DRG-0329 NAME OF SUBSTANCE Tucaresol [USPD 2000; p 747] REGISTRY NUMBER 84290-27-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 09/27/00.] STANDARD CHEMICAL NAME Benzoic acid, 4-((2-formyl-3-hydroxyphenoxy)methyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 09/27/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 311A DISEASES STUDIED/TREATED Tucaresol is an immunomodulatory agent being investigated for its use in the management of HIV infection. [Glaxo Wellcome. Research and Development. Available at: http://science.glaxowellcome.com. Accessed 08/22/00.] CLASSIFICATION CODE Immunologic adjuvant [Glaxo Wellcome. Research and Development. Available at: http://science.glaxowellcome.com. Accessed 08/22/00.] CLASSIFICATION CODE Immunomodulator [Protocol ID: 311A ] OTHER MAJOR USES Tucaresol has been studied for the treatment of sickle cell anemia. Tucaresol is also being investigated as an immunomodulatory agent in patients with hepatitis B and metastatic malignant melanoma. [Glaxo Wellcome. Research and Development. Available at: http://science.glaxowellcome.com. Accessed 08/22/00.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Tucaresol is a substituted benzaldehyde that provides a co-stimulatory signal to T-lymphocytes in the induction of immune responses. At the chemical level, T-cells express surface carbonyl and amine groups that bind covalently with those of antigen-presenting cells (APCs), resulting in T-cell activation. Tucaresol mimics the natural carbonyl donor and binds, through Schiff-base formation, with amines on the T-cell surface. Tucaresol has been shown to enhance CD4 T-helper cell and CD8 cytotoxic T-cell responses in vivo. Cytokine production, specifically interleukin-2 and gamma interferon production, may also be enhanced. [J Mol Med 1996 Sep;74(9):497-504] CHEMICAL/PHYSICAL DATA Molecular Formula: C15-H12-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 09/27/00.] CHEMICAL/PHYSICAL DATA Molecular Weight: 272.25 [USPD 2000; p 747] CHEMICAL/PHYSICAL DATA Melting Point: 239-240 C [U.S. Patent and Trademark Office. Patent # 4,535,183. Available at: http://www.uspto.gov/patft/index.html. Accessed 08/22/00] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.17%, H4.44%, O29.38% [U.S. Patent and Trademark Office. Patent # 4,535,183. Available at: http://www.uspto.gov/patft/index.html. Accessed 08/22/00.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow crystals [U.S. Patent and Trademark Office. Patent # 4,535,183. Available at: http://www.uspto.gov/patft/index.html. Accessed 08/22/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [Glaxo Wellcome. Research and Development. Available at: http://science.glaxowellcome.com. Accessed 08/22/00.] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 REFERENCES MED/98353264. Peck RW, Wootton R, Wiggs R, Layton G, Posner J. Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers. Br J Clin Pharmacol. 1998 Jul;46(1):83-6. MED/97422548. Chen H, Hall S, Heffernan B, Thompson NT, Rogers MV, Rhodes J. Convergence of Schiff base costimulatory signaling and TCR signaling at the level of mitogen-activated protein kinase ERK2. J Immunol. 1997 Sep 1;159(5):2274-81. MED/97047134. Chen H, Rhodes J. Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. J Mol Med. 1996 Sep;74(9):497-504. Review. MED/97007288. Rhodes J. Covalent chemical events in immune induction: fundamental and therapeutic aspects. Immunol Today. 1996 Sep;17(9):436-41. Review. MED/95388146. Rhodes J, Chen H, Hall SR, Beesley JE, Jenkins DC, Collins P, Zheng B. Therapeutic potentiation of the immune system by costimulatory Schiff-base-forming drugs. Nature. 1995 Sep 7;377(6544):71-5. MED/95367409. Rolan PE, Mercer AJ, Wootton R, Posner J. Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers. Br J Clin Pharmacol. 1995 Apr;39(4):375-80. MED/93249832. Rolan PE, Parker JE, Gray SJ, Weatherley BC, Ingram J, Leavens W, Wootton R, Posner J. The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a potential anti-sickling agent, following oral administration to healthy subjects. Br J Clin Pharmacol. 1993 Apr;35(4):419-25. ENTRY MONTH 200008 LAST REVISION DATE 20001025 20 UNIQUE IDENTIFIER DRG-0328 NAME OF SUBSTANCE Nonoxynol-9 [USPD 2000 p. 507] SYNONYMS Advantage S [Protocol ID: HIVNET 008 ] SYNONYMS Conceptrol [Protocol ID: HIVNET 016 ] SYNONYMS Advantage 24 [Protocol ID: HIVNET 008 ] PROTOCOL ID NUMBERS Complete NIAID HIVNET 008 PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 016 CLASSIFICATION CODE Investigational - Virucidal agent [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CLASSIFICATION CODE Spermicide [USPD 2000; p 507] CHEMICAL/PHYSICAL DATA Molecular Formula: C33-H60-O10 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] MANUFACTURERS 0000003589: Columbia Research Laboratories Inc 100 North Village Ave / Suite 32 Rockville Centre, NY 11570 Contact: Dr Howard Levine (516)766-2660 MANUFACTURERS 0000005380: Advanced Care Products 1001 US Hwy 202 Raritan, NJ 08869 Contact: Dr Howard Levine (516)766-2660 MANUFACTURERS 0000003589: Columbia Research Laboratories Inc 100 North Village Ave / Suite 32 Rockville Centre, NY 11570 REFERENCES Centers for Disease Control and Prevention. National Center for HIV, STD and TB Prevention - Divisions of HIV/AIDS Prevention. Nonoxynol-9 Trial: The Implications. Available at: http://www.cdc.gov/hiv/pubs/mmwr/mmwr11aug00.- htm. Accessed October 25, 2000. Centers for Disease Control and Prevention. Notice to readers: CDC statement on study results of product containing nonoxynol-9. Morbidity and Mortality Weekly Report. 2000 Aug 11;49(31):717-8. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm49- 31a4.htm. Accessed October 25, 2000. MED/20047613. Uckun FM, D'Cruz OJ. Prophylactic contraceptives for HIV. AIDS. Hum Reprod Update. 1999 Sep-Oct;5(5):506-14. Review. MED/20023377. Gross M, Celum CL, Tabet SR, Kelly CW, Coletti AS, Chesney MA. Acceptability of a bioadhesive nonoxynol-9 gel delivered by an applicator as a rectal microbicide. Sex Transm Dis. 1999 Nov;26(10):572-8. MED/20017536. Krebs FC, Miller SR, Malamud D, Howett MK, Wigdahl B. Inactivation of human immunodeficiency virus type 1 by nonoxynol-9, C31G, or an alkyl sulfate, sodium dodecyl sulfate. Antiviral Res. 1999 Oct;43(3):157-73. MED/98363662. Roddy RE, Zekeng L, Ryan KA, Tamoufe U, Weir SS, Wong EL. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med. 1998 Aug 20;339(8):504-10. MED/98327265. Gross M, Buchbinder SP, Celum C, Heagerty P, Seage GR 3rd. Rectal microbicides for U.S. gay men. Are clinical trials needed? Are they feasible? HIVNET Vaccine Preparedness Study Protocol Team. Sex Transm Dis. 1998 Jul;25(6):296-302. MED/98253862. Rosenstein IJ, Stafford MK, Kitchen VS, Ward H, Weber JN, Taylor-Robinson D. Effect on normal vaginal flora of three intravaginal microbicidal agents potentially active against human immunodeficiency virus type 1. J Infect Dis. 1998 May;177(5):1386-90. MED/96183929. Pauwels R, De Clercq E. Development of vaginal microbicides for the prevention of heterosexual transmission of HIV. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Mar 1;11(3):211-21. Review. MED/95263076. Weir SS, Roddy RE, Zekeng L, Feldblum PJ. Nonoxynol-9 use, genital ulcers, and HIV infection in a cohort of sex workers. Genitourin Med. 1995 Apr;71(2):78-81. MED/93312953. Roddy RE, Cordero M, Cordero C, Fortney JA. A dosing study of nonoxynol-9 and genital irritation. Int J STD AIDS. 1993 May-Jun;4(3):165-70. MED/93305222. Zekeng L, Feldblum PJ, Oliver RM, Kaptue L. Barrier contraceptive use and HIV infection among high-risk women in Cameroon. AIDS. 1993 May;7(5):725-31. ENTRY MONTH 200006 LAST REVISION DATE 20000921 21 UNIQUE IDENTIFIER DRG-0327 NAME OF SUBSTANCE Somatropin [USPD 1998; p. 677] REGISTRY NUMBER 12629-01-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Somatotropin [USPD 1998; p. 677] SYNONYMS Genotropin [USP DI 2000; p. 1658] SYNONYMS Humatrope [USP DI 2000; p. 1658] SYNONYMS Nutropin [USP DI 2000; p. 1658] SYNONYMS Saizen [USP DI 2000; p. 1658] SYNONYMS Serostim [USP DI 2000; p. 1658] PROTOCOL ID NUMBERS Recruiting FDA 317A PROTOCOL ID NUMBERS Suspended NIAID ACTG P1011 CLASSIFICATION CODE Growth hormone [USP DI 2000; p 1654] CHEMICAL/PHYSICAL DATA Molecular Formula: C990-H1528-N262-O300-S7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 22,125.19 [USPD 1998; p. 677] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Clinical Trial Information (888)566-5593 MANUFACTURERS 0000005254: Serono Laboratories Inc 100 Longwater Circle Norwell, MA 02061 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000005254: Serono Laboratories Inc 100 Longwater Circle Norwell, MA 02061 Contact: Dr Don Francis (415)255-5806 MANUFACTURERS 0000005254: Serono Laboratories Inc 100 Longwater Circle Norwell, MA 02061 Contact: Unspecified (800)821-8590 ENTRY MONTH 200004 LAST REVISION DATE 20000801 22 UNIQUE IDENTIFIER DRG-0326 NAME OF SUBSTANCE Dextrin 2-sulfate [Protocol ID: 309A ] SYNONYMS Viraldon [Protocol ID: 309A ] PROTOCOL ID NUMBERS No longer recruiting FDA 309A CLASSIFICATION CODE Investigational - Antiviral [Protocol ID: 309A ] MANUFACTURERS 0000005196: ML Laboratories Innovation House Kelburn Court Warrington, Contact: Unspecified (192)584-4700 MANUFACTURERS 0000005196: ML Laboratories Innovation House Kelburn Court Warrington, Contact: Unspecified (282)827-3631 MANUFACTURERS 0000005147: IVEX Pharmaceuticals Ltd Old Belfast Road Co Antrim , ENTRY MONTH 200003 LAST REVISION DATE 20000801 23 UNIQUE IDENTIFIER DRG-0325 NAME OF SUBSTANCE Lamivudine/Zidovudine/Abacavir [Protocol ID: 308A ] SYNONYMS Trizivir [Protocol ID: 308A ] PROTOCOL ID NUMBERS No longer recruiting FDA 307A PROTOCOL ID NUMBERS No longer recruiting FDA 308A PROTOCOL ID NUMBERS Recruiting FDA 308B PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5103 CLASSIFICATION CODE Antiretroviral [Protocol ID: 308A ] CLASSIFICATION CODE Antiviral [Protocol ID: 308A ] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 ENTRY MONTH 200003 LAST REVISION DATE 20000801 24 UNIQUE IDENTIFIER DRG-0324 NAME OF SUBSTANCE Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed [Protocol ID: ACTG 402 ] SYNONYMS Acel-Imune [USP DI 2000; p 1281] SYNONYMS Tripedia [USP DI 2000; p 1281] SYNONYMS Infanrix [USP DI 2000; p 1281] PROTOCOL ID NUMBERS Recruiting NIAID ACTG 402 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1024 CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 1277] MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr Amy Baim (914)732-2147 MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Dr John Riefler (914)732-2035 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (610)647-9452 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Unspecified (800)934-5556 ENTRY MONTH 200002 LAST REVISION DATE 20010328 25 UNIQUE IDENTIFIER DRG-0323 NAME OF SUBSTANCE IM862 [Protocol ID: 306A ] PROTOCOL ID NUMBERS No longer recruiting FDA 306A PHARMACOLOGICAL ACTION IM862 shows dose-dependent inhibition of tumor growth. Although it has no demonstrable effect on endothelial cell proliferation or migration, it inhibits angiogenesis in vivo such as chorioallantoic membrane (CAM) assays. IM862 suppresses production of IL-4, IL-6, and IL-10 (known to weaken the immune system) and enhances production of IL-12, stimulating natural killer cells. Due to its small molecular weight, IM862 is bioavailable through the mucosa when administered as a nose drop. In a Phase I/II clinical trial, 44 patients with AIDS-related KS received IM862 as intranasal drops at a dose of 5 mg. Of these patients, 71% had received prior systemic chemotherapy, and the median CD4+ cell count was 165 cells/mm3 (range 2 to 716). Four complete and 9 partial remissions were documented for a total major response rate of 37%. The median duration of response was 28+ weeks. Clinical trials of IM862 in AIDS-related KS are ongoing. [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abstract no. 2065.; Drug Discovery Online: Digital Marketplace for the drug development industry. Available at: http://news.drugdiscoveryonline.com. Accessed: May 15, 2000.; R&D News 1999 Jun 16.; Curr Opin Oncol 1998 Sep;10(5):413-21] DISEASES STUDIED/TREATED IM862 is under investigation for use as a treatment for mucocutaneous AIDS-related Kaposi's sarcoma (KS). [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abstract no. 2065.; Protocol ID: 306A ] CLASSIFICATION CODE Angiogenesis inhibitor [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abst. 2065] OTHER MAJOR USES IM862 is under investigation for use in treating malignant tumors, age-related macular degeneration, and vascular diseases. The manufacturer is conducting a Phase I/II ovarian cancer trial and is planning clinical trials in other cancers. [Drug Discovery Online: Digital Marketplace for the drug development industry. Available at: http://news.drugdiscoveryonline.com. Accessed: May 15, 2000.; R&D News 1999 Jun 16.] ADVERSE EFFECTS Adverse effects experienced in a Phase I/II trial included mild and transient headaches, fatigue, tingling, and nausea. There were no hematologic adverse effects attributed to treatment. [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abstract no. 2065.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: IM862 is a naturally occurring thymic dipeptide consisting of tryptophan and glutamic acid. [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abstract no. 2065.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Intranasal drops. [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abstract no. 2065.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intranasal. [Proc Annu Meet Am Soc Clin Oncol 1999 35th Annual; Abstract no. 2065.] MANUFACTURERS 0000005070: Cytran Inc 10230 NE Points Dr Suite 530 Kirkland, WA 98033 Contact: Unspecified (425)889-8822 REFERENCES Tulpule A, Espina BM, Cabriales S, Vergara S, Dharmapala D, Jacobs C, Gill PS. IM862 nasal solution is an active anti-angiogenic agent in the treatment of AIDS-related Kaposi's sarcoma. 35th Ann Meet Amer Society of Clin Oncol. 1999 May 15-18 (abstract no. 2065). MED/99016493. McGarvey ME, Tulpule A, Cai J, Zheng T, Masood R, Espina B, Arora N, Smith DL, Gill PS. Emerging treatments for epidemic (AIDS-related) Kaposi's sarcoma. Curr Opin Oncol 1998 Sep;10(5):413-21. Gill PS, Scadden DT, Tulpule A, Espina BM, Shea K, Cabriales S, Todd S, Green L. Preliminary results of IM-862 nasal solution in the treatment of patients with AIDS-related Kaposi's sarcoma. 2nd National AIDS Malignancy Conf. 1998 April 6-8 (abstract no. 54). ENTRY MONTH 199909 LAST REVISION DATE 20000801 26 UNIQUE IDENTIFIER DRG-0321 NAME OF SUBSTANCE Atorvastatin calcium [USPD 1998; p. 68] REGISTRY NUMBER 134523-03-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-- methylethyl)-3-phenyl-4 -[(phenylamino)carbonyl]-, calcium salt (2:1),[R-(R*,R*)]- [USPD 1998; p 68] SYNONYMS Lipitor [USP DI 2000; p. 494] PROTOCOL ID NUMBERS Complete NIAID ACTG A5047 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5108 PHARMACOLOGICAL ACTION MODE OF ACTION: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, and by increasing the number of hepatic LDL (low-density lipoprotein) receptors on the cell surface to enhance uptake and catabolism of LDL. Atorvastatin also reduces LDL production and the number of LDL particles. Atorvastatin reduces total-C (cholesterol), LDL-C, and apolipoprotein B (apo B) in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin reduces total-C, LDL-C, very low density lipoprotein cholesterol (VLDL-C), apo B, triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C) and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces intermediate density lipoprotein cholesterol in patients with dysbetalipoproteinemia. The effect of atorvastatin on cardiovascular morbidity and mortality has not been determined. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage rather than systemic drug concentration correlates better with LDL-C reduction. Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. The absolute bioavailability of atorvastatin is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9% respectively, LDL-C reduction is similar whether atorvastatin is given with or without food. Atorvastatin is 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives, and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. [PDR 1999; p 2293-6 (2293-4)] DISEASES STUDIED/TREATED Lipid disorders associated with HIV infection and antiretroviral therapy are of growing concern. Persistently elevated cholesterol and triglyceride levels may represent a significant risk factor in the development of coronary artery disease. Lipid-lowering agents, such as atorvastatin, are studied to determine their safety and efficacy in the treatment of HIV patients with lipid disorders. [GMHC Treat Issues 1998 May;12(5); p 4-5, 8; Protocol ID: ACTG A5047 ] CLASSIFICATION CODE Antihyperlipidemic [USP DI 2000; p. 491] CLASSIFICATION CODE HMG-CoA reductase inhibitor [USP DI 2000; p. 491] OTHER MAJOR USES Atorvastatin is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. [PDR 1999; p 2293-6 (2294)] SUBSTANCE INTERACTIONS The risk of myopathy during treatment with other drugs of this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin, or azole antifungals. When atorvastatin and Maalox (antacid) suspension were coadministered, plasma concentrations of atorvastatin decreased approximately 35%. However, LDL-C reduction was not altered. Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone. Atorvastatin plasma concentrations and LDL-C reduction were not altered by coadministration of cimetidine. In healthy individuals, plasma concentrations of atorvastatin increased approximately 40% with coadministration of erythromycin, a known inhibitor of cytochrome P450 3A4. Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. Caution should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. Clinical investigations to determine possible interactions between atorvastatin (and other statins) and protease inhibitors used in the treatment of HIV disease are under way. [PDR 1999; p 2293-6 (2295)] ADVERSE EFFECTS Atorvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. In controlled clinical studies of 2,502 patients, less than 2 percent of patients were discontinued due to adverse experiences attributable to atorvastatin. The most frequent adverse events thought to be related to the drug were constipation, flatulence, dyspepsia, and abdominal pain. HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Liver function tests should be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of more than 3 times the upper limit of normal persist, reduction of dose or withdrawal of atorvastatin is recommended. [PDR 1999; p 2293-6 (2295-6)] CONTRAINDICATIONS Active liver disease or unexplained persistent elevations of serum transaminases. Hypersensitivity to any component of this medication. HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol. [PDR 1999; p 2293-6 (2295-6)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Atorvastatin calcium is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. [PDR 1999; p 2293-6 (2293)] CHEMICAL/PHYSICAL DATA Molecular Formula: C66-H68-Ca-F2-N4-O10 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 1155.37 [USPD 1998; p. 68] CHEMICAL/PHYSICAL DATA Elemental Comp: C70.95%, H6.31%, F3.40%, N5.01%, O14.32% [Merck Index 1996; p. 146] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in aqueous solutions of pH 4 and below. Slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol. [PDR 1999; p 2293-6 (2293)] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder. [PDR 1999; p 2293-6 (2293)] SUBSTANCE DELIVERY DATA DOSAGE FORM: White, elliptical, film-coated tablets of atorvastatin calcium containing 10-, 20-, or 40-mg atorvastatin. [PDR 1999; p 2293-6 (2296)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [PDR 1999; p 2293-6 (2296)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled temperature 20 C to 25 C (68 F to 77 F). [PDR 1999; p 2293-6 (2296)] MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)223-0432 MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 REFERENCES MED/99275750. Nakad A, Bataille L, Hamoir V, Sempoux C, Horsmans Y. Atorvastatin-induced acute hepatitis with absence of cross-toxicity with simvastatin [letter]. Lancet 1999 May 22;353(9166):1763-4. MED/99231729. Bertolotto A, Bandinelli S, Ruocco L, Lo Faro A, Penno G, Navalesi R. More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolemia [letter]. Atherosclerosis 1999 Apr;143(2):455-7. MED/99215537. Singhal MK, Bhaskaran S, Szabo T, La Rosa R. No difference in plasma fibrinogen levels between CAPD patients taking atorvastatin and simvastatin [letter]. Perit Dial Int 1999 Jan-Feb;19(1):89-91. MED/99266795. Crouse JR 3rd, Frohlich J, Ose L, Mercuri M, Tobert JA. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol 1999 May 15;83(10):1476-7,A7. MED/99250857. Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999 May;39(5):501-4. MED/98430548. Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J. Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities [letter]. Lancet 1998 Sep 26;352(9133):1031-2. MED/99195504. Hoogerbrugge N. Effects of atorvastatin on serum lipids of patients with familial hypercholesterolaemia. J Intern Med 1998 Aug;244(2):143-7. AIDS/99704162. Gilden D. A further point about statins.... GMHC Treat Issues 1998 Jun;12(6):8. AIDS/98703871. Sonnabend J. Heart disease in people with HIV: an interview with Joseph Sonnabend, M.D. [interview by Dave Gilden]. GMHC Treat Issues 1998 May;12(5):4-5, 8. MED/98305951. Henry K, Melroe H, Huebesch J, Hermundson J, Levine C, Swensen L, Daley J. Severe premature coronary artery disease with protease inhibitors [letter]. Lancet 1998 May 2;351(9112):1328. ENTRY MONTH 199907 LAST REVISION DATE 20000801 27 UNIQUE IDENTIFIER DRG-0320 NAME OF SUBSTANCE Simvastatin [USPD 1998; p. 668] REGISTRY NUMBER 79902-63-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tet- rahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1alpha,3alpha,7beta,8beta(2S*,4S*),8abet- a]]- [USPD 1998; p 668] SYNONYMS Zocor [USP DI 2000; p. 1721] PROTOCOL ID NUMBERS Complete NIAID ACTG A5047 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5108 PHARMACOLOGICAL ACTION MODE OF ACTION: Simvastatin has been shown to reduce both normal and elevated LDL-C (low-density lipoprotein cholesterol) concentrations. LDL is formed from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL cholesterol concentration and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apolipoprotein B (Apo B) also falls substantially during treatment with simvastatin. As each LDL particle contains 1 molecule of Apo B, and since in patients with predominant elevations in LDL-C (without accompanying elevations in VLDL) little Apo B is found in other lipoproteins, this strongly suggests that simvastatin does not merely cause cholesterol to be lost from LDL, but that it also reduces the concentration of circulating LDL particles. In addition, simvastatin reduces VLDL and TG (triglycerides) and increases HDL-C (high-density lipoprotein cholesterol). Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. This conversion is an early step in the biosynthetic pathway for cholesterol. In a multicenter clinical trial, the effect of improving lipoprotein levels with simvastatin on total mortality was assessed in 4,444 patients with coronary heart disease (CHD) and baseline total cholesterol of 212-309 mg/dl (5.5-8.0 mmol/l). The patients were followed for a median of 5.4 years. Simvastatin reduced the risk of mortality by 30%, of CHD mortality by 42%, of having a hospital-verified non-fatal myocardial infarction by 37%, and of undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%. Following an oral dose of C14-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (simvastatin plus C14-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. In rats, simvastatin-derived radioactivity crossed the blood-brain barrier. Both simvastatin and its beta-hydroxyacid metabolite are approximately 95% bound to human plasma proteins. The major active metabolites of simvastatin present in human plasma are the beta-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. [PDR 1999; p 1921-5] DISEASES STUDIED/TREATED Lipid disorders associated with HIV infection and antiretroviral therapy are of growing concern. Persistently elevated cholesterol and triglyceride levels may represent a significant risk factor in the development of coronary artery disease. Lipid-lowering agents, such as simvastatin, are studied to determine their safety and efficacy in the treatment of HIV patients with lipid disorders. [GMHC Treat Issues 1998 May;12(5); p 4-5, 8; Protocol ID: ACTG A5047 ] CLASSIFICATION CODE Antihyperlipidemic [USP DI 2000; p. 1717] CLASSIFICATION CODE HMG-CoA reductase inhibitor [USP DI 2000; p. 1717] OTHER MAJOR USES Therapy with lipid-altering agents such as simvastatin should be considered in those individuals at increased risk for atherosclerosis-related clinical events as a function of cholesterol level, the presence of coronary heart disease, or other risk factors. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacologic measures alone has been inadequate. [PDR 1999; p 1921-5 (1923)] SUBSTANCE INTERACTIONS Simvastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy. Coadministration of mibefradil, cylosporine, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, HIV protease inhibitors, or nefazodone may increase the incidence and severity of myopathy. Since simvastatin is metabolized by the cytochrome P450 isoform 3A4, this does not preclude an interaction with other drugs metabolized by the same isoform. Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Simvastatin modestly potentiated the effect of coumarin anticoagulants (warfarin). Clinical investigations to determine possible interactions between atorvastatin (and other statins) and protease inhibitors used in the treatment of HIV disease are under way. [PDR 1999; p 1921-5 (1924)] ADVERSE EFFECTS In pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse experiences attributable to simvastatin. Adverse reactions have usually been mild and transient. Simvastatin has been evaluated for serious adverse reactions in more than 21,000 patients; it was generally well tolerated. [PDR 1999; p 1921-5 (1925)] CONTRAINDICATIONS Hypersensitivity to any component of the simvastatin medication (i.e., ZOCOR). Simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. Simvastatin and other HMG-CoA reductase inhibitors occasionally cause myopathy, which is manifested as muscle pain or weakness, associated with grossly elevated creatine kinase. Patients starting simvastatin therapy should be advised of the risk of myopathy and told to report promptly unexplained muscle pain, tenderness, or weakness. The drug should be used with caution in patients who consume substantial quantities of alcohol or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin. It is recommended that liver function tests be performed before the initiation of treatment, and periodically thereafter. [PDR 1999; p 1921-5 (1923-4)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding beta-hydroxyacid form. This form is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. [PDR 1999; p 1921-5 (1921)] CHEMICAL/PHYSICAL DATA Molecular Formula: C25-H38-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 418.58 [USPD 1998; p. 668] CHEMICAL/PHYSICAL DATA Melting Point: 135-138 C [Merck Index 1996; p. 1465] CHEMICAL/PHYSICAL DATA Elemental Comp: C71.74%, H9.15%, O19.11% [Merck Index 1996; p. 1465] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water, and freely soluble in chloroform, methanol, and ethanol. [PDR 1999; p 1921-5 (1921)] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white, nonhygroscopic crystalline powder. [PDR 1999; p 1921-5 (1921)] SUBSTANCE DELIVERY DATA DOSAGE FORM: 5-mg, 10-mg, 20-mg, 40-mg, or 80-mg film-coated tablets. [PDR 1999; p 1921-5 (1925)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. Recommended dosage range is 5-80 mg/day. [PDR 1999; p 1921-5 (1925)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 5-30C (41-86 F). [PDR 1999; p 1921-5 (1925)] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES MED/99310065. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999 Jun 19;353(9170):2093-9. MED/99312184. Ito MK, Stolley SN, Morreale AP, Lin JC, Marcus DB. Rationale, design, and baseline results of the Pravastatin-to-Simvastatin Conversion Lipid Optimization Program (PSCOP). Am J Health Syst Pharm 1999 Jun 1;56(11):1107-13. MED/99275750. Nakad A, Bataille L, Hamoir V, Sempoux C, Horsmans Y. Atorvastatin-induced acute hepatitis with absence of cross-toxicity wih simvastatin [letter]. Lancet 1999 May 22;353(9166):1763-4. MED/99270773. Tobert JA, Vega JM, Dobrinska M, Gruer PJ. Calcium channel blocker-simvastatin interaction [letter]. Clin Pharmacol Ther 1999 May;65(5):583-5. MED/99266795. Crouse JR 3rd, Frohlich J, Ose L, Mercuri M, Tobert JA. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol 1999 May 15;83(10):1476-7, A7. Leslie H. Body fat changes: more than lipodystrophy. Bulletin of Experimental Treatments for AIDS 1999 Jan. MED/98403985. Carr A, Samaras K, Chisholm DJ, Cooper DA. Abnormal fat distribution and use of protease inhibitors [letter; comment]. Lancet 1998 Jun 6;351(9117):1736. ICA12/98387988. Dong K, Flynn MM, Dickinson BP, Rich JD, Tashima K, Flanigan TP, Carpenter CC. Changes in body habitus in HIV(+) women after initiation of protease inhibitor therapy. Int Conf AIDS. 1998;12:88 (abstract no. 177/12373). ICA12/98387094. Henry K. Lipid abnormalities associated with use of protease inhibitors: prevalence, clinical sequelae and treatment. Int Conf AIDS 1998;12:77 (abstract no. 12319). MED/99183494. Cziraky M. Clinical positioning of HMG-CoA reductase inhibitors in lipid management protocols. Pharmacoeconomics 1998;14 Suppl 3:29-38. ENTRY MONTH 199907 LAST REVISION DATE 20000801 28 UNIQUE IDENTIFIER DRG-0319 NAME OF SUBSTANCE Pravastatin sodium [USPD 1998; p. 597] REGISTRY NUMBER 81131-70-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Naphthaleneheptanoic acid, 1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydrox- y-2-methyl-8-(2-methyl- 1-oxobutoxy)-,monosodium salt, [1S-[1alpha(betaS*,deltaS*),2alpha, 6alpha,8beta(R*),8aalpha]]- [USPD 1998; p 597] SYNONYMS Pravachol [USP DI 2000; p. 1721] PROTOCOL ID NUMBERS Complete NIAID ACTG A5047 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5108 PROTOCOL ID NUMBERS Suspended NIAID ACTG A5087 PHARMACOLOGICAL ACTION MODE OF ACTION: Pravastatin sodium produces its lipid-lowering effect in the following ways: (1) Reversible inhibition of HMG-CoA reductase activity, effecting modest reductions in intracellular pools of cholesterol (C). This results in an increase in the number of LDL (low-density lipoprotein) receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. (2) Inhibition of LDL production by inhibiting hepatic synthesis of VLDL (very low-density lipoprotein), the LDL precursor. Clinical studies have shown that treatment with pravastatin reduces total-C, and apolipoprotein B. Pravastatin also reduced VLDL-C and TG (triglycerides) and produced variable increases in HDL-C (high-density lipoprotein cholesterol) and apolipoprotein A. In a large scale study, the effect of improving lipoprotein levels with pravastatin on fatal and nonfatal coronary heart disease (CHD) was assessed in 6,595 men, without a previous myocardial infarction, and with LDL-C levels between 156-254 mg/dl. The patients were followed for a median of 4.8 years. In this study, pravastatin reduced the risk of a first coronary event by 31%, and decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft surgery or coronary angioplasty) by 37%. Cardiovascular deaths were decreased by 32% and there was no increase in death from non-cardiovascular causes. In clinical pharmacology studies, pravastatin was rapidly absorbed, with peak plasma levels of parent compound attained 1 to 1.5 hours following ingestion. The average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with meals or 1 hour prior to meals. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ration 0.66), which is its primary site of action and the primary site of cholesterol synthesis and of LDL-C clearance. Approximately 20% of a radiolabeled oral dose of pravastatin was excreted in urine and 70% in the feces. [PDR 1999; p 853-7] DISEASES STUDIED/TREATED Lipid disorders associated with HIV infection and antiretroviral therapy are of growing concern. Persistently elevated cholesterol and triglyceride levels may represent a significant risk factor in the development of coronary artery disease. Lipid-lowering agents, such as pravastatin, are studied to determine their safety and efficacy in the treatment of HIV patients with lipid disorders. [GMHC Treat Issues 1998 May;12(5); p 4-5, 8; Protocol ID: ACTG A5047 ] CLASSIFICATION CODE Antihyperlipidemic [USP DI 2000; p. 1717] CLASSIFICATION CODE HMG-CoA reductase inhibitor [USP DI 2000; p. 1717] OTHER MAJOR USES Pravastatin is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, and TG levels in patients with primary hypercholesterolemia and mixed dyslipidemia. In hypercholesterolemic patients with or without clinically evident coronary heart disease, pravastatin is indicated to reduce the risk of new or recurrent myocardial infarction, of having to undergo myocardial revascularization procedures, and of cardiovascular mortality with no increase in death from non-cardiovascular causes. [PDR 1999; p 853-7 (854)] SUBSTANCE INTERACTIONS The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with erythromycin, cyclosporine, niacin, or fibrates. In vitro and in vivo data indicate that pravastatin is not metabolized by cytochrome P450 3A4 to a clinically significant extent. Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of pravastatin. The mean AUC and C/max for pravastatin were increased by factors of 1.7 and 2.5, respectively, when given with itraconazole as compared to placebo. Since concomitant administration of pravastatin had no effect on the clearance of antipyrine, interactions with other drugs metabolized via the same hepatic cytochrome isozymes are not expected. When pravastatin was administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. Pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin. In a crossover trial the bioavailability parameters of digoxin were not affected. In another study with concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. Combination therapy with pravastatin and gemfibrozil is generally not recommended. Clinical investigations to determine possible interactions between pravastatin (and other statins) and protease inhibitors used in the treatmnet of HIV disease are under way. [PDR 1999; p 853-7 (855)] ADVERSE EFFECTS Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4-month long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant. In long-term studies, the most common reasons for discontinuation were asymptomatic serum transaminase increases and mild, non-specific gastrointestinal complaints. During clinical trials the overall incidence of adverse events in the elderly was not different from the incidence observed in younger patients. It is recommended that liver function tests be performed prior to and at 12 weeks following initiation of therapy with pravastatin or the elevation of dose. Patients who develop increased transaminase levels or signs and symptoms of liver disease should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 times the upper limit of normal or greater persist, withdrawal of PRAVACHOL therapy is recommended. [PDR 1999; p 853-7 (856)] CONTRAINDICATIONS Hypersensitivity to any component of pravastatin. Active liver disease or unexplained, persistent elevations in liver function tests. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Since there are dual routes of elimination, the potential exists both for compensatory excretion by the alternate route and for accumulation of drug and/or metabolites in patients with renal or hepatic insufficiency. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. [PDR 1999; p 853-7 (855)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Pravastatin is a mevinic acid-derivative antilipidemic agent. The drug is a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor and is structurally and pharmacologically related to mevastatin, lovastatin, and simvastatin. [AHFS Drug Information 1999; p 1561] CHEMICAL/PHYSICAL DATA Molecular Formula: C23-H35-Na-O7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 446.52 [USPD 1998; p. 597] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.87%, H7.90%, Na5.15%, O25.08% [Merck Index 1996; p. 1323] CHEMICAL/PHYSICAL DATA Solubility: Soluble in methanol and water (less than 300 mg/ml), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether. [PDR 1999; p 853-63] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Odorless, white to off-white, fine or crystalline powder. [PDR 1999; p 853] SUBSTANCE DELIVERY DATA DOSAGE FORM: 10-mg, 20-mg, or 40-mg tablets. [PDR 1999; p 853-7 (857)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The recommended dosage range is generally 10- to 40-mg tablets administered once a day at bedtime. [PDR 1999; p 853-7 (857)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Do not store above 30 C (86 F). Keep tightly closed (protect from moisture). Protect from light. [PDR 1999; p 853-7 (857)] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/99310065. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999 Jun 19;353(9170):2093-9. MED/99312184. Ito MK, Stolley SN, Morreale AP, Lin JC, Marcus DB. Rationale, design, and baseline results of the Pravastatin-to-Simvastatin Conversion Lipid Optimization Program (PSCOP). Am J Health Syst Pharm 1999 Jun 1;56(11):1107-13. PMID/10385495. Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes: the RECIFE (Reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 1999 Jun 29;99(25):3227-33. MED/99295260. Riggs JE, Schochet SS Jr. Myotonia associated with sarcoidosis: marked exacerbation with pravastatin. Clin Neuropharmacol 1999 May-Jun;22(3):180. MED/99261349. Katznelson S. Immunosuppressive and antiproliferative effects of HMG-CoA reductase inhibitors. Transplant Proc 1999 May;31(3B Suppl):22S-24S. MED/99249302. Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pravastatin. Am J Gastroenterol 1999 May;94(5):1388-90. Leslie H. Body fat changes: more than lipodystrophy. Bulletin of Experimental Treatments for AIDS 1999 Jan. AIDS/99704162. Gilden D. A further point about statins.... GMHC Treatment Issues 1998 Jun;12(6). MED/98403985. Carr A, Samaras K, Chisholm DJ, Cooper DA. Abnormal fat distribution and use of protease inhibitors [letter; comment]. Lancet 1998 Jun 6;351(9117):1736. ICA12/98387094. Henry K. Lipid abnormalities associated with use of protease inhibitors: prevalence, clinical sequelae and treatment. Int Conf AIDS 1998;12:77 (abstract no. 12319). ENTRY MONTH 199907 LAST REVISION DATE 20000801 29 UNIQUE IDENTIFIER DRG-0318 NAME OF SUBSTANCE Bromine epiandrosterone [Protocol ID: 303A ] REGISTRY NUMBER 28507-02-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed July 17, 2001.] STANDARD CHEMICAL NAME Androstan-17-one, 16-bromo-3-hydroxy-, (3beta,5alpha,16alpha)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed July 17, 2001.] PROTOCOL ID NUMBERS Recruiting FDA 303A PHARMACOLOGICAL ACTION MODE OF ACTION: In uninfected cells there is a balance of cellular components necessary for normal cellular functions. Glucose-6-phosphate dehydrogenase (G6PDH) controls the rate of cellular energy production cycles referred to as the pentose phosphate pathway. Hormones produced by the body control G6PDH activity. In HIV-infected cells, natural hormone levels are depleted resulting in increased G6PDH activity. This stimulates the pentose phosphate pathway, increasing the output of energy and nucleic acid precursors needed for viral replication. HE2000 therapy acts as a noncompetitive inhibitor of G6PDH activity, resulting in regulation of the pentose phosphate pathway, depleting available energy and nucleic acids needed for viral replication. This emphasis on restoring the molecular balance within the infected cells to deprive viruses of the energy molecules and proteins needed for viral synthesis is different from more traditional approaches that involve substances that inhibit HIV replication by interacting directly with the virus. The drug developer believes that because of its novel mechanism of action, HE 2000 may not be susceptible to development of typical drug resistance by the virus. Thus, studies conducted in vitro with HE2000 have demonstrated significant inhibition of viral replication of isolates from multi-nucleoside and multi-protease inhibitor-resistant patients. These studies demonstrated that the drug is active against HIV mutants that are resistant to the most widely used antiviral therapies available today. Also, because of the demonstrated low toxicity of HE2000, it may have fewer side effects than other approved antiviral drugs. Studies in pigtailed macaques infected with highly pathogenic SHIV 229, and having very low CD4 counts and extremely high viral load, demonstrated that HE2000 was active in arresting the disease processes and extending the life of these animals. Still, even though the macaques' viral levels fell 95%, detectable levels remained, indicating HE2000 did not completely eliminate the virus. Further, when drug administration stopped, viral load increased, suggesting the need for periodic dosing cycles. The depth and duration of viral response appear to vary with dosing parameters. [Hollis-Eden Pharmaceuticals. Available at: http://www.holliseden.com. Accessed: May 15, 2000.; 1999 Jun 17; Natl AIDS Treatment Advocacy Project (NATAP). Available at: http://www.natap.org. Accessed: May 15, 2000.; 1999 Jun 12] DISEASES STUDIED/TREATED Now in Phase I/II study of the safety, tolerance, pharmacokinetics, drug-interaction, and anti-HIV activity in HIV-infected patients on salvage therapy. [Protocol ID: 303A ] CLASSIFICATION CODE Biological response modifier [Hollis-Eden Pharmaceuticals. Available at http://www.holliseden.com/html/products_frame- set.html. Accessed July 17, 2001.] CLASSIFICATION CODE Enzyme inhibitor [J Pharm Sci 1981 Oct;70(10):1154-7] OTHER MAJOR USES In laboratory tests HE2000 has shown activity against malaria, cytomegalovirus, polio, and influenza. Work will begin with the Navy on preclinical testing of HE2000 against malaria. [AIDS Treat News 1999 Jun 4;320] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic derivative of dehydroepiandrosterone (DHEA). [Anti-HIV and AIDS Therapeutics Drug Index Listing. Available at: http://www.niaid.nih.gov/daids/dtpdb/index.ht- m. Accessed: May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H29-Br-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed July 17, 2001.] CHEMICAL/PHYSICAL DATA Molecular Weight: 369.34 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: July 17, 2001.] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.79%, H7.92%, Br21.63%, O8.66% [Calculation. ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 25-, 50-, 100-, 200-mg doses in injectable form. [Protocol ID: 303A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection [Protocol ID: 303A ] MANUFACTURERS 0000004961: Hollis-Eden Pharmaceuticals Inc 9333 Genesee Ave San Diego, CA 92121 Contact: Robert Marsella (619)587-9333 REFERENCES GWAIDS/0001613. Gray C, Frincke J, Maila H, Reading C, Baraldi E, Beale M, Gray G. The immunological effects of HE2000 in drug-naive HIV-1 infected patients. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. TuPeB3194. MED/10954862. Senior K. HE2000 AIDS drug shows promise in clinical trials. Mol Med Today 2000 Sep;6(9):333-4. MED/10851716. HE2000 corrects immune system dysregulation in HIV-positive patients. AIDS Read 2000 May;10(5):282. MED/11366467. Frincke J. HE2000 begins clinical trials: interview with James Frincke, Ph.D. Interview by John S. James. AIDS Treat News 1999 Jun 4;(No 320):4-7. MED/10842861. HE2000 shows efficacy. AIDS Patient Care STDS 1999 Jun;13(6):375. MED/11268428. Christeff N, Nunez EA, Gougeon ML. Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy. Ann N Y Acad Sci 2000;917:962-70. MED/11268427. Clerici M, Galli M, Bosis S, Gervasoni C, Moroni M, Norbiato G. Immunoendocrinologic abnormalities in human immunodeficiency virus infection. Ann N Y Acad Sci 2000;917:956-61. MED/9264144. Clerici M, Trabattoni D, Piconi S, Fusi ML, Ruzzante S, Clerici C, Villa ML. A possible role for the cortisol/anticortisols imbalance in the progression of human immunodeficiency virus. Psychoneuroendocrinology 1997;22 Suppl 1:S27-31. MED/9264142. Christeff N, Gherbi N, Mammes O, Dalle MT, Gharakhanian S, Lortholary O, Melchior JC, Nunez EA. Serum cortisol and DHEA concentrations during HIV infection. Psychoneuroendocrinology 1997;22 Suppl 1:S11-8. MED/8024587. Yang JY, Schwartz A, Henderson EE. Inhibition of 3'azido-3'deoxythymidine-resistant HIV-1 infection by dehydroepiandrosterone in vitro. Biochem Biophys Res Commun 1994 Jun 30;201(3):1424-32. MED/7692906. Yang JY, Schwartz A, Henderson EE. Inhibition of HIV-1 latency reactivation by dehydroepiandrosterone (DHEA) and an analog of DHEA. AIDS Res Hum Retroviruses 1993 Aug;9(8):747-54. MED/1381206. Henderson E, Yang JY, Schwartz A. Dehydroepiandrosterone (DHEA) and synthetic DHEA analogs are modest inhibitors of HIV-1 IIIB replication. AIDS Res Hum Retroviruses 1992 May;8(5):625-31. ENTRY MONTH 199906 LAST REVISION DATE 20010717 30 UNIQUE IDENTIFIER DRG-0317 NAME OF SUBSTANCE gp160 MN/LAI-2 [Protocol ID: RV124 ] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 034 PROTOCOL ID NUMBERS No longer recruiting FDA RV124 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-04-006 CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 034 ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 ENTRY MONTH 199906 LAST REVISION DATE 20000801 31 UNIQUE IDENTIFIER DRG-0316 NAME OF SUBSTANCE Lopinavir/Ritonavir [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.] SYNONYMS Kaletra [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 285A PROTOCOL ID NUMBERS No longer recruiting FDA 285B PROTOCOL ID NUMBERS No longer recruiting FDA 285C PROTOCOL ID NUMBERS No longer recruiting FDA 285D PROTOCOL ID NUMBERS No longer recruiting FDA 285E PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5014 PROTOCOL ID NUMBERS Recruiting FDA 285F PROTOCOL ID NUMBERS Recruiting FDA 285G PROTOCOL ID NUMBERS Recruiting FDA 298D PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5015 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5116 PHARMACOLOGICAL ACTION Oral administration of lopinavir produces only low and transient levels of the drug in the plasma due to rapid and extensive metabolism by cytochrome P-450 (CYP) 3A enzymes. However, lopinavir metabolism is inhibited by the coadministration of low dose ritonavir, resulting in significant increases in lopinavir bioavailability and duration of action. Lopinavir is approximately 98 to 99% bound to plasma proteins at therapeutic concentrations. Peak lopinavir plasma levels occur approximately 5 hours after administration of the combination. Administration with food enhances overall drug levels. Steady-state lopinavir/ritonavir plasma concentration appears to be reached within 2 weeks of start of therapy with the drug. [Antimicrob Agents Chemother 1998 Dec;42(12):3218-24.; Conf Retroviruses Opportunistic Infect 1998 Feb 1-5; 8th:82 (abstract no. 647); Protocol ID: ACTG A5014 ; Conf Retroviruses Opportunistic Infect 1998 Feb 1-5; 8th:82 (abstract no. 647)] DISEASES STUDIED/TREATED The lopinavir/ritonavir combination is approved by the FDA for use in combination with other antiretrovirals in the treatment of HIV infection in adults and children 6 months of age or older. [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.] CLASSIFICATION CODE Antiretroviral [Protocol ID: ACTG A5014 ] CLASSIFICATION CODE Antiviral [Protocol ID: ACTG A5014 ] CLASSIFICATION CODE Protease inhibitor [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.] SUBSTANCE INTERACTIONS Since lopinavir is metabolized predominantly by the CYP liver enzymes, there is potential for pharmacokinetic interaction between lopinavir and other drugs metabolized by this system, including other protease inhibitors. The following medications should not be given with lopinavir/ritonavir: astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, ergot derivatives (ergotamine, dihydroergotamine), rifampin, lovastatin, simvastatin, and atorvastatin. For rifabutin, sildenafil, and other drugs that are extensively metabolized by CYP3A, a dose reduction may be necessary during co-administration with lopinavir/ritonavir. Dosing of didanosine and lopinavir/ritonavir should be separated by at least 2.5 hours. [Protocol ID: ACTG A5014 ; Protocol ID: 285D ] ADVERSE EFFECTS Side effects associated with the use of lopinavir/ritonavir include diarrhea, loose stools, nausea, vomiting, fatigue, headache, and rash. Elevated cholesterol, triglyceride, or liver enzyme levels also are reported. Increases in blood glucose, redistribution of body fat, and pancreatitis also may be associated with lopinavir/ritonavir use. The rate of discontinuation of therapy due to side effects is low. [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.; Protocol ID: ACTG A5015 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lopinavir and ritonavir are peptidomimetic substrate analogues that inhibit the activity of HIV protease. They are structurally related to each other. [Protocol ID: ACTG A5014 ; Antimicrob Agents Chemother 1998 Dec;42(12):3218-24] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules containing 133.3 mg lopinavir and 33.3 mg ritonavir; liquid containing 400 mg lopinavir and 100 mg ritonavir per teaspoon. [Abbott Laboratories. Press Release. Available at: www.abbott.com/news/press_release.cfm?id=206. Accessed 09/18/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The drug should be stored at 2-8 C (36-46 F) until dispensed. Patients can keep the drug at room temperature if used within 2 months of dispensing. [Abbott Laboratories. Press Release. Available at: www.abbott.com/news/press_release.cfm?id=206. Accessed 09/18/00.] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/99350240. Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, Yao Y, Surber B, Thomas S, Granneman GR. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction. Drug Metab Dispos. 1999 Aug;27(8):902-8. MED/99102138. Kumar GN, Jayanti V, Lee RD, Whittern DN, Uchic J, Thomas S, Johnson P, Grabowski B, Sham H, Betebenner D, Kempf DJ, Denissen JF. In vitro metabolism of the HIV-1 protease inhibitor ABT-378: species comparison and metabolite identification. Drug Metab Dispos. 1999 Jan;27(1):86-91. MED/99054868. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Norbeck DW, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998 Dec;42(12):3218-24. MED/99011455. Molla A, Vasavanonda S, Kumar G, Sham HL, Johnson M, Grabowski B, Denissen JF, Kohlbrenner W, Plattner JJ, Leonard JM, Norbeck DW, Kempf DJ. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology. 1998 Oct 25;250(2):255-62. MED/98362159. Carrillo A, Stewart KD, Sham HL, Norbeck DW, Kohlbrenner WE, Leonard JM, Kempf DJ, Molla A. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol. 1998 Sep;72(9):7532-41. Kempf D, Xu Y, Brun S, King M, Mo H, Real K, Bernstein B, Hertogs K, Larder B, Molla A, Japour A, Sun E, et al. Baseline genotype and phenotype do not predict response to ABT-378/ritonavir in PI-experienced patients at 24 and 48 weeks. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2; 7th (abstract no. 731). Available at: http://www.retroconference.org/2000/abstracts- /731.htm. Accessed 09/18/00. Deeks S, Brun S, Xu Y, Real K, Benson C, Kessler H, Murphy R, Wheeler D, Hicks C, Eron J, Feinberg J, Gulick R, Sax P, Stryker R, Riddler S, Thompson M, King M, Potthoff A, Hsu A, Bertz R, Molla A, Mo H, Kempf D, Japour A, Sun E. ABT-378/ritonavir (ABT-378/r) suppresses HIV RNA to <400 copies/ml in 84% of PI-experienced patients at 48 weeks. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2; 7th (abstract no. 532). Available at: http://www.retroconference.org/2000/abstracts- /532.htm. Accessed 09/18/00. Gulick R, King M, Brun S, Real K, Murphy R, Hicks C, Eron J, Thommes J, Thompson M, White C, Benson C, Albrecht M, Kessler H, Hsu A, Bertz R, Kempf D, Sun E, Japour A. ABT-378/ritonavir (ABT-378/r) in antiretroviral naive HIV+ patients: 72 weeks. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2; 7th (abstract no. 515). Available at: http://www.retroconference.org/2000/abstracts- /515.htm. Accessed 09/18/00. AIDS/20711360. Mo H, Chernyavskiy T, Lu L, Kohlbrenner W, Sun E, Kempf D, Molla A. Multiple pathways to resistance to ABT-378 observed by in vitro selection. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:89 (abstract no. 117). ENTRY MONTH 199906 LAST REVISION DATE 20000921 32 UNIQUE IDENTIFIER DRG-0315 NAME OF SUBSTANCE Tetanus and Diphtheria Toxoids Adsorbed [Protocol ID: ACTG 402 ] PROTOCOL ID NUMBERS Recruiting NIAID ACTG 402 CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 1273] MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Unspecified (610)647-9452 ENTRY MONTH 199905 LAST REVISION DATE 20000801 33 UNIQUE IDENTIFIER DRG-0314 NAME OF SUBSTANCE BMS-232632 [Protocol ID: 302A ] PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-03-005 PROTOCOL ID NUMBERS Recruiting FDA 302A PROTOCOL ID NUMBERS Recruiting FDA 302B PROTOCOL ID NUMBERS Recruiting FDA 302C PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1020-A PHARMACOLOGICAL ACTION BMS-232632 inhibits HIV-1 replication via inhibition of proteolytic cleavage of the viral gag precursor polyprotein. The compound displays significant activity against both laboratory and primary HIV-1 isolates in both cell lines and primary peripheral blood mononuclear cells (PBMCs) (EC50 value of 2 to 5nM; EC90 value of 9 to 15nM). BMS-232632 is demonstrated to be more potent (2- to 20-fold) than other protease inhibitors. In addition, BMS-232632 is highly selective for HIV-1 protease and exhibits cytotoxicity at concentrations 6,500- to 23,000-fold higher than concentrations required for therapeutic anti-viral activity. This selectivity index is comparable to or better than that of other protease inhibitors. BMS-232632 is shown to have an in vitro HIV-1 resistance pattern that differs from that of the peptidomimetic protease inhibitors. Resistance develops less rapidly than it does to nelfinavir or ritonavir. The mutational pattern resulting in resistance to BMS-232632 is not yet determined but is known to require the presence of several mutations. Mutations at sites N88S and I84V have been identified. HIV-1 strains resistant to BMS-232632 may be sensitive to some of the peptidomimetic protease inhibitors. Also, sensitivity to BMS-232632 is retained among isolates resistant to 1 or 2 of the peptidomimetic protease inhibitors; however, isolates resistant to 3 or more protease inhibitors appear to be less sensitive to BMS-232632. A favorable pharmacokinetic profile has emerged for BMS-232632 following several single-, multiple-, and ascending-dose studies. BMS-232632 was rapidly absorbed at all doses and demonstrated a favorable bioavailability of approximately 68% (mean). Of 2 formulations studied, the capsule formulation exhibited a bioavailability of 60% relative to that of the oral solution. In dose-escalating studies, the peak plasma concentrations (Cmax) and area under the curve versus time (AUC) values increased in a proportion greater than the increase in increment of dose. Administration of BMS-232632 following a light meal resulted in an increase in both mean Cmax and mean AUC relative to administration with a high-fat meal and administration in the fasting state. For doses above 300 mg, plasma concentrations remained above EC50 values for more than 24 hours, supporting the possibility of once-daily dosing. The mean apparent terminal half-life ranged from approximately 3 to 7 hours. [Antimicrob Agents Chemother 2000 Aug;44(8):2093-9; Protocol ID: AIEDRP AI-03-005 ; Antimicrob Agents Chemother 2000 Aug;44(8):2093-9; Protocol ID: AIEDRP AI-03-005 ; Intersci Conf Antimicrob Agents Chemother 40th:(abstract no. 2114); Antimicrob Agents Chemother 2000 Sep;44(9):2319-26; Intersci Conf Antimicrob Agents Chemother 40th:(abstract no. 2114); Protocol ID: AIEDRP AI-03-005 ] DISEASES STUDIED/TREATED BMS-232632 is an investigational protease inhibitor currently being studied for combination therapy in the treatment of acute and chronic HIV infection. [Bristol-Myers Squibb. Our Commitment. Available at: http://www.tequin.com/tcommi/data/commit.html- . Accessed 10/19/00.] CLASSIFICATION CODE Investigational - Protease inhibitor [Protocol ID: 302A ] SUBSTANCE INTERACTIONS In vitro, combinations of BMS-232632 and either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected PBMCs yielded additive to moderately synergistic antiviral effects. In addition, the drug pair combinations did not exhibit antagonistic anti-HIV activity or increased cytotoxic effects. BMS-232632 acts as both a cytochrome P450 (CYP) 3A4 inhibitor and substrate. The significance of this activity in clinical experience is as yet unclear. Coadministration of BMS-232632 and ketoconazole, a potent inhibitor of CYP3A4, was studied in healthy subjects. Ketoconazole administration did not have a clinically relevant effect on the pharmacokinetics of BMS-232632. A nucleoside interaction pharmacokinetic study in healthy individuals showed that coadministration of BMS-232632 and didanosine reduces BMS-232632 exposure by four-fold as assessed by AUC. However, this reduction was believed to be mediated by the antacid in the formulation of didanosine and was avoided by administering BMS-232632 one hour after didanosine. Another drug interaction study demonstrated increased exposure to saquinavir after the addition of BMS-232632 to a saquinavir regimen. [Antimicrob Agents Chemother 2000 Aug;44(8):2093-9; Intersci Conf Antimicrob Agents Chemother 40th:(abstract no. 1646); Protocol ID: AIEDRP AI-03-005 ; Conf Retroviruses Opportunistic Infect. 7th:(abstract no. 504). Available at http://www.retroconference.org/2000/abstracts- /504.htm. Accessed 11/06/00.] ADVERSE EFFECTS Based on results from embryo-fetal development and genetic toxicology animal studies, BMS-232632 is not teratogenic in rats or rabbits and does not present a genotoxic risk to humans. In clinical studies in humans to date, no limiting toxicity has been defined for BMS-232632. A laboratory abnormality occasionally observed with BMS-232632 therapy is hyperbilirubinemia not associated with liver enzyme elevations. This is thought to result from the drug's competitive inhibition of UDP-GT 1A1, the enzyme responsible for catalysis of bilirubin conjugation. Isolated elevation of unconjugated bilirubin has not been associated with serious clinical consequences in adults. The occurrence of this adverse effect requires dose reduction in 10 to 15% of patients taking BMS-232632. Upon discontinuation of the drug, bilirubin levels return to normal. Another adverse effect that has been observed in study subjects is microscopic hematuria (defined as greater than 5 red blood cells [RBCs] per high-powered field). Uric acid crystals were also observed in some urine samples. Evaluation of data is underway to determine whether a relationship to the drug can be ascertained. Common side effects observed in clinical trials include diarrhea, infection, and nausea. [Protocol ID: AIEDRP AI-03-005 ; Intersci Conf Antimicrob Agents Chemother 40th:(abstract no. 1645); Protocol ID: AIEDRP AI-03-005 ; Protocol ID: AIEDRP AI-03-005 ; Intersci Conf Antimicrob Agents Chemother 40th:(abstract no. 691)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: BMS-232632 is an azapeptide protease inhibitor that differs structurally from the currently approved peptidomimetic protease inhibitors. The unique structure of this agent allows for an HIV-1 resistance pattern that is distinct from that of other protease inhibitors. In addition, BMS-232632 may have unique additive or synergistic activity with these protease inhibitors in combination therapies. [Protocol ID: AIEDRP AI-03-005 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200 mg capsules [Protocol ID: AIEDRP AI-03-005 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Clinical experience with BMS-232632 has demonstrated virologic control in most patients receiving at least 200 mg of the drug once daily. The 400 mg daily dose is highly effective in reducing HIV-1 RNA to levels below 200 copies/ml by Week 24. This dose may ultimately be the one selected for most indications. However, the 600 mg dose may be more appropriate for rapid reduction of viremia in primary infection, which may facilitate a virus-specific immune response without interference from ongoing viremia. Dose reductions to 400 mg or 200 mg daily can then be initiated as required. [Protocol ID: AIEDRP AI-03-005 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Capsules should be stored at room temperature, 15-30 C (59-86 F). [Protocol ID: AIEDRP AI-03-005 ] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 REFERENCES MED/20408553. Gong YF, Robinson BS, Rose RE, Deminie C, Spicer TP, Stock D, Colonno RJ, Lin PF. In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother. 2000 Sep;44(9):2319-26. MED/20356909. Robinson BS, Riccardi KA, Gong YF, Guo Q, Stock DA, Blair WS, Terry BJ, Deminie CA, Djang F, Colonno RJ, Lin PF. BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents. Antimicrob Agents Chemother. 2000 Aug;44(8):2093-9. MED/98387867. Bold G, Fassler A, Capraro HG, Cozens R, Klimkait T, Lazdins J, Mestan J, Poncioni B, Rosel J, Stover D, Tintelnot-Blomley M, Acemoglu F, Beck W, Boss E, Eschbach M, Hurlimann T, Masso E, Roussel S, Ucci-Stoll K, Wyss D, Lang M. New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development. J Med Chem. 1998 Aug 27;41(18):3387-401. OMara EM, Mummaneni V, Randall D, Burchell B, Baty D, Tanner T, Atillosoy E, Geraldes M. Assessment of the effect of uridine diphosphate-glucuronosyl transferase (UDP-GT) 1A1 genotype on indirect bilirubin elevations in healthy subjects dosed with BMS-232632. Intersci Conf Antimicrob Agents Chemother. 2000 Sept 17-20;40th: (abstract no. L-13). Colonno RJ, Hertogs K, Larder BA, Limoli K, Heilek-Snyder G, Parkin N. Efficacy of BMS-232632 against a panel of HIV-1 clinical isolates resistant to currently used protease inhibitors. Intersci Conf Antimicrob Agents Chemother. 2000 Sept 17-20;40th: (abstract no. 2114). OMara EM, Randall D, Mummaneni V, Uderman H, Knox L, Schuster A, Geraldes M, Raymond R. Steady-state pharmacokinetic interaction study between BMS-232632 and ketoconazole in healthy subjects. Intersci Conf Antimicrob Agents Chemother. 2000 Sept 17-20;40th: (abstract no. 1646). OMara EM, Mummaneni V, Burchell B, Randall D, Geraldes M. Relationship between uridine diphosphate-glucuronosyl transferase (UDP-GT) 1A1 genotype and total bilirubin elevations in healthy subjects receiving BMS-232632 and saquinavir. Intersci Conf Antimicrob Agents Chemother. 2000 Sept 17-20;40th: (abstract no. 1645). Sanne I, Piliero P, Wood R, Kelleher T, Cross A, Mongillo A, Schnittman S. Safety and antiviral efficacy of a once-daily HIV-1 protease inhibitor BMS-232632: 24 week results from a phase II clinical trial. Intersci Conf Antimicrob Agents Chemother. 2000 Sept 17-20;40th: (abstract no. 691). Sanne I, Piliero P, Wood R, Kelleher T, Cross A, Mongillo A, Schnittman S. Safety and antiviral efficacy of a once-daily HIV-1 protease inhibitor, BMS232632: preliminary results from a phase II clinical trial. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 672). OMara E, Mummaneni V, Randall D, Sagali N, Olsen S, Tanner T, Schuster A, Raymond R, Kaul S. BMS-232632: a summary of multiple dose pharmacokinetic, food effect and drug interaction studies in healthy subjects. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 504). OMara EM, Smith J, Olsen SJ, Tanner T, Schuster AE, Kaul S. BMS-232632: single and multiple oral dose safety and pharmacokinetic study in healthy volunteers. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th: (abstract no. 604). ENTRY MONTH 199905 LAST REVISION DATE 20000801 34 UNIQUE IDENTIFIER DRG-0313 NAME OF SUBSTANCE Tetanus Toxoid Vaccine [Protocol ID: ACTG A5046s ] SYNONYMS Component of Acel-Imune [USPD 1998; p. 721] SYNONYMS Component of Tetramune [USPD 1998; p. 721] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5046s PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5069 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1006 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PHARMACOLOGICAL ACTION MODE OF ACTION: Tetanus toxoid adsorbed and fluid are prepared by growing the tetanus bacilli Clostridium tetani on a protein-free, semi-synthetic medium. The tetanus toxin produced by these bacilli is detoxified by using formaldehyde. This forms the tetanus toxoid. For tetanus toxoid adsorbed, aluminum phosphate or aluminum potassium sulfate is used as a mineral adjuvant to adsorb the tetanus antigens. This prolongs and enhances the antigenic properties by retarding the rate of absorption into the body. Following intramuscular injection of the adsorbed preparation, or intramuscular or subcutaneous injection of the tetanus toxoid fluid, an antigenic response is produced in the immunized patient, causing the formation of tetanus antibodies. The tetanus toxoid fluid does not provide as great an antigenic stimulation as does the adsorbed preparation, but it does provide protective levels. It is generally believed that the immunity lasts for 10 or more years, following a primary series or a booster of tetanus toxoid. [USP DI 1999; p 2760-1] DISEASES STUDIED/TREATED In an ongoing clinical study, patients with moderately advanced HIV disease who have already received 52 weeks of either highly active antiretroviral therapy (HAART) or HAART plus interleukin-2 are vaccinated with Remune (an inactivated, gp120-depleted virus intended to stimulate HIV-specific immune responses) and a control recall immunogen, tetanus toxoid, to evaluate whether these patients can develop new CD4 T cell and CD8 T cell responses to HIV-related antigens. [Protocol ID: ACTG A5046s ] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 2923] OTHER MAJOR USES Tetanus prophylaxis. [USP DI 1999; p 2760] SUBSTANCE INTERACTIONS There may be interactions or related problems when tetanus toxoid is used in patients on immunosuppressants or radiation therapy. Because normal defense mechanisms are suppressed in such cases, the patient's antibody responses to tetanus toxoid may be decreased. When possible, immunosuppressive therapy should be interrupted when immunization is required because of a tetanus-prone wound. [USP DI 1999; p 2761] ADVERSE EFFECTS Local reactions such as erythema, induration, and tenderness are common after administration of tetanus toxoid. Systemic reactions such as fever, chills, myalgia, and headaches also may occur. Neurological complications such as convulsions, encephalopathy, and various mono- and polyneuropathies including Guillain-Barre syndrome have been reported following administration of preparations containing tetanus antigen. Urticaria, erythema multiforme or other rashes, arthralgias, and, more rarely, a severe anaphylactic reaction also have been reported following administration of preparations containing tetanus antigen. [PDR 1999; 1544] CONTRAINDICATIONS This medication should not be used when there is febrile illness, acute respiratory disease, or tetanus infection (tetanus antitoxin should be used for tetanus infections). Patients allergic to thimerosal may be allergic to the tetanus toxoid available in the US and Canada because it may contain a small amount of thimerosal. For inadequately immunized pregnant women, it is recommended that immunization with tetanus toxoid be started or continued during the last two trimesters. [USP DI 1999; p 2761] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Tetanus toxoid is indicated for immunization against tetanus in order to prevent tetanus infection and the severe complications, including death, that arise from the toxins produced by Clostridium tetani. [USP DI 1999; p 2760] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Tetanus toxoid is a sterile suspension of formaldehyde-treated products of the growth of Clostridium tetani. A second form, tetanus toxoid adsorbed, is the substance adsorbed onto aluminum hydroxide, aluminum phosphate, or potassium alum. [AHFS Drug Information 1999; p 2892] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tetanus toxoid fluid: 4 Lf per 0.5 ml (Lf is quantity of toxoid as assessed by flocculation); tetanus toxoid adsorbed: 5 Lf per 0.5 ml. [USP DI 1999; p 2762-3] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Tetanus toxoid fluid by intramuscular or subcutaneous injection. Tetanus toxoid adsorbed by intramuscular injection. [USP DI 1999; p 2762] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tetanus toxoid and tetanus toxoid adsorbed should be refrigerated at 2-8 C and should not be frozen. The toxoid should be free from clumps after vigorous shaking and should not be used if resuspension cannot be achieved. [AHFS Drug Information 1999; p 2892] MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr Amy Baim (914)732-2147 MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Dr John Riefler (914)732-2035 MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Unspecified (610)647-9452 REFERENCES MED/99101467. Marinaro M, Boyaka PN, Jackson RJ, Finkelman FD, Kiyono H, Jirillo E, McGhee JR. Use of intranasal IL-12 to target predominantly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin. J Immunol 1999 Jan 1;162(1):114-21. MED/99075303. Talesnik E, Vial PA, Labarca J, Mendez C, Soza X. Time course of antibody response to tetanus toxoid and pneumococcal capsular polysaccharides in patients infected with HIV. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Dec 15;19(5):471-7. MED/98209294. Li Pira G, Oppezzi L, Seri M, Westby M, Caroli F, Fenoglio D, Lancia F, Ferraris A, Bottone L, Valle MT, et al. Repertoire breadth of human CD4+ T cells specific for HIV gp120 and p66 (primary antigens) or for PPD and tetanus toxoid secondary antigens). Hum Immunol 1998 Mar;59(3):137-48. Bayon-Auboyer MH, Boussin FD, Le Grand R, Birraux G, Dormont D. BCG and anti-tetanus vaccinations induce a transient increase of viral load and env gene variability in HIV-2 infected macaques. Int Conf AIDS 1996 Jul 7-12;11(1):279 (abstract no. Tu.A.2083). ICA11/96922297 MED/96196122. Takahashi I, Marinaro M, Kiyono H, Jackson RJ, Nakagawa I, Fujihashi K, Hamada S, Clements JD, Bost KL, McGhee JR. Mechanisms for mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J Infect Dis 1996 Mar;173(3):627-35. AIDS/97920698. Gomez KC, Laraque F, Cervia JS, Drago T, Sia C, Sypek J, He S, Noel GJ, Ho JL. Altered cellular immunity to HIV proteins and tetanus toxoid in HIV-infected children: in vitro restoration by interleukin-12. Conf Adv AIDS Vaccine Dev 1996 Feb 11-15:124 [Poster 4]. AIDS/96920231. Ostrowski M, Stanley S, Justement JS, Gantt K, Goletti D, Fauci AS. Increased in-vitro tetanus specific isolation after in-vivo tetanus immunization of HIV infected individuals. 3rd Conf Retro and Opportun Infect 1996 Jan 28-Feb 1:95. MED/95347089. Somasundaram R, Jacob L, Herlyn D. Tetanus toxoid-specific T cell responses in severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood lymphocytes. Clin Exp Immunol 1995 Jul;101(1):94-9. AIDS/95920983. Mascart-Lemone F, Gerard M, Lybin M, Lambrechts A, Crusiaux A, Franchioly P, Goldman M, Clumeck N. Differential antibody responses to pneumococcal and tetanus vaccines in asymptomatic HIV-infected patients: a serological and cellular study. Program Abstr Intersci Conf Antimicrob Agents Chemother 1994 Oct 4-7:235. MED/95132851. McGhee JR, Xu-Amano J, Miller CJ, Jackson RJ, Fujihashi K, Staats HF, Kiyono H. The common mucosal immune system: from basic principles to enteric vaccines with relevance for the female reproductive tract. Reprod Fertil Dev 1994;6(3):369-79. ENTRY MONTH 199905 LAST REVISION DATE 20000801 35 UNIQUE IDENTIFIER DRG-0312 NAME OF SUBSTANCE Diphtheria and Tetanus Toxoids Adsorbed [Protocol ID: ACTG 402 ] PROTOCOL ID NUMBERS Recruiting NIAID ACTG 402 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5102 CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 1273] MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Unspecified (610)647-9452 ENTRY MONTH 199904 LAST REVISION DATE 20000801 36 UNIQUE IDENTIFIER DRG-0311 NAME OF SUBSTANCE Peldesine [USPD 1998; p. 554] REGISTRY NUMBER 133432-71-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4H-Pyrrolo(3,2-d)pyrimidin-4-one, 2-amino-3,5-dihydro-7-(3-pyridinylmethyl)- [USPD 1998; p 554] PROTOCOL ID NUMBERS No longer recruiting FDA 301A PHARMACOLOGICAL ACTION Peldesine (BCX-34) is a potent inhibitor of normal human T-cell proliferation induced by antigenic or IL-2 stimulation. Peldesine in normal human T-cells has a deoxyguanosine-independent mechanism to suppress in vitro proliferation. Peldesine appears to have little effect on T-cell viability. The results of one study demonstrated that peldesine inhibits human PNP and T-cell proliferation, is orally bioavailable in rodents, and pharmacologically active in vivo in rodents after oral dosing with no apparent side effects or toxicity. In another study of peldesine as an immunosuppressive agent, the substance showed a complete inhibitory effect on the proliferation of T-cells in an in vitro system, whereas no influence was observed in B-cell lines. It was shown that this inhibitory effect was not due to the suppression of interleukin-2 production. Peldesine may, therefore, be useful in treating human T-cell proliferative inflammatory disorders. Also, peldesine might be a potentially useful drug that can be used in combination, not competition, with cyclosporine A and FK506. [Immunopharmacology 1998 July 40(1); p 1; Immunopharmacology 1996 Oct 35(1); p 53; Artif Organs 1996 Aug 20(8); p 849] DISEASES STUDIED/TREATED Being tested in AIDS studies that involve suppressing T cells to stop viral growth. This is a radically different approach to treating HIV infection. Peldesine (BCX-34) is expected to reduce the speed with which the virus develops resistance. The drug's action is highly reversible. T-cell counts return to pretreatment levels within two weeks after the drug is discontinued. [AIDS Alert 1997 Jul;12(7); p 77; Business Wire 1997 April 30 HealthWire] CLASSIFICATION CODE Antineoplastic [USPD 2000 p. 542] CLASSIFICATION CODE Antipsoriatic [USPD 2000 p. 542] OTHER MAJOR USES Peldesine (BCX-34) is in Phase III studies for cutaneous T-cell lymphoma and for psoriasis, and has proven safe for both those conditions. [Business Wire 1997 April 30 HealthWire] SUBSTANCE INTERACTIONS Peldesine (BCX-34) might be a potentially useful drug that can be used in combination, not competition, with cyclosporine A and FK506. [Artif Organs 1996 Aug 20(8); p 849] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Peldesine (BCX-34), a new purine nucleoside phosphorylase inhibitor, has selective immunosuppressive activity with potential therapeutic value in T-cell-mediated disease. [J Chromatogr B Biomed Sci Appl 1997 Mar 7;690(1-2); p 295] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H11-N5-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 241.25 [USPD 1998; p. 554] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [Protocol ID: 301A ] MANUFACTURERS 0000004846: BioCryst Pharmaceuticals Inc 2190 Parkway Lake Dr Birmingham, AL 35244 Contact: Jennifer Braddock (205)444-4600 REFERENCES MED/99165646. Litsky ML; Hohl CM; Lucas JH; Jurkowitz MS. Inosine and guanosine preserve neuronal and glial cell viability in mouse spinal cord cultures during chemical hypoxia. Brain Res 1999 Mar 13;821(2):426-432. MED/98447368. Conry RM; Bantia S; Turner HS; Barlow DL; Allen KO; LoBuglio AF; Montgomery JA; Walsh GM. Effects of a novel purine nucleoside phosphorylase inhibitor, BCX-34, on activation and proliferation of normal human lymphoid cells. Immunopharmacology 1998 Jul;40(1):1-9. MED/98344768. Jurkowitz MS; Litsky ML; Browning MJ; Hohl CM. Adenosine, inosine, and guanosine protect glial cells during glucose deprivation and mitochondrial inhibition: correlation between protection and ATP preservation. J Neurochem 1998 Aug;71(2):535-48. MED/98300026. Iwata H; Wada Y; Walsh M; Montgomery JA; Hirose H; Mendez R; Cicciarelli J; Iwaki Y. In vitro study of BCX-34: a new human T-lymphocyte-specific purine phosphorylase inhibitor. Transplant Proc 1998 Jun;30(4):983-6. AIDS/97702685. New AIDS study suppresses T cells to stop viral growth. AIDS Alert. 1997 Jul;12(7):77-8. Biocryst Pharmaceuticals begins HIV trial in humans with oral formulation of BCX-34. BUSINESS WIRE HealthWire, April 30, 1997. MED/97259957. Yan J; Lu Z; Walsh GM; Wheeler RH; Diasio RB. High-performance liquid chromatographic determination of 9-(3-pyridylmethyl)-9-deazaguanine (BCX-34) in biological fluids. J Chromatogr B Biomed Sci Appl 1997 Mar 7;690(1-2):295-303. MED/97070869. Bantia S; Montgomery JA; Johnson HG; Walsh GM. In vivo and in vitro pharmacologic activity of the purine nucleoside phosphorylase inhibitor BCX-34: the role of GTP and dGTP. Immunopharmacology 1996 Oct;35(1):53-63. MED/97006501. Wada Y; Yagihashi A; Terasawa K; Miyao N; Hirata K; Cicciarelli J; Iwaki Y. BCX-34: a novel T-cell selective immunosuppressant: purine nucleoside phosphorylase (PNP) inhibitor. Artif Organs 1996 Aug;20(8). ENTRY MONTH 199903 LAST REVISION DATE 20000801 37 UNIQUE IDENTIFIER DRG-0310 NAME OF SUBSTANCE L-756423 [Protocol ID: 300A ] PROTOCOL ID NUMBERS No longer recruiting FDA 300A PROTOCOL ID NUMBERS Suspended FDA 300B CLASSIFICATION CODE Investigational - Protease inhibitor [Protocol ID: 300A ] MANUFACTURERS 0000003415: Merck Research Laboratories 126 East Lincoln Ave Rahway, NJ 07065 Contact: Carol Sable ENTRY MONTH 199902 LAST REVISION DATE 20000801 38 UNIQUE IDENTIFIER DRG-0309 NAME OF SUBSTANCE Broxuridine [USPD 1998; p. 111] REGISTRY NUMBER 59-14-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Uridine, 5-bromo-2'-deoxy- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Recruiting CC 97 I-0189 PHARMACOLOGICAL ACTION To understand the mechanism behind immunodeficiency in HIV patients it becomes advantageous to quantitatively track lymphocyte replication and destruction. This can be done by infusing bromodeoxyuridine (BrDU), a thymidine analog, into patients where it is incorporated into the DNA of target cells (i.e., lymphocytes). Measurement of BrDU in subpopulations of cells can be used to determine the replication rate of these cells. In other studies, cell DNA synthesis in peripheral blood lymphocytes was measured ex vivo using BrDU incorporation. BrDU detection was performed using the DNAse method with an FITC-conjugated anti-BrDU antibody. Cells were surface-stained with paris of phycoerythrin or tricolor-conjugated antibodies, and three-color fluorescence was analyzed in a FACScan cytometer to determine which peripheral blood lymphocyte subpopulations were incorporating BrDU. [Protocol ID: 97-I-0189 ; Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 263 (abstract no. 21121)] DISEASES STUDIED/TREATED Marker for incorporation into cellular DNA to measure lymphocyte kinetics [Protocol ID: 97-I-0189 ] CLASSIFICATION CODE Radiation-sensitizing agent [USP DI 2000; p. 3293] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H11-Br-N2-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 307.10 [USPD 1998; p. 111] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Infusion into a vein. [Protocol ID: 97-I-0189 ] MANUFACTURERS 0000004883: NeoPharm Inc 225 East Deerpath / Suite 250 Lake Forest, IL 60045 Contact: Unspecified (847)295-8678 REFERENCES MED/99090823. Kogure K, Zhang YQ, Shibata H, Kojima I. Immediate onset of DNA synthesis in remnant rat liver after 90% hepatectomy by an administration of follistatin. J Hepatol 1998 Dec;29(6):977-84. MED/99095542. Boutonnat J, Barbier M, Rousselle C, Muirhead KA, Mousseau M, Seigneurin D, Ronot X. Usefulness of PKHs for studying cell proliferation. C R Acad Sci III 1998 Nov;321(11):901-7. MED/99057050. Rolink AG, Andersson J, Melchers F. Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity, Eur J Immunol 1998 Nov;28(11):3738-48. MED/98294602. Tissot O, Viard JP, Rabian C, Ngo N, Burgard M, Rouzioux C, Penit C. No evidence for proliferation in the blod CD4+ T-cell pool during HIV- 1 infection and triple combination therapy. AIDS 1998 May 28;12(8):879-84. AIDS/9839852. Viard JP, Tissot O, Rabian C, Ngo N, Burgard M, Rouzioux C, Penit C. No evidence for proliferation in blood CDA+ T cells during HIV infection and treatment. Int Conf AIDS. 1998;12:263 (abstract no. 21121). MED/98263366. Rosenzweig M, DeMaria MA, Harper DM, Friedrich S, Jain RK, Johnson RP. Increased rates of CD4(+) and CD8(+) T lymphocyte turnover in simian immunodeficiency virus-infected macaques. Proc Natl Acad Sci U S A 1998 May 26;95(11):6388-93. MED/98136242. Mohri H, Bonhoeffer S, Monard S, Perelson AS, Ho DD. Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science 1998 Feb 20;279(5354):1223-7. MED/98119886. Tough DF, Sprent J. Lifespan of gamma/delta T cells. J Exp Med 1998 Feb 2;187(3):357-65. MED/98005849. Schwyn U, Kaser-Hotz B, Hauser B, Fodor G, Ruckstuhl H, Crompton NE. [Determination of the potential doubling time of tumors using bromodeoxyuridine and flow cytometry. Bromodeoxyuridin and Durchflusszytometrie.] Schweiz Arch Tierheilkd 1997;139(10):441-8. MED/98075897. Activated cell cycle checkpoints in epirubicin-treated breast cancer cells studied by BrDUrd-flow cytometry. Hedenfalk IA, Baldetorp B, Borg A, Oredsson SM. Cytometry 1997 Dec 1;29(4):321-7. MED/96018796. Ernst B, Surh CD, Sprent J. Thymic selection and cell division. J Exp Med. 1995 Oct 1;182(4):961-71. ENTRY MONTH 199902 LAST REVISION DATE 20000801 39 UNIQUE IDENTIFIER DRG-0308 NAME OF SUBSTANCE Calanolide A [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 142632-32-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2H,6H,10H-Benzo(1,2-b:3,4-b':5,6-b)tripyran-- 2-one, 11,12-dihydro-12-hydroxy-6,6,10,11-tetramethy- l-4-propyl-,(10R-(10alp ha,11beta,12alpha))- [Sarawak MediChem Pharmaceuticals ] PROTOCOL ID NUMBERS No longer recruiting FDA 297A PROTOCOL ID NUMBERS No longer recruiting FDA 297B PHARMACOLOGICAL ACTION Calanolide A, is a novel inhibitor of HIV-1, and is essentially inactive against the less common HIV-2. In one study, the compound inhibited a wide variety of laboratory strains of HIV-1, with EC50 values ranging from 0.10 to 0.17 microM. The compound similarly inhibited promonocytotropic and lymphocytotropic isolates from patients in various stages of HIV disease, as well as drug-resistant strains. Viral life-cycle studies indicated that calanolide A acted early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2',3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibited recombinant HIV-1 RT but not cellular DNA polymerases or HIV-2 RT within the concentration range tested. Serial passage of the virus in host cells exposed to increasing concentrations of calanolide A yielded a calanolide A resistant virus strain. RT from the resistant virus was not inhibited by calanolide A, but retained sensitivity to other nonnucleoside as well as nucleoside RT inhibitors, including 3'-azido-2',3'-dideoxythymidine triphosphate and nevirapine. Another study showed that calanolide A inhibited HIV-1 RT by a complex mechanism involving two calanolide A binding sites. It bound near the active site of the enzyme and interfered with deoxynucleotide triphosphate binding. At certain concentrations, calanolide A bound HIV-1 RT in a mutually exclusive fashion with respect to both the pyrophosphate analog, phosphonoformic acid, and the acyclic nucleoside analog 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thioura- cil. This indicates that calanolide A shares some binding domains with both sutstances, presumably reflecting that it interacts with RT near both the pyrophosphate binding site and the active site of the enzyme. [J Pharmacol Exp Ther 1996 Nov;279(2); p 645-51; J Pharmacol Exp Ther 1996 Nov;279(2); p 652-61] DISEASES STUDIED/TREATED (+)-Calanolide A is a novel non-nucleoside reverse transcriptase inhibitor with potent in vitro activity against HIV-1 and unique pharmacokinetic properties. [Conf Retroviruses Opportunistic Infect 5th 1998 Feb 1-5; p 202] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE INTERACTIONS Calanolide A inhibited HIV-1 RT (reverse transcriptase) in a synergistic fashion with nevirapine, further distinguishing it from the general class of nonnucleoside RT inhibitors. In vitro studies have shown the compound to be active against HIV-1 strains resistant to AZT, nevirapine and other nucleoside RT inhibitors, and to show synergistic anti-HIV activity when used in combination with AZT, nevirapine, ddI, ddC and carbovir. [J Pharmacol Exp Ther 1996 Nov;279(2); p 652-61] ADVERSE EFFECTS A phase IA single, escalating-dose study in HIV-1-negative subjects showed that (+)-calanolide A was generally well tolerated in doses up to 600 mg. The most common adverse event observed in the first 3 cohorts was an oily aftertaste in 19 of 32 patients. Fourteen subjects reported transient dizziness which was mild (12 subjects), to moderate (2 subjects). Headache occurred in 8 of 32 subjects, and 5 subjects reported dyspepsia. The only significant abnormal laboratory finding was a single report of Grade 3 lipase which was completely asymptomatic and which resolved spontaneously. [Conf Retroviruses Opportunistic Infect 5th 1998 Feb 1-5; p 202 (abstract no. 652)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: (+)-Calanolide A, a novel dipyranocoumarin from the Malaysian tree Caulophyllum lanigerum var. austrocoriaceum is a representative of a distinct class of nonnucleoside HIV-1 specific reverse-transcriptase inhibitor under development as an AIDS drug. (+/-)-Calanolide A has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1]. [J Nat Prod 1998 Oct;61(10); p 1252-6] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H26-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 370.44 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water. Soluble in methanol, ethanol and a variety of other organic solvents. It is also soluble in vegetable oils and propylene glycol. [Sarawak MediChem Pharmaceuticals Manufacture Contact] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow-brown amorphous solid. [Sarawak MediChem Pharmaceuticals Manufacture Contact] SUBSTANCE DELIVERY DATA DOSAGE FORM: Soft Gelatin capsules [Sarawak MediChem Pharmaceuticals Manufacture Contact] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [PR Newswire 1998 Feb 5] MANUFACTURERS 0000004850: Sarawak MediChem Pharmaceuticals Inc 12305 South New Ave Lemont, IL 60439 Contact: Bipul Dutta (630)257-1500 REFERENCES ICA12/98387981. Buckheit R, Russell J, Boltz VF, Pallansch LA, Xu ZQ, Flavin M. Combination anti-HIV interactions and resistance profile of the nonnucleoside RT inhibitor (+)-calanolide A. Int Conf AIDS. 1998;12:86-7 (abstract no. 12366). UI/99003371. McKee TC, Covington CD, Fuller RW, Bokesch HR, Young S, Cardellina II JH, Kadushin MR, Soejarto DD, Stevens PF, Cragg GM, et al. Pyranocoumarins from tropical species of the genus Calophyllum: a chemotaxonomic study of extracts in the National Cancer Institute collection. J Nat Prod 1998 Oct;61(10):1252-6. (PRn) Sarawak Medichem Pharmaceuticals Begins Phase 1B Clinical Trial of Plant-Based Anti-HIV Agent PRNewswire - Wednesday September 30, 1998. AIDS/98929583. Creagh T, Xu ZQ, Ray L, Giltner J, Nayer T, Ruckle J. Preliminary clinical safety profile of (+)-calanolide A-a new novel NNRTI. 5th Conf Retrovir Oppor Infect. 1998 Feb 1-5;:202 (abstract no. 652). (PRn) Sarawak Medichem Pharmaceuticals' (+)-Calanolide A Anti-HIV Compound Meets Phase 1A Trial Endpoints. PR Newswire;Thursday February 5, 1998. AIDS/97926569. Frank P, Flavin MT, Roca-Acin J, Xu ZQ.; Safety assessment of (+)-calanolide A, a naturally occurring anti-HIV agent. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:106 (abstract no. 225). UI/97083823. Currens MJ, Gulakowski RJ, Mariner JM, Moran RA, Buckheit RW Jr, Gustafson KR, McMahon JB. Boyd MR. Antiviral activity and mechanism of action of calanolide A against the human immunodeficiency virus type-1. J Pharmacol Exp Ther 1996 Nov;279(2):645-51. UI/97083824. Currens MJ, Mariner JM, McMahon JB, Boyd MR. Kinetic analysis of inhibition of human immunodeficiency virus type-1 reverse transcriptase by calanolide A. J Pharmacol Exp Ther 1996 Nov;279(2):652-61. UI/97049116. Galinis DL, Fuller RW, McKee TC, Cardellina JH 2nd, Gulakowski RJ, McMahon JB, Boyd MR. Structure-activity modifications of the HIV-1 inhibitors (+)-calanolide A and (-)- calanolide B. J Med Chem 1996 Oct 25;39(22). MED/96251034. Flavin MT, Rizzo JD, Khilevich A, Kucherenko A, Sheinkman AK, Vilaychack V, Lin L, Chen W, Greenwood EM, Pengsuparp T, et al. Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers. J Med Chem. 1996 Mar 15;39(6):1303-13. ENTRY MONTH 199901 LAST REVISION DATE 20000801 40 UNIQUE IDENTIFIER DRG-0307 NAME OF SUBSTANCE SU5416 [Protocol ID: 294A ] PROTOCOL ID NUMBERS No longer recruiting FDA 294A PROTOCOL ID NUMBERS No longer recruiting FDA 310A PROTOCOL ID NUMBERS No longer recruiting FDA 310B PHARMACOLOGICAL ACTION MODE OF ACTION: Vascular endothelial growth factor (VEGF) is a protein secreted by tumor cells which triggers angiogenesis (new blood vessel formation) by binding to and activating the signaling of the Flk-1/KDR tyrosine kinase receptor. Angiogenesis is required by a tumor to provide enough nourishment to grow and spread (metastasize). As a small molecule inhibitor of the Flk-1/KDR receptor, SU5416 has the potential to block the angiogenic process and growth of the tumor. Kaposi's sarcoma is a highly vascularized tumor that provides an excellent clinical target for demonstrating the potential clinical activity of an angiogenesis inhibitor such as SU5416. There is strong evidence to support the critical role of VEGF signaling through the Flk-1/KDR receptor in angiogenesis and in the development of these tumors. In, SU5416 was shown to inhibit isolated Flk-1 receptor kinase with an IC50 = 20 nM @ 1 uM ATP. SU5416 was found to exert a potent (70 nM), selective (>700-fold), fast-acting (5 min), and long-lived (>72 hr) anti-proliferative effect on VEGF-stimulated human endothelial cells. Drug treatment in animals resulted in tumor growth inhibition of eight cell lines of varied tissue origin yet did not inhibit the growth of these tumor cells in tissue culture. Tumor inhibition was associated with an apparent decrease in tumor vascularization following drug treatment. In, Phase I/II studies have started to evaluate the safety and effectiveness of SU5416 for the treatment of Kaposi's sarcoma. Participants will receive varying doses of SU5416 as an intravenous infusion twice a week for 4 weeks. Participants who respond well to SU5416 and do not experience any significant side effects will be offered SU5416 in 4-week cycles for up to 1 year. [Sugen Inc Press Release, May 15, 1998; http://www.sugen.com/press98/19980515.html; Proc Annu Meet Am Assoc Cancer Res 1998;39; BETA 1998 Jul; 1998 Jul; p 43-5, 54] DISEASES STUDIED/TREATED The safety and efficacy of SU5416 in patients with Kaposi's sarcoma, who have failed currently available therapy, is being investigated in phase I/II clinical trials. [Sugen Inc Press Release, May 15, 1998; http://www.sugen.com/press98/19980515.html] CLASSIFICATION CODE Angiogenesis inhibitor [Protocol ID: 294A ] OTHER MAJOR USES Administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumors. [Cancer Res 1999 Jan 1;59(1); p 99-106] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: SU5416 is an angiogenesis inhibitor. Angiogenesis inhibitors are drugs that block the development of new blood vessels that supply tumors and other tissues. Solid tumors cannot grow beyond the size of a pinhead without inducing the formation of new blood vessels to supply the nutritional and other needs of the tumor. By blocking the development of such vessels, the tumor's supply of oxygen and nutrients is cut off and therefore continued growth and spread to other parts of the body is restricted. [NCI 1999 Mar 30 Information; http://www.nci.nih.gov.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. In animals, also active via oral route. [BETA 1998 Jul; 1998 Jul; p 43-5, 54; Proc Annu Meet Am Assoc Cancer Res 1998;39] MANUFACTURERS 0000004817: SUGEN Inc 230 East Grand Ave South San Francisco, CA 94080 Contact: Alison L. Hannah (650)553-8300 REFERENCES MED/99107211. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (FlK-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999 Jan 1;59(1):99-106. AIDS/99703973. Stephenson K. Open clinical trials for HIV/AIDS treatments. BETA. 1998 Jul;:43-5, 54. Initiating Phase I/II Clinical Trial of SU5416 Angiogenesis Inhibitor in Kaposi's Sarcoma. BUSINESS WIRE; Friday, May 15, 1998. Mitsuyasu R. Novel Treatments for Kaposi's Sarcoma. Clinical Care Options Conference Summary - 2nd National AIDS Malignancy Conference: April 7, 1998. MED/99107211. Fong TAT, Shawver LK, App H, Sun L, Tang C, Rice A, Kim YH, Schreck R, Chen J, Dowd B, et al. SU5416: a potent and selective Flk-1/KDR kinase inhibitor that blocks Flk-1 phosphorylation, endothelial cell mitogenesis, and tumor growth. PROC. AMER. ASSOC. CANCER RES. 39, March 1998. #3811. Vajkoczy P, Menger MD, Vollmar B, Schilling L, Schmiedek P, Ullrich A, Hirth KP, Fong TAT. Effect of the F1k-1 antagonist SU5416 on tumor growth, angiogenesis and micro-hemodynamics. PROC. AMER. ASSOC. CANCER RES. 39, March 1998. #651. MED/98023638. Ortega N, Jonca F, Vincent S, Favard C, Ruchoux MM, Plouet J. Systemic activation of the vascular endothelial growth factor receptor KDR/flk-1 selectively triggers endothelial cells with an angiogenic phenotype. Am J Pathol 1997 Nov;151(5):1215-24. MED/97102411. Albini A, Soldi R, Giunciuglio D, Giraudo E, Benelli R, Primo L, Noonan D, Salio M, Camussi G, Rockl, et al. The angiogenesis induced by HIV-1 that protein is mediated by the Flk- 1/KDR receptor on vascular endothelial cells. Nat Med 1996 Dec;2(12):1371-5. MED/96357179. Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, et al. Flk-1 as a target for tumor growth inhibition. Cancer Res 1996 Aug 1;56(15):3540-5. MED/96181313. Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 1996 Apr 1;56(7):1615-20. ENTRY MONTH 199810 LAST REVISION DATE 20000801 41 UNIQUE IDENTIFIER DRG-0306 NAME OF SUBSTANCE T-20 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 295A PROTOCOL ID NUMBERS No longer recruiting FDA 295B PROTOCOL ID NUMBERS No longer recruiting FDA 295C PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG P1005 PROTOCOL ID NUMBERS Not yet recruiting CC IRP-027 PHARMACOLOGICAL ACTION MODE OF ACTION: When HIV attacks the surface of a human immune cell its gp120 protein binds to a particular host cell receptor, and is then stripped away from the virus. Certain peptide domains within the gp41 protein of the virus then rearrange and bind to each other very tightly to form a coiled structure that mediates the fusion of the virus and the host cell membranes. The virus then injects its RNA into the cell. However, if T-20 is present in the blood stream, it binds to one of the two peptide domains within gp41 and blocks its ability to form a natural coil structure. As a result, the tip of the gp41 protein does not effectively penetrate the host cell membrane, and the virus is unable to infect the host cell with its RNA. In one clinical study, T-20 was administered intravenously (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30, and 100 mg twice daily). Four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. In several trials, T-20 showed a high degree of antiviral activity and no toxicity. RESISTANCE: HIV resistant to T-20 have been created in laboratory tests. This resistance may be slow to develop, however, because the sequence which T-20 binds to in gp41 is highly conserved among different strains of HIV. When part of a virus stay much the same from strain to strain, it usually means that the region is critical, and changes there could produce a defective virus which is not viable. The T-20 (amino-acid) sequence can vary somewhat, but HIV seems to have less freedom here than it does elsewhere. [Trimeris Inc Information; http://www.trimeris.com/t-20Model.htm; Nat Med 1998 Nov;4(11); p 1302-7; AIDS Treat News 1998 Apr 17;293; p 1-6] DISEASES STUDIED/TREATED T-20 blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. Fusion of a viral envelope with a target cell membrane is required for the initiation of infection and, therefore, virus replication. [Nat Med 1998 Nov;4(11); p 1302-7; Trimeris Inc Information; http://www.trimeris.com] CLASSIFICATION CODE Investigational - Fusion inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES T-20 is active only against HIV-1; however, the same mechanism (i.e., fusion inhibition) may lead to the development of similar drugs active against other enveloped viruses--a group which includes influenza, hepatitis B, hepatitis C, and Ebola fever. [AIDS Treat News 1998 Apr 17;293] SUBSTANCE INTERACTIONS T-20, which has a unique mechanism of action relative to existing therapies, demonstrates positive drug-drug interactions with representative RT and protease inhibitors. Computer analysis from results of one trial demonstrated that AZT and T-20, and 3TC and T-20 combinations were synergistic. Likewise, synergistic interactions were observed with indinavir and T-20 and with nelfinavir and T-20. [Antiviral Res 1998 Mar;37(3); p A54 (abstract no. 48)] ADVERSE EFFECTS In one study, no subject had to withdraw because of side effects. T-20 may have been responsible for mild-to-moderate headaches; lymph node tenderness/swelling; and dizziness. [Treat Update 1998 Dec;10(10) TU 94] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: T-20 is a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein (a 36-amino acid portion of gp41). [Nat Med 1998 Nov;4(11); p. 1302-7] CHEMICAL/PHYSICAL DATA Molecular Weight: 4491.92 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: In a clinical trial, T-20 was given for 28 days to 78 HIV+ adults via continuous subcutaneous infusion or subcutaneous injection. Twice-daily injection may be a feasible method to deliver T-2. [Business Wire 1999 Jan 25] MANUFACTURERS 0000004790: Trimeris Inc 4727 Univ Dr Durham, NC 27707 Contact: Alex Dusek (919)419-6050 REFERENCES T-20, First HIV Fusion Inhibitor, Receives Fast Track Designation From FDA. BW HealthWire. 1999 Feb 4. MED/99025409. Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med. 1998 Nov;4(11):1302-7. AIDS/99704121. James JS. T-20: new trial enrolling, 9 U.S. cities. AIDS Treat News. 1998 Aug 7;300:1-3. AIDS/99704002. James JS. Fusion inhibitors, T-20; chemokine variants; tat and interferon antibodies: Gallo describes three new treatment approaches. AIDS Treat News. 1998 Jul 17;299:4-5. AIDS/98703787. Gilden D. T-20 and adefovir for salvage therapy--expect no miracles. GMHC Treat Issues. 1998 Apr;12(4):6-7. AIDS/98703775. James JS. T-20 and Trimeris. AIDS Treat News. 1998 Apr 17;293:1-6. AIDS/98930143. Barney S, Guthrie K, Davis D, Hopkins S, Johnson MR, Lambert DM. Pentafuside (T20), a novel inhibitor of HIV-1 fusion and infection, is synergistic when used in combination with reverse transcriptase (RT) and protease inhibitors in vitro. Antiviral Res. 1998 Mar;37(3):A54 (abstract no. 48). AIDS/97926791. Hopkins S, Lambert DM, Recny MR, Johnson MR, Saag M. Pentafuside (T-20), a novel inhibitor of HIV-1 fusion: pharmacokinetics in rodents, monkeys and man. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:105 (abstract no. 224). AIDS/97926500. Black PL, Wood OL, Broud DD, Bacho MA, Kunder SC, Papermaster SF, Lambert DM, Barney S, Ussery MA. T-20, a novel inhibitor of HIV-1 fusion blocks HIV-1 infection in vitro in human PBMC and macrophages and in vivo in the HuPBMC-SCID mouse model. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:105 (abstract no. 223). ICA11/97926892. Black P, Wood O, Bacho M, Lambert D, Guthrie K, Barney S, Ussery M. T-20 and T-1052, novel inhibitors of HIV fusion, block infection of human macrophages by HIV-1. Int Conf AIDS. 1996 Jul 7-12;11(Program Supplement): 24(abstract no. LB.A.6015). ENTRY MONTH 199810 LAST REVISION DATE 20010104 42 UNIQUE IDENTIFIER DRG-0305 NAME OF SUBSTANCE ALVAC(2)120(B,MN)GNP (vCP1452) [Protocol ID: AVEG 034 ] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5058s PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 034 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 326 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5024 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5057 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5068 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-04-006 PROTOCOL ID NUMBERS Recruiting FDA B012 PROTOCOL ID NUMBERS Recruiting NIAID HIVNET 026 PROTOCOL ID NUMBERS Recruiting NIAID HVTN 203 PHARMACOLOGICAL ACTION ALVAC vaccines are recombinant live vector vaccines that are utilized primarily to induce cellular immune responses, but they also can elicit humoral responses. In addition, when ALVAC is used as a primary immunization, the antibody response can be augmented substantially by subsequent boost with recombinant subunit protein vaccines. The ALVAC line of vaccines is based on the canarypox vector. Canarypox is a member of the pox virus family, of which vaccinia (cowpox) is also a member. The canarypox virus, which originates in birds, is considered safer than vaccinia because it does not reproduce in humans. Another advantage of the canarypox virus is its ability to transport large amounts of foreign genes. ALVAC vCP1452 is a preparation of a modified recombinant canarypox virus, ALVAC(2), expressing the gene products of the HIV-1 env, gag, and the protease-encoding portion of the pol gene; and a synthetic polypeptide encompassing the known human CTL epitopes from the nef and pol gene products. ALVAC(2) is a plaque-purified isolate of an attenuated canarypox virus into which the vaccinia virus E3L and K3L coding sequences are inserted. In vitro infection of cells by ALVAC vCP1452 is associated with the production of pseudovirions, which provides for the potential expression of conformational epitopes of envelope protein and the presentation of envelope, gag, and protease that may have the capacity to induce antibody responses. The ALVAC vCP1452 vector is an extremely efficient producer of particles, exceeding ALVAC vCP205 (see ALVAC-HIV MN120TMG (vCP205)) by greater than 10-fold. In animal and human subjects, gag-specific CTLs are observed more commonly than envelope-specific CTLs. The addition of nef and pol CTL epitopes should expand the breadth of CTL specificity induced by the vaccine. The expression of E3L and K3L gene products may impair the ability of interferon or dsRNA to activate a specific protein kinase (PKR). The PKR activation is responsible for inhibition of cellular and viral protein synthesis and induction of cellular apoptosis. Inhibition of this activation may increase and prolong antigen production and also may improve immunogenicity. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.; Protocol ID: ACTG A5057 ; Protocol ID: AVEG 203 ] DISEASES STUDIED/TREATED ALVAC vaccines are investigated as preventative vaccines for HIV infection. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 034 ] ADVERSE EFFECTS The canarypox virus does not replicate in the human host; therefore, recombinants are unlikely to cause disease in recipients or be transmitted to unvaccinated contacts. Adverse reactions reported after ALVAC vaccine administration are similar to those observed in healthy adults who have received marketed vaccines. Local and systemic side effects are mild to moderate and usually resolve within 72 hours after immunization. Local effects include transient pain, tenderness, redness, and swelling at the site of injection. Less common systemic effects include headache, malaise, fever, dizziness, and nausea. No severe adverse reactions have been reported. [Protocol ID: AVEG 202 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ALVAC vCP1452 is a preparation of a modified recombinant canarypox virus expressing the products of the HIV-1 env, gag, and the protease-encoding portion of the pol gene; and a synthetic polypeptide encompassing several known human CTL epitopes from the nef and pol gene products. Recombinant ALVAC vCP1452 is generated by insertion of the vector modifying sequences encoding E3L and K3L into the C6 site of recombinant vCP1433 (see ALVAC(1)120(B,MN)GNP (vCP1433)). It is cultivated in specific pathogen-free chick embryo fibroblasts. The recombinant virus is suspended in a serum- and antibiotic-free culture medium to which a virus stabilizer is added. The solution is then lyophilized. [Protocol ID: AVEG 034 ; Protocol ID: ACTG 326 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The vaccine is supplied as single-dose vials of sterile, lyophilized product with accompanying diluent. [Protocol ID: ACTG A5057 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The contents of the vial are reconstituted with 1 ml of the supplied diluent. The vial should be refrigerated at 2-8 C (35-46 F) until just prior to injection. When ready for administration, the mixture should be swirled gently for 10 seconds. The 1 ml dose should be withdrawn from the vial and administered intramuscularly. In adults, the vaccine is administered with a 22-gauge 1.5-inch needle into the deltoid muscle. [Protocol ID: ACTG A5057 ; Protocol ID: ACTG 326 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The lyophilized powder should be stored at 2-8 C (35-46 F). The reconstituted vaccine should be stored at 2-8 C (35-46 F) and used within two hours after reconstitution. Freezing of both forms should be avoided. [Protocol ID: AVEG 034 ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 REFERENCES Nabel G. The state of HIV vaccine research. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. L2). Jin X, Bauer D, Binley J, Chen D, Ramanathan M, Barsoum S, Schiller D, Hurley A, He T, El Habib R, Limbach K, Zhang L, Ho D, Markowitz M. Safety and immunogenicity study on vCP1452/gp160 vaccine in patients treated with HAART for over two years. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 346). Larsson M, Engelmayer J, Lee M, Cox W, Steinman R, Bhardwaj N. Dendritic cells infected with recombinant canarypox virus induce potent anti-HIV cytolytic and helper T cell responses from chronically infected individuals. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 830). Ignatius R, Lewis M, Cox WI, Frankel S, Mascola J, Villamide L, Mehlhop E, Steinman RM, Pope M. In vivo T cell priming in rhesus macaques by reinjected immature and mature dendritic cells bearing soluble or recombinant viral vector-encoded antigens. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 434). AIDS/20710224. Evans TG; Keefer MC; Belshe RB; Schwartz D; Graham BS; Corey L; Mulligan MJ; Stablein D. Rates and determinants of positive HIV screening test results in uninfected participants in phase I/II trials of candidate HIV-1 vaccines. Natl HIV Prev Conf. 1999 Aug 29-Sep 1; (abstract no. 293). MED/99326725. Evans TG, Keefer MC, Weinhold KJ, Wolff M, Montefiori D, Gorse GJ, Graham BS, McElrath MJ, Clements-Mann ML, Mulligan MJ, Fast P, Walker MC, Excler JL, Duliege AM, Tartaglia J. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J Infect Dis. 1999 Aug;180(2):290-8. MED/97030197. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11349-53. Review. MED/95341166. Perkus ME, Tartaglia J, Paoletti E. Poxvirus-based vaccine candidates for cancer, AIDS, and other infectious diseases. J Leukoc Biol. 1995 Jul;58(1):1-13. Review. MED/95317468. Plotkin SA, Cadoz M, Meignier B, Meric C, Leroy O, Excler JL, Tartaglia J, Paoletti E, Gonczol E, Chappuis G. The safety and use of canarypox vectored vaccines. Dev Biol Stand. 1995;84:165-70. ENTRY MONTH 199807 LAST REVISION DATE 20001107 43 UNIQUE IDENTIFIER DRG-0304 NAME OF SUBSTANCE ALVAC(1)120(B,MN)GNP (vCP1433) [Protocol ID: AVEG 034 ] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 034 PHARMACOLOGICAL ACTION ALVAC vaccines are recombinant live vector vaccines that are utilized primarily to induce cellular immune responses, but they also can elicit humoral responses. In addition, when ALVAC is used as a primary immunization, the antibody response can be augmented substantially by subsequent boost with recombinant subunit protein vaccines. The ALVAC line of vaccines is based on the canarypox vector. Canarypox is a member of the pox virus family, of which vaccinia (cowpox) is also a member. The canarypox virus, which originates in birds, is considered safer than vaccinia because it does not reproduce in humans. Another advantage of the canarypox virus is its ability to transport large amounts of foreign genes. Various HIV genes have been inserted into this vector. The genes originate from the clade B virus, which is the predominant subtype of HIV-1 found in the US and Europe. After administration of ALVAC vCP1433 vaccine, several HIV-1 genes are expressed in the host cell. The gag gene expresses a polyprotein, which matures into core proteins (p24, p17, and p15). The pol gene expresses the protease enzyme, which catalyzes the partition of p15 into p9 and p6. The nef and pol genes also encode for peptides that contain multiple CTL epitopes. The nef and pol gene sequences are arranged in scrambled, interspersed order relative to their positions in the native nef and pol proteins to ensure that a functional nef protein and a functional reverse transcriptase are not expressed. The proteins form virus-like particles that are enveloped by the products of env gene expression. The viral particles bud from the cell membrane and are similar to HIV virions in their appearance and structure, but not infectivity. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.; AIDS Vaccine Evaluation Group (AVEG). Listing of candidate HIV vaccines used in AVEG studies. Available at: http://www.scharp.org/public/index.htm. Accessed August 7, 2000.; Protocol ID: AVEG 034 ; AIDS Vaccine Evaluation Group (AVEG). Listing of candidate HIV vaccines used in AVEG studies. Available at: http://www.scharp.org/public/index.htm. Accessed August 7, 2000.] DISEASES STUDIED/TREATED ALVAC vaccines are investigated as preventative vaccines for HIV infection. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 034 ] ADVERSE EFFECTS The canarypox virus does not replicate in the human host; therefore, recombinants are unlikely to cause disease in recipients or be transmitted to unvaccinated contacts. Adverse reactions reported after ALVAC vaccine administration are similar to those observed in healthy adults who have received marketed vaccines. Local and systemic side effects are mild to moderate and usually resolve within 72 hours after immunization. Local effects include transient pain, tenderness, redness, and swelling at the site of injection. Less common systemic effects include headache, malaise, fever, dizziness, and nausea. No severe adverse reactions have been reported. [Protocol ID: AVEG 202 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ALVAC vCP1433 is a preparation of a modified recombinant canarypox virus expressing the products of the HIV-1 env, gag and the portion of the pol gene encoding the protease genes, and a synthetic polypeptide encompassing the known human CTL epitopes from the nef and pol gene products. ALVAC vCP1433 is generated by insertion of an expression cassette encoding a synthetic polypeptide containing several of the known human pol CTL epitopes and all of the known human nef CTL epitopes into vCP205 (see ALVAC-HIV MN120TMG (vCP205)). It is cultivated in specific pathogen-free chick embryo fibroblasts. [Protocol ID: AVEG 034 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The vaccine is supplied as single-dose vials of sterile lyophilized product with accompanying diluent (sterile water for injection that is adjusted to a pH of 5.0 to 7.0). [Protocol ID: AVEG 034 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The contents of the vial are reconstituted with 1 ml of the supplied diluent. The vial should be refrigerated at 2-8 C (35-46 F) until just prior to injection. When ready for administration, the mixture should be swirled gently for 10 seconds. The 1 ml dose should be withdrawn from the vial and administered intramuscularly into the deltoid muscle. [Protocol ID: AVEG 034 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The lyophilized powder should be stored at 2-8 C (35-46 F). The reconstituted vaccine should be stored at 2-8 C (35-46 F) and used within 2 hours after reconstitution. Freezing of both forms should be avoided. [Protocol ID: AVEG 034 ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 REFERENCES Larsson M, Engelmayer J, Lee M, Cox W, Steinman R, Bhardwaj N. Dendritic cells infected with recombinant canarypox virus induce potent anti-HIV cytolytic and helper T cell responses from chronically infected individuals. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 830). Ignatius R, Lewis M, Cox WI, Frankel S, Mascola J, Villamide L, Mehlhop E, Steinman RM, Pope M. In vivo T cell priming in rhesus macaques by reinjected immature and mature dendritic cells bearing soluble or recombinant viral vector-encoded antigens. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 434). AIDS/20710224. Evans TG; Keefer MC; Belshe RB; Schwartz D; Graham BS; Corey L; Mulligan MJ; Stablein D. Rates and determinants of positive HIV screening test results in uninfected participants in phase I/II trials of candidate HIV-1 vaccines. Natl HIV Prev Conf. 1999 Aug 29-Sep 1; (abstract no. 293). MED/99326725. Evans TG, Keefer MC, Weinhold KJ, Wolff M, Montefiori D, Gorse GJ, Graham BS, McElrath MJ, Clements-Mann ML, Mulligan MJ, Fast P, Walker MC, Excler JL, Duliege AM, Tartaglia J. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J Infect Dis. 1999 Aug;180(2):290-8. MED/97030197. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11349-53. Review. MED/95341166. Perkus ME, Tartaglia J, Paoletti E. Poxvirus-based vaccine candidates for cancer, AIDS, and other infectious diseases. J Leukoc Biol. 1995 Jul;58(1):1-13. Review. MED/95317468. Plotkin SA, Cadoz M, Meignier B, Meric C, Leroy O, Excler JL, Tartaglia J, Paoletti E, Gonczol E, Chappuis G. The safety and use of canarypox vectored vaccines. Dev Biol Stand. 1995;84:165-70. ENTRY MONTH 199807 LAST REVISION DATE 20000921 44 UNIQUE IDENTIFIER DRG-0302 NAME OF SUBSTANCE Emivirine [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] REGISTRY NUMBER 149950-60-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4(1H,3H)-Pyrimidinedione, 1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylm- ethyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Coactinon [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 292A PROTOCOL ID NUMBERS No longer recruiting FDA 292B PROTOCOL ID NUMBERS No longer recruiting FDA 292C PROTOCOL ID NUMBERS Terminated FDA 292D PROTOCOL ID NUMBERS Terminated FDA 292E PHARMACOLOGICAL ACTION MODE OF ACTION: MKC-442 is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It is highly selective for HIV-1 reverse transcriptase (RT). It interacts directly with HIV-1 RT; phosphorylation does not occur and is unnecessary for antiviral activity. In cell culture, the drug potently inhibits HIV-1 with IC50 and IC90 values of 1.5 nM and 10 nM respectively. In animals, the drug is 68% bioavailable and has good CSF penetration. MKC-442 is metabolized by cytochrome P450. Small scale phase IB studies with HIV-infected volunteers at 100 mg bid, 250 mg qd, 250 mg bid, 350 mg bid, 500 mg qd, and 500 mg bid showed that 500 mg twice daily treatments brought about superior reduction in viral load. There was no change in the CD4+ count except in the 500 mg bid group. To date no cross-resistance between MKC-442 and nucleoside RT inhibitors (e.g., AZT, 3TC) has been detected. Cross-resistance patterns with other NNRTIs varies depending on the nature of the HIV-1 strain. Preclinical testing showed that neither MKC-442 nor its primary metabolite, 6-benzyl-5-isopropyl uracil, had significant toxicity. The drug was highly bound (78.2-95.5%) to human serum proteins. In rats, elimination studies with radioactive MKC-442 showed that 37.4% of radioactivity was eliminated in the urine and the rest in the feces. [Triangle Pharmaceuticals MKC-442 Investigator's Brochure; p 79-81; AmfAR Treat Dir 1998;9(2); 1998;9(2); p 16; Drugs Fut 1998, 23(7); p 720-4] DISEASES STUDIED/TREATED Being tested in Phase II studies against HIV infection [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 16] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE INTERACTIONS MKC-442 is metabolized in the liver by cytochrome P450 and should be used with caution in patients using other drugs that are metabolized by or may affect liver metabolism by cytochrome P450. [Triangle Pharmaceuticals MKC-442 Investigator's Brochure; p 79-81] ADVERSE EFFECTS In Phase I trials, headaches and nausea were the most frequent adverse events following either single or repeated oral doses of MKC-442. Two patients on repeated doses of the drug had to discontinue treatment because of rashes. Minor elevation of liver transferase levels were observed in some 50% of patients receiving repeated doses of MKC-442. No significant changes in blood pressure, pulse ECG or other laboratory values were experienced. [Triangle Pharmaceuticals MKC-442 Investigator's Brochure; p 81] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: MKC-442 is structurally related to nucleoside analogs, but it acts as a non-nucleoside reverse transcriptase inhibitor (NNRTI). [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 35] CHEMICAL/PHYSICAL DATA Molecular Formula: C17-H22-N2-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 302.37 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 100 and 250 mg tablets [Triangle Pharmaceuticals MKC-442 Investigator's Brochure; p 79] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [Triangle Pharmaceuticals MKC-442 Investigator's Brochure; p 79] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Stability data demonstrate that the dosage form is stable for up to 9 months at 25 C at 60% RH and for up to 3 months at 40 C at 75% RH. [Triangle Pharmaceuticals MKC-442 Investigator's Brochure; p 79] MANUFACTURERS 0000004441: Triangle Pharmaceuticals Inc 4 Univ Place / 4611 Univ Dr Durham, NC 27707 Contact: Jill W. Buckley, PharmD (919)402-2234 MANUFACTURERS 0000004441: Triangle Pharmaceuticals Inc 4 Univ Place / 4611 Univ Dr Durham, NC 27707 REFERENCES MED/99092570. Tanaka H, Walker RT, Hopkins AL, Ren J, Jones EY, Fujimoto K, Hayashi M, Miyasaka T, Baba M, Stammers DK, et al. Allosteric inhibitors against HIV-1 reverse transcriptase: design and synthesis of MKC-442 analogues having an omega-functionalized acyclic structure. Antivir Chem Chemother. 1998 Jul;9(4):325-32. AIDS/98930168. Harris J, Borroto-Esoda K, Hill E, Moxham C, Rousseau F, McCreedy B. Development of genotypic and phenotypic resistance to MKC-442, a potent and selective inhibitor of HIV-1 replication. Antiviral Res. 1998 Mar;37(3):A60 (abstract no. 73). AIDS/98930144. Hill E, Taylor N, Borroto-Esoda K, Furman P, Moxham C, Painter G. In vitro synergy studies with MKC-442, a non-nucleoside HIV-1 reverse transcriptase inhibitor. Antiviral Res. 1998 Mar;37(3):A54(abstract no. 49). ICA12/98387995. Blum MR, Moxham CP, Kargl DJ, Quinn JB, Barry DW, Rousseau FS. A pharmacokinetic interaction evaluation of MKC-442 and nelfinavir (NFV) in healthy male and female volunteers. Int Conf AIDS. 1998;12:89 (abstract no. 12380). ICA12/98387989. Moxham C, Blum MR, Kargl DJ, Quinn JB, Rousseau FS, Barry DW. Evaluation of potential interactions between MKC-442 and zidovudine (ZDV)-lamivudine (3TC), and stavudine (d4T)-didanosine (ddi) in healthy volunteers. Int Conf AIDS. 1998;12:88 (abstract no. 12374). ICA12/98387977. Yuasa S, Nakade K, Piras J, Baba M. Drug combination studies on MKC-442 with RT inhibitors in long-term culture of HIV-1-infected cells. Int Conf AIDS. 1998;12:85-6 (abstract no. 12362). Furman PA, Moxham C. MKC-442. A potent and selective nonnucleoside reverse transcriptase inhibitor. Drugs Fut 1998, 23(7):718-724. MED/97239103. Piras G, Nakade K, Yuasa S, Baba M. Three-drug combination of MKC-442, lamivudine and zidovudine in vitro: potential approach towards effective chemotherapy against HIV-1. AIDS 1997 Mar 15;11(4):469-75. AIDS/97926456. Furman P, Barry DW, Borroto-Esoda K, Moxham C, Richman D, Sommadossi JP, Endoh R, Niwa T, Yamamoto M, Szczech G. Preclinical development of MKC-442, a potent and selective non-nucleoside inhibitor of HIV reverse transcriptase. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:170 (abstract no. 571). AIDS/97926013. Moxham CP, Borroto-Esoda K, Noel D, Furman PA, Szczech GM, Barry DW. Preliminary efficacy and safety of repeated multiple doses of MKC-442 in HIV-infected volunteers. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:206 (abstract no. LB1). ENTRY MONTH 199803 LAST REVISION DATE 20001106 45 UNIQUE IDENTIFIER DRG-0301 NAME OF SUBSTANCE Voriconazole [USPD 1998; p. 783] REGISTRY NUMBER 137234-62-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Pyrimidineethanol, alpha-(2,4-difluorophenyl)-5-fluoro-beta-meth- yl-alpha-(1H-1,2,4-tria zol-1-ylmethyl)-, (R-(R*,S*))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting CC 97 I-0164 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0028 PHARMACOLOGICAL ACTION Voriconazole, a new antifungal triazole derivative, was studied in vitro against 650 clinical isolates, representing yeasts, nolds and dermatophytes, and was compared with fluconazole, amphotericin B, and griseofulvin. The mean minimum inhibitory concentrations (MICs) of voriconazole were 0.06 microgram/ml against yeasts (n = 187), 0.74 microgram/ml against moulds (n = 260), and 0.10 microgram/ml against dermatphytes (n = 203). Data from these in vitro studies showed that voriconazole was more potent than fluconazole against most species studied, but particularly against the isolates of moulds and dermatophytes. The in vitro results confirmed that voriconazole has indeed a broad antifungal spectrum and could also be effective against a wide range of fungal infections. Voriconazole has potent activity against various fungit hat are inherently resistant to fluconazole, such as Candida krusei. A study compared the effect of subinhibitory concentrations of voriconazole and fluconazole on sterol biosynthesis of fluconazole-resistant and -susceptible Candida albicans strains, as well as C.krusei, in an effort to delineate the precise mode of action of voriconazole. C.krusei cells treated with voriconazole accumulated the following biosynthetic intermediates: squalene, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol. Accumulation of these methylated sterols is consistent with the premise that this agent functions by inhibiting fungal P-450-dependent 14alpha-demethylase. As expected, treating C. Krusei with fluconazole minimally inhibited ergosterol synthesis. These data indicate that voriconazole is more effective than fluconazole in blocking candidal sterol biosynthesis, consistent with the different antifungal potencies of these compounds. Invasive aspergillosis is an increasing problem in patients with acute leukemia, bone marrow transplantation, immunosuppression after solid organ transplantation, or AIDS. Despite available antifungal treatment, the mortality approaches 100% in patients with dissemination of the infection into the central nervous system (CNS). Voriconazole, was used successfuly to treate an Aspergillus brain abscess in a patient with acute leukemia. Drug levels above the minimal fungicidal concentration for Aspergillus species were detected in cerebrospinal fluid specimens, and the treatment achieved an objective response. [Arzneimittelforschung 1997 Nov;47(11); p 1257-63; Antimicrob Agents Chemother 1997 Nov;41(11); p 2492-6; Br J Haematol 1997 Jun;97(3); p 663-5] DISEASES STUDIED/TREATED Being tested for treatment of aspergillosis. [AmfAR Treat Dir 1997 Dec; p 72] CLASSIFICATION CODE Antifungal [AmfAR Treat Dir 1997 Dec; p 72] CHEMICAL/PHYSICAL DATA Molecular Formula: C16-H14-F3-N5-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 349.32 [USPD 1998; p. 783] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: oral [AmfAR Treat Dir 1997 Dec; p 72] MANUFACTURERS 0000001187: Pfizer Global Research and Development Eastern Point Rd Groton, CT 06340 Contact: Robert Myers (203)441-3817 REFERENCES MED/98109332. Marco F, Pfaller MA, Messer S, Jones RN. In vitro activities of voriconazole (UK-109,496) and four other antifungal agents against 394 clinical isolates of Candida spp. Antimicrob Agents Chemother 1998 Jan;42(1) : 161-3. MED/98090677. Wildfeuer A, Seidl HP, Paule I, Haberreiter A. In vitro activity of voriconazole against yeasts, moulds and dematophytes in comparison with fluconazole, amphotericin B and griseofulvin. Arzneimittelforschung 1997 Nov;47(11):1257-63. MED/98092243. Espinel-Ingroff A. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic filamentous and dimorphic fungi and common and emerging yeast pathogens. J Clin Microbiol 1998 Jan;36(1):198-202. MED/98037406. Sanati H, Belanger P, Fratti R, Ghannoum M. A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrob Agents Chemother 1997 Nov;41(11):2492-6. MED/97400279. McGinnis MR, Pasarell L, Sutton DA, Fothergill AW, Cooper CR Jr, Rinaldi MG. In vitro evaluation of voriconazole against some clinically important fungi. Antimicrob Agents Chemother 1997 Aug;41(8):1832-4. MED/97351042. Schwartz S, Milatovic D, Thiel E. Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia (see comments). Br J Haematol 1997 Jun;97(3):663-5. MED/97242502. Radford SA, Johnson EM, Warnock DW. In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emrging and less-common mold pathogens. Antimicrob Agents Chemother 1997 Apr;41(4):841-3. MED/97209074. Murphy M, Bernard EM, Ishimaru T, Armstrong D. Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis. Antimircrob Agents Chemother 1997 Mar;41(3):696-8. MED/97135208. Martin MV, Yates J, Hitchcock CA. Comparison of voriconazole (UK-109,496) and itraconazole in prevention and treatment of Aspergillus fumigatus endocarditis in guinea pigs. Antimicrob Agents Chemother 1997 Jan;41(1):13-6. AIDS/98927679. Sutton DA, Fothergill AW, Barchiesi FJ, Rinaldi MG. In vitro activity of voriconazole against dimorphic fungi. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:114 (abstract no. F85). ENTRY MONTH 199803 LAST REVISION DATE 20001107 46 UNIQUE IDENTIFIER DRG-0300 NAME OF SUBSTANCE Capravirine [Agouron Pharmaceuticals Inc. Available at: http://www.agouron.com. Accessed: May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 286A PROTOCOL ID NUMBERS No longer recruiting FDA 286D PROTOCOL ID NUMBERS No longer recruiting FDA 286E PROTOCOL ID NUMBERS Suspended FDA 286B PROTOCOL ID NUMBERS Suspended FDA 286C CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 451.38 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] MANUFACTURERS 0000004438: Lexigen Pharmaceuticals 125 Hartwell Ave Lexington, MA 02421 Contact: Unspecified (781)861-5300 MANUFACTURERS 0000003726: Agouron Pharmaceuticals Inc 11095 Torreyana Rd San Diego, CA 92121 Contact: Carolyn Peterson (888)847-2237 ENTRY MONTH 199803 LAST REVISION DATE 20000922 47 UNIQUE IDENTIFIER DRG-0299 NAME OF SUBSTANCE Bexarotene [USPD 2000 p. 93] STANDARD CHEMICAL NAME 4-[1-(3,5,5,8,8-pentamethyl-5, 6,7,8-tetrahydro-2-naphthalenyl)-1-ethenyl]-b- enzoic acid [Protocol ID: 287A ] SYNONYMS Targretin [USPD 2000 p. 93] PROTOCOL ID NUMBERS No longer recruiting FDA 287A PHARMACOLOGICAL ACTION Targretin (LGD1069) is a compound which selectively activates a subclass of retinoid receptors called RXRs which play an important role in several cellular activities, most importantly in an activity called apoptosis (programmed cell death). In a clinical trial of tagretin topical, 59 patients with biopsy proven Kaposi'sarcoma (KS) were randomized at 5 study sites in an unblinded fashion to either 0.5% vs. 1.0% gel, BID and increasing to 1.0% QID, or the maximum dose tolerated. Response was defined as complete flattening of greater than or equal to 50% of raised lesions or greater than or equal to 50% decrease of the total area of lesions. Of 46 patients evaluable for response (on study greater than or equal 12 weeks of therapy), 7 (15.2%) had a partial response: 1 at 0.1% BID, 1 at 0.5% QD, 1 at 1.0% BID, 1 at 1.0% TID and 3 at 1.0% QID. Three of 46 patients (7%) met partial response criteria with a complete flattening of at least 50% of the raised treated index lesion. No patient had a complete response in all treated lesions, although some lesions had a complete response. Targretin appears to have some efficacy for KS lesions and is accompanied by cutaneous irritation and the need for multiple applications. It may be most suitable for those patients who have limited early disease. [Int Conf AIDS 1996 Jul 7-12;11(2); p 98 (abstract no. We.B.3241); PR Newswire 1996 Jan 5] DISEASES STUDIED/TREATED Being tested as topical treatment against Kaposi's sarcoma [PR Newswire 1996 Jan 5] CLASSIFICATION CODE Antineoplastic [USPD 2000 p. 93] OTHER MAJOR USES Being tested as a topical treatment of mycosis fungoides (cutaneous T-cell lymphoma) [PR Newswire 1996 Jan 5] ADVERSE EFFECTS In a clinical study with targretin topical gel, involving 59 patients with Kaposi's sarcoma, no patient developed adverse drug effects (ADEs) at 0.1% concentration. Eleven of 33 patients (33%), while at 0.5% QD/BID experienced possibly / probably / definitely related ADEs of rash, exfoliative dermatitis, maculopapular rash, eczema, or pain; none on TID/QID dosing. Twelve or 45 patients (26% on 1.0% QD/BID experienced possible/probable/definite related ADE. Two patients randomized to 0.5% required dose reduction to 0.1%; no non-dermatologic ADEs were found at any strenght. ADEs were classified as mild in 18 patients, moderate in 11 patients and severe in 1 patient. [Int Conf AIDS 1996 Jul 7-12;11(2); p 98 (abstract no. We.B.3241)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Tetrahydronaphthalene derivative [Protocol ID: 287A ] CHEMICAL/PHYSICAL DATA Molecular Formula: C24-H28-O2 [USPD 2000 p. 93] CHEMICAL/PHYSICAL DATA Molecular Weight: 348.49 [USPD 2000 p. 93] SUBSTANCE DELIVERY DATA DOSAGE FORM: Gel [PR Newswire 1996 Jan 5] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topically [PR Newswire 1996 Jan 5] MANUFACTURERS 0000004054: Ligand Pharmaceuticals 10275 Science Center Drive San Diego, CA 92121 Contact: Susan Atkins (619)550-7687 MANUFACTURERS 0000004054: Ligand Pharmaceuticals 10275 Science Center Drive San Diego, CA 92121 Contact: Unspecified (619)550-7500 REFERENCES ICA11/96923593. Leoung GS, Aboulafla D, Millikan L, Duvic M, MacGregor RR, Gill G, Truglia J, Yocum R. Treatment of kaposi's sarcoma using Targretin (LGD1069), a topical retinoid gel. Int Cont AIDS. 1996 Jul 7-12;11(2):98 (abstract no. We.B.3241). AIDS/95700426. Aboulafia DM. The epidemiology, pathogenesis and treatment of Kaposi's sarcoma. STEP Perspect. 1995 Spring;7(1):9-12. Atkins S. Ligand updates market on targretin (TM) (LGD1069) topical at Hambrecht & Quist life sciences conference. PR Newswire - 05 Jan 96. ENTRY MONTH 199802 LAST REVISION DATE 20000921 48 UNIQUE IDENTIFIER DRG-0298 NAME OF SUBSTANCE GEM 132 [Hybridon Inc ] PHARMACOLOGICAL ACTION GEM 132 is an antisense oligonucleotide. Such compounds usually are short pieces of DNA that work inside HIV-infected cells by homing in on the virus's genes and stopping them from working. GEM 132 is a 20-mer hybrid phosphorothioate with 2 bases at the 5' end and 4 bases at the 3' end being 2'0 methylated. This modification should improve metabolic stability. GEM 132 is designed to be complementary to the intron-exon boundary of the UL36 and UL37 pre-mRNA transcripts of human CMV. In vitro studies have shown GEM 132 to be about 1,000 times more potent than ganciclovir. The tolerance and PK of single ascending doses of GEM 132 by 2-hour IV infusion were assessed in healthy male volunteers in an open-label study. Eighteen subjects were included, six at each of the following doses: 0.125 mg/kg, 0.25mg/kg and 0.5mg/kg. Subjects were followed for safety assessments as inpatients for 48 hours and in an ambulatory setting for a total of two weeks after administration of study drug. Plasma concentrations of GEM 132 were measured for 48 hours after dosing. The pharmacokinetics of GEM 132 were nonlinear with increasing dose. AUC and C(max) increased disproportionately and Vd(ss) and C1p decreased as the dose was escalated. GEM 132 is being evaluated for both systemic and intravitreal administration in immunocompromised patients. [PR Newswire 1997 Apr 7; p 121 (abstract no. 309)] DISEASES STUDIED/TREATED Under investigation for intravitreal use against ocular CMV infection, and for systemic use against CMV infections in AIDS patients. [PR Newswire 1997 Apr 7; PR NewsWire April 7, 1997; PR Newswire 1997 Apr 7; PR Newswire January 23, 1997] CLASSIFICATION CODE Antisense [Hybridon Inc ] ADVERSE EFFECTS The most frequently reported adverse event in one clinical trial was headache in 5 of 18 subjects which occurred at all dose levels and resolved rapidly and without sequelae. A minor and transient increase in aPTT was observed immediately after the end of the infusion in one subject dosed with 0.5 mg/kg 132. No other treatment-related events were observed. [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 121 (abstract no. 309)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Antisense oligonucleotide [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 121 (abstract no. 309)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Infusion [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 121 (abstract no. 309)] MANUFACTURERS 0000004425: Hybridon Inc 155 Fortune Blvd Milford, MA 01757 Contact: Margaret A Flanagan (508)482-7500 REFERENCES AIDS/97926754. Guinot P, Martin R, Bonvoisin B, Toneatti C, Bourque A, Cohen A, Dvorchik B, Schechter P. First phase I study of a new systemic anti-CMV antisense compound (GEM 132) in healthy male volunteers. 4Th Conf Retro and Oppotun Infect. 1997 Jan 22-26;:121 (abstract no. 309). ENTRY MONTH 199802 LAST REVISION DATE 20000801 49 UNIQUE IDENTIFIER DRG-0297 NAME OF SUBSTANCE Zintevir [Protocol ID: 290A ] PROTOCOL ID NUMBERS No longer recruiting FDA 290A PHARMACOLOGICAL ACTION Zintevir belongs to a class of novel oligonucleotides. Preclinical studies have indicated that Zintevir inhibits the HIV integrase enzyme, one of the key steps in the life cycle of the HIV virus. Oligonucleotides that can form a highly stable intramolecular four-stranded DNA structure containing two stacked guanosine-quartets (G-quartets) have been reported to inhibit the replication of the human immunodeficiency virus type 1 (HIV-1) in cell culture. Two possible mechanisms for the observed antiviral activity have been proposed: interference with virus adsorption to the cell and/or inhibition of HIV-1 integrase. The molecular intercation of G-quartet-containing oligonucleotides with HIV-1 integrase in comparison with random oligonucleotides and dextran sulphate was investigated. Zintevir, the prototypical G-quartet-containing oligonucleotide, inhibited the overall integration reaction with an IC50 value of 80 nM. Preclinical studies have shown that Zintevir is a very stable molecule widely distributed throughout the body, and that tissue concentration of the are maintained for periods exceeding five days following single doses. A single dose rising study and a two-week, multiple-dose escalation study, which involved a total of 27 HIV-positive patients, have been completed. Results indicate that Zintevir, administered at doses up to 6mg/kg, is extremely well tolerated. No clinically significant adverse events were reported. Results also indicate that Zintevir (TM) plasma concentrations exceeded in vitro inhibitory concentration for the HIV virus for periods of up to 10 hours following administration of the higher doses. [Mol Pharmacol 1998 Feb;53(2); p 340-5; PR Newswire 1996 Nov 12] DISEASES STUDIED/TREATED Anti-HIV activity. Currently in clinical phase I trials [Mol Pharmacol 1998 Feb;53(2); p 340-5] CLASSIFICATION CODE Investigational - Integrase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Results of Phase I clinical trials indicated that Zintevir, administered at doses up to 6mg/kg, is extremely well tolerated. No clinically significant adverse events were reported. [PR Newswire 1996 Nov 12] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Zintevir is a 17-base oligonucleotide composed of deoxyguanosines and thymidines on a phosphodiester backbone supplemented by phosphorothioate internucleoside linkages at the 5' and 3' ends [Int Conf AIDS 1996 Jul 7-12;11(1); p 21] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: By infusion. [Int Conf AIDS 1996 Jul 7-12;11(1); p 21 (abstract no. Th.B.946)] MANUFACTURERS 0000004419: Aronex Pharmaceuticals Inc 8707 Technology Forest Place The Woodlands, TX 773811191 Contact: Unspecified (281)367-1666 REFERENCES MED/98130706. Este JA, Cabrera C, Schols D, Cherepanov P, Gutierrez A, Witvrouw M, Pannecouque C, Debyser Z, Rando RF, Clotet B, et al. Human Immunodeficiency virus glycoprotein gp120 as the primary target for the antiviral action of AR177 (Zintevir). Mol Pharmacol. 1998 Feb;53(2):340-5. MED/98016250. Cherepanov P, Este JA, Rando RF, Ojwang JO, Reekmans G, Steinfeld R, David G, De Clercq E, Debyser Z, Mode of interaction of G-quarters with the integrase of human immunodeficiency virus type 1. Mol. Pharmacol. 1997 Nov;52(5):771-80. ICA11/97926876. Kahn J, Graham E, Deeks S, Gambertoglio J, Brewer T, Wallace T, Kennedy B, Cossum P. Phase I study of AR-177 (Zintevir), an HIV-1 inhibitor with significant activity against integrase protein: safety, pharmokinetics, immunologic and virologic activity. Int Conf AIDS. 1996 Jul 7-12;11(Program Supplement):21(abstract no. Th.B.946). ENTRY MONTH 199802 LAST REVISION DATE 20000801 50 UNIQUE IDENTIFIER DRG-0296 NAME OF SUBSTANCE MN rgp120/HIV-1 and A244 rgp120/HIV-1 [Protocol ID: AVEG 203 ] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 036 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 202 PROTOCOL ID NUMBERS No longer recruiting FDA VAX 002 PROTOCOL ID NUMBERS No longer recruiting FDA VAX 003 PHARMACOLOGICAL ACTION MODE OF ACTION: Each AIDSVAX formulation is created from recombinant copies of the gp120 protein from the surface of two types of HIV. The vaccine being used in test sites across North America is formulated to protect against infection by the major types of HIV-1 virus most typical of infections in the Americas, Western Europe and Australia (AIDSVAX B/B). The formulation of the vaccine to be used in the Thai trial is designed to protect against the major types of the virus typical of infections in Southeast Asia and the Pacific Rim (AIDSVAX B/E). This approach is based on the observation that in a trial with a recombinant gp120 vaccine (MN-rgp120), six out of seven vaccinees, who became infected with HIV during the trial, showed a virus strain different from that used in the trial vaccine. These results suggested that the breakthrough infections might be related to incomplete immunization or to infection with viruses that differed from the vaccine immunogen at important virus-neutralizing epitopes. AIDSVAX B/B has been through phases I and II testing. After immunization, essentially all recipients developed a robust antibody response, including binding and neutralizing antibodies. The neutralizing antibodies peaked after a 12-month boost. Excellent memory was induced. Two phase III trials of two bivalent formulations will evaluate their efficacy. The ongoing trial in North America is using a bivalent subtype B formulation. It involves 5000 gay men and heterosexual women at high risk. The Phase III trial in Bangkok started in February, 1999 among 2,500 HIV-negative volunteers who are at high-risk of contracting HIV infection because of infection drug use. This clinical trial is being performed in 17 methadone drug treatment centers of the Bangkok Metropolitan Administration. It uses a bivalent subtype B/subtype E formulation (i.e., AIDSVAX B/E). Both studies are randomized, double-blinded and placebo-controlled. The volunteers will be followed for 3 years. The end points of the studies are infection, as defined by seroconversion to standard diagnostic tests, and viral load, as defined by commercial polymerase chain reaction (PCR) tests. [Science 1998 Jan 30:279(5351); p 650; AIDS Res Hum Retroviruses 1998 Oct;14 Suppl 3; p S325-31; Business Wire 1999 February 9] DISEASES STUDIED/TREATED To prevent HIV infection. The end points of the ongoing clinical studies are infection, as defined by seroconversion to standard diagnostic tests, and viral load, as defined by commercial polymerase chain reaction (PCR) tests. [Business Wire 1999 February 9] CLASSIFICATION CODE Vaccine [Protocol ID: VAX 002 ] ADVERSE EFFECTS In both design and clinical testing, AIDSVAX has an excellent safety profile. Because the highly purified proteins in AIDSVAX B/B and B/E are prepared using recombinant DNA technology, there is no possibility of these vaccines causing HIV infection. Having been administered to over 1200 people in several studies, the only side effects attributable to AIDSVAX have been local pain and inflammation at the injection site. [AIDS Res Hum Retroviruses 1998 Oct;14 Suppl 3; p S325-31] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Vaccine produced from a genetically engineered HIV surface protein gp120. [Science 1998 Jan 30:279(5351); p 650] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: By injection [AIDS Res Hum Retroviruses 1998 Oct;14 Suppl 3; p S325-31] MANUFACTURERS 0000004404: VaxGen Inc 1000 Marina Boulevard / Suite 200 Brisbane, CA 94005 Contact: Marlene Chernow (650)624-1030 REFERENCES Thai Authorities Approve Large-Scale Testing of VaxGen's HIV Vaccine Trial Focused on HIV Epidemic in Asia and Pacific Rim. Business Wire, February 9, 1999. Maggie Fox. US firm starts test of AIDS vaccine in Thailand Reuters NewMedia. February 9, 1999. MED/99030126. Francis DP, Gregory T, McElrath MJ, Belshe RB, Gorse GJ, Migrasena S, Kitayaporn D, Pitisuttitham P, Mathews T, Schwartz DH, et al. Advancing AIDSVAX to phase 3. Safety, immunogenicity, and plans for phase 3. AIDS Res Hum Retroviruses. 1998 Oct;14 Suppl 3:S325-31. MED/98401692. Wadman M. NIH institute to work with trial of AIDS vaccine, despite concerns [news]. Nature. 1998 Aug 27;394(6696):818. AIDS/99703955. Highleyman L. Large-scale HIV vaccine trial to begin this summer. BETA. 1998 Jul;:3. MED/98314403. First AIDS vaccine trial launched [news] Science. 1998 Jun 12;280(5370):1697. ICA12/98398865. Francis D, Berman PW, Migasena S, Kitayaporn D, Gregory T. AIDSVAX B/B and AIDSVAX B/E: likely to protect. But how well and for how long must await results of planned efficacy trials. Int Conf AIDS. 1998;12:637 (abstract no. 33223). ENTRY MONTH 199802 LAST REVISION DATE 20000801 51 UNIQUE IDENTIFIER DRG-0295 NAME OF SUBSTANCE MN rgp120/HIV-1 and GNE8 rgp120/HIV-1 [Protocol ID: AVEG 203 ] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 027 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 202 PROTOCOL ID NUMBERS No longer recruiting FDA VAX 002 PROTOCOL ID NUMBERS No longer recruiting FDA VAX 004 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 326 PROTOCOL ID NUMBERS Recruiting NIAID HVTN 203 CLASSIFICATION CODE Vaccine [Protocol ID: VAX 002 ] ADVERSE EFFECTS The safety and immunogenicity of AIDSVAX has been evaluated through administration of monovalent subtype B formulations (MN and IIIB) to over 1,000 humans. A second geography-specific antigen was selected, produced, combined with MN, and administered to humans in the United States and in Thailand using bivalent formulations - B/B for the U.S. (120 volunteers) and B/E for Thailand (90 volunteers). Minimal injection site reactions are the only associated adverse reactions observed. [Int Conf AIDS 1998 Jun] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Vaccine produced from a genetically engineered HIV surface protein gp120. [Science 1998 Jan 30:279(5351); p 650] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: By injection [Protocol ID: VAX 002 ] MANUFACTURERS 0000004404: VaxGen Inc 1000 Marina Boulevard / Suite 200 Brisbane, CA 94005 Contact: Marlene Chernow (650)624-1030 REFERENCES MED/98314403. First AIDS vaccine trial launched [news]. Science.1998 Jun 12;280(5370):1697. MED/98125992. Graham BS, McElrath MJ, Connor RI, Schwartz DH, Gorse GJ, Keefer MC, Mulligan MJ, Matthews TJ, Wolinsky SM, Montefiori DC, et al. Analysis of intercurrent human immunodeficiency virus type 1 infections in phase I and II trials of candidate AIDS vaccines. AIDS Vaccine Evaluation Group, and the Correlates of HIV Immune Protection Group. J Infect Dis. 1998 Feb;177(2)310-9. MED/98125991. Corey L, McElrath MJ, Weinhold K, Matthews T, Stablein D, Graham B, Keefer M, Schwartz D, Gorse G. Cytotoxic T cell and neutralizing antibody responses to human immunodefficiency virus type 1 envelope with a combination vaccine regimen. AIDS Vaccine Evaluation Group. J Infect Dis. 1998 Feb;177(2):301-9. MED/98140699. Bolognesi DP, Matthews TJ. HIV vaccines. Viral envelope fails to deliver? [news] Nature. 1998 Feb12;391(6668):638-9. MED/98129144. Balter M. Impending AIDS vaccine trial opens old wounds [news]. Science. 1998 Jan 30;279(5351):650. MED/97379381. Berman PW, Gray AM, Wrin T, Vennari JC, Eastman DJ, Nakamura GR, Francis DP, Gorge G, Schwartz DH. Genetic and immunologic characterization of viruses infecting MN-rgp120-vaccinated volunteers. J Infect Dis. 1997 Aug;176(2):384-97. MED/98004261. Li D, Forrest BD, Li Z, Xue P, Hanson CV, Duan S, Cheng H, Li M, Wang CY, Koff WC. International clinincal trials of HIV vaccines: II. phase I trial of an HIV-1 synthetic peptide vaccine evaluating an accelerated immunization schedule in Yunnan, China. Asian Pac J Allergy Immunol. 1997 Jun;15(2):105-13. MED/97071928. Gorse GJ, Yang EY, Belshe RB, Berman PW. Salivary binding antibodies induced by human immunodeficiency virus type 1 recombinant gp120 vaccine. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Nov;3(6):769-73. MED/97048118. Girard M, Yue L, Barre-Sinoussi F, van der Ryst E, Meignier B, Muchmore E, Fultz PN. Failure of a human immunodeficiency virus type 1 (HIV-1) subtype B-derived vaccine to prevent infection of chimpanzees by an HIV-1 subtype E strain. J Virol. 1996 Nov;70(11):8229-33. MED/96132463. Berman PW, Murthy KK, Wrin T, Vennari JC, Cobb EK, Eastman DJ, Champe M, Nakamura GR, Davison D, Powell MF, et al. Protection of MN-rgp120-immunized chimpanzees from heterologous infection with a primary isolate of human immunodeficiency virus type 1. J Infect Dis. 1996 Jan;173(1):52-9. ENTRY MONTH 199802 LAST REVISION DATE 20000801 52 UNIQUE IDENTIFIER DRG-0294 NAME OF SUBSTANCE Interleukin-6 [Protocol ID: ACTG 928 ] PHARMACOLOGICAL ACTION MODE OF ACTION: Interleukin-6 (IL-6) is a member of the family of cytokines collectively termed the interleukin-6 type cytokines. IL-6 expression is regulated by a variety of factors, including steroidal hormones, at both the transcriptional and post-transcriptional levels. IL-6 achieves its effets through the ligand-specific IL-6 receptor (IL-6R). Unlike most other cytokine receptors, the IL-6R is active in both membrane bound and soluble forms. Defining mechanisms to control IL-6 or IL-6R expression forms. Defining mechanisms to control IL-6 or IL-6R expression may prove useful for therapy of the many clinical disorders in which IL-6 plays a role. Overproduction of IL-6 is associated with a number of diseases, which include: polyclonal B-cell activation or autoimmune diseases (cardiac myxoma, rheumatoid arthritis, Castleman's disease, alcoholic liver cirrhosis, type I diabetes); malignancies (multiple myeloma, cholangiocarcinoma, plasmacytoma, lymphoma, leukemia, and renal cell carcinoma); chronic proliferative diseases (mesangial proliferative glomerulonephritis, psoriasis, and Kaposi's sarcoma); and other diseases (AIDS, sepsis, osteoporosis, Fanconi anemia, and hepatitis type B). Indeed, these associations with clinical disease suggest that IL-6 have potential therapeutic and diagnostic roles. Preclinical anti-tumor studies with IL-6 have provided rationale for its utilization in the therapy of certain malignancies. However, phase I trials with IL-6 have yet to demonstrate an antitumor effect in patients with advanced cancer and hence suggests a supportive rather than primary role for this cytokine in immunotherapy. In particular, a recent study demonstrated that the combination of B7-1, IL-6, and IL-12 promoted the generation of tumor-specific cytotoxic T lymphocytes in vitro; this proposal may potentially be applied to immunotherapeutic approaches in patients with specific types of cancer. [Front Biosci 1996 Dec 1; p d340-57; In Vivo Veritas 1996 January; p 1-3] DISEASES STUDIED/TREATED Human IL-6 is characterized as a glycoprotein consisting of 212 amino acids with numerous post-translational modifications including phosphorylations as well as N- and O-linked glycosylations. [Front Biosci 1996 Dec 1; p d340-57; In Vivo Veritas 1996 January; p 1-3] CLASSIFICATION CODE Immunomodulator [Protocol ID: ACTG 928 ] OTHER MAJOR USES Possible utilization in the therapy of certain malignancies. [In Vivo Veritas 1996 January; p 1-3] MANUFACTURERS 0000003153: Natl Inst of Allergy & Infect Dis / Cln Ctr 9000 Rockville Pike / RM 11C304 Bethesda, MD 20892 Contact: Unspecified (800)411-1222 REFERENCES MED/98380419. Williams DM, Grubbs BG, Darville T, Kelly K, Rank RG. A role for interleukin-6 in host defense against murine Chlamydia trachomatis infection. Infect Immun. 1998 Sep;66(9):4564-7. MED/98375851. Murakami-Mori K, Mori S, Nakamura S. Endogenous basic fibroblast growth factor is essential for cyclin E-CDK2 activity in multiple external cytokine-induced proliferation of AIDS-associated Kaposi's sarcoma cells: dual control of AIDS-associated Kaposi's sarcoma cell growth and cyclin E-CDK2 activity by endogenous and external signals. J Immunol. 1998 Aug 15;161 (4):1694-704. MED/98368644. Bewnveniste O, Vaslin B, Le Grand R, Dormont D. Comparing IL-6, TNF-alpha, and IL-1beta responses to acute infection with attenuated nef-truncated or pathogenic SIVmac251 in macaque peripheral blood mononuclear cells [letter] J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Aug 1;18(4):389-90. MED/98283303. de Martino M, Rossi ME, Azzari C, Gelli MG, Galli L, Vierucci A. Different meaning of CD38 molecule expression on CD4+ and CD8+ cells of children perinatally infected with human immunodeficiency virus type 1 infection surviving longer than five years. Pediatr Res. 1998 Jun;43(6):752-8. MED/98287066. Haslett PA. Anticytokine approaches to the treatment of anorexia and cachexia. Semin Oncol. 1998 Apr;25(2 Suppl 6):53-7. MED/98268879. Haas DW, Lederman MM, Clough LA, Wallis RS, Chernoff D, Crampton SL. Proinflammatory cytokine and human immunodeficiency virus RNA levels during early Mycobacterium avium complex bacteremia in advanced AIDS. J Infect Dis. 1998 Jun;177(6):1746-9. AIDS/98929742. Russell DG. Immunomodulation in Mycobacterium infections. 5th Conf Retrovir Oppor Infect. 1998 Feb 1-5;:236 (abstract no. S31). AIDS/98929649. Haas DW, Lederman M, Clough LA, Wallis RS, Feiler JR. Effect of clarithromycin prophylaxis on circulating TNF-alpha and IL-6 levels in advanced HIV infection. 5th Conf Retrovir Oppor Infect. 1998 Feb 1-5;:215 (abstract no. 725). MED/98085839. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998 Jan 15;128(2):127-37. MED/98226689. Wang XJ. Taga T. Yoshida K. Saito M. Kishimoto T. Kikutani H. gp130, the cytokine common signal-transducer of interleukin-6 cytokine family, is downregulated in T cells in vivo by interleukin-6. Blood. 1998 May 1;91(9):3308-14. ENTRY MONTH 199801 LAST REVISION DATE 20000801 53 UNIQUE IDENTIFIER DRG-0293 NAME OF SUBSTANCE CPI-1189 [Protocol ID: 289A ] PROTOCOL ID NUMBERS No longer recruiting FDA 289A PROTOCOL ID NUMBERS No longer recruiting FDA 289B CLASSIFICATION CODE Antidementia [Protocol ID: 289A ] MANUFACTURERS 0000004294: Centaur Pharmaceuticals Inc 484 Oakmead Parkway Sunnyvale, CA 94086 Contact: Claire Kwan (408)822-4102 ENTRY MONTH 199801 LAST REVISION DATE 20000801 54 UNIQUE IDENTIFIER DRG-0292 NAME OF SUBSTANCE Posaconazole [USPD 2000 p. 583] PROTOCOL ID NUMBERS No longer recruiting FDA 288A PROTOCOL ID NUMBERS No longer recruiting FDA 305A PHARMACOLOGICAL ACTION SCH 56592 has a low water solubility (less than 2 micrograms/ml) which increases at acidic pH, is stable at accelerated conditions of temperature and light, and is compatible with a wide variety of pharmaceutical excipients. SCH 56592 is a triazole antifungal agent. Triazole antifungals are known to block sterol biosynthesis by inhibiting the enzyme lanosterol, a-C14 demthylase (CYP51). In a study, examining the effect of SCH 56592 on fungal sterol synthesis, it was found that SCH 56592 inhibits sterol C14 demethylation in candida albicans with an estimated IC50 comparable to that of itraconazole. In the case of aspergillus flavus and aspergillus fumigatus, SCH 56592 is at least ten-fold more potent than itraconazole. The results suggest that the superior in vitro and in vivo activities of SCH 56592, against aspergillus are related to its activity against CYP51. Another study investigated the in vitro activity of SCH 56592, itraconazole, fluconazole, amphotericin B, and 5- fluorocytosine against 268 clinical isolates of candida species. SCH 56592 was equivalent to itraconazole and greater than or equal to 8-fold more active than fluconazole. In another study, it was found that SCH 56592 was effective against murine pulmonary aspergillosis. Based on these studies, SCH 56592 has promising antigungal activity and warrants further in vitro and in vivo investigation. A multicenter, randomized, double-blind, Phase II study to evaluate the safety, tolerance and efficacy of multiple doses of SCH 56592 versus fluconazole in the treatment of oropharyngeal candidiasis in HIV-positive patients is being started. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 117 (abstract no. F103); Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 115 (abstracts no. F94, F87, FDA-00983] CLASSIFICATION CODE Antifungal [GMHC Treat Issues 1996] OTHER MAJOR USES SCH 56592 is the most powerful sterol biosynthesis inhibitor ever tested against trypanosoma cruzi and could be useful in the treatment of chagas disease in humans. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 117 (abstract no. F102)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: SCH 56592 has been shown to be very potent against Aspergillus, Candida, Cryptococcus and other opportunistic fungi both in vitro and in animal models. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 117 (abstract no. F103)] CHEMICAL/PHYSICAL DATA Molecular Formula: C37-H42-F2-N8-O4 [USPD 2000 p. 583] CHEMICAL/PHYSICAL DATA Molecular Weight: 700.33 [USPD 2000 p. 583] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 115] MANUFACTURERS 0000001199: Schering - Plough Research 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Professional Information (800)526-4099 REFERENCES AIDS/98927696. Nomeir AA, Kumari P, Loebenberg D, Cacciapuoti A, Hare R, Miller G, Sangekar S, Mahashabde S, Sequeira J, Vadino Wa. Bioavailability of SCH 56592, a new broad spectrum triazole antifungal agent, from various formulations. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:117 (abstract no. F103). AIDS/98927694. Wheat J, Bick C, Connolly P, Smedema M, Durkin M, Kohler S, Loebenberg D. Comparison of a new triazole, Schering 56592, with itraconazole and amphotericin B for treatment of murine histoplasmosis. Program abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:117 (abstract no. F101). AIDS/98927693. Lutz JE, Clemons KV, Stevens DA. Efficacy of SCH 56592 (SCH) in a murine model of systemic Coccidioidomycosis. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:117 (abstract no. F100). AIDS/98927692. Graybill J, Najvar L, Bocanegra R, Fothergill A, Luther M. Treatment of murine pulmonary Aspergillosis with SCH 56592 (SCH). Program Abstr Intersci Conf Antimicrob agents Chemother. 1996 Sep 15-18;:117 (abstract no.F99). AIDS/98927691. Patterson TF, Kirkpatrick WR. Mcatee RK, Loebenberg D. Efficacy of SCH 56592 in a rabbit model of invasive aspergillosis. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:116 (abstract no.F98). AIDS/98927686. Dupont B, Improvisi L, Dromer F. In vitro and in vivo activity of a new antifungal agent SCH 56592 (SCH). Program Abstr Intersci Conf Antimicrob agents Chemother. 1996 Sep 15-18;:116 (abstract no. F93). AIDS/98927684. Yarosh-Tomaine T, Munayyer H, Shaw KJ, Hare RS, Heimark L, Pramanik B, Greene JR. Studies on fungal resistance to SCH 56592. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:115 (abstract no. F91). AIDS/98927683. Oakley KL, Moore CB, Denning DW. In vitro activity of SCH-56592 against Aspergillus spp. And comparison with itraconazole and amphotericin B. Program Abstr Intersci Conf Antimirob Agents Chemother. 1996 Sep 15-18;:115 (abstract no. F90). AIDS/98927681. Law D, Denning DW. In vitro activity of Schering 56592, compared with fluconazole and itraconazole against Candida spp. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:115 (abstract no. F88). AIDS/98927680. Pfaller MA, Zerva L, Messer S, Jones R. Antifungal activity of a new triazole, SCH 56592, compared with four other antifungal agents tested against clinical isolates of Candida spp. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:115 (abstract no. F87). ENTRY MONTH 199801 LAST REVISION DATE 20000801 55 UNIQUE IDENTIFIER DRG-0291 NAME OF SUBSTANCE Lopinavir [USPD 2000 p. 420] REGISTRY NUMBER 192725-17-0 [USPD 2000 2000; p 420] STANDARD CHEMICAL NAME (1S-(1R*(R*),3R*,4R*))-N-(4-(((2,6-Dimethylph- enoxy)acetyl)amino)-3-h ydroxy-5-phenyl-1-(phenylmethyl)pentyl)tetrah- ydro-alpha-(1-methyleth yl)-2-oxo-1(2H)-pyrimidineacetamide [USPD 2000 2000; p 420] SYNONYMS component of Kaletra [U.S. Food and Drug Administration. FDA Talk Paper. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01036.html. Accessed 09/18/00.] PHARMACOLOGICAL ACTION Lopinavir has a tenfold greater activity against HIV-1 than ritonavir in vitro, and its activity is less affected by binding to serum proteins. However, oral administration of lopinavir to humans produces only low and transient levels of drug in the plasma. The drug is quickly and extensively metabolized by the cytochrome P-450 (CYP) enzymes. Monotherapy with lopinavir is not effectual due to its very low bioavailability and rapid clearance from the body. Because ritonavir has been shown to inhibit the CYP-mediated metabolism of other protease inhibitors when given concurrently, the effect of ritonavir on lopinavir was studied. A single coadministration of ritonavir with lopinavir produced a 77-fold enhancement of area-under-the curve (AUC) over a 24-hour period. Maximum serum concentration of lopinavir and duration over the antiviral 50% effective concentration (EC50) was also increased. This potent pharmacokinetic enhancement of lopinavir by ritonavir is the rationale for further study of this combination. (See Lopinavir/Ritonavir) [Antimicrob Agents Chemother 1998 Dec;42(12):3218-24] DISEASES STUDIED/TREATED Lopinavir is being developed for coadministration with low-dose ritonavir for the treatment of HIV infection. (See Lopinavir/Ritonavir) [Protocol ID: 285D ] CLASSIFICATION CODE Investigational - Antiretroviral [USPD 2000 2000; p 420] CLASSIFICATION CODE Investigational - Antiviral [USPD 2000 2000; p 420] CLASSIFICATION CODE Investigational - Protease inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lopinavir is a peptidomimetic substrate analogue that inhibits the activity of HIV protease. It is a chemical derivative of ritonavir, another protease inhibitor. [Protocol ID: ACTG A5014 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C37-H48-N4-O5 [USPD 2000 2000; p 420] CHEMICAL/PHYSICAL DATA Molecular Weight: 628.82 [USPD 2000 2000; p 420] CHEMICAL/PHYSICAL DATA Elemental Comp: C70.67%, H7.69%, N8.91%, O12.72% MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/99350240. Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, Yao Y, Surber B, Thomas S, Granneman GR. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction. Drug Metab Dispos. 1999 Aug;27(8):902-8. MED/99102138. Kumar GN, Jayanti V, Lee RD, Whittern DN, Uchic J, Thomas S, Johnson P, Grabowski B, Sham H, Betebenner D, Kempf DJ, Denissen JF. In vitro metabolism of the HIV-1 protease inhibitor ABT-378: species comparison and metabolite identification. Drug Metab Dispos. 1999 Jan;27(1):86-91. MED/99054868. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Norbeck DW, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998 Dec;42(12):3218-24. MED/99011455. Molla A, Vasavanonda S, Kumar G, Sham HL, Johnson M, Grabowski B, Denissen JF, Kohlbrenner W, Plattner JJ, Leonard JM, Norbeck DW, Kempf DJ. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology. 1998 Oct 25;250(2):255-62. MED/98362159. Carrillo A, Stewart KD, Sham HL, Norbeck DW, Kohlbrenner WE, Leonard JM, Kempf DJ, Molla A. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol. 1998 Sep;72(9):7532-41. Kempf D, Xu Y, Brun S, King M, Mo H, Real K, Bernstein B, Hertogs K, Larder B, Molla A, Japour A, Sun E, et al. Baseline genotype and phenotype do not predict response to ABT-378/ritonavir in PI-experienced patients at 24 and 48 weeks. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2; 7th (abstract no. 731). Available at: http://www.retroconference.org/2000/abstracts- /731.htm. Accessed 09/18/00. Deeks S, Brun S, Xu Y, Real K, Benson C, Kessler H, Murphy R, Wheeler D, Hicks C, Eron J, Feinberg J, Gulick R, Sax P, Stryker R, Riddler S, Thompson M, King M, Potthoff A, Hsu A, Bertz R, Molla A, Mo H, Kempf D, Japour A, Sun E. ABT-378/ritonavir (ABT-378/r) suppresses HIV RNA to <400 copies/ml in 84% of PI-experienced patients at 48 weeks. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2; 7th (abstract no. 532). Available at: http://www.retroconference.org/2000/abstracts- /532.htm. Accessed 09/18/00. Gulick R, King M, Brun S, Real K, Murphy R, Hicks C, Eron J, Thommes J, Thompson M, White C, Benson C, Albrecht M, Kessler H, Hsu A, Bertz R, Kempf D, Sun E, Japour A. ABT-378/ritonavir (ABT-378/r) in antiretroviral naive HIV+ patients: 72 weeks. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2; 7th (abstract no. 515). Available at: http://www.retroconference.org/2000/abstracts- /515.htm. Accessed 09/18/00. AIDS/20711360. Mo H, Chernyavskiy T, Lu L, Kohlbrenner W, Sun E, Kempf D, Molla A. Multiple pathways to resistance to ABT-378 observed by in vitro selection. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:89 (abstract no. 117). ENTRY MONTH 199801 LAST REVISION DATE 20000919 56 UNIQUE IDENTIFIER DRG-0290 NAME OF SUBSTANCE Tenofovir disoproxil fumarate [USPD 2000; p 696] STANDARD CHEMICAL NAME 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]metho- xy]- phosphinoyl]methoxy]propyl]adenine fumarate [Protocol ID: 283A ] PROTOCOL ID NUMBERS No longer recruiting FDA 283A PROTOCOL ID NUMBERS No longer recruiting FDA 283B PROTOCOL ID NUMBERS No longer recruiting FDA 283C PROTOCOL ID NUMBERS No longer recruiting FDA 283D PROTOCOL ID NUMBERS No longer recruiting FDA 283E PROTOCOL ID NUMBERS No longer recruiting FDA 283F PROTOCOL ID NUMBERS Recruiting FDA 283G PROTOCOL ID NUMBERS Recruiting FDA 283H PROTOCOL ID NUMBERS Recruiting FDA 285G PHARMACOLOGICAL ACTION MODE OF ACTION: PMPA (9-(2-phosphonylmethoxypropyl)adenine) is an acyclic nucleotide analogue which has shown significant efficacy in the prevention of SIV infection in macaques. In addition, treatment of chronically SIV infected animals with PMPA resulted in a 2-3 log drop in SIV RNA levels. Resistance has not been observed. Results of the first human trial with PMPA show viral load reductions of 1.1 log after one week, theoretically the most possible decline after one week of treatment. In order to improve the low oral bioavailability of PMPA, researchers evaluated a large number of potential prodrugs and selected bis [(isopropyloxycarbonyl)oxymethyl] PMPA as a clinical candidate. Bis(POC)PMPA was chemically stable in solution over a broad pH range and exhibited 30% oral bioavailability in dogs, with minimal toxicity in a five day repeat dose administration at 60 mg/kg/day of PMPA equivalents. Bis(POC)PMPA showed enhanced membrane permeability as evidenced in tissue culture by 100 x increased antiviral activity and increased intracellular concentrations of the triphophate analogue relative to PMPA. When evaluated in murine sarcoma virus infected SCID mice, oral administration of Bis(POC)PMPA resulted in significantly delayed tumor appearance. Bis(POC)PMPA is a promising agent for the treatment and prophylaxis of HIV infections. [AIDS Treat News p 104 (abstract no. 214); Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 104 (abstract no. 214)] CLASSIFICATION CODE Investigational - Acyclic nucleoside phosphonate analog [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CLASSIFICATION CODE Investigational - Antiretroviral [USPD 2000; p 696] CLASSIFICATION CODE Investigational - Nucleotide reverse transcriptase inhibitor [USPD 2000; p 696] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Bis [(isopropyloxycarbonyl)oxymethyl] is a prodrug of the antiretroviral agent (9-(2-phosphonylmethoxyprophyl)adenine) (PMPA). It makes PMPA orally more readily available. [AIDS Treat News p 3] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H30-N5-O10-P.C4-H4-O4 [USPD 2000; p 696] CHEMICAL/PHYSICAL DATA Molecular Weight: 635.52 [USPD 2000; p 696] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AIDS Treat News p 3] MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: James Rooney (415)572-6597 REFERENCES MED/97311522. Tsai CC, Follis KE, Beck TW, Sabo A, Bischofberger N, Dailey PJ. Effects of (R)-9-(2-phophonylmethoxypropyl)adenine monotherapy on chronic SIV infection in macaques. AIDS Res Hum Retroviruses. 1997 May 20;13(8):707-12. AIDS/97702542. James JS. PMPA--first human results. AIDS Treat News. 1997 Apr 18;(No 269):3, 6. AIDS/97926475. Bischofberger N, Naesens L, de Clercq E, Fridland A, Srinivas RV, Robbins BL, Arimilli M, Cundy K, Kim C, et al. Bis(POC)PMPA, an orally bioavailable prodrug of the antiretroviral agent PMPA. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:104 (abstract no. 214). AIDS/97926379. Merrill DP, Manion DJ, Walker BD, Hirsch MS. Drug susceptiblities of HIV-1 clinical isolates to (R)PMPA in vitro. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:93 (abstract no. 155). MED/96193652. Balzarini J, Aquaro S, Perno CF, Witvrouw M, Holy A, De Clercq E. Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)-adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopuri- ne against human immunodeficiency virus in different human cell systems. Biochem Biophys Res Commun. 1996 Feb 15;219(2):337-41. MED/96072971. Tsai CC, Follis KE, Sabo A, Beck TW, Grant RF, BischofbergerN, Benveniste RE, Black R. Prevention of SIV infection in macaques by (R)-9-(2-phophonymethoxypropyl)adenine [see comments]. Science. 1995 Nov 17;270(5239):1197-9. MED/94079379. Srinivas RV, Robbins BL, Connelly MC, Gong YF, Bischofberger N, Fridland A. Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates. Antimicrob Agents Chemother. 1993 Oct;37(100):2247-50. ENTRY MONTH 199712 LAST REVISION DATE 20010518 57 UNIQUE IDENTIFIER DRG-0289 NAME OF SUBSTANCE Hepatitis A Vaccine (Inactivated) [USP DI 2000; p. 1698] SYNONYMS Havrix [USP DI 2000; p. 1698] SYNONYMS Vaqta [USP DI 2000; p. 1698] PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5046s PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG P1008 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1006 PHARMACOLOGICAL ACTION Hepatitis A virus (HAV) is one of several hepatitis viruses that cause systemic infection with pathology in the liver. The predominant mode of transmission is person-to person via the fecal oral-route. In some developing countries, 90% of children are infected by age 5. In developed countries, infections are rare and occur more in adults, where the disease is more severe and more likely to be fatal. In the US, infection rates have increased from 9.2 per 100,000 in 1983 to 14.6 per 100,000 in 1989. The presence of antibodies to HAV confers protection against hepatitis A vaccine, inactivated, in healty adults, specific humoral antibodies against HAV were elicited in 96% of the subjects 1-month after vaccination. In other studies in which booster shots of the vaccine were given 6 month following the initial dose, 100% of the vaccines were seropositive 1 month after the booster dose. A study of the influence of HIV infection and vaccination schedule on the immunogenicity of hepatitis A vaccine (HAC) showed that seroconversion after two vaccinations occurred more frequently in HIV-negative men. Anti-HAV titler after two vaccinations was also significantly greater in HIV-negative men. HIV-positive men who responded to vaccination had significantly more CD4 cells at baseline than those who did not. The vaccine schedule did not affect response. Vaccination of susceptible patients against hepatitis A should be recommended early in HIV infection using the shorter course to encourage compliance. At present, duration of the protection afforded by the vaccine has not been established. [J Infect Dis 1997 Oct;176(4):1064-7; p 1064-7; PDR 1997; p 1805, 2663-5] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 1695] OTHER MAJOR USES Active immunization of persons, 2 years of age or older, against disease caused by hepatitis A. Primary immunization should be completed at least 2 weeks before expected exposure to hepatitis A. [PDR 1997; p 2663-5] SUBSTANCE INTERACTIONS Preliminary results indicate that the concomitant administration of a wide variety of other vaccines is unlikely ti interfere with hepatitis vaccine A, inactivated (Havrix). As with other intramuscular injections, the hepatitis vaccine should be given with caution to individuals on anticoagulant therapy. [PDR 1997; p 2663-5] ADVERSE EFFECTS During clinical trials involving more than 31,000 individuals, hepatitis A, inactivated (Havrix), has been well tolerated. The most frequent adverse effect reported by trial volunteers was injection-site soreness. Heasdache was reported by 14% of adults and 9% of children. [PDR 1997; p 2663-5] CONTRAINDICATIONS Contraindicated in people with known hypersensitivity to any component of the vaccine. [PDR 1997; p 2663-5] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Hepatitis A virus vaccine inactivated is a noninfectious, sterile suspension of a cell-culture adapted, attenuated strain of hepatitis A. After inactivation with formaldehyde and purification, it is absorbed onto an aluminum hydroxide adjuvant. [AHFS Drug Information 1997; p 2581] SUBSTANCE DELIVERY DATA DOSAGE FORM: 360, 720, or 1440 EL.U./0.5 mL in single dose vials. (Havrix).[EL.U or ELISA Units. Viral antigen activity is referenced to a standard using an enzyme-linked immunosorbent assay (ELISA)]. [PDR 1997; p 2663-5] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [PDR 1997; p 2663-5] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 2-8 c (36-47 F). Do not freeze. Discard product that has been frozen. Do not dilute to administer. [PDR 1997; p 2663-5] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES MED/97472343. Neilsen GA, Bodsworth, Watts N. Response to hepatitis A vaccination in human immunodeficiency virus-infected and -uninfected homosexual men. J Infect Dis 1997 Oct;176(4):1064-7 MED/97425672. Flehmig B, Staedele H, Xueref C, Vidor E, Zuckerman J, Zuckerman A. Early appearance of neutralizing antibodies after vaccination with an inactivated hepatitis A vaccine. J Infect 1997 Jul;35(1):37-40. MED/98034018. CDC sets interim strategy for hepatitis A control [news]. Am J Health Syst Pharm 1997 Mar 15;54(6):625. MED/97284068. Goilav C, Zuckerman J, Lafrenz M, Vidor E, Briantais P, Lauwers S, Ratheau C, Benichou G, Zuckerman A. Persistence of antibodies after inactivated hepatitis A vaccines in a comparative study [letter]. J Infect 1997 Mar;34(2):158. MED/97237442. Fujiyama S, Odoh K, Tanaka M, Kuramoto I, Tomita K. Evaluation of the timing of the booster injection after a primary vaccination against hepatitis A. J Gastroenterol Hepatol 1997 Feb;12(2):172-5 MED/97133527. Vidor E, Xueref C, BLondeau C, Bajard A, Francon A, Goudeau A, Peyron F, Brasseur P, Zuckerman A. Analysis of the antibody response in humans with a new inactivated hepatitis A vaccine. Biological 1996 Sep;24(3):235-42. MED/96189976. Bader TF. Hepatitis A vaccine [See comments in: Am Gastroentero; 1996 Aug;91(8): 1670-1]. MED/97111917. Carlsson U, Brudin L, Eliasson I, Hansson BG. Hepatitis A vaccination by intracutaneous low dose administration: a less expensive alternative. Scand J Infect Dis 1996;28(5):435-8. MED/97005143. Iwarson S. Immunisation against hepatitis A--active or passive? Infection 1996 Jan-Feb;24(1):2-4. MED/95348667. Hess G, Clemens R, Bienzle U, Schonfeld C, Schunck B, Bock HL. Immunogenicity and safety of an inactivated hepatitis A vaccine in anti-HIV positive and negative homosexual men. J Med Virol. 1995 May;46(1):40-2. ENTRY MONTH 199712 LAST REVISION DATE 20000801 58 UNIQUE IDENTIFIER DRG-0288 NAME OF SUBSTANCE Topotecan [USPD 1998; p. 747] REGISTRY NUMBER 119413-54-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1H-Pyrano(3',4':6,7)indolizino(1,2-b)quinolin- e-3,14(4H,12H)-dione, 10-((dimethylamino)methyl)-4-ethyl-4,9-dihydr- oxy-, (S)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Hycamtin [USP DI 2000; p. 3022] PROTOCOL ID NUMBERS No longer recruiting FDA 284A PHARMACOLOGICAL ACTION MODE OF ACTION: Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents realignment of these single strand breaks. Cytotoxicity of the substance is thought to be due to double strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I and DNA. Mammalian cells cannot efficiently repair these double strand breaks. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Binding of the drug to plasma proteins is about 35%. Topotecan undergoes reversible, pH-dependent hydrolysis of its lactone moiety. It is the lactone form that is pharmacologically active. At around pH 4 the lactone form is present, whereas the ring-opened form predominates at physiologic pH. About 30% of the dose is excreted in the urine and renal clearance is an important determinant of topotecan elimination. [PDR 1997; p 2665] DISEASES STUDIED/TREATED Non-Hodgkin's Lymphoma. [AmfAR Treat Dir 1997;8(3); p 190] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3018] OTHER MAJOR USES Studied in clinical trials of patients with metastatic ovarian carcinoma. [PDR 1997; p 2665] SUBSTANCE INTERACTIONS Interaction of topotecan with other concomitantly administered medications have not been formally investigated. In vitro studies using marker substrates known to be metabolized by human P450 enzymes of dihydropyrimidine dehydrogenase indicate that the activity of these enzymes were not inhibited by topotecan. Concomitant administration of G-CSF can prolong the duration of neutropenia. Myelosuppression was more severe when topotecan hydrochloride was given in combination with cisplatin. [PDR 1997; p 2665-6] ADVERSE EFFECTS The dose-limiting toxicity of topotecan is leukopenia. White blood cell count decreases with increasing topotecan dose. Bone marrow suppression (primarily neutropenia) is another does-limiting toxicity of topotecan. Neutropenia is not cumulative over time. Grade 4 thrombocytopenia occurred in 26% of patients, while severe anemia occurred in 40% of patients. Incidence of nausea was 77% and vomiting occurred in 58% of patients. Total alopecia occurred in 42% of patients. Grade 1 transient elevation in SGOT/AST and SGPT/ALT occurred in 5 % of patients. The drug may cause fetal harm when administered to pregnant women. [PDR 1997; p 2666] CONTRAINDICATIONS Contraindicated in patients who have a history of hypersensitivity to topotecan preparations or any of their ingredients. Should not be used in patients who are pregnant or breast-feeding, or those with severe bone marrow depression. [PDR 1997; p 2666] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Topotecan hydrochloride is a semisynthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity. [PDR 1997; p 2665] CHEMICAL/PHYSICAL DATA Molecular Formula: C23-H23-N3-O5.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 457.92 [USPD 1998; p. 747] CHEMICAL/PHYSICAL DATA Elemental Comp: C65.55%, H5.50%, N9.97%, O18.98% (base) [Merck Index 1996; p. 1629] CHEMICAL/PHYSICAL DATA Solubility: Hydrochloride is soluble in water. [PDR 1997; p 2665] SUBSTANCE DELIVERY DATA DOSAGE FORM: Hycamtin (topotecan hydrochloride) for injections is supplied in 4 mg (free base) single-dose vials. [PDR 1997; p 2667] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [PDR 1997; p 2667] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store vials protected from light at controlled temperature between 20-25 C (68-77 F). [PDR 1997; p 2667] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 REFERENCES MED/97466819. Gerrits CJ, de Jonge MJ, Schellens JH, Stoter G, Verweij J. Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development. Br J Cancer 1997;76(7):952-62. MED/97446301. Swisher EM, Mutch DG, Rader JS, Elbendary A, Herzog TJ. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997 Sep;66(3):480-6. MED/97377926. Gwyther S, Bolis G, Gore M, ten Bokkel Huinink W, Verweij J, Hudson IR, Despax R, Jimenez-Lacave A. Experience with independent radiological review during a topotecan trial in ovarian cancer. Ann Oncol 1997 May;8(5):463-8. MED/97388935. Kraut EH, Walker MJ, Staubus A, Gochnour D, Balcerzak SP. Phase II trial of topotecan in malignant melanoma. Cancer Invest 1997;15(4):318-20. MED/97291241. Zhang JL, Sharma PL, Li CJ, Dezube BJ, Pardee AB, Crumpacker CS. Topotecan inhibits human immunodeficiency virus type 1 infection through a topoisomerase-independent mechansim in a cell line with altered topoisomerase I. Antimicrob Agents Chemother 1997 May;41(5):977-81. MED/97339531. ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, Broom C, Scarabelli C, Davidson N, Spancynski M, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer [see comments in: J Clin Oncol 1997 Jun;15(6):2177-80]. J Clin Oncol 1997 Jun;15(6):2183-93. MED/97339529. Ozols RF. Treatment of recurrent ovarian cancer: increasing options--recurrent results [editorial; comment in J Clin Oncol 1997 Jun;15(6):2183-93]. J Clin Oncol 1997 Jun;15(6):2177-80. MED/97268177. Masson E, Zamboni WC. Pharmacokinetic optimisation of cancer chemotherapy. Effect on outcomes. Clin Pharmacokinet 1997 Apr;32(4):324-43. MED/97310591. Robert F, Soong SJ, Wheeler RH. A phase II study of topotecan in patients with recurrent head and neck cancer. Indentification of an active new agent. Am J Clin Oncol 1997 Jun;20(3):298-302. MED/97307007. Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, Giaccone G, Schaefer B, Wanders J, Verweij J. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997 May;15(5):2090-6. ENTRY MONTH 199710 LAST REVISION DATE 20000801 59 UNIQUE IDENTIFIER DRG-0287 NAME OF SUBSTANCE HIV p24/MF59 Vaccine [Protocol ID: 095 ] PROTOCOL ID NUMBERS No longer recruiting FDA 095 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 032 PHARMACOLOGICAL ACTION This vaccine preparation is built around p24 (capsid), the major core protein of HIV-1. It is derived from HIV's gag gene. The gag protein, and particularly its p24 component, is an important target of CD4+ and CD8+ T cell responses directed against HIV-1. Thus p24 is a candidate HIV-1 vaccine antigen that may enhance anti-HIV-1 cellular immunity in vaccine recipients. In this preparation, the p24 component is combined with an adjuvant (a substance included in a vaccine to enhance its immune-stimulating properties) called MF59. In mice this vaccine preparation induced class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) responses as well as antibodies to p24. Studies performed in guinea pigs and baboons showed that the p24/MF59 vaccine induced antibodies in both species. Toxicology studies for local, systemic, or mutagenic effects of the vaccine preparation revealed no significant toxicities. In an initial Phase I trial (1997), the p24/MF59 vaccine was administered to 30 healthy, HIV-1 uninfected human volunteers. Preliminary results showed no serious adverse events related to the vaccination. Serum antibodies specific to HIV-1 p24 antigen have been detected. Cellular immune responses in these volunteers have been evaluated; LPA results to date are negative. CTL results were negative in 10 tested volunteers. Additional studies to test this vaccine in healthy, HIV-1 seronegative adults are ongoing. Other ongoing clinical trials are testing the safety and effectiveness of the p24/MF59 preparation when given simultaneously with the recombinant canarypox ALVAC-HIV vCP205 preparation, or, mixed in MF59, with the recombinant subunit HIV-1 SF-2 rgp120 preparation and the ALVAC-HIV vCP205 vaccine. [Protocol ID: AVEG 032 ; Protocol ID: 095 ] DISEASES STUDIED/TREATED The vaccine is being tested in healthy volunteers to evaluate its safety and immunogenicity. [Protocol ID: 095 ] CLASSIFICATION CODE Vaccine [Protocol ID: 095 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: This p24 subunit vaccine is derived from the SF-2 isolate of HIV-1 and is expressed in genetically engineered Saccharomyces cerevisiae yeast organisms. The vaccine is combined with the adjuvant M59, an oil-in-water emulsion containing metabolizable oil squalene and the surfactants Tween 80 and Span 85. [Protocol ID: AVEG 032 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection in the deltoid muscle. [Protocol ID: 095 ] MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 REFERENCES ICA12/98395999. Moss R, Wallace MR, Lanza P, Giermakowska WK, Jensen FC, Theofan G, Chamberlin C, Richieri SP, Carlo. P24 antigen stimulated immune responses after treatment with an inactivated gp 120-depleted HIV-1 immunogen (REMUNE) in HIV-1 seropositive subjects. Int Conf AIDS 1998;12:525 (abstract no. 31151). MED/98244601. Liu MA. Vaccine developments. Nat Med 1998 May;4(5 Suppl):515-9. MED/98162955. O'Hagan DT. Recent advances in vaccine adjuvants for systemic and mucosal administration. J Pharm Pharmacol 1998 Jan;50(1):1-10. AIDS/97926054. Barnett SW, Duliege AM, Sinangil F, Walker CM, Hansen L, Boggio K, Steimer KS. HIV vaccine efforts at Chiron: polynucleotide, protein subunit, and prime/boost approaches. 4th Conf Retro and Opportun Infect 1997 Jan 22-26:219 (abstract no. S30). ICA11/96921186. Schwartz DH, Arrango-Jaramillo S, Castillo R, Sridharan G, Clements ML. In vitro resistance to HIV in PBMC cultures from recently infected participants in HIV vaccine trials is CD8 dependent. Int Conf AIDS 1996 Jul 7-12;11(1):75 (abstract no. Mo.A.1117). AIDS/97920773. Fuller DH, Murphey-Corb M, Barnett S, Steimer K, Haynes J. Gene gun-based DNA immunization primes for the induction of vigorous immune responses in rhesus macaques when followed by a recombinant subunit or vaccinia boost. Conf Adv AIDS Vaccine Dev 1996 Feb 11-15:201 [Poster 81]. MED/96057688. Ott G, Barchfeld GL, Chernoff D, Radhakrishnan R, van Hoogevest P, Van Nest G. MF59. Design and evaluation of a safe and potent adjuvant for human vaccines. Pharm Biotechnol 1995;6:277-96. MED/95015893. Valensi JP, et al. Systemic cytokine profiles in BALB/c mice immunized with trivalent influenza vaccine containing MF59 oil emulsion and other advanced adjuvants. J Immunol 1994 Nov 1;153(9):4029-39. ENTRY MONTH 199709 LAST REVISION DATE 20000801 60 UNIQUE IDENTIFIER DRG-0286 NAME OF SUBSTANCE Terbinafine hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 78628-80-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Naphthalenemethanamine, N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-, (E)-, monohydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Lamisil [USP DI 2000; p. 2917] PROTOCOL ID NUMBERS No longer recruiting FDA 282A PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of action of terbinafine hydrochloride's antifungal activity has not been determined. The drug interferes with sterol biosynthesis, inhibiting the enzyme squalene monoxygenase. The resulting accumulation of squalene in the cells, and the decreased amount of sterols, especially ergosterol, are thought to contribute to the antifungal action. The drug may be fungicidal or fungistatic depending on concentration and the species tested. The drug is well absorbed following oral administration. Bioavailability of the drug in tablet form is about 40% as a result of first-pass metabolism. Peak plasma concentrations of 1 microgram/mL appear within 2 hours after a single 250 mg dose. In plasma, terbinafine is 90% bound to plasma proteins. No effect of gender on blood levels of the drug was detected. Prior to, terbinafine is extensively metabolized, but no metabolites have been identified that have antifungal activities similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine. Systemic absorption of terbinafine hydrochloride applied topically in 1% ointment form to various skin areas was highly variable. Maximum measured plasma concentration of terbinafine was 11.4 nanogram/mL. Urinary excretion accounted for up to 9% of the topically applied dose. [AHFS Drug Information 1997; p 104-5; PDR 1997; p 2393-5] DISEASES STUDIED/TREATED In clinical trial against fluconazole-resistant candidiasis. [AmfAR Treat Dir 1997;8(3); p 178] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 2915] OTHER MAJOR USES Terbinafine hydrochloride is used orally in the treatment of dermatophytic infections of toenails and fingernails (onychomycosis). It is used topically for the treatment of tinea pedis, t. corporis, and t. cruris caused by Epidermophyton floccosum, Trichophyton mentagrophytes or T. rubrum. [AHFS Drug Information 1997; p 105, 2704] SUBSTANCE INTERACTIONS In vitro, terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporin. In humans, terbinafine does not affect the clearance of antipyrine, digoxin and the antihistamine terfenadine. Terbinafine clearance is increased 100% by rifampin and decreased 33% by cimetidine. Clearance is unaffected by cyclosporine. [PDR 1997; p 2395] ADVERSE EFFECTS Adverse effects reported after oral use of terbinafine hydrochloride encompass GI symptoms (diarrhea, dyspepsia, abdominal pain), liver test abnormalities, rashes, urticaria, pruritus and taste disturbances. [PDR 1997; p 2395] CONTRAINDICATIONS Clearance of orally administered terbinafine may be decreased substantially in patients with renal impairment or in those with preexisting liver disease. The drug is not recommended in patients with such dysfunctions. [AHFS Drug Information 1997; p 106] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Terbinafine hydrochloride is a synthetic allylamine antifungal agent. [AHFS Drug Information 1997; p 104] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H25-N.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 327.9 [USP DI 2000; p. 2916] CHEMICAL/PHYSICAL DATA Melting Point: 195-198 C [Merck Index 1996; p. 1564] CHEMICAL/PHYSICAL DATA Elemental Comp: C86.55%, H8.65%, N4.81% (base) [Merck Index 1996; p. 1564] CHEMICAL/PHYSICAL DATA Solubility: The hydrochloride is freely soluble in methanol and methylene chloride, soluble in ethanol, and slightly soluble in ether. [PDR 1997; p 2394] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Terbinafine hydrochloride is a white to off-white fine crystalline powder. [PDR 1997; p 2393] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets containing 250 mg of terbinafine hydrochloride or cream form containing 1% of the drug. [PDR 1997; p 2394-5] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Orally in tablets or topically in cream form. [PDR 1997; p 2394-5] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store tablets below or at 25 C (77 F) in tight container. Protect from light. Store cream between 5 and 30 C (41 and 86 F). [PDR 1997; p 2394-5] MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (888)669-6682 REFERENCES MED/97046213. Sanglard D, Ischer F, Monod M, Bille J. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996 Oct;40(10):2300-5. MED/97058012. Chiritescu MM, Chiritescu ME, Scher RK. Newer systemic antifungal drugs for the treatment of onychomycosis. Clin Podiatr Med Surg. 1996 Oct;13(4):741-58. MED/96296376. Nandwani R, Parnell A, Youle M, Lacey CJ, Evans EG, Midgley J, Cartledge J, Hawkins DA. Use of terbinafine in HIV-positive subjects: pilot studies in onychomycosis and oral candidiasis. Br J Dermatol. 1996 Jun;134 Suppl 46:22-4: discussion 39. MED/96302588. Aly R, Berger T. Common superficial fungal infections in patients with AIDs. Clin Infect Dis. 1996 May; 22 Suppl 2: S128-32. MED/96159652. Cirioni O, Giacometti A, Balducci M, Burzacchini F, Scalise G. In-vitro activity of terbinafine, atovaquone and co-trimoxazole against Pneumocystis carinii [letter]. J Antimicrob Chemother. 1995 Oct;36(4):740-2. MED/94358244. Degreef HJ, DeDoncker PR. Current therapy of dermatophytosis. J Am Acad Dermatol. 1994 Sep; 31 (3 Pt 2):S25-30. MED/94085017. Schafer-Korting M. Pharmacokinetic optimisation of oral antifungal therapy. Clin Pharmacokinet. 1993 Oct;25(4):329-41. MED/90048735. Dupont B. [Treatment of mycoses and new antifungal agents]. Rev Prat. 1989 Sep 1;39(19):1688-94. ENTRY MONTH 199708 LAST REVISION DATE 20001106 61 UNIQUE IDENTIFIER DRG-0285 NAME OF SUBSTANCE Lamivudine/Zidovudine [Protocol ID: 280A ] SYNONYMS Combivir [USP DI 2000; p. 1888] PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS No longer recruiting FDA 238K PROTOCOL ID NUMBERS No longer recruiting FDA 238T PROTOCOL ID NUMBERS No longer recruiting FDA 264P PROTOCOL ID NUMBERS No longer recruiting FDA 280A PROTOCOL ID NUMBERS No longer recruiting FDA 280B PROTOCOL ID NUMBERS No longer recruiting FDA 280C PROTOCOL ID NUMBERS No longer recruiting FDA 280D PROTOCOL ID NUMBERS No longer recruiting FDA 307A PROTOCOL ID NUMBERS No longer recruiting FDA 308A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 388 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS Recruiting FDA 039F PROTOCOL ID NUMBERS Recruiting FDA 302C PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1012 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-01-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting FDA B009 PROTOCOL ID NUMBERS Suspended FDA 286B PROTOCOL ID NUMBERS Suspended FDA 286C PROTOCOL ID NUMBERS Suspended NIAID ACTG P1022 PROTOCOL ID NUMBERS Terminated NIAID ACTG 374 PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PHARMACOLOGICAL ACTION MODE OF ACTION: Intracellularly, both lamivudine and zidovudine are phosphorylated to their active 5'-triphosphate metabolites. Combinations of the two drugs (as in combivir) have synergistic antiretroviral activity. In patients receiving monotherapy with lamivudine or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients become resistant to lamivudine in 12 weeks. The combination therapy delayed the emergence of mutations conferring resistance to zidovudine, however HIV-1 strains resistant to both drugs have been isolated from patients after prolonged combination therapy. One combivor tablet is bioequivalent to one EPIVIR (150 mg lamivudine) plus on RETROVIR tablet (300 mg zidovudine) following single dose administration to fasting healthy subjects. The extent of absorption of the two drugs following administration of comivir with food was similar when compared to fasting healthy subjects. Systemic clearance of lamivudine is 0.33 L/tvkg and of zidovudine is 1.6 L/tvkg. A meta-analysis of the events in clinical trials was conducted to determine whether treatment with lamivudine/zidovudine was also associated with a clinical benefit. The combination treatment delays the progression of CDC B/C disease compared with control treatments. In another study the safety and efficacy of combination therapy was studied in antiretroviral-naive patients. This showed superior treatment effects compared with monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts, cellular viremia, and viral load measured. Observed changes were sustained to 48 weeks for patients continuing to receive combination therapy at week 24 showed improvements in CD4+ cell count and viral load to week 48. Mutation results suggested that mutations associated with zidovudine resistance may have developed more slowly over the first 24 weeks in patients receiving combination therapy. In contrast, mutations associated with lamivudine resistance appeared to develop rapidly, despite sustained antiviral treatment effect. CONCLUSIONS--The combination of lamivudine and zidovudine results in a potent and sustained antiviral effect in antiretroviral-naive patients that is superior to that observed with zidovudine monotherapy. [Glaxo Wellcome Inc Package Insert Sept 1997; p 1; AIDS 1997 Mar 15;11(4):477-83; p 477-83; JAMA 1996 Jul 10;276(2); p 118-25] DISEASES STUDIED/TREATED Lamivudine/zidovudine reduces HIV RNA and raises CD4 counts relative to control treatments. FDA approved the combination drug on 9/29/97 for the treatment of HIV infection. [AIDS 1997 Mar 15;11(4):477-83; p 477-83] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1888] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 624, 669] SUBSTANCE INTERACTIONS Co-administration of ganciclovir, interferon-alpha or other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. [Glaxo Wellcome Inc Package Insert Sept 1997; p 2] ADVERSE EFFECTS No statistically significant differences in incidence or severity of clincally manifested or laboratory-measured toxic effects were noted between patients on lamivudine/zidovudine treatment and those being treated with either drug alone. [JAMA 1996 Jul 10;276(2); p 118-25] CONTRAINDICATIONS Contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the product. Combivir is a fixed dose combination of lamivudine and zidovudine; it should not be co-administered with either drug. Combivir should be used with caution in patients who show bone marrow compromise. Reduction of the dosage of the combination is recommended in patients with impaired renal function. Zidovudine is excreted in breast milk. There is no relevant data available on combivir, but mothers should be instructed not to nurse their infants if they are receiving the combination drug. [Glaxo Wellcome Inc Package Insert Sept 1997; p 2] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Combivir tablets are combination tablets of lamivudine (EPIVIR, 3TC) and zidovudine (RETROVIR, AZT) two synthetic nucleoside analogs active against HIV. [Glaxo Wellcome Inc Package Insert Sept 1997; p 1] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Film-coated tablets containing 150 mg of lamivudine and 300 mg of zidovudine plus inactive ingredients. [Glaxo Wellcome Inc 1996 April; p 1] SUBSTANCE DELIVERY DATA DOSAGE FORM: Combivir tablets containing 150 mg of lamivudine and 300 mg of zidovudine, are white film-coated, modified-capsule shaped tablets, available in 60 tablets/bottle. [Glaxo Wellcome Inc Package Insert Sept 1997; p 2] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The recommended oral dose of combivir for adults and adolescents (at least 12 years of age) is one tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) twice daily. [Glaxo Wellcome Inc Package Insert Sept 1997; p 2] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 2 and 30 C (36 and 86 F). [Glaxo Wellcome Inc Package Insert Sept 1997; p 2] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97239104. Staszewski S, Hill AM, Bartlett J, Eron JJ, Katlama C, Johnson J, Sawyer W, McDage H. Reductions in HIV-1 disease progression for zidovudine/lamivudine relative to control treatments: a meta-analysis of controlled trials. AIDS. 1997 Mar 15;11(4):477-83. ICA11/97926878. Stazewski S, Bartlett I, Erin J, Katlama C, Johnson J, Hill AM. Reductions in HIV-1 disease progression for AZT/3TC relative to control treatments: a meta analysis. Int Conf AIDS. 1996 Jul 7-12;11(Program Supplement):21 (abstract no. Th.B.948). MED/96272951. Katlama C, Ingrand D, Loveday C, Clumeck N, Mallolas J, Stazewski S, Johnson M, Hill AM, Pearce G, McDade H. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group [see comments]. JAMA. 1996 Jul 10;276(2):118-25. MED/96272950. Staszewski S, Loveday C, Picazo JJ, Dellarnonica P, Skinhoj P, Johnson MA, Danner SA, Harrigan PR, Hill AM, Verity L, et al. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group [see comments]. JAMA. 1996 Jul 10;276(2):111-7. MED/96314090. Staszewski S, Miller V, Rehmet S, Stark T, De Cree J, De Brabander M, Peeters M, Andries K, Moeremans M, De Raeymakerk M, et al. Virological and immunological analysis of a triple combination pilot study with loviride, lamivudine and zidovudine in HIV-1-infected patients. AIDS. 1996 May;10(5):F1-7. MED/96173469. Staszewski S. Zidovudine and lamivudine: results of phase III studies. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 10 Suppl 1:S57. ENTRY MONTH 199708 LAST REVISION DATE 20000801 62 UNIQUE IDENTIFIER DRG-0284 NAME OF SUBSTANCE Fozivudine tidoxil [USPD 1998; p. 328] REGISTRY NUMBER 141790-23-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME (2RS)-2-(Decyloxy)-3-(dodecylthio)propyl hydrogen 3'-azido-3'-deoxy-5'-thymidylate [USPD 2000; p 324] PROTOCOL ID NUMBERS No longer recruiting FDA 277A PHARMACOLOGICAL ACTION MODE OF ACTION: Determination of the anti-HIV activity and cytotoxicity of the new anti-AIDS compound BM 21.1290 (Foxivudine tidoxil) in different in vitro cell systems indicated that BM 21.1290, AZT and DDI inhibit virus infection and propagation concentration independantly, as measured by RT activity, p24 core antigen concentration and infectious virus production. The IC50 values for BM 21.1290 ranged between 0.02-0.2 micromolar (15-150 ng/ml), dependent on the cell type studied, the HIV isolate used and the parameters for anti-HIV activity measured. Anti-HIV activity of BM 21.1290 was most pronounced in infected human T cells and PBLs. On the other side, BM 21.1290 was generally much less toxic to HIV-infected cells compared to AZT or DDI. This finding is in accordance with the lack of bone marrow toxicity of BM 21.1290 in vitro and in vivo. The results indicate that BM 21.1290 has a higher differential selectivity index in vitro in comparison to standard therapeutics. Evaluation of the antiviral activity of BM 21.1290 under prophylactic and therapeutic i.p. and p.o. treatment conditions in the retroviral murine Friend-leukemia-virus(FLV) animal model revealed a dose- and time-dependent reduction in virus-induced splenomegaly, reverse transcriptase titers in the plasma and a highly significant increase in survival time. The conjugate was also very well tolerated by different species, including mouse, rat, monkey, and human. Recently, in an one week oral clinical phase Ib study in HIV-1+ humans, BM 21.1290 in a dose dependent manner reduced the plasma virus load. After having successfully passed pharmacological/toxicological and clinical phase I development, BM 21.1290 has entered phase II efficacy studies in ARC/AIDS patients in January 1996. [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 64 (abstract no. Mo.A.1057); Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 92] CLASSIFICATION CODE Investigational - Antiviral [Protocol ID: 277A ] ADVERSE EFFECTS Very well tolerated by different species, including mouse, rat, monkey, and human. [USAN 1997; p 92 (abstract no.149); Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 92] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Thioetherlipid nucleotide conjugate potent with anti-HIV activity in different in vitro systems. [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 92 (abstract no. 149)] CHEMICAL/PHYSICAL DATA Molecular Formula: C35-H64-N5-O8-P-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 745.97 [USPD 1998; p. 328] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [USAN 1997; p 92 (abstract no.149); Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 92] MANUFACTURERS 0000004053: Boehringer Mannheim Corp 101 Orchard Ridge Dr Gaithersburg, MD 20878 Contact: Unspecified (800)628-2672 REFERENCES AIDS/97926567. Herrmann DB, Opitz HG, Kucera LS. Anti-AIDS drug in vivo. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:92 (abstract no.149). ICA11/96921127. Herrmann DB, Kucera LS, Zilch H, Mertens A, Opitz HG. BM 21.1290: in vitro evaluation of a potential new anti-AIDS compound. Int Conf AIDS. 1996 Jul 7-12;11(1):64 (abstract no. Mo.A.1057). ENTRY MONTH 199708 LAST REVISION DATE 20000801 63 UNIQUE IDENTIFIER DRG-0283 NAME OF SUBSTANCE Rifapentine [USPD 1998; p. 637] REGISTRY NUMBER 61379-65-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 275A PHARMACOLOGICAL ACTION MODE OF ACTION: The dose-response activity of rifabutin and the comparative activities of rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium avium complex (MAC) infection. Despite favorable in vitro susceptibility results, rifabutin and rifapentine had activities in the spleens against only two of the five MAC isolates. For these two MAC isolates, rifabutin was more active than rifapentine. Rifapentine may be a useful drug for the treatment of toxoplasmosis in immunocopromised individuals. Rifapentine has a long half-life, and has the potential to lengthen intermittent treatment for tuberculosis. It is believed that this long half-life may mean it can maintain a higher blood level and thereby maintain better effectiveness than rifabutin against fast-growing MAC organisms. [USAN 1997; p 234-7; AIDS Alert 1995 Nov;10(11); p 138-9; Antimicrob Agents Chemother 1996 Jun;40(6); p 138-9] DISEASES STUDIED/TREATED Prophylactic against Mycobacterium Avium Complex in AIDS patients with CD4 count less than or equal to 75/cubic mm. [USP DI 1997; p 3121] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 2677] CHEMICAL/PHYSICAL DATA Molecular Formula: C47-H64-N4-O12 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 877.05 [USPD 1998; p. 637] CHEMICAL/PHYSICAL DATA Melting Point: 179-180 C [Merck Index 1996; p. 1415] CHEMICAL/PHYSICAL DATA Elemental Comp: C64.37%, H7.36%, N6.39%, O21.89% [Merck Index 1996; p. 1415] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [USAN 1997; p 174] MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 REFERENCES MED/97070558. Moghazeh SL, Pan X, Arain T, Stover CK, Musser JM, Kreiswirth BN. Comparative antimycobacterial activities of rifampin, rifapentine, and KRM-1648 against a collection of rifampin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations. Antimicrob Agents Chemother. 1996 Nov;40(11):2655-7. MED/97127285. Mitchison DA. Modern methods for assessing the drugs used in the chemotherapy of mycobacterial disease. Soc Appl Bacteriol Symp Ser. 1996;25:72S-80S. MED/96338344. Araujo FG, Khan AA, Remington JS. Rifapentine is active in vitro and in vivo against Toxoplasma gondii. Antimicrob Agents Chemother. 1996 Jun;40(6):1335-7. MED/97299003. Kenny MT, Reynolds DL, Brackman MA, Dulworth JK. Comparison of biological and chemical assays for the quantitation of rifapentine in human plasma. Diagn Microbiol Infect Dis. 1997 Apr;27(4):107-11. MED/96163839. Grassi C, Peona V. New drugs for tuberculosis. Eur Respir J Suppl. 1995 Sep;20:714s-718s. AIDS/96700982. Researchers find new drugs to fight MAC. AIDS Alert. 1995 Nov;10(11):138-9. MED/95040297. Chapuis L, Ji B, Truffot-Pernot C, O'Brien RJ, Raviglione MC, Grosset JH. Preventive therapy of tuberculosis with rifapentine in immunocompetent and nude mice. Am J Respir Crit Care Med. 1994 Nov;150(5 Pt 1):1355-62. MED/94249992. Klemens SP, Grossi MA, Cynamon MH. Comparative in vivo activities of rifabutin and rifapentine against Mycobacterium avium complex. Antimicrob Agents Chemother. 1994 Feb;38(2):234-7. MED/92305504. Fattorini L, Hu CQ, Jin SH, Santoro C, Tsang AY, Mascellino MT, Mandler F, Orefici G. Activity of antimicrobial agents against Mycobacterium avium-intracellulare complex (MAC) strains isolated in Italy from AIDS-patients. Int J Med Microbiol Virol Parasitol Infect Dis. 1992 Apr;276(4):512-20. MED/92027610. Perronne C, Gikas A, Truffot-Pernot C, Grosset J, Vilde JL, Pocidalo JJ. Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobacterium avium complex within human macorphages. Antimicrob Agents Chemother. 1991 Jul;35(7):1356-9. ENTRY MONTH 199708 LAST REVISION DATE 20000801 64 UNIQUE IDENTIFIER DRG-0282 NAME OF SUBSTANCE L-743,872 [Protocol ID: 267A ] PROTOCOL ID NUMBERS Complete FDA 267A PROTOCOL ID NUMBERS Terminated FDA 267B PHARMACOLOGICAL ACTION MODE OF ACTION: Extensive in vitro susceptibility testing with L-743,872 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans and Aspergillus was conducted to determine minimum inhibitory and fungicidal concentrations. Susceptibility testing using panels of antifungal-resistant species of Candida and C. neoformans isolates showed L-743,872 had MFC values comparable to those against susceptible isolates. Serum studies using between 0% to 50% pooled human or mouse sera established that fungal susceptibility with L-743,873 was not significantly influenced by the presence of human or mouse sera. The intravenous pharmacokinetics of L-743,872 were investigated in mice, rats, rhesus monkeys and chimpanzees. In contrast to previous pneumocandins, this compound behaves consitently across species. Serum protein binding of L-743,872 was determined to be 97% in mouse and human serum. The compound exhibits a high affinity for human serum albumin and, additionally, at least two lipid components. Some measure of accumulation is predicted for all tissues. Dosage scaling for man was simulated by using a graphical comparison of circulatory levels in the chimpanzee vs. both rodent model species over a 24 hour treatment cycle. A planned, multicenter clinical study will evaluate the potency of different doses of L-743,872 compared to amphotericin B in people with oral and eosphageal candidiasis who have failed on fluconazole therapy (200 mg daily for 7 days), and the relative safety and efficacy of both. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 105 (abstract no. F32); Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 107 (abstract no. F44); BETA 1997 June] DISEASES STUDIED/TREATED In combination with other antifungal agents, being test against Cryptococcus neoformans infections. [Antimicrob Agents Chemother 1997 Feb;41(2); p 331-6] CLASSIFICATION CODE Antifungal [Protocol ID: 267A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: L-743872 is a water soluble cyclic lipopeptide 1,3 beta-D-glucan synthesis inibitor with proven efficacy as a parenteral agent in animal models of Pneumocystis carinii pneumonia and of disseminated candidiasis and aspergillosis. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 106 (abstract no. F40)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Parenteral [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 106 (abstract no. F4O)] MANUFACTURERS 0000003415: Merck Research Laboratories 126 East Lincoln Ave Rahway, NJ 07065 Contact: Carol Sable REFERENCES AIDS/98927664. Hajdu R, Pelak B, Sundelof J, Thompson R, Rosen H, Kropp H. Pharmacokinetics of L-743,872 in the mouse, rat, rhesus and chimpanzee. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:107 (abstract no. F44). AIDS/98927663. Najvar L, Graybill J, Montalbo E, Barchiesi F, Luther M. Evaluation of L-743,872 (872) in the treatment of murine histoplasmosis. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:107 (abstract no. F43). AIDS/98927662. Powles MA, Anderson J, Liberator P, Schmatz DM. Efficacy of semisynthetic pneumocandin analog L-743,872 against Pneumocystis carinii in murine models. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:107 (abstract no. F42). AIDS/98927660. Flattery AM, Abruzzo GK, Smith JG, Gill CJ, Rosen H, Kropp H, Bartizal K. Activity of pneumocandin L-743872 in a CD4+ T-cell deficient mouse model or oropharyngeal and gastrointestinal Candidiasis. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sept 15-18;:106 (abstract no. F40). AIDS/98927659. Najvar L, Fothergill A, Luther M, Graybill J. Efficacy of L-743,872 (872) in murine disseminated Candidiasis. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:106 (abstract no. F38). AIDS/98927657. Franzot SP, Casadevall A. In vitro synergy of pneumocandin L-743,872 with fluconazole and amphotericin B against Cryptococcus neoformans. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:106 (abstract no. F36). AIDS/98927651. Fothergill AW, Sutton DA, Rinaldi MG, Antifungal susceptibility testing of Merck L-743,872 against a broad range of fungi. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:105. (abstract no. F29). AIDS/98927649. Bouffard FA. Dropinski JF, Balkovec JM, Black RM, Hammond ML, Nollstadt KH, Dreikorn S. L-743,872, a novel antifungal lipopeptide: synthesis and structure-activity relationships of new aza-substituted pneumocandins. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:104 (abstract no. F27). AIDS/98927654. Bartizal K, Flattery A, Lynch L, Pacholok C, Gill CJ, Rosen H, Scott P, Kropp H. In vitro preclinical evaluation studies with pneumocandin antifungal L-743872. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:105 (abstract no. F32). MED/97173282. Franzot SP, Casadevall A. Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob Agents Chemother. 1997 Feb;41(2):331-6. ENTRY MONTH 199708 LAST REVISION DATE 20000801 65 UNIQUE IDENTIFIER DRG-0281 NAME OF SUBSTANCE Alitretinoin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 5300-03-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 9-cis-Retinoic acid [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 27 (abstract no Mo.B.432)] SYNONYMS Panretin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 271A PROTOCOL ID NUMBERS No longer recruiting FDA 272A PHARMACOLOGICAL ACTION MODE OF ACTION: 9-cis-Retinoic acid binds to different retinoid receptors than the all-trans retinoic acid. Sixty-three patients with biopsy-proven, multiple KS (Kapsoi's Sarcoma) lesions applied 0.05% or 0.1% ALRT1057 gel to selected index lesions 1-4 times daily. Selected untreated control lesions could be converted to treatment after 8 to 16 weeks. Response was evaluated by measuring area and elevation and supported by standardized serial photography. Partial response was defined using ACTG criteria applied to topical therapy as a complete flattening greater than or equal to 50% of raised lesions or greater than or equal 50% decrease in the sum of area. Topical ALRT1057 was well-tolerated with minimal perilesional irritation and no systemic absorption. Responses were seen in patients with a wide range of CD4 counts, including 4 with counts below 50/mm3. Responses were sustained with a median patient follow-up of 16 weeks (maximum 42 weeks). Only 4 of 28 lesions relapsed after a median of 12 weeks. ALRT1057 gel appears to be a safe and well-tolerated new therapy for KS which is capable of producing partial to complete resolution of lesions in patients with low CD4 counts. This the first topical therapy evaluated for KS, which lends itself to patient-controlled, conservative management in the early phases of disease. [AmfAR Treat Dir 1997;8(3); p 67; Int Conf AIDS 1996 Jul 7-12;11(1):18; p 27 (abstract no.Mo.B.432)] DISEASES STUDIED/TREATED Therapy for Kaposi's Sarcoma. [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 27 (abstract no Mo.B.432)] CLASSIFICATION CODE Antineoplastic [USPD 2000 p. 32] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE INTERACTIONS 9-cis-Retinoic acid and beta-human chorionic gonadotropin can induce remission of KS lesions. [J Int Assoc Physicians AIDS Care 1995 Jun;1(5)] ADVERSE EFFECTS Topical ALRT1057 was well-tolerated with minimal perilesional irritation and no systemic absorption. [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 27 (abstract no Mo.B.432)] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H28-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.05% and 0.1% gel. [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 27 (abstract no Mo.B.432)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical. [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 27(abstract no. Mo.B.432)] MANUFACTURERS 0000004054: Ligand Pharmaceuticals 10275 Science Center Drive San Diego, CA 92121 Contact: Susan Atkins (619)550-7687 MANUFACTURERS 0000004054: Ligand Pharmaceuticals 10275 Science Center Drive San Diego, CA 92121 Contact: Unspecified (619)550-7500 REFERENCES ICA11/96920939. Duvic M, Friedman-Kien AE, Galpin J, Miles SA, Looney DJ, Myskowski PL, Gill G, Truglia J, Yocum R. Phase I-II clinical trial supports safety and efficacy of ALRT1057 topical retinoid gel for Kaposi's sarcoma. Int Conf AIDS. 1996 Jul 7-12;11(1):27 (abstract no Mo.B.432). AIDS/96701082. Vitamin A type drug for Kaposi's Sarcoma. Treat Rev. 1995 Nov;(no 20):5. AIDS/96700645. Mascolini M. Oncologists scout new directions for KS and lymphoma therapies. J Int Assoc Physicians AIDS Care. 1995 Jun;1(5):10-4. ENTRY MONTH 199708 LAST REVISION DATE 20000801 66 UNIQUE IDENTIFIER DRG-0280 NAME OF SUBSTANCE Salmonella typhi CVD 908-HIV-1 LAI gp 120 (VVG 203) [Protocol ID: AVEG 028 ] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 028 PHARMACOLOGICAL ACTION MODE OF ACTION: HIV is known to enter the host at parenteral and mucosal sites and consequently, an effective vaccine should stimulate immunity at both routes of entry. One approach toward stimulating HIV-specific mucosal and systemic immunity is the use of candidate live oral Salmonella typhi vector vaccine, strain CVD 908, which has been shown to stimulate mucosal and systemic immunity in volunteers. Using recombinant DNA techniques, an expression cassette which comprises the 1pp promoter (P1pp) and sequences encoding recombinant gp120 (rgp120) was constructed. When the P1pp-rgp120 expression cassette is integrated into the chromosome of CVD 908 in the delta aroC allele, high levels of recombinant gp120 expression are observed. It is likely that effective immunity against HIV in humans will require immunization with multiple HIV antigens. Hence, a second expression cassette, encoding two additional HIV antigens with vaccine potential, p24 (a HIV-1 gap gene product) and Nef (a putative regulator of HIV-1 gene expression) has been constructed. It is planned to integrate the p24-Nef-encoding expression cassette into the aroD locus in the chromosome of CVD 908 delta aroC::rgp120 in a stable manner to produce a CVD 908-HIV vector vaccine that expresses multiple HIV antigens. High level expression of rgp120 in Salmonella vectors is necessary to stimulate a gp120-specific immune response in mice. Also, Salmonella::rgp120 stimulates a gp120-specific Th1 response in mice. This is the first report to describe the construction of a Salmonella::rgp120 vector vaccine that is immunogenic in mice. [Dev Biol Stand 1994;82; p 159-62; Vaccine 1995 Dec; 13(17); p 1697-705] DISEASES STUDIED/TREATED Anti-HIV vaccine [Vaccine 1995 Dec; 13(17); p 1697-705] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 028 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Using recombinant DNA techniques, an expression cassette, which comprises the 1pp promoter (P1pp) and sequences encoding recombinant gp120 (rgp120) was constructed. The preparation uses live oral Salmonella typhi vector vaccine, strain CVD 908, which has been shown to stimulate mucosal and systemic immunity in volunteers. [Dev Biol Stand 1994;82; p 159-62] MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 REFERENCES MED/97130053. Sizemore DR, Elsinghorst EA, Eck LC, Branstrom AA, Hoover DL, Warren RL, Rubin FA. Interaction of Salmonella typhi strains with cultured human monocyte-derived macrophages. Infect Immun. 1997 Jan;65(1):309-12. MED/96363710. Fouts TR, Tuskan RG, Chada S, Hone DM, Lewis GK. Construction and immunogenicity of Salmonella typhimurium vaccine vectors that express HIV-1 gp120. Vaccine. 1995 Dec; 13(17):1697-705. MED/96065464. Fouts TR, Lewis GK, Hone DM. Construction and characterization of a Salmonella typhi-based human immunodeficiency virus type 1 vector vaccine. Vaccine. 1995 Apr;13(6):561-9. MED/95046928. Hone DM, Lewis GK, Beier M, Harris A, McDaniels T, Fouts TR. Expression of human immunodeficiency virus antigens in an attenuated Salmonella typhi vector vaccine. Dev Biol Stand. 1994;82:159-62. ASM93/93291832. Branstrom A, Benson J, Aggarwal A, Franchini G, Sadoff J, Warren R. Expression of HIV-1 genes placed under the control of the lac promoter in pUC18 tested in various potential bacterial carrier strains. Abstr Gen Meet Am Soc Microbiol. 1993;93:437 (abstract no. T-30). MED/88073375. Tagliabue A, Nencioni L, Romano M, Villa L, De Magistris MT, Boraschi D. Antibacterial activity of lymphocytes armed with IgA. Adv Exp Med Biol. 1987;216A:511-6. MED/85263719. Kleinerman ES, Ceccorulli LM, Zwelling LA, Twilley T, Herberman RB, Jacob J, Gelmann EP. Activation of monocyte-mediated tumoricidal activity in patients with acquired immunodeficiency syndrome. J Clin Oncol. 1985 Jul; 3(7):1005-12. AIDS/97927146. Hone DM, Pascual DW, Wu S, Lewis GK. Induction of mucosal and systemic responses against HIV-1 gp120 in mice after oral immunization with a single dose of a Salmonella-HIV vector. Conf Adv AIDS Vaccine Dev. 1997 May 4-7;:182 (Poster 77). ASM95/96171221. Powell RJ, Wu S, Pascual DW, Van Cott J, McGhee J, Lewis GK, Hone DM. Oral immunization of mice with a live attenuated Salmonella vector expressing recombinant gp120 of HIV-1 on the surface of the vector, induces mucosal and systemic immunity against gp120. Abstr Gen Meet Am Soc Microbiol. 1995;95:294 (abstract no. E-79). ENTRY MONTH 199708 LAST REVISION DATE 20000801 67 UNIQUE IDENTIFIER DRG-0279 NAME OF SUBSTANCE Erythromycin [USPD 1998; p. 281] REGISTRY NUMBER 114-07-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS E-Base (base) [USP DI 2000; p. 1435] SYNONYMS E-Mycin (base) [USP DI 2000; p. 1435] SYNONYMS EES (ethylsuccinate salt) [USP DI 2000; p. 1436] SYNONYMS Ery-Tab (base) [USP DI 2000; p. 1435] SYNONYMS ERYC (base) [USP DI 2000; p. 1435] SYNONYMS EryPed (ethylsuccinate salt) [USP DI 2000; p. 1436] SYNONYMS Erythrocin (stearate salt) [USP DI 2000; p. 1438] SYNONYMS Ilosone (estolate) [USP DI 2000; p. 1435] SYNONYMS Ilotycin (base) (glucepatate salt) [USP DI 2000; p. 1435, 1437] SYNONYMS PCE Dispertab (base) [USP DI 2000; p. 1435] PROTOCOL ID NUMBERS No longer recruiting FDA 200G PHARMACOLOGICAL ACTION MODE OF ACTION: Erythromycin is usually bacteriostatic; however, in high concentrations or against highly susceptible organisms it may be bacteriocidal. It inhibits protein synthesis in susceptible organisms by binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of erythromycin is the same as that of other antibiotics such as oleandomycin, clindamycin or lincomycin. Erythromycin exerts its effects only against multiplying organisms. It penetrates the cell wall of gram-positive bacteria more readily than that of gram-negative bacteria. It is most active against gram-positive cocci and bacilli, but it also has some actibity against gram-negative organisms such as Haemophilus influenza. It is also active against Chlamydia and treponema. Orally administered erythromycin is readily absorbed. It diffuses readily into body fluids. Only low concentration are normally observed in the spinal fluid; passage of the drug across the blood-brain barrier increases in meningitis. The drug is concentrated in the liver and excreted in bile. Less than 5% is excreted in active form in the urine. [AHFS Drug Information 1997; p 2102; PDR 1997; p 430] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 1430] OTHER MAJOR USES Erythromycin is used against infections by (among others): streptococcus pyogenes, Alpha-hemolytic syreptococci, Staphylococcus aureus, Streptococcus pneumoniae, Mycoplasma pneumoniae, Hemophilus influenza, Chlamdia trachomatis, Treponema pallidum, Corynebacterium diphtheriae, Entamoeba histolytica, Listeria monocytogenes, Neisseria gonorrhoeae, Bordetella pertussis, organism causing Legionnaire's Disease. [PDR 1997; p 430-1] SUBSTANCE INTERACTIONS Concomitant use with high doses of theophylline may increase theophylline toxicity. Use of erythromycin with digoxin may cause high serum digoxin levels. Erythromycin may decrease clearance of triazolam and increase the pharmacological effects of the latter. Use of erythromycin with drugs metabolized by the cytochrome P450 system may be associated with elevations in serum erythromycin with carbamazepine, cyclosporine, hexobarbital and phenytoin. Cases of rhabdomyolysis have been reported in seriously ill patients receiving erythromycin and lovastatin. [PDR 1997; p 431] ADVERSE EFFECTS The most frequent side effects of oral erythromycin are gastrointestinal; they are dose-related. Symptoms of hepatic dysfunction and/or abnormal liver function tests may occur. There have been isolated reports of: transient CNS side effects, cardiac arrhythmias and other cardiovasuclar symptoms, reversible hearing loss, and allergic reactions. [PDR 1997; p 431] CONTRAINDICATIONS Contraindicated in patients with know hypersensitivities to it. Use of erythromycin may result in overgrowth of nonsusceptible organisms including fungi. [AHFS Drug Information 1997; p 2103] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Erythromycin is a macrolide antibiotic obtained from cultures of streptomyces erythraeus. [AHFS Drug Information 1997; p 2668] CHEMICAL/PHYSICAL DATA Molecular Formula: C37-H67-N-O13 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 733.94 [USPD 1998; p. 281] CHEMICAL/PHYSICAL DATA Melting Point: 135-140 C [Merck Index 1996; p. 626] CHEMICAL/PHYSICAL DATA Elemental Comp: C60.55%, H9.20%, N1.91%, O28.34% [Merck Index 1996; p. 625] CHEMICAL/PHYSICAL DATA Solubility: Solubility of approx. 1 mg/mL in water; soluble in alchohol. [AHFS Drug Information 1997; p 2668] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White or slightly yellow, odorless, bitter crystalline powder. [AHFS Drug Information 1997; p 2668] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg capsules, 250 mg, 333mg and 500 mg delayed release tablets, 2% ophthalmic ointment, 2% topical gel, 2% ointment, 1.5% and 2% solution. [AHFS Drug Information 1997; p 231, 2103, 2669] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Orally, topically. [AHFS Drug Information 1997; p 231, 2103, 2669] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be stored at 15-30 C (59-86 F). [AHFS Drug Information 1997; p 230, 2102, 2668] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001092: Barr Laboratories Inc 2 Quaker Rd / PO Box D-2900 Pomona, NY 10970 Contact: Unspecified (800)633-9110 MANUFACTURERS 0000005218: Knoll Pharmaceutical Co 3000 Continental Drive North Mount Olive, NJ 078281234 Contact: Unspecified (914)362-1100 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)526-0221 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)633-9110 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Unspecified (800)223-0432 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/97318713. Young H, Moyes A, McMillian A. Azithromycin and erythromycin resistant Neisseria gonorrhoeae following treatment with azithromycin. Int J STD AIDS. 1997. May;8(50:299-302. MED/97054988. Yau TH, Butrus SI. Presumed bilateral herpes zoster ophthalmicus in an AIDS patient: a case report. Cornea. 1996 Nov;15(6):633-4. MED/97069023. Nakagawa M, Nakahara K, Maruyama Y, Kawabata M, Higuchi I, Kubota H, Izumo S, Arimura K, Osame M. Therapeutic trials in 200 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. J Neurovirol. 1996 Oct;2(5):345-55. MED/97008636. Chang AD, Drachenberg CI, James SP. Bacillary angiomatosis angiomatosis associated with extensive esophageal polyposis: a new mucocutaneous manifestation of acquired immunodeficiency disease (AIDS). Am J Gastroenterol. 1996 Oct;91(10):2220-3. MED/97081329. Schmidt HU, Kaliebe T, Poppinger J, Buhler C, Sander A. Isolation of Bartonella quintana from an HIV-positive patient with bacillary angiomatosis. Eur J Clin Microbiol Infect Dis. 1996 Sep;15(9):736-41. MED/97050104. Ross JD, Crean A, McMillian A. Efficacy of anti-chlamydial therapy with oxytetracycline and erythromycin. Int J STD AIDS. 1996 Aug-Sep;7(5):373-4. MED/96260596. Barrio J, Lecona M, Hernanz JM, Sanchez M, Gurbindo MD, Lazaro P, Barrio JL. Rosacea-like demodicosis in an HIV-positive child. Dermatology. 1996;192(2):143-5. MED/96245961. Eden CG, Marker A, Pryor JP. Human immunodeficiency virus-related bacillary angiomatosis of the penis. Br J Urol. 1996 Feb;77(2):323-4. MED/97059723. Kimani J, Bwayo JJ, Anzala AO, MacLean I, Mwatha A, Choudri SH, Plummer FA, Ronald AR. Low dose erythromycin regimen for the treatment of chancroid. East Afr Med J. 1995 Oct;72(10):645-8. MED/96292823. Ramirez Ramirez CR, Saavedra S, Ramirez Ronda c. Bacillary angiomatiosis: microbiology, histopathology, clinical presentation, diagnosis and management. Bol Asoc Med P R. 1995 Jul-Sep;87(7-9):140-6. ENTRY MONTH 199707 LAST REVISION DATE 20000801 68 UNIQUE IDENTIFIER DRG-0278 NAME OF SUBSTANCE Bupivacaine hydrochloride [USPD 1998; p. 115] REGISTRY NUMBER 14252-80-3 [USPD 1998] STANDARD CHEMICAL NAME 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Marcaine [USP DI 2000; p. 160] SYNONYMS Sensorcaine [USP DI 2000; p. 160] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 031 PHARMACOLOGICAL ACTION MODE OF ACTION: Local anesthetics like bupivacaine hydrochloride block the generation and the conduction of nerve impulses. Clinically the order of the loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Systemic absorption produces effects on the cardiovascular system. Following systemic absorption, local anesthetics can produce CNS stimulation, depression or both. The rate of systemic absorption depends on total dose, concentration of the drug, route of administration, vascularity of the injection site, and presence or absence of epinephrine in the anesthetic solution. Bupivacaine has a long duration of action. Onset of anesthesia following 0.25% or 0.5% solution in epidural, including caudal block and peripheral or sympathetic nerve block, occurs in about 4-17 minutes and lasts from 3-7 hours. After epidural or caudal administration of 125 or 150 mg of bupivacaine hydrochloride, peak plasma concentrations of 0.45-1.25 microgram/mL have been demonstrated. The elimination half-life of bupivacaine hydrochloride is 1.5-5.5 hours in adults. It is principally metabolized to pipecolylxylidene (PPX) by N-dealkylation probably in the liver. It is excreted in the urine as small amounts of PPX, unchanged drug (5%), and other metabolites as yet unidentified. [PDR 1997; p 2446; AHFS Drug Information 1997; p 2493-4] CLASSIFICATION CODE Anesthetic [USP DI 2000; p. 154] OTHER MAJOR USES Used for infiltration anesthesia and for peripheral, sympathetic, nerve, and epidural (including caudal) block anesthesia. [AHFS Drug Information 1997; p 2494] SUBSTANCE INTERACTIONS Administration of local anesthetic solutions containing epinephrine or norepinehrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Some commercially available formulations of bupivacaine hydrochloride contain metabisulfite. The latter may cause severe allergic reactions in susceptible individuals. [PDR 1997; p 2446] ADVERSE EFFECTS The most commonly encountered acute adverse reactions with bupivacaine hydrochloride are related to the central nervous and cardiovascular systems. These effects are generally dose-related and are due to high plasma levels or unintentional intravascular or subarachnoid injection of the drug. Neurological effects, following epidural or caudal anethesia, may include such effects as spinal block of varying magnitude, urinary retention, fecal and urinary incontinence and loss of perineal sensation and sexual function. [PDR 1997; p 2448] CONTRAINDICATIONS Contraindicated in patients with a known hypersensitivity to the bupivacaine hydrochloride, to any local anesthetic agent of the amide type or to other components of the bupivacaine solutions. [PDR 1997; p 555] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Bupivacaine hydrochloride is a local anesthetic of the amide type with a long duration of action. It is available commercially in sterile water solution. It is also available with epinephrine or epinephrine bitartrate. [AHFS Drug Information 1997; p 2493] CHEMICAL/PHYSICAL DATA Molecular Formula: C18-H28-N2-O.H-Cl.H2-O [USPD 1998; p. 115] CHEMICAL/PHYSICAL DATA Molecular Weight: 342.91 [USPD 1998; p. 115] CHEMICAL/PHYSICAL DATA Elemental Comp: C74.96%, H9.78%, N9.71%, O5.55% (base) [Merck Index 1996; p. 246] CHEMICAL/PHYSICAL DATA Solubility: The hydrochloride monohydrate is soluble in water or alcohol, and slightly soluble in acetone, chloroform or ether. [Merck Index 1996; p 246] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: The hydrochloride monohydrate is a white crystalline powder. [PDR 1997; p 2446] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.25%, 0.5%, 0.75% aqueous solutions; 0.75% in 8.25 dextrose solution; 0.25% or 0.75% solutions with epinephrine bitartrate (1:200,00 of epinephrine). [AHFS Drug Information 1997; p 2494-5] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Parenteral injection. [AHFS Drug Information 1997; p 2494-5] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Solutions should be stored at 15-30 C (59-86 F). [PDR 1997; p 557] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000004004: Apollon Inc One Great Valley Parkway Malvern, PA 19355 Contact: Dr Richard Ginsberg (610)647-9452 MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Unspecified (800)633-9110 REFERENCES MED/97366403. Stevens RA, Frey K, Liu SS, Kao TC, Mikat-Stevens M, Beardsley D, Holman S, White JL. Sympathetic block during spinal anesthesia in volunteers using lidocaine, tetracaine, and bupivacaine. Reg Anesth. 1997 Jul-Aug;22(4):325-31. MED/97377402. Leonard M, Moore L, Algozzine R, Gregorino J, Giles B. Recovery times from subarachnoid blocks using bupivacaine hydrochloride and tetracaine hydrochloride with and without epinephrine. AANA J. 1997 Jun;65(3):260-4. MED/97346497. Rucci FS, Barbagli R, Pippa P, Boccaccini A. The optimal dose of local anaesthetic in the orthogonal two-needle technique. Extent of sensory block after the injection of 20, 30 and 40 mL of anaesthetic solution. Eur J Anaesthesiol. 1997 May;14(3):281-6. MED/97273190. Meyer RJ. Antimicrobial properties of bupivacaine [letter]. Anaesth Intensive Care. 1997 Apr;25(2):200. MED/97295136. Mikawa K, Akamatsu H, Nishina K, Shiga M, Maekawa N, Obara H, Niwa Y. Inhibitory effect of local anaesthetics on reactive oxygen species production by human neutrophils. Acta Anaesthesiol Scand. 1997 Apr;41(4):524-8. MED/97272387. Abbott PJ Jr, Sullivan G. Cardiovascular toxicity following preincisional intra-articular injection of bupivacaine [letter]. Arthroscopy. 1997 Apr;13(2):282. MED/97037973. Myers KG, George RJ. Painful neuropathy of the lateral cutaneous nerve of the thigh in patients with AIDS: successful treatment by injection with bupivacaine and triamcinolone [letter]. AIDS. 1996 Sep;10(11):1302-3. MED/96432872. Collazos J, Mayo J, Martinez E, Callejo A, Blanco I. Celiac plexus block as treatment for refractory pain related to sclerosing cholangitis in AIDS patients. J Clin Gastroenterol. 1996 Jul;23(1):47-9. ENTRY MONTH 199707 LAST REVISION DATE 20001106 69 UNIQUE IDENTIFIER DRG-0277 NAME OF SUBSTANCE Albendazole [USPD 1998; p. 28] REGISTRY NUMBER 54965-21-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Carbamic acid, (5-(propylthio)-1H-benzimidazol-2-yl)-, methyl ester [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Albenza [USP DI 2000; p. 40] PROTOCOL ID NUMBERS No longer recruiting FDA 274A PHARMACOLOGICAL ACTION MODE OF ACTION: Causes degenerative alterations in the tegument and intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. This leads to impairment in the uptake of glucose by the larval and adult stages of the susceptible parasites and depletes their glycogen stores. Due to diminished energy production the parasite is immobilized and eventually dies. Albendazole itself is poorly absorbed from the GI tract and concentrations in plasma are negligible or undetectable. However, prior to reaching systemic circulation it is rapidly converted to the sulfoxide - its primary active metabolite--in the liver. Oral bioavailability is enhanced when the drug is administered with a fatty meal. Maximal plasma concentration of the sulfoxide averages 1.31mcg/mL 2 to 5 hours after administration of a 400 mg dose. Terminal elimination of the sulfoxide ranges from 8 to 12 hours. The sulfoxide is further metabolized in the liver to albendazole sulfone and other oxidation products. Urinary excretion of the sulfoxide is less than 1 %. Billiary elmination presumably accounts for a portion of the elimination. [USP DI 1997; p 29; PDR 1997; p 2629] DISEASES STUDIED/TREATED Under investigation for treatment of microsporidiosis. [AmfAR Treat Dir 1997;8(3); p 67] CLASSIFICATION CODE Anthelmintic [USP DI 2000; p. 36] OTHER MAJOR USES Active antihelmintic against: ascariasis, capillariasis, enterobiasis, hookwork infection, hydatid disease, neurocysticercosis (caused by pork tapeworm), strongyloidiasis, taeniasis, trichostrongyliasis, and trichuriasis. [USP DI 1997; p 29] SUBSTANCE INTERACTIONS Steady state through concentrations of albendazole sulfoxide were about 56% higher when coadministered with dexamethasone. Coadministration of praziquantel or cimetidine also increased plasma concentrations of the sulfoxide. [PDR 1997; p 2629] ADVERSE EFFECTS Adverse events differ between hydatid disease and neurocysticercosis. Abnormal liver function tests and abdominal pain were rare but somewhat more frequent under the former condition. [PDR 1997; p 2629] CONTRAINDICATIONS Risk-benefit should be considered in case of hepatic impairment or hypersensitivity to albendazole. [USP DI 1997; p 29-30] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Orally administered broad-spectrum antihelmintic. [PDR 1997; p 2629] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H15-N3-O2-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 265.34 [USPD 1998; p. 28] CHEMICAL/PHYSICAL DATA Melting Point: 208-210 C [Merck Index 1996; p. 39] CHEMICAL/PHYSICAL DATA Elemental Comp: C54.32%, H5.70%, N15.84%, O12.06%, S12.09% [Merck Index 1996; p. 39] CHEMICAL/PHYSICAL DATA Solubility: Soluble in dimethylsulfoxide and strong acids and bases. Slightly soluble in methanol, chloroform, ethyl acetate and acetonitrile. Practically insoluble in water. [PDR 1997; p 2629] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white powder. [PDR 1997; p 2629] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (200 mg). [PDR 1997; p 2631] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [USP DI 1997; p 31] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 20-25 C (68-77 F). [PDR 1997; p 2631] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 REFERENCES MED/97160925. Weber R, Deplazes P, Flepp M, Mathis A, Baumann R, Sauer B, Kuster H, Luthy R. Cerebral microsporidiosis due to Encephalitozoon cuniculi in a patient with human immunodeficiency virus infection. N Engl J Med. 1997 Feb 13;336(7):474-8. MED/97052552. Field AS, Marriott DJ, Milliken ST, Brew BJ, Canning EU, Kench JG, Darveniza P, Harkness JL. Myositis associated with a newly described microsporidian, Trachipleistophora hominis, in a patient with AIDS. J Clin Micorbiol. 1996 Nov;34(11):2803-11. MED/97037972. Dionishio D, Sterrantino G, Meli M, Leoncini F, Orsi A, Nicoletti P. Treatment of isosporiasis with combined albendazole and ornidazole in patients with AIDS [letter]. AIDS. 1996 Sep;10(11):1301-2. MED/96404994. Rigano R, Profumo E, Teggi A, Siracusano A. Production of IL-5 and IL-6 by peripheral blood mononuclear cells (PMBC) from patients with Echinococcus granulosus infection. Clin Exp Immunol. 1996 Sep;105(3):456-9. MED/96320334. Rossi RM, Wanke C, Federman M. Microsporidian sinusitis in patients with the acquired immunodeficiency syndrome. Laryngoscope. 1996 Aug;106(8):966-71. MED/96356947. Kelly P, Lungu F, Keane E. Albendazole may reduce diarrhea in HIV patients. Nurs Times. 1996 May 22-28;92(21):12-3. MED/96249612. Didier ES, Rogers LB, Brush AD, Wong S, Traina-Dorge V, Bertucci D. Diagnosis of disseminated microsporidian Encephalitozoon hellem infection by PCR-Southern analysis and successful treatment with albendazole and fumagillin. J Clin Microbiol. 1996 Apr;34(4):947-52. MED/97224644. Brasil P, Sodre FC, Cuzzi-Maya T, Gutierrez MC, Mattos H, Moura H. Intestinal microsporidiosis in HIV-positive patients with chronic unexplained diarrhea in Rio de Janeiro, Brazil: diagnosis, clinical presentation and follow-up. Rev Inst Med Trop Sao Paulo. 1996 Mar-Apr;38(2):97-102. MED/97005700. Corcoran GD, Isaacson JR, Daniels C, Chiodini PL. Urethritis associated with disseminated microsporidiosis: clinical response to albendazole. Clin Infect Dis. 1996 Mar;22(3):592-3. MED/96197785. Joste NE, Rich JD, Busam KJ, Schwartz DA. Autopsy verification of Encephalitozoon intestinalis (microsporidiosis) eradication following albendazole therapy. Arch Pathol Lab Med. 1996 Feb;120(2):199-203. ENTRY MONTH 199707 LAST REVISION DATE 20001107 70 UNIQUE IDENTIFIER DRG-0276 NAME OF SUBSTANCE APL 400-047 [Protocol ID: AVEG 031 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 033 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 031 CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 031 ] MANUFACTURERS 0000004004: Apollon Inc One Great Valley Parkway Malvern, PA 19355 Contact: Dr Richard Ginsberg (610)647-9452 ENTRY MONTH 199707 LAST REVISION DATE 20000801 71 UNIQUE IDENTIFIER DRG-0275 NAME OF SUBSTANCE Cyclosporine [USPD 1998; p. 203] REGISTRY NUMBER 59865-13-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Cyclo(((E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(m- ethylamino)-6-octenoyl) -L-2-aminobutyryl-N-methylglycyl-N-methyl-L-l- eucyl-L-valyl-N-methyl- L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-- N-methyl-L-leucyl-N-met hyl-L-valyl) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Neoral [USP DI 2000; p. 1163] SYNONYMS Sandimmune [USP DI 2000; p. 1163] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 334 PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of action of cyclosporine is unknown. Experimental evidence suggests that its effectiveness is due to specific and reversible inhibition of immunocompetent lymphocytes in the G0 or G1 phase of the cell cycle. Cyclosporine also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor. Cyclosporine does not cause bone marrow suppression. Absorption from the GI tract is incomplete and variable. Peak concentrations (Cmax) in blood and plasma are achieved in 3.5 hours. Cmax is approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood. In blood distribution is concentration-dependent; 33%-97% in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. Disposition from blood is biphasic with a terminal half-life of ca. 19 hours. Elimination is primarily biliary with only 6% of the dose excreted in the urine. Cyclosporine is extensively metabolized but there is no major metabolic pathway. [PDR 1997; p 2416] DISEASES STUDIED/TREATED Study of immune activaton and HIV expression in early HIV disease. [Protocol ID: ACTG 334 ] CLASSIFICATION CODE Antipsoriatic [USP DI 2000; p. 1163] CLASSIFICATION CODE Antirheumatic [USP DI 2000; p. 1163] CLASSIFICATION CODE Immunosuppressant [USP DI 2000; p. 1163] CLASSIFICATION CODE Investigational - Viral Packaging Inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogenic transplants. [PDR 1997; p 2419] SUBSTANCE INTERACTIONS Careful monitoring of renal function should be practiced when cyclosporine is used with nephrotoxic drugs. Drugs that exhibit such nephrotoxic synergy are: gentamycin, tobramycin, vancomycin, amphotericin B, ketoconazole, melphalan, cimetidine, ranitidine, diclofenac, trimethoprim with sulfamethoxazole, azapropazone. Since cyclosporine is extensively metabolized by the liver, other drugs that affect hepatic microsomal enzymes, and particularly the cytochrome P-450 system, may influence the circulating levels of cyclosporine. Substances know to inhibit these enzymes will increase cyclosporine levels, while substances that are inducers of cytochrome P-450 activity will increase hepatic metabolism and thereby decrease cyclosporine levels. Reduced clearance of prednisolone, digoxin, and lovastatin has been observed when these drugs are administered with cyclosporine. Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur. During treatment with cyclosporine, vaccinations may be less effective, and the use of live vaccines should be avoided. [PDR 1997; p 2417] ADVERSE EFFECTS The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremors, hirsutism, hypertension, and gum hyperplasia. Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. [PDR 1997; p 2418] CONTRAINDICATIONS Risk-benefit of cyclosporine administration should be considered when the following medical conditions exist: chickenpox (existing or recent), herpes zoster, hepatic function impairment, hyperkalemia, infections, malabsorption, renal function impairment, sensitivity to cyclosporine. [USP DI 1997; p 1110] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Member of a group of nonpolar cyclic oligopeptides with immunosuppressant activity. Produced by Tolypocladium inflatum Gams and other Fungi imperfecti. [Merck Index 1996; p 464] CHEMICAL/PHYSICAL DATA Molecular Formula: C62-H111-N11-O12 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 1202.64 [USPD 1998; p. 203] CHEMICAL/PHYSICAL DATA Melting Point: 148-151 C [Merck Index 1996; p. 465] CHEMICAL/PHYSICAL DATA Solubility: Relatively insoluble in water and generally soluble in lipids and organic solvents. [AHFS Drug Information 1997; p 2862] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White prismatic needles from acetone. [Merck Index 1996; p 465] SUBSTANCE DELIVERY DATA DOSAGE FORM: Soft gelatine capsules (25 mg, 50 mg, or 100 mg); 50 mL bottles containing 100 mg of cyclosporine per mL; and for intravenous infusion, 5 mL sterile ampules containing 50 mg of cyclosporine per mL. [PDR 1997; p 2419] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, or i.v. infusion. [PDR 1997; p 2419] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: In the original unit-dose containers at temperatures below 86 F (30 C). [PDR 1997; p 2419] MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (888)669-6682 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 REFERENCES MED/97354217. St'astny M, Ulbrich K, Strohalm J, Rossmann P, Rihova B. Abnormal differentiation of thymocytes induced by free cyclosporine is avoided when cyclosporine bound to N-(2-hydroxypropyl)methacrylamide copolymer carrier is used. Transplantation. 1997 Jun 27;63(12):1818-27. MED/97331506. Lesnoni La Parola I, Masini C, Nanni G, Diociaiuti A, Panocchia N, Cerimele D. Kaposi's sarcoma in renal-transplant recipients: experience at the Catholic University in Rome, 1988-1996. Dermatology. 1997; 194(3):229-33. MED/97295475. Waldmann V, Kempf W, Burg G, Dummer R. Kaposi sarcoma in cyclosporin A therapy of actinic reticuloid. Hautarzt. 1997 Apr;48(4):462-5. MED/97184541. Braaten D, Ansari H, Luban J. The hydrophobic pocket of cyclophilin is the binding site for the human immunodeficiency virus type 1 Gag polyprotein. J Virol. 1997 Mar;71(3):2107-13. MED/97149469. Shapiro J, Lui H, Tron V, Ho V. Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: a clinical and immunopathologic evaluation. J Am Acad Dermatol. 1997 Jan;36(1):114-7. MED/97131728. Sun Y, Pinchuk LM, Agy MB, Clark EA. Nuclear import of HIV-1 DNA in resting CD4+ T cells requires a cyclosporin A-sensitive pathway. J Immunol. 1997 Jan 1;158(1):512-7. MED/97152503. Briggs CJ, Tozser J, Oroszlan S. Effect of cyclosporin A on the replication cycle of human immunodeficiency virus type 1 derived from H9 and Molt-4 producer cells. J Gen Virol. 1996 Dec;77(Pt 12):2963-7. MED/96400134. Franke EK, Luban J. Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction. Virology. 1996 Aug 1;222(1):279-82. MED/96357041. Braaten D, Aberham C, Franke EK, Yin L, Phares W, Luban J. Cyclosporine A-resistant human immunodeficiency virus type 1 mutants demonstrate that Gag encodes the functional target of cyclophilin A. J Virol. 1996 Aug;70(8):5170-6. MED/96433987. Andrada-Serpa MJ, Schor D, Araujo AQ, Rumjanek VM. Immunolgical features of HTLV-I myelopathy in Rio de Janeiro, Brazil, and in vitro effects of cyclosporin A. J Neurol Sci. 1996 Jul;139(1):7-14. ENTRY MONTH 199707 LAST REVISION DATE 20001107 72 UNIQUE IDENTIFIER DRG-0274 NAME OF SUBSTANCE Infant Formula [Protocol ID: ACTG 247 ] PROTOCOL ID NUMBERS Recruiting NIAID ACTG 247 DISEASES STUDIED/TREATED Under investigation as a caloric supplementation to improve growth in HIV-infected infants. [Protocol ID: ACTG 247 ] CLASSIFICATION CODE Nutritional supplement [USP DI 1998; p. 1642] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration. [Protocol ID: ACTG 247 ] MANUFACTURERS 0000003921: Abbott Laboratories / Ross Products Division 625 Cleveland Ave Columbus, OH 432151724 Contact: Ms Julia Byard (614)624-7006 ENTRY MONTH 199705 LAST REVISION DATE 20000801 73 UNIQUE IDENTIFIER DRG-0273 NAME OF SUBSTANCE Diphenhydramine hydrochloride [USPD 1998; p. 244] REGISTRY NUMBER 147-24-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2-(Diphenylmethoxy)-N,N-Dimethylethylamine hydrochloride [USPD 1998; p 244] SYNONYMS Benadryl [USP DI 2000; p. 3419] PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PHARMACOLOGICAL ACTION MODE OF ACTION: Antihistamines act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. They antagonize the effects of histamine such as urticaria and pruritus. The anticholinergic effects of antihistamines provide a drying effect on the nasal mucosa. Diphenyhdramine is well absorbed following oral administration. It undergoes first-pass metabolism through the liver and only 40-60% of the oral dose reaches systemic circulation. The drug appears in plasma within 15 minutes. Following single oral doses of 50 and 100 mg in healthy adults, peak plasma concentrations of 37-83 and 81-159 ng/mL respectively have been reported. In vitro, diphenhydramine is approximately 80-85% bound to plasma protein. Terminal elimination half-life appears to be 2.4-9.3 hours in healthly adults. Following a single 100-mg dose in healthy adults, about 50-70% is excreted in the urine within 4 days, almost completely as metabolites. [USP DI 1997; p 319; AHFS Drug Information 1997; p 20-1] CLASSIFICATION CODE Antidyskinetic [USP DI 2000; p. 343] CLASSIFICATION CODE Antiemetic [USP DI 2000; p. 343] CLASSIFICATION CODE Antihistamine [USP DI 2000; p. 343] CLASSIFICATION CODE Sedative-hypnotic [USP DI 2000; p. 343] OTHER MAJOR USES For amelioration of allergic reactions; temporary relief of cough caused by minor throat and bronchial irritation; treatment of nausea, vomiting, and/or vertigo associated with motion sickness; short-term management of insomnia. [AHFS Drug Information 1997; p 21] SUBSTANCE INTERACTIONS Additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.). MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines. [PDR 1998; p 2076] ADVERSE EFFECTS Adverse effects include the following, general: drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, and dryness of mouth, nose, and throat; cardiovascular system: hypotension, headache, palpitations, tachycardia, and extrasystoles; hematologic system: hemolytic anemia, thrombocytopenia, and agranulocytosis; nervous system: sedation, sleepiness, dizziness, disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomania, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, neuritis, and convulsions; GI system: epigastric distress anorexia, nausea, vomiting, diarrhea, and constipation; GU system: urinary frequency, difficult urination, urinary retention, and early menses; respiratory system: thickening of bronchial secretions, tightness of chest or throat and wheezing, and nasal stuffiness. The most frequent adverse effects include sedation, sleepiness, dizziness, disurbed coordination, epigastric distress, and thickening of bronchinal secretions. [PDR 1998; p 2076] CONTRAINDICATIONS Should not be used in neonates or premature infants, nursing mothers, patients with hypersensitivity to diphenhydramine hydrochloride and other antihistamine of similar chemical structure. Antihistamines should be used with considerable caution in patients with narrow-angle glaucoma, stenosing peptic ulcers, pyloroduodenal obstruction, sympotomatic prostatic hypertrophy or bladder-neck obstruction. [PDR 1998; p 2076] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Antihistamine with anticholinergic and sedative side effects. [PDR 1998; p 2075] CHEMICAL/PHYSICAL DATA Molecular Formula: C17-H21-N-O.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 291.82 [USPD 1998; p. 244] CHEMICAL/PHYSICAL DATA Melting Point: 166-170 C [Merck Index 1996; p. 561] CHEMICAL/PHYSICAL DATA Elemental Comp: C79.96%, H8.29%, N5.49%, O6.27% (base) [Merck Index 1996; p. 561] CHEMICAL/PHYSICAL DATA Solubility: Soluble in Water, alcohol, chloroform, and acetone. Very slightly soluble in benzene, ether. [Merck Index 1996; p 561] CHEMICAL/PHYSICAL DATA Stability: Slowly darkens when exposed to light. [Merck Index 1996; p 561] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, odorless, cyrstalline powder, slowly darken on exposure to air. Bitter taste. [AHFS Drug Information 1997; p 20; Merck Index 1996; p 561] SUBSTANCE DELIVERY DATA DOSAGE FORM: 25 mg and 50 mg capsules or tablets; 10mg/mL and 50mg/mL parenteral injections, 12.5mg/5ml elixir, 1% or 2% topical cream. [AHFS Drug Information 1997; p 22] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Usually oral; when that is not feasible, by deep IM, or preferably IV, injection. [AHFS Drug Information 1997; p 21] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be stored at 15-30 C (59-86 F) in light-resistant containers and protected from moisture. Freezing of liquid preparations should be avoided. [AHFS Drug Information 1997; p 20] MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)223-0432 MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES AIDS/95921074. Saavedra A, Rodriguez N, Rivera-Vazquez CR, Ramirez-Ronda CH, Bermudez RH. Trimethoprim-sulfamethoxazole (TMP-SMZ) desensitization in patients (PTS) with HIV infection who have non-life threatening allergy to TMP-SMZ. Initial report. Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:62. ICA9/93335041. Rich JD, Greineder D, Sullivan TJ, Kazanjian PH. Successful oral desensitization to TMP/SMX in persons with HIV infection and prior hypersensitive reactions. Int Conf AIDS. 1993 Jun 6-11;9(1):382 (abstract no.PO-B10-1482). MED/93076569. Gearhart MO, Bhutani MS. Intravenous pentamidine-induced bronchospasm. Chest. 1992 Dec;102(6):1891-2. MED/92016907. Toma E, Fournier S. Adverse reactions to co-trimoxazole in HIV infection [letter;comment]. Lancet. 1991 Oct 12;338(8772):954. MED/85108363. Gibbons RB, Lindauer JA. Successful treatment of Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole in hypersensitive AIDS patients. [letter]. JAMA. 1985 Mar 1;253(9):1259-60. ENTRY MONTH 199705 LAST REVISION DATE 20000801 74 UNIQUE IDENTIFIER DRG-0272 NAME OF SUBSTANCE Tenofovir [USPD 2000; p 696] REGISTRY NUMBER 147127-20-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 05/18/01.] STANDARD CHEMICAL NAME Phosphonic acid, (((1R)-2-(6-amino-9H-purin-9-yl)-1-methyletho- xy)methyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 05/18/01.] PROTOCOL ID NUMBERS No longer recruiting FDA 269A DISEASES STUDIED/TREATED Under investigation for the treatment of primary HIV infections. [Protocol ID: 269A ] CLASSIFICATION CODE Investigational - Acyclic nucleoside phosphonate analog [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CLASSIFICATION CODE Investigational - Antiretroviral [USPD 2000; p 696] CLASSIFICATION CODE Investigational - Nucleotide reverse transcriptase inhibitor [USPD 2000; p 696] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: PMPA is an acyclic nucleotide analogue. [PDR 1997; p 104] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H14-N5-O4-P [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 05/18/01.] CHEMICAL/PHYSICAL DATA Molecular Weight: 305.23 [USPD 2000; p 696] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration. [Protocol ID: 269A ] MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: James Rooney (415)572-6597 REFERENCES AIDS/97702542. James JS. PMPA-first human results. AIDS Treat News,1997 Apr 18,No269,3,6. AIDS/97926475. Bischofberger N, Naesens L, de Clercq E, Fridland A, Srinivas RV, Robbins BL, Arimilli M, Cundy K, Kim C, Lacy S, et al. Bis (POC) PMPA, an orally bioavailable prodrug of the antiretroviral agent PMPA. 4 Conf Retro and Opportun Infect. 1997 Jan 22-26;:104 (abstract no. 214). AIDS/97926379. Merrill DP, Manion DJ, Walker BD, Hirsch MS. Drug susceptibilities of HIV-1 clinical isolates to (R)PMPA in vitro. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:93 (abstract no.155). MED/97070544. Van Rompay KK, Cherrington JM, Marthas ML, Berardi CJ, Mulato AS, Spinner A, Tarara RP, Canfield DR, Telm S, Bischofberger N, et al. 9-[2-(Phosphonomethoxy)propyl] adenine therapy of established simian immunodeficiency virus infection in infant rhesus macaques. Antimicrob Agents Chemother. 1996 Nov;40(11):2586-91. MED/97189101. Perno CF, Santoro N, Balestra E, Aquaro S, Cenci A, Lazzarino G, Di Pierro D, Tavazzi B, Balzarini J, Garaci E, et al. Red blood cells mediated delivery of 9-(2-phosphonylmethoxyethyl) adenine to primary macrophages: efficiency metabolism and activity against human immunodeficiency virus or herpes simplex virus. Antiviral Res. 1997 Feb;33(3):153-64. ENTRY MONTH 199705 LAST REVISION DATE 20010518 75 UNIQUE IDENTIFIER DRG-0271 NAME OF SUBSTANCE Valganciclovir [USPD 2000; p 751] REGISTRY NUMBER 175865-60-8 [USPD 2000; p 751] REGISTRY NUMBER 175865-59-5 (hydrochloride) [USPD 2000; p 751] STANDARD CHEMICAL NAME L-Valine, 2-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)m- ethoxy)-3-hydroxypropyl ester, monohydrochloride [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] SYNONYMS Valcyte [U.S. FDA. CDER. New Drug Approval Packages. Available at http://www.fda.gov/cder/approval/v.htm. Accessed 06/11/01.] PROTOCOL ID NUMBERS No longer recruiting FDA 268A PROTOCOL ID NUMBERS No longer recruiting FDA 268B PROTOCOL ID NUMBERS No longer recruiting FDA 268C PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5030 PHARMACOLOGICAL ACTION Valganciclovir is a prodrug of ganciclovir that is converted rapidly to ganciclovir by intestinal and hepatic esterases. In CMV-infected cells ganciclovir is phosphorylated initially to the monophosphate by the viral protein kinase pUL97, and then to the triphosphate by cellular kinases. As this phosphorylation process is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. Ganciclovir triphosphate inhibits replication of human CMV by inhibiting viral DNA synthesis. After oral administration, valganciclovir is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir tablets following administration with food is about 60 percent. Systemic exposure to valganciclovir is transient and low; valganciclovir area under the plasma concentration-time curve (AUC) and maximum serum concentration (Cmax) values have been shown to be approximately 1 and 3 percent of those of ganciclovir, respectively. Administration of valganciclovir with food results in increased ganciclovir steady-state AUC and Cmax. This AUC is comparable to that achieved with intravenous ganciclovir; however, the ganciclovir Cmax is 40 percent lower. Ganciclovir AUC and Cmax following oral ganciclovir administration, however, are lower relative to those achieved after valganciclovir or intravenous ganciclovir dosing. Plasma protein binding of valganciclovir/ganciclovir is low. No other metabolites of valganciclovir have been detected. The major route of elimination of valganciclovir is by renal excretion as ganciclovir via glomerular filtration and active tubular secretion. Dosage reductions are required in patients with renal impairment. The elimination half-life (t 1/2) of ganciclovir following administration of valganciclovir tablets and intravenous ganciclovir is shown to be about 4 and 3.8 hours, respectively. Resistance can arise after prolonged treatment with valganciclovir. Selection of mutations in the viral protein kinase gene (UL97) results in resistance to ganciclovir; selection in the viral polymerase gene (UL54) may result in resistance to ganciclovir and cross-resistance to other antivirals with a similar mechanism of action. CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance also has been observed in individuals receiving prolonged treatment for CMV retinitis with ganciclovir. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] DISEASES STUDIED/TREATED Valganciclovir hydrochloride is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It is also under investigation as CMV prophylaxis in this population. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.; NLM. ClinicalTrials.gov. Available at http://www.clinicaltrials.gov. Accessed June 25, 2001.] CLASSIFICATION CODE Antiviral [USPD 2000; p 751] OTHER MAJOR USES Valganciclovir hydrochloride is under investigation as CMV prophylaxis and treatment in transplant recipients. [NLM. ClinicalTrials.gov. Available at http://www.clinicaltrials.gov. Accessed June 25, 2001.] SUBSTANCE INTERACTIONS Because valganciclovir is rapidly and extensively converted to ganciclovir, drug interactions associated with ganciclovir would be expected for valganciclovir. Drugs with potential for clinically significant interactions with ganciclovir include bone marrow depressants, nephrotoxic medications, probenecid, zidovudine, and didanosine. Concurrent use of bone marrow depressants and valganciclovir may increase the hematologic effects of the latter. Nephrotoxic medications may increase the chance of renal function impairment and may cause toxic accumulation of ganciclovir in the body. Probenecid reduces ganciclovir clearance and also may lead to ganciclovir toxicity. Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia; concomitant therapy may lead to increased adverse effects and/or pharmacokinetic interactions. Finally, ganciclovir has been shown to increase significantly the AUC of didanosine, which warrants monitoring for evidence of didanosine toxicity. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] ADVERSE EFFECTS Valganciclovir has the potential to cause adverse effects similar to those that are known to be associated with ganciclovir use. Valganciclovir may be carcinogenic and/or mutagenic, and may cause fertility and pregnancy complications. Valganciclovir also may cause hematologic reactions, including leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia. Adverse effects reported by participants in clinical trials of valganciclovir include diarrhea, nausea, and vomiting; fever, headache, insomnia, and peripheral neuropathy. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] CONTRAINDICATIONS Valganciclovir is contraindicated in patients with hypersensitivity to valganciclovir or ganciclovir. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Valganciclovir hydrochloride is a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic analogue of 2-deoxyguanosine. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] CHEMICAL/PHYSICAL DATA Molecular Formula: C14-H22-N6-O5.H-Cl [USPD 2000; p 751] CHEMICAL/PHYSICAL DATA Molecular Weight: 390.83 [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf on June 11, 2001] CHEMICAL/PHYSICAL DATA Elemental Comp: C43.02%, H5.93%, N21.51%, O20.47%, Cl9.07% [Calculation. ] CHEMICAL/PHYSICAL DATA Solubility: Soluble at 70 mg/ml in water at 25 C and pH of 7.0. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 450 mg tablet, containing 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone, and stearic acid. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 25 C (77 F); excursions permitted to 15 to 30 C (59 to 86 F). [U.S. FDA. CDER. Valcyte monograph. Available at http://www.fda.gov/cder/foi/label/2001/21304l- bl.pdf. Accessed June 11, 2001.] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000003531: Roche Global Development 3401 Hillview Ave Palo Alto, CA 943041397 Contact: Professional Services (800)526-6367 REFERENCES MED/21152773. Paltiel AD, Goldie SJ, Losina E, Weinstein MC, Seage GR 3rd, Kimmel AD, Zhang H, Freedberg KA. Preevaluation of clinical trial data: the case of preemptive cytomegalovirus therapy in patients with human immunodeficiency virus. Clin Infect Dis 2001 Mar 1;32(5):783-93. MED/21144849. Piper H, Ciulla TA, Danis RP, Pratt LM. Changing therapeutic paradigms in CMV retinitis in AIDS. Expert Opin Pharmacother 2000 Dec;1(7):1343-52. MED/20516000. Hoffman VF, Skiest DJ. Therapeutic developments in cytomegalovirus retinitis. Expert Opin Investig Drugs 2000 Feb;9(2):207-20. MED/20285418. Sugawara M, Huang W, Fei YJ, Leibach FH, Ganapathy V, Ganapathy ME. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci 2000 Jun;89(6):781-9. MED/20142931. Nichols WG, Boeckh M. Recent advances in the therapy and prevention of CMV infections. J Clin Virol 2000 Feb;16(1):25-40. GWAIDS/0005612. Martin D, Sierra-Madero J, Walmsley S, Wolitz R, Brown F, Robinson C. Valganciclovir vs. IV ganciclovir as induction therapy for newly diagnosed cytomegalovirus (CMV) retinitis: a randomized, controlled study. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7:119 (abstract no. 231). MED/99424622. Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet 1999 Aug;37(2):167-76. MED/99363075. Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol 1999 Aug;39(8):800-4. AIDS/97926031. Brown F, Arum I, Francis G, Patel M, Malcolm S. Ganciclovir prodrug (RS-79070) - multiple dose, dose-ranging study with effect of food. Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:209 (abstract no. LB19). ENTRY MONTH 199705 LAST REVISION DATE 20010625 76 UNIQUE IDENTIFIER DRG-0270 NAME OF SUBSTANCE MN rgp120/HIV-1 [Protocol ID: AVEG 203 ] PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 014C PROTOCOL ID NUMBERS Recruiting NIAID HIVNET 026 PHARMACOLOGICAL ACTION MODE OF ACTION: The vaccine producing company (Genentech Inc.) has halted development of gp120 as a potential treatment for HIV positive individuals. Their gp120 model, designed to slow the development of AIDS-related symptoms, has shown no clinical benefit in trials involving 573 asymptotic HIV+ individuals with CD4 counts greater than 600/mm3. The vaccine was also tested in HIV seronegative individuals. It was safe and immunogenic. Three injections induced antibodies that neutralized MN rgp120, SF-2 or IIIB strains of HIV-1. [AmfAR Treat Dir 1997;8(3); p 59; J Infect Dis 1996 Feb;173(2); p 340-8; Int Conf AIDS 1993 Jun 6-11;9(1); p 491 (abstract no. PO-B27-2137)] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 014C ] ADVERSE EFFECTS No clinically adverse events attributable to MN rgp120 HIV-1 occured in the phase 1 study. [AmfAR Treat Dir 1997;8(3); p 59; JAMA 1994 Aug 10;272(6); p 475-80] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Genetically engineered form of envelope glycoprotein gp120 derived from HIV-1 strain MN. [AmfAR Treat Dir 1997;8(3); p 58] MANUFACTURERS 0000004404: VaxGen Inc 1000 Marina Boulevard / Suite 200 Brisbane, CA 94005 Contact: Marlene Chernow (650)624-1030 REFERENCES AIDS/95921086. Belshe RB. Cross-reactive neutralizing antibody induced by (MN or MN+IIIB) rgp120/HIV-1 vaccines in low risk volunteers. Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;: 64. MED/97213946. Binley JM, Klasse PJ, Cao Y, Jones I, Markowitz M, Ho DD, Moore JP. Differential regulation of the antibody responses to Gag and Env proteins of human immunodeficiency virus type 1. J Virol. 1997 Apr; 71(4):2799-809. MED/97240668. Zolla-Pazner S, Alving C, Belshe R, Berman P, Burda S, Chigurupati P, Clements ML, Duliege AM, Excler JL, Hioe C, et al. Neutralization of a clade B primary isolate by sera from human immunodeficiency virus-uninfected recipients of candidate AIDS vaccines. J Infect Dis. 1997 Apr; 175(4):764-74 AIDS/97920693. Belshe RB, Bolognesi D, Clements ML, Corey L, Fast P, Graham B, Keefer M, Mestecky J, Mulligan M. Candidate HIV-1 vaccines: what is available for expanded clinical trials? Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;: 107. MED/96301139. Graham BS, Keefer MC, McElrath MJ, Gorse GJ, Schwartz DH, Weinhold K, Mattews TJ, Esterlitz Jr, Sinangil F, Fast PE. Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. Ann Intern Med, 1996 Aug 15, 125:4,270-9. AIDS/97288124. Lambert JS, McNamara J, Katz S, Livingston R, Moye J. Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children. Pediatric AIDS clinical Trials Group Study ACTG 218. American Pediatric Association and Society for Pediatric Research annual meeting; 1996 May 6-10; Washington, D.C. Pediatr AIDS HIV Infect, 1996 Aug, 7:4, 279 (unnumbered abstract). ICA11/96920851. Berman PW, Gray A, Ashby M, Eastman D, Wrin T, Vennari Ja, Francis D, Gregory T, Fast P, Schwartz D; et. al. Genetic and immunologic characterization of viruses infecting MN-rgp120 vaccinated volunteers. Int Conf AIDS, 1996 Jul 7-12, 11:1, 10 (abstract no. Mo. A.285). ICA11/96920850. McElrath MJ, Montefiori D, Wolff M, Clements M, Gorse G, Keefer M, Graham B, Duliege AM, Francis D, Matthews T; et.al. Safety, immunity, and risk behavior in HIV-1-uninfected volunteers representing diverse risk populations following recombinant envelope vaccinations: a three-year followup. Int Conf AIDS, 1996 Jul 7-12, 11:1, 10 (abstract no. Mo.A.284). MED/97120481. Cleland JL, Barron L, Daugherty A, Eastman D, Kensil C, Lim A, Weissburg RP, Wrin T, Vennari J, Powell MF. Development of a single-shot subunit vaccine for HIV-1. 3. Effect of adjuvant and immunization schedule on the duration of the humoral immune response to recombinant MN gp120. J Pharm Sci. 1996 Dec; 85(12):1350-7. MED/97071928. Gorse GJ, Yang EY, Belshe RB, Berman PW. Salivary binding antibodies induced by human immunodeficiency virus type 1 recombinant gp120 vaccine. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Nov; 3(6):769-73. MED/96400824. Gorse GJ, Patel GB, Newman FK, Belshe RB, Berman PW, Gregory TJ, Matthews TJ. Antibody to native human immunodeficiency virus type 1 envelope glycoproteins induced by IIIB and MN recombinant gp120 vaccines. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Jul; 3(4):378-86. AIDS/97920667. Zolla-Pazner S, Berman P, Xu S, Gregory T. Detection of primary isolate-neutralizing antibodies in the sera of humans immunized with a rgp120MN vaccine. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:36. MED/96162091. Mascola JR, Snyder SW, Weislow OS, Belay SM, Belshe RB, Schwartz DH, Clements ML, Dolin R, Graham BS, Gorse GJ, et al. Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. J Infect Dis. 1996 Feb;173(2):340-8. ICA9/93335754. Allan JD, Conant M, Lavelle J, Mitsuya ENTRY MONTH 199704 LAST REVISION DATE 20000801 77 UNIQUE IDENTIFIER DRG-0269 NAME OF SUBSTANCE Efavirenz [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SYNONYMS Sustiva [USP DI 2000; p. 1389] PROTOCOL ID NUMBERS Complete NIAID ACTG 368 PROTOCOL ID NUMBERS Complete NIAID ACTG A5039 PROTOCOL ID NUMBERS No longer recruiting FDA 075-00 MERCK PROTOCOL ID NUMBERS No longer recruiting FDA 225D PROTOCOL ID NUMBERS No longer recruiting FDA 229R PROTOCOL ID NUMBERS No longer recruiting FDA 229S PROTOCOL ID NUMBERS No longer recruiting FDA 232J PROTOCOL ID NUMBERS No longer recruiting FDA 238R PROTOCOL ID NUMBERS No longer recruiting FDA 244F PROTOCOL ID NUMBERS No longer recruiting FDA 246K PROTOCOL ID NUMBERS No longer recruiting FDA 246N PROTOCOL ID NUMBERS No longer recruiting FDA 259G PROTOCOL ID NUMBERS No longer recruiting FDA 264F PROTOCOL ID NUMBERS No longer recruiting FDA 264N PROTOCOL ID NUMBERS No longer recruiting FDA 281A PROTOCOL ID NUMBERS No longer recruiting FDA 281C PROTOCOL ID NUMBERS No longer recruiting FDA 281D PROTOCOL ID NUMBERS No longer recruiting FDA 283E PROTOCOL ID NUMBERS No longer recruiting FDA 285E PROTOCOL ID NUMBERS No longer recruiting FDA 295B PROTOCOL ID NUMBERS No longer recruiting FDA 296A PROTOCOL ID NUMBERS No longer recruiting FDA 299A PROTOCOL ID NUMBERS No longer recruiting FDA 307A PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0147 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 388 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 057 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5108 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG P1021 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 259H PROTOCOL ID NUMBERS Recruiting FDA 285G PROTOCOL ID NUMBERS Recruiting FDA 298C PROTOCOL ID NUMBERS Recruiting FDA 302C PROTOCOL ID NUMBERS Recruiting FDA 308B PROTOCOL ID NUMBERS Recruiting CC 99 C-0118 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 382 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5043 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5093 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5103 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5116 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-05-003 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended FDA 298B PHARMACOLOGICAL ACTION MODE OF ACTION: Efavirenz was chosen for clinical evaluation because the compound was a potent inhibitor of the wild-type HIV-1 reverse transcriptase (Ki = 2.93 nM) and exhibited a 95% inhibitory concentration of 1.5 mM for the inhibition of HIV-1 replicative spread in cell culture. In addition, efavirenz was found to be capable of inhibiting a panel of NNRTI-resistant mutant viruses, each of which expressed a single RT amino acid substitution. Efavirenz activity is mediated predominantly by non-competitive inhibition of HIV-1 RT. HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma, and delta are not inhibited by efavirenz. The manufacturer warns that resistant virus emerges rapidly when NNRTIs are administered as monotherapy. Therefore, efavirenz should always be initiated in combination with at least one other antiretroviral agent to which the patient has not been previously exposed. A clinical trial of efavirenz alone and in combination with indinavir has been completed. Following 2 weeks of monotherapy with efavirenz, a mean reduction in HIV-RNA of 1.68 log and an increase in CD4+ count of 96 cells/mm3 were reported. However, 12 weeks on efavirenz plus indinavir caused an HIV-RNA reduction of 2.2 log. These data were not statistically significant when compared to patients receiving indinavir monotherapy. Studies of HIV changes in clinical trials of efavirenz plus indinavir or zidovudine/lamivudine (ZDV/3TC) did not show additional novel mutations of the RT gene of the virus that could be associated with resistance to efavirenz. No evidence was seen of major changes in the spectrum of mutations associated with efavirenz treatment failure in the presence or absence of ZDV/3TC. Addition of efavirenz to treatment regimens that include 2 NRTIs plus indinavir adds substantially to activity without causing a significant change in tolerability for patients with prior NRTI exposure. In contrast to nevirapine and delavirdine, efavirenz appears to be effective in patients with high baseline viral loads (>100,000 copies/ml). [Sustiva Home Page. Available at: http://www.sustiva.com. Accessed: May 15, 2000.; Conf Retroviruses Opportunistic Infect 5th 1998 Feb 1-5; p 210 (abstract no. 703); Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 332 (abstract no. 22343)] DISEASES STUDIED/TREATED The FDA approved efavirenz on 9/18/98 for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. According to the December 1998 Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents, efavirenz is the only NNRTI listed among the preferred antiretroviral agents to be used in first-line combination treatment regimens for HIV-infected individuals who are naive to antiretroviral treatment. [Sustiva Home Page. Available at: http://www.sustiva.com. Accessed: May 15, 2000.; Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Available at: http://www.hivatis.org/guidelines/guidelines.- pdf. Accessed: May 15, 2000.] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1386] CLASSIFICATION CODE Nonnucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 610] SUBSTANCE INTERACTIONS Efavirenz metabolism is mediated primarily by the 3A isoenzyme of the P450 family. Efavirenz has been shown to be an inducer of this metabolic pathway, and coadministration with other drugs metabolized by the P4503A enzyme may result in lower plasma concentrations of those drugs. Efavirenz appears to increase nelfinavir's concentration (area-under-the-curve, or AUC) by 20%. However, coadministration of efavirenz and indinavir has been reported to reduce indinavir's AUC by approximately 35%. A modification of standard indinavir doses to 1000 q8h has been recommended. Coadministration of efavirenz and amprenavir decreases the amprenavir AUC by 36%, while efavirenz levels are slightly higher than controls. Coadministration of efavirenz with Fortovase brand saquinavir reduces saquinavir levels by about 60%. Efavirenz has no significant interaction with azithromycin. While it reduced the clarithromycin AUC by 39%, it increased the active metabolite by 34%. In a single-dose interaction study, efavirenz increased levels of ethinyl estradiol. However, the manufacturer recommends using barrier methods of birth control since the clinical significance of this finding is unknown. Efavirenz should not be administered concurrently with astemizole, cisapride, midazolam, triazolam, or ergot derivatives. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 34] ADVERSE EFFECTS Efavirenz is well tolerated. The most commonly reported adverse event has been rash. Most patients experience some CNS side effects during the first few days to weeks of therapy. These include dizziness, vivid dreams or nightmares, difficulty concentrating, and a feeling of what is sometimes described as disconnectedness. Taking the drug in the evening decreases the severity of these side effects for most patients. [The Hopkins HIV Report 1999 Jan;11(1); AmfAR Treat Dir 1998;9(2); 1998;9(2); p 34] CONTRAINDICATIONS Women should avoid becoming pregnant while taking efavirenz. On 3/17/98, the Division of AIDS Services released a pregnancy safety alert on severe birth defects in 3 of 13 monkeys (23%) born to efavirenz-treated mothers. The doses used in the monkeys were equivalent to those being studied in humans. There were no adverse effects observed in the mother monkeys. [GMHC Treat Issues 1998 Mar;12(3); AmfAR Treat Dir 1998;9(2); 1998;9(2); p 34] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Member of the 1,4-dihyro-2H-3, 1-benzoxazin-2-ones; a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). [Antimicrob Agents Chemother 1995 Dec;39(12); p 2602-5] CHEMICAL/PHYSICAL DATA Molecular Formula: C14-H9-Cl-F3-N-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 315.68 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water (less than 10 microgram/ml). [Sustiva Home Page. Available at: http://www.sustiva.com. Accessed: May 15, 2000.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to slightly pink crystalline powder. [Sustiva Home Page. Available at: http://www.sustiva.com. Accessed: May 15, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200-mg, 100-mg, and 50-mg capsules. [Sustiva Home Page. Available at: http://www.sustiva.com. Accessed: May 15, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Efavirenz is available in capsule form to be administered orally. [USP DI 2000; p. 1389] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Capsules should be stored at 25 C; excursions permitted to 15-30 C. [Sustiva Home Page. Available at: http://www.sustiva.com. Accessed: May 15, 2000.] MANUFACTURERS 0000004866: DuPont Pharmaceuticals Co Chestnut Run Plaza / 974 Centre Rd Wilmington, DE 19805 Contact: Unspecified MANUFACTURERS 0000004866: DuPont Pharmaceuticals Co Chestnut Run Plaza / 974 Centre Rd Wilmington, DE 19805 REFERENCES MED/99367599. Tashima KT, Caliendo AM, Ahmad M, Gormley JM, Fiske WD, Brennan JM, Flanigan TP. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1 infected patients receiving combination therapy. J Infect Dis 1999 Sep;180(3):862-4. MED/99376517. Piketty C, Race E, Castiel P, Belec L, Peytavin G, Si-Mohamed A, Gonzalez-Canali G, Weiss L, Glavel F, Kazatchkine MD. Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple-drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy. AIDS 1999 Jul 30;13(11):F71-77. MED/99275537. Gazzard BG. Efavirenz in the management of HIV infection. Int J Clin Pract 1999 Jan-Feb;53(1):60-64. AIDS/99704001. James J. Efavirenz (Sustiva) may equal or exceed protease inhibitor in initial antiretroviral combination. AIDS Treat News 1998 Jul 17;(No 299):1-3. AIDS/99703962. Baker R. Efavirenz and Fortovase. BETA 1998 Jul:9. AIDS/98703782. Cadman J. Efavirenz Pregnancy Warning. Treatment Issues 1998 Mar;12:No 3. AIDS/98929628. Bacheler L, George H, Hollis G, Abremski K. Resistance to efavirenz (SUSTIVA) in vivo. 5th Conf Retrovir Oppor Infect 1998 Feb 1-5:210 (abstract no. 703). AIDS/98929627. Jeffrey S, Baker D, Tritch R, Rizzo C, Logue K, Bacheler L. A resistance and cross resistance profile for SUSTIVA (efavirenz, DMP 266). 5th Conf Retrovir Oppor Infect 1998 Feb 1-5:210 (abstract no. 702). AIDS/98929623. Hicks C, Hass D, Seekins D, Cooper R, Gallant J, Carpenter C, Ruiz NM, Manion DJ, Ploughman LM, Labriola DF. A phase II, double-blind, placebo-controlled, dose ranging study to assess the antiretroviral activity and safety of DMP 266 (efavirenz, SUSTIVA) in combination with open-label zidovudine (ZDV) with lamivudine (3TC) [DMP 266-005]. 5th Conf Retrovir Oppor Infect 1998 Feb 1-5:209 (abstract no. 698). AIDS/98929618. Kahn J, Mayers D, Riddler S, Stein D, Bach M, Havlir D, Ruiz N, Manion D, Friedman P, Labriola DF, et al. Durable clinical anti-HIV-1 activity (60 weeks) and tolerability for efavirenz (DMP 266) in combination with indinavir (IDV) suppression to less than 1 copy/ml (OD=background) by Amplicor as a predictor of virologic treatment response [DMP 266-003, cohort IV]. 5th Conf Retrovir Oppor Infect 1998 Feb 1-5:208 (abstract no. 692). ENTRY MONTH 199703 LAST REVISION DATE 20000801 78 UNIQUE IDENTIFIER DRG-0268 NAME OF SUBSTANCE Tin ethyl etiopurpurin [Protocol ID: 261A ] REGISTRY NUMBER 113471-15-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Tin, (ethyl 3,4,20,21-tetrahydro-4,9,14,19-tetraethyl-18,- 19-dihydro-3,8,13,18-te tramethyl-20-phorbinecarboxylato(2-)-N23,N24,- N25,N26)-, (SP-4-2)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 261A PHARMACOLOGICAL ACTION MODE OF ACTION: Photodynamic therapy (PDT) involves drugs that are activated by light to selectively destroy diseased cells, such as cancer, with minimal effects on normal tissue. Tin ethyl etiopurpurin (SnET2) is a drug being evaluated clinically for such activity. Phase I and II clinical studies were carried out to define a PDT consisting of drug (SnET2 by infusion) and light doses to elicit response/remission of cutaneous AIDS-associated Kaposi's sarcoma (KS) and to determine the response/remission rate of KS lesions in an expanded population of AIDS patients. The Phase I threshold SnET2 dose required for clinical tumor response was greater than 0.8 mg/kg. At 1.2 mg/kg, the respnse rate [CR (complete response rate) and PR (partial response rate)] was 78%. The overall response rate among the Phase II trial patients was 34% for macular stage KS lesions (22% CR and 12% PR) and 84% for papular stage KS (32% CR and 53% PR). Over a 12-week evaluation interval, 3/24 macular stage control lesions changed in morphology to papular or nodular stage KS. Conclusions from these trials were that SnET2-PDT resulted in clinical responses of cutaneous KS lesions in AIDS patients with advanced disease. A therapeutic drug dose of SnET2 at 1.2 mg/kg with light irradiation at 300 J/cm2 elicited a response rate of 88% among papular stage KS, and 37% among macular stage KS demonstrating the potential clinical utility of SnEt2-PDT in the management of local KS disease. [Int Conf AIDS 1996 Jul 7-12;11(2); p 98 (abstract no. We.B.3243); Business Wire 1996 July 11] DISEASES STUDIED/TREATED Treatment of Kaposi's sarcoma [Int Conf AIDS 1996 Jul 7-12;11(2); p 98 (abstract no. We.B.3243)] CLASSIFICATION CODE Photochemotherapeutic [Protocol ID: 261A ] OTHER MAJOR USES SnET2-based photodynamic therapy is being tested in phase II/III studies for the treatment of cutaneous metastatic breast cancer. It is also being tested in phase I/II PDT studies for the treatment of certain serious eye diseases. [Business Wire 1996 July 11; J Surg Oncol 1998 Feb;67(2); p 121-5] ADVERSE EFFECTS In a limited clinical trial, treatment with SnET2 and irradiation was generally found to be well tolerated. The most common side effect was mild, transient sensitivity of the skin to sunlight. This did not require treatment. No clinically significant abnormal trends were noted in laboratory parameters. [Business Wire 1996 July 11] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Substance used to augment photodynamic therapy (with laser light) on kaposi's sarcoma and other skin tumors. [Int Conf AIDS 1996 Jul 7-12;11(2); p 98 (abstract no. We.B.3243)] CHEMICAL/PHYSICAL DATA Molecular Formula: C37-H42-N4-O2-Sn [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Solution. [Protocol ID: 261A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Infusion [Int Conf AIDS 1996 Jul 7-12;11(2); p 98 (abstract no. We.B.3243)] MANUFACTURERS 0000003563: Clinical Solutions 103 Carnegie Ctr / Suite 106 Princeton, NJ 08540 Contact: Unspecified (609)243-0110 REFERENCES UI/98146189. Kaplan MJ, Somers RG, Greenberg RH, Ackler J. Photodynamic therapy in the management of metastatic cutaneous adenocarcinomas: case reports from phase 1/2 studies using tin ethyl etiopurpurin (SnET2). J Surg Oncol 1998 Feb;67(2):121-5. UI/98048429. Hill RA, Crean DH, Doiron DR, Ghosheh F, Ryan JA, Kelly H, Booth M, Liaw LH, Newman L, Berns MW. Photodynamic therapy of the ciliary body with tin ethyl etiopurpurin and tin octaethyl benzochlorin in pigmented rabbits. Ophthalmic Surg Lasers 1997 Nov;28(11):948-53. UI/97294851. Peyman GA, Moshfeghi DM, Moshfeghi A, Khoobehi B, Doiron DR, Primbs GB, Crean DH. Photodynamic therapy for choriocapillaris using tin ethyl etiopurpurin (SnET2). Ophthalmic Surg Lasers 1997 May;28(5):409-17. UI/97238341. Rocklin GB, Kelly HG, Anderson SC, Edwards LE, Gimpelson RJ, Perez RE. Photodynamic therapy of rat endometrium sensitized with tin ethyl etiopurpurin. J Am Assoc Gynecol Laparosc 1996 Aug;3(4):561-70. UI/97038244. Coats WD Jr, Currier JW, Mejias Y, Narciso HL, Faxon DP. Tin ethyl etiopurpurin significantly inhibits vascular smooth muscle cell proliferation in vivo. ICA11/96923595. Grekin R, Razum N, Trommer R, Doiron D, Snyder A, Tin ethyl etiopurpurin (SNET2) photodynamic therapy (PDT): results of a phase I/II clinical study conducted at UCSF for the treatment of AIDS-associated cutaneous Kaposi's sarcomas. Int Conf AIDS. 1996 Jul 7-12;11(2):98 (abstract no. We.B.3243). PDT Inc. and UCSF present photodynamic-therapy KS data at World AIDS Conference. Business wire, July 11, 1996. UI/95368514. Kongshaug M, Moan J, Cheng LS, Morgan AR. Binding of etiopurpurin to human plasma proteins. Delivery in cremophor EL and dimethyl sulphoxide. III. Int J Bichem Cell Biol 1995 May;27(5):481-92. UI/95277603. Kongshaug M, Cheng LS, Moan J, Morgan AR, Binding of etiopurpurin and tin-coordinated etiopurpurin to human plasma proteins. Delivery in cremophore EL and dimethyl Sulfoxide (paper II). Int J Biochem Cell Biol 1995 Jan;27(1):71-87. AIDS/97229493H. PDT Therapy for KS shows promising results [news]. Aids Patient Care STDs. 1996 Apr;10(2):135. ENTRY MONTH 199703 LAST REVISION DATE 20001106 79 UNIQUE IDENTIFIER DRG-0267 NAME OF SUBSTANCE Memantine [USPD 1998; p. 449] REGISTRY NUMBER 19982-08-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3,5-Dimethyl-1-adamantamine [USPD 1998; p 449] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 301 PHARMACOLOGICAL ACTION MODE OF ACTION: Glutamate receptor antagonists (such as memantine) with selective action at the N-methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neurophyschiatric disorders. The Ki-value of memantine at eht phencyclidine (PCP) binding site of the NMDA receptor is 0.5 micorM in human frontal cortex. The serum levels ranged from 0.025 to 0.529 microM with daily doses between 5 and 30 mg. CSF levels were highly correlated to serum levels. Memantine, as well as the antagonist MK-801, prevented the effects of gp120 (a protein that protrudes from the HIV surface and binds to CD4+ T cells) on cortical cell cultures at micromolar concentrations. [Nervenarzt 1996 Jan;67(1); p 77-82; Int Conf AIDS 1994 Aug 7-12;10(1); Abstract no.PB0202] DISEASES STUDIED/TREATED The cytoprotective effect of memantine in cortical cell cultures may qualify the drug for the treatment of AIDS-related dementia. [Eur J Pharmacol 1993 Aug 10;240(1); p 209-14] CLASSIFICATION CODE Antiparkinsonian [Merck Index 1996; p. 994] CLASSIFICATION CODE Muscle relaxant [Merck Index 1996; p. 994] OTHER MAJOR USES Memantine is currently used in the neurodegenerative disease such as spasticity, Parkinson's disease and dementia syndrome. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); Abstract no.PuA.6184; J Neural Transm 1995;46 Suppl; p 97-105] SUBSTANCE INTERACTIONS The clinical observation that co-administration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Combination therapy should allow the use of lower doses of both drugs which may reduce the occurences of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl. [J Neural Transm Gen Sect 1994;98(1); p 57-67] ADVERSE EFFECTS Amantadine and memantine have been administered to human patients with idiopathic Parkinson's disease and spasticity for many years without serious adverse effects. [Nervenarzt 1996 Jan;67(1); p 77-82] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H21-N [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 179.31 [USPD 1998; p. 449] CHEMICAL/PHYSICAL DATA Elemental Comp: C80.38%, H11.80%, N7.81% [Merck Index 1996; p. 993] CHEMICAL/PHYSICAL DATA Solubility: Oil. [Merck Index 1996; p 994] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Hydrochloride, crystals from alcohol/ether. [Merck Index 1996; p 994] MANUFACTURERS 0000003839: Neurobiological Technologies Inc 3260 Blume Drive Suite 500 Richmond, CA 94806 Contact: Dr Jeffrey S Price (510)215-8000 REFERENCES MED/98221370. Stroke, Alzheimer's patients may benefit from AIDS dementia drug [news]. Dent Today. 1997 Feb;16(2):29. ASHM9/98095095. Brew BJ. HIV neurological disease:--developments and new therapies. Annu Conf Australas Soc HIV Med. 1997 Nov 13-16;9:57 (abstract no. IS 29). MED/97343848. Lipton SA. Treating AIDS dementia [letter; comment]. Science, 1997 Jun 13,276:5319,1629-30. MED/97255662. Melton ST, Kirkwood CK, Ghaemi SN. Pharmacotherapy of HIV dementia. Ann Pharmacother, 1997 Apr,31:4,457-73. MED/97124661. Raber J, Toggas SM, Lee S, Bloom FE, Epstein CJ, Mucke L. Central nervous system expression of HIV-1 Gp120 activates the hypothalamic-pituitary-adrenal axis: evidence for involvement of NMDA receptors and nitric oxide sythase. Virology 996 Dec 15;226(2):362-73. MED/96314092. Pittaluga A, Pattarini R, Severi P, Raiteri M. Human brain N-methyl-D-aspartate receptors regulating noradrenaline release are positively modulated by HIV-1 coat protein gp120. AIDS, 1996 May,10:5,463-8. MED/96420092. Muller WE, Pergande G, Ushijima H, Schleger C, Kelve M, Perovic S. Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmological intervention. Prog Mo1 Subcell Biol. 1996;16:44-57. MED/96419614. Toggas SM, Masliah E, Mucke L. Preventive of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brian Res. 1996 Jan 15;706(2):303-7. MED/93261588. Kornhuber J, Bormann J, Neuroprotective effects of memantine (letter;comment). Neurology. 1993 May;43(5):1054-5. MED/93049850. Muller WE, Schroder HC, Ushijima H, Dapper J, Bormann J. Gp120 of HIV-1 induces apoptosis in rat cortical cell cultures: prevention by memantine. Eur J Pharmacol. 1992 Jul 1;226(3):209-14. MED/92319302. Lipton SA. Memantine prevents HIV coat protein-induced neuronal injury in vitro (see comment in: Neurology 1993 May;43(5):1054-5]. Neurology. 1992 Jul;42(7):1403-5. ENTRY MONTH 199702 LAST REVISION DATE 20000801 80 UNIQUE IDENTIFIER DRG-0266 NAME OF SUBSTANCE Maribavir [USPD 2000 p. 430] PROTOCOL ID NUMBERS No longer recruiting FDA 263A PHARMACOLOGICAL ACTION MODE OF ACTION: 1263W94 is one of a class of benzimidazole ribosides which selectively inhibits human cytomegalovirus (CMV) replication in vitro. 1263W94 is not active against HSV 1 or 2, VZV, murine CMV, HIV, HBV, or HPV. The activity against CMV laboratory strain AD169 ranged from 0.12-2.0 micromolar in a plaque reduction assay. In a DNA hypridization assay, the mean 1263W94 IC50 and IC90 values against AD169 were 0.046 micromolar and 0.5 micromolar, respectively (n=3). The IC50 values for 1263W94 against ten clinical isolates ranged from 0.03 to 0.13 micromolar. 1263W94 was active against strains of CMV carrying clinically significant ganciclovir (GCV)-resistant mutations in the UL97 gene, and against CMV strains bearing mutations in the DNA polymerase associated with GCV or HPMPC resistance. 1263W94 blocks CMV replication by inhibiting viral DNA synthesis. The mechanism is apparently novel, since it is not mediated through inhibition of CMV DNA polymerase by nucleotide anabolites of 1263W94. No phosphorylated forms of 1263W94 were detected in CMV-infected cells incubated with 5 micromolar 1263W94. A phase I double-blind, randomized, placebo-controlled study was conducted to evaluate the safety/PK of single oral doses of 1263W94 in HIV-infected volunteers with CD4+ less than 150/microliter and no HCMV (human cytomegalovirus) disease. The 17 subjects enrolled were male, 30-53 yrs of age, weighed 61-90 kg, and each received 3 single escalating doses of 1263W94 (100-1600 mg) and 1 dose of placebo. Plasma total and free 1263W94 reached levels well above in vitro anti-HCMV IC(50) (0.03 microgram/mL). [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 189 (abstract no. 674); Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 178 (abstract no.H85)] DISEASES STUDIED/TREATED In testing for treatment of cytomegalovirus infection [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 189 (abstract no. 674)] CLASSIFICATION CODE Antiviral [USPD 2000 p. 430] SUBSTANCE INTERACTIONS The combination of 1263W94 and ganciclovir was additive against CMV. 1263W94 did not interfere with the anti-HIV activity of AZT, ddI, ddC, 3TC, or nevirapine. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 178 (abstract no. H85)] ADVERSE EFFECTS 1263W94 was well tolerated by all 12 volunteers at all dose levels with no serious adverse events reported. A frequently reported adverse effect (by 9 subjects) was bitter or stale taste in mouth occurring with dose-dependent frequency and intensity. No patient withdrew due to this effect. Other infrequent drug-related events included: headache (4), drowsiness/dizziness (3), and feeling sleepy (1). There were no abnormal or clinically significant findings in vital signs, ECG and clinical laboratory values. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 168 (abstract no. H28)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: 1263W94 is a benzimidazole riboside exhibiting potent and selective inhibition of human cytomegalovirus. [Prog Abst Intersci Conf Antimicrob Agents Chemother 1996 Sep; p 168 (abstract no. H28)] CHEMICAL/PHYSICAL DATA Molecular Formula: C15-H19-Cl2-N3-O4 [USPD 2000 p. 430] CHEMICAL/PHYSICAL DATA Molecular Weight: 376.24 [USPD 2000 p. 430] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 189 (abstract no. 674)] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 REFERENCES AIDS/98929686. Lalezari JP, Aberg JA, Wang LH, Miner RC, Wire MB, Jacobson MA, Drew WL. In vivo anti-CMV activity, safety and pharmacokinetics (PK) of oral 1263W94 in HIV-infected subjects with asymptomatic CMV shedding. 5th Conf Retrovir Oppor Infect. 1998 Feb 1-5;:221 (abstract no. 762). MED/98124951. Hebart H, Kanz L, Jahn G, Einsele H. Management of cytomegalovirus infection after solid-organ or stem-cell transplantation. Current guidelines and future prospects. Drugs. 1998 Jan;55(1):59-72. AIDS/98703061. Cadam J. CMV trials struggle to enroll. GMHC Treat Issues. 1997 Sep;11(9):4-5. AIDS/97926719. Wang LH, Peck R, Chan PQ, Youle M, Eaves J, Bye A. A phase I tolerability and pharmacokinetic (PK) trial of 1263W94, a novel anti-HCMV agent, in HIV-infected volunteers. 4th Conf Retro and Opportun Infect, 1997 Jan22-26,189(abstract no.674). AIDS/98927771. Biron KK, Davis MG, Stanat SC, Walton LM, Smith A, Koszalka GW, Drach JC, Townsend LB, Harvey RJ. Antiviral activity and mechanism of action of 1263w94, a benzimidazole riboside inhibitor of human cytomegalovirus. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:178 (abstract no. H85). AIDS/98927755. Wang LH, Lyogendran S, Weller S, Wiggs R, Bye A. A phase I trial evaluating the tolerability and pharmacokinets (PK) of 1263W94 following single oral administration of escalating doses in normal healthy volunteers. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:168 (abstrat no. H28). AIDS/98927754. Frick LW, Hsieh AY, Good SS. Pharmacokinetics and metabolism in rats and monkeys of 1263W94, a potent and selective inhibitor of human cytomegalvirus. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:168 (abstract no. H27). Bartnof H, Chang H, New drug 1263W94 effective against ganciclovir-resistant cytomegalovirus in vitro. Bulletin of Experimental Treatments for AIDS (BETA), No. 31, December 1996. ENTRY MONTH 199702 LAST REVISION DATE 20000801 81 UNIQUE IDENTIFIER DRG-0265 NAME OF SUBSTANCE Influenza Virus Vaccine [USPD 1998; p. 378] SYNONYMS FluShield [USP DI 2000; p. 3459] SYNONYMS Fluvirin [USP DI 2000; p. 3459] SYNONYMS Fluzone [USP DI 2000; p. 3459] PROTOCOL ID NUMBERS Complete CC 98 C-0011 PROTOCOL ID NUMBERS Complete NIAID ACTG 340 PHARMACOLOGICAL ACTION MODE OF ACTION: Influenza virus vaccine promotes active immunity to influenza virus by inducing production of specific antibodies. Protection is provided only against those strains of virus from which the vaccine is prepared and closely related strains. Vaccine has been shown to induce both a systemic (i.e., in serum) and, to a lesser extent, local (i.e., in upper respiratory tract) immune response. Local mucosal immunity in the respiratory tract (e.g., in tonsils) confers the initial line of defense against influenza. Possibly, migration of activated B cells, particularly IgA-committed B cells, via lymphatic drainage from the injection site to the mucosal surface of the tonsils is responsible for the local response after vaccination. Influenza-specific antibodies are predominantly IgG and IgM in serum and IgA in oral fluids. The development of antibody response to immunization occurs after approximately 2 weeks. Duration of immunity varies widely but lasts approximately 1 year. The vaccine is available as either a whole-virus or split-virus preparation. The split-virus vaccine is produced by chemically treating a whole-virus preparation to cause inactivation and disruption of significant portions of the virus into smaller subunit particles called subvirions. [AHFS Drug Information 1997; p 2598-9] DISEASES STUDIED/TREATED Prophylactic to prevent influenza in HIV-infected persons. [AHFS Drug Information 1997; p 2599] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 1777] OTHER MAJOR USES To stimulate active immunity to the influenza virus strains contained in the vaccine. [AHFS Drug Information 1997; p 2599] SUBSTANCE INTERACTIONS Antiviral agents such as amantadine and rimantadine do not appear to interfere with the antibody response to influenza virus. Vaccination should be deferred until immunosuppressive therapy (e.g., corticosteroids, alkylating agents, corticotropin, antimetabolites, radiation therapy) is discontinued. Patients on warfarin should be monitored for possible enhanced anticoagulant effects when influenza vaccine is administered. Increased serum concentrations of theophylline have been reported after vaccination. Patients on this medication should be observed for toxicity. Concurrent administration of influenza vaccine and polyvalent pneumococcal vaccine, or routine pediatric vaccines including mmR, poliovirus vaccine live oral (OPV), and hemophilus b vaccines (at different sites), can be considered. Interleukin-2 or aspirin have been shown to increase the antibody response to influenza vaccine in geriatric patients. [AHFS Drug Information 1997; p 2604-5] ADVERSE EFFECTS In adults adverse effects to influenza vaccine are generally mild and occur rarely; they are more frequent in children. Subvirion and purified antigen preparations (split-virus vaccines) have been associated with fewer adverse effects than the whole-virion preparations, especially in children. The most frequent adverse effects of influenza virus vaccine are local effects including soreness, tenderness, erythema, and induration at the injection site. These local reactions generally are slight to moderate in severity and persist up to 2 days. [AHFS Drug Information 1997; p 2603] CONTRAINDICATIONS Influenza virus should not be administered to individuals with history of immediate hypersensitivity - and especially anaphylactic reactions - to chicken eggs or egg products or to other ingredients in the respective vaccine formulations. [AHFS Drug Information 1997; p 2603-4] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Noninfectious suspensions of suitably inactivated influenza virus types A and B or virus subunits, formulated annually; representative of the strains of influenza virus that are likely to circulate in the US in the upcoming winter. [AHFS Drug Information 1997; p 2598] CHEMICAL/PHYSICAL DATA Stability: Potency is destroyed by freezing. [AHFS Drug Information 1997; p 2598] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Influenza Virus Vaccine 1966-1977, Trivalent Types A and B. Can be: purified surface antigen, subvirion or whole virion depending on type of product and manufacturer. [AHFS Drug Information 1997; p 2598] SUBSTANCE DELIVERY DATA DOSAGE FORM: Parenteral suspension. [AHFS Drug Information 1997; p 2606] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Although it has been administered subcutaneously in prior years, IM injections are preferred. Should not be given IV. [AHFS Drug Information 1997; p 2605] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 2 - 8 C. Do not freeze. [AHFS Drug Information 1997; p 2598] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000004009: Parke-Davis Pharmaceutical Research 2800 Plymouth Rd Ann Arbor, MI 48105 Contact: Dr J Tyler Martin (313)997-3556 MANUFACTURERS 0000005231: Medeva Pharmaceuticals Inc PO Box 1710 Rochester, NY 14603 Contact: Unspecified (800)934-5556 MANUFACTURERS 0000003865: Pasteur Merieux Connaught / Connaught Laboratories Route 611 / Box 187 / 1 Discovery Drive Swiftwater, PA 183700187 Contact: Unspecified (888)963-3382 MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 Contact: Bill Laps, Regulatory Affairs (570)839-6176 REFERENCES MED/97366923. Fowke KR, D'Amico R, Chernoff DN, Pottage JC Jr, Benson CA, Sha BE, Kessler HA, Landay AL, Shearer GM. Immunologic and virologic evaluation after influenza vaccination of HIV-1-infected patients. AIDS, 1997 Jul, 11:8, 1013-21. AIDS/97927188. Moss RB, Wallace MR, Turner JL, Giermakowska W, Lanza P, Ferre F, Trauger RI, Daigle AE, Richieri SP, Theofan G; at.al. A comparison of the effect of immunization with a gp120 depleted inactivated HIV-1 in incomplete Freund's adjuvant (HIV-1 immunogen) compared with immunization with an influenza vaccine on virus specific immune function. Conf Adv AIDS Vaccine Dev, 1997 May 4-7,:224 (Poster 119). ICA11/96923719. Salassa B, Zucco S, Macor A, Sciullo D, Ruffatto R, Piro F, Soranzo ML. Influenza vaccine response in HIV patients. Int Conf AIDS, 1996 Jul 7-12, 11:2, 121 (abstract no. We.B.3371). ICA11/96923172. Ward C, Salvato P, Thompson C. HIV RNA changes in HIV-positive patients following influenza vaccination. Int Conf AIDS, 1996 Jul 7-12, 11:2, 18 (abstract no. We.B.114). AIDS/96920424. Jackson CR, Vavro CL, Pennington KN, Lanier ER, Valentine ME, McKinney RE, Dilibert JH, Wilfert CM, Katz SL, St Claire MH. Effect of influenza immunization on immunologic and virologic parameters in HIV+ pediatric patients. 3rd Conf Retro and Opportun Infect, 1996 Jan 28-Feb 1:132. MED/97094140. Glesby MJ, Hoover DR, Farzadegan H, Margolick JB, Saah AJ. The effect of influenza vaccination on human immunodeficiency virus type 1 load: a randomized, double-blind, placebo-controlled study. J Infect Dis. 1996 Dec; 174(6):1332-6. MED/96417670. Pau AK, McNicholl IR, Pursell KJ. Active immunization in HIV-infected patients. Pharmacotherapy. 1996 Mar-Apr; 16(2):163-70. MED/97005607. Ramilo O, Hicks PJ, Borvak J, Gross LM, Zhong D, Squires JE, Vitetta ES. T cell activation and human immunodeficency virus replication after influenza immunization of infected children. Pediatr Infect Dis J. 1996 Mar;15(3):197-203. AIDS/97920716. Crowley-Nowick PA, Bell MC, Edward RP, Brockwell RC, Partridge EE, Mestecky J. Rectal immunization with the flu vaccine elicits genital tract reponses. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:142 [Poster 22]. MED/95289357. Simonsen L, Buffington J, Shapiro CN, Homan RC, Strine TW, Grossman BJ, Williams AE, Schonberger LB. Multiple false reactions in viral antibody screening assays after influenza vaccination. Am J Epidemiol. 1995 Jun 1; 141(11):1089-96. ENTRY MONTH 199702 LAST REVISION DATE 20000801 82 UNIQUE IDENTIFIER DRG-0264 NAME OF SUBSTANCE Nandrolone decanoate [USPD 1998; p. 497] REGISTRY NUMBER 360-70-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Estr-4-en-3-one, 17-((1-oxodecyl)oxy)-, (17beta)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Deca-Durabolin [USP DI 2000; p. 128] SYNONYMS Hybolin Decanoate [USP DI 2000; p. 128] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 329 PHARMACOLOGICAL ACTION MODE OF ACTION: All anabolic steroids are approximately equal in efficacy. They are synthetic derivatives of testosterone. Deletion of the C-19 methyl group results in reduction -- but not total elimination -- of androgenic properties, and retention of the anabolic, tissue-building properties. Anabolic steroids reverse catabolic processes and negative nitrogen balance by promoting protein anabolism and stimulating appetite. Anabolic steroids are antianemic by increasing production of erythropoietin, hemoglobin and red blood cell volume. For nandrolone decanoate, a 100mg intramuscular dose reaches peak concentration in 3-6 days. When nandrolone decanoate was given for 16 weeks to HIV+ men who had lost 5-15% of their usual body weight, there were significant increases in weight (mean, 0.14 kg per week) and lean body mass (mean, 3 kg by anthropometry). Quality of life parameters, especially functionality, increased significantly during the trial. No subject experienced toxicity. [USP DI 1998; p 103; AIDS 1996 Jun;10(7); p 745-52] DISEASES STUDIED/TREATED Treatment of hypogonadism associated with megestrol acetate administration in HIV+ women. Used in the management of HIV associated anorexia and weight loss. [AmfAR Treat Dir 1997 Dec; p 57; Proc Annu Conf Australas Soc HIV Med 1997 Nov 13-16;9; p 91] CLASSIFICATION CODE Anabolic steroid [USP DI 2000; p. 125] CLASSIFICATION CODE Antianemic [USP DI 2000; p. 125] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 125] OTHER MAJOR USES Nandrolone decanoate is used for the treatment of anemia associated with renal insufficiency. [USP DI 1998; p 105] SUBSTANCE INTERACTIONS Anabolic steroids can interact with anticoagulants, adrenocorticoids (especially those with significant mineralocorticoid activity), sodium-containing medications or foods, or hepatotoxic medications. [USP DI 1998; p 104] ADVERSE EFFECTS Virilism in females and prepubertal males; bladder irritability, breast soreness (gynecomastia), priapism in males; hypercalcemia in females; iron deficiency, edema, gastric irritation, suppression of clotting factors (in both males and females). Many of the side effects of anabolic steroids are dose-related; therefore, patients should be placed on the lowest possible effective dose. [USP DI 1998; p 104-5] CONTRAINDICATIONS Breast cancer in males and females, severe hepatic function impairment, hypercalcemia, nephrosis, prostatic cancer. [USP DI 1998; p 104] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Injectable anabolic steroid. [AmfAR Treat Dir 1997 Dec; p 57] CHEMICAL/PHYSICAL DATA Molecular Formula: C28-H44-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 428.66 [USPD 1998; p. 497] CHEMICAL/PHYSICAL DATA Melting Point: 32-35 C [Merck Index 1996; p. 1093] CHEMICAL/PHYSICAL DATA Solubility: Insol. in water, freely soluble in ethanol, ether, acetone, chloroform, oils. [Merck Index 1996; p 1093] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to yellow crystals [Merck Index 1996; p 1093] SUBSTANCE DELIVERY DATA DOSAGE FORM: 50mg/ml, 100mg/ml or 200mg/ml dosage forms are available. [USP DI 1998; p 106] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection, 50-100mg (females) or 50-200mg (males) at 1 to 4 week intervals. [USP DI 1998; p 106] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store below 40 C preferably between 15 and 30 C. [USP DI 1998; p 106] MANUFACTURERS 0000003692: Organon Inc 375 Mount Pleasant Ave West Orange, NJ 07052 Contact: Unspecified (800)631-1253 MANUFACTURERS 0000003692: Organon Inc 375 Mount Pleasant Ave West Orange, NJ 07052 Contact: Unspecified (800)238-5282 MANUFACTURERS 0000005216: Hyrex Pharmaceuticals 3494 Democrat Road / PO Box 18385 Memphis, TN 381180385 REFERENCES MED/98287074. Muurahainen N, Mulligan K. Clinical trials update in human immunodeficiency virus wasting. Semin Oncol. 1998 Apr;25(2 Suppl 6):104-11. ASHM9/98095152. Batterham M, Garsia R. Randomised prospective medium-term comparison of megestrol acetate, nandrolone decanoate and dietary therapy alone for HIV associted weight loss. Annu Conf Australas Soc HIV Med. 1997 Nov 13-16;9:91 (abstrat no. IS 87). AIDS/98703400. Corcoran CP, Grinspoon S. Diagnosis and treatment of endocrine disorders in the HIV-infected patient. J Int Assoc Physicians AIDS Care. 1998 Feb;4(2):10-4, 34. ASHM8/97153642. Gold J, High H, Li Y, Michelmore H, Bodsworth N, Finlayson R, Furner V, Allen B, Oliver C. Use of DECA durabolin (nandrolone decanoate) in the treatment of wasting in HIV patients. Annu Conf Australas Soc HIV Med. 1996 Nov 14-17;8:70 (abstract no. 62). AIDS/96701937. Anonymous. Anabolic steroid boosts weight. GMHC Treat Issues,1996 Sep,10:9,8-9. ICA11/96920934. Bucher G, Berger DS, Fields-Gardner C, Jones R, Reiter WM. A prospective study on the safety and effect of nanadrolone decanoate in HIV-positive patients. Int Conf AIDS. 1996 Jul 7-12; 11(1): 26 (abstract no.Mo.B.423). MED/96399354. Gold J, High HA, Li Y, Michelmore h, Bodsworth NJ, Finlayson R, Furner VL, Allen BJ, Oliver CJ. Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection. AIDS. 1996 Jun; 10(7):745-52. ASHM6/95291840. Gold J, High H, Michelmore H, Oliver C. The effect of the anabolic steroid, nandrolone decanoate, on lean body mass and quality of life in HIV+ men--a preliminary analysis. Annu Conf Austalas Soc HIV Med. 1994 Nov 3-6; 6:264 (unnumbered poster). ENTRY MONTH 199701 LAST REVISION DATE 20001107 83 UNIQUE IDENTIFIER DRG-0263 NAME OF SUBSTANCE Nelfinavir mesylate [USPD 1998; p. 502] REGISTRY NUMBER 159989-65-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME (3S,4aS,8aS)-N-tert-Butyl-2-[(2R,3R)-3-(3,2-c- resotamido) -2-hydroxy-4-(phenylthio)butyl]decahydro-3-is- oquinoline- carboxamide monomethanesulfonate (salt) (for nelfinavir mesylate) [USPD 1998; p 502] SYNONYMS Viracept [USP DI 2000; p. 3545] PROTOCOL ID NUMBERS Complete NIAID ACTG 359 PROTOCOL ID NUMBERS Complete NIAID ACTG 378 PROTOCOL ID NUMBERS Complete NIAID ACTG A5047 PROTOCOL ID NUMBERS No longer recruiting FDA 039E PROTOCOL ID NUMBERS No longer recruiting FDA 039G PROTOCOL ID NUMBERS No longer recruiting FDA 200F PROTOCOL ID NUMBERS No longer recruiting FDA 225C PROTOCOL ID NUMBERS No longer recruiting FDA 228E PROTOCOL ID NUMBERS No longer recruiting FDA 229G PROTOCOL ID NUMBERS No longer recruiting FDA 229H PROTOCOL ID NUMBERS No longer recruiting FDA 229J PROTOCOL ID NUMBERS No longer recruiting FDA 229K PROTOCOL ID NUMBERS No longer recruiting FDA 229P PROTOCOL ID NUMBERS No longer recruiting FDA 232E PROTOCOL ID NUMBERS No longer recruiting FDA 232H PROTOCOL ID NUMBERS No longer recruiting FDA 238J PROTOCOL ID NUMBERS No longer recruiting FDA 244C PROTOCOL ID NUMBERS No longer recruiting FDA 244D PROTOCOL ID NUMBERS No longer recruiting FDA 245D PROTOCOL ID NUMBERS No longer recruiting FDA 246H PROTOCOL ID NUMBERS No longer recruiting FDA 246R PROTOCOL ID NUMBERS No longer recruiting FDA 259A PROTOCOL ID NUMBERS No longer recruiting FDA 259B PROTOCOL ID NUMBERS No longer recruiting FDA 259C PROTOCOL ID NUMBERS No longer recruiting FDA 259D PROTOCOL ID NUMBERS No longer recruiting FDA 259E PROTOCOL ID NUMBERS No longer recruiting FDA 259F PROTOCOL ID NUMBERS No longer recruiting FDA 259G PROTOCOL ID NUMBERS No longer recruiting FDA 264A PROTOCOL ID NUMBERS No longer recruiting FDA 264M PROTOCOL ID NUMBERS No longer recruiting FDA 264P PROTOCOL ID NUMBERS No longer recruiting FDA 280C PROTOCOL ID NUMBERS No longer recruiting FDA 285C PROTOCOL ID NUMBERS No longer recruiting FDA 286D PROTOCOL ID NUMBERS No longer recruiting FDA 286E PROTOCOL ID NUMBERS No longer recruiting FDA 292A PROTOCOL ID NUMBERS No longer recruiting FDA 316A PROTOCOL ID NUMBERS No longer recruiting CC 95 C-0192 PROTOCOL ID NUMBERS No longer recruiting CC 97 C-0119 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0147 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 341 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 353 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 377 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 380 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 388 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 397 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 403 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 042 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 057 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5108 PROTOCOL ID NUMBERS Recruiting FDA 039F PROTOCOL ID NUMBERS Recruiting FDA 259H PROTOCOL ID NUMBERS Recruiting FDA 302A PROTOCOL ID NUMBERS Recruiting FDA 316B PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 356 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 382 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5043 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5093 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-01-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-05-003 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-08-002 PROTOCOL ID NUMBERS Recruiting FDA B009 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended FDA 286B PROTOCOL ID NUMBERS Suspended FDA 286C PROTOCOL ID NUMBERS Suspended NIAID ACTG P1022 PROTOCOL ID NUMBERS Terminated CC 99 I-0062 PROTOCOL ID NUMBERS Terminated NIAID ACTG 374 PHARMACOLOGICAL ACTION MODE OF ACTION: Nelfinavir is a selective, competitive, reversible inhibitor of HIV protease, an aspartic endopeptidase that functions as a homodimer, and plays an essential role in the HIV replication cycle and the formation of infectious virus. By interfering with the formation of essential proteins and enzymes, nelfinavir blocks maturation of the virus and causes the formation of immature, noninfectious virions. Nelfinavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly. The antiviral activity of nelfinavir does not depend on conversion to an active metabolite. Nelfinavir is a highly specific inhibitor of HIV protease and does not appear to interfere with similar human enzymes at clinically relevant concentrations. Nelfinavir is well absorbed following oral administration. Peak plasma concentrations are attained within 2-4 hours when 500-800 mg doses are administered with food. Nelfinavir is more than 98% bound to plasma protein. It is not known whether nelfinavir crosses the human placenta. While it is not known whether nelfinavir is distributed into human milk, the drug is distributed into milk in rats. Nelfinavir is metabolized to many oxidative metabolites in the liver, and is excreted principally in the feces, both as unchanged drug and as metabolites. HIV variants resistant to nelfinavir emerge rapidly when the drug is used as monotherapy, but such emergence appears to be delayed when nelfinavir is used in combination with nucleoside analogues. There is evidence that some degree of cross-resistance can occur among various HIV protease inhibitors. Cross-resistance between nelfinavir and NRTIs and NNRTIs is highly unlikely since the drugs target different enzymes. [AHFS Drug Information 1999; p 594-6; AmfAR Treat Dir 1998;9(2); 1998;9(2); p 26] DISEASES STUDIED/TREATED FDA approved 03/14/97 for the treatment of HIV infection when antiretroviral therapy is warranted in adults and pediatrics >=2 years old. [PDR 1999; p 485] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 2229] CLASSIFICATION CODE Protease inhibitor [AHFS Drug Information 2000; p. 628] SUBSTANCE INTERACTIONS Nelfinavir metabolism is mediated, in part, by the cytochrome P450 enzyme CYP3A. Therefore, other drugs that induce this isoenzyme may reduce nelfinavir plasma concentration. Conversely, concomitant administration of nelfinavir with drugs that inhibit CYP3A may increase nelfinavir plasma concentrations. Also, nelfinavir may alter the pharmacokinetics of other drugs metabolized by CYP3A; these include amiodarone, astemizole, cisapride, ergot alkaloids and derivatives, midazolam, quinidine, terfenadine, and triazolam. Rifampin and nelfinavir should not be given concomitantly. Rifabutin dosage should be reduced by 50% when given with nelfinavir. Coadministration of antimycobacterial agents and nelfinavir can affect plasma concentrations. This must be considered in the treatment of TB or MAC infection in HIV-positive patients. Concomitant administration of nelfinavir and delavirdine may affect the pharmacokinetics of both drugs. Clinically important drug interactions with dideoxynucleoside reverse transcriptase inhibitors have not been reported. The plasma concentrations of ethinyl estradiol and norethindrone may be reduced by coadministrations with nelfinavir. [AHFS Drug Information 1999; p 599-600] ADVERSE EFFECTS Adverse events include loose stools, poor concentration, intermittent headaches, moderate hypertension, and elevated liver enzymes. No unexpected adverse events have been reported in patients receiving concomitant nucleoside analogues. Metabolic abnormalities, redistribution of body fat, and diabetes have been observed with all four protease inhibitors. [Int Conf AIDS 1996 Jul 7-12;11(1):18; Abstract no. Mo.B.173; AmfAR Treat Dir 1998;9(2); 1998;9(2); p 26; AHFS Drug Information 1999; p 597] CONTRAINDICATIONS Taking nelfinavir may increase the risk of spontaneous bleeding in patients with hemophilia. Hyperglycemia, new-onset diabetes mellitus, or exacerbation of existing diabetes may occur in patients receiving nelfinavir. The drug should be used with caution in patients with hepatic impairment. Safety and efficacy of the drug in children younger than 2 years have not been established. [AHFS Drug Information 1999; p 598-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Nelfinavir is an inhibitor of the HIV-1 protease. Inhibition of viral protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus. [PDR 1999; p 484] CHEMICAL/PHYSICAL DATA Molecular Formula: C32-H45-N3-O4-S.C-H4-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 663.91 [USPD 1998; p. 502] CHEMICAL/PHYSICAL DATA Solubility: Solubility in water is 4.5 mg/ml (mesylate). Freely soluble in alcohol. [AHFS Drug Information 1999; p 594] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg tablets and 50 mg nelfinavir per g oral powder (with aspartame). [AHFS Drug Information 1999; p 601] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. Nelfinavir was originally approved for patients over age 13 at a dose of 750 mg 3 times daily. In November 1999, the FDA approved nelfinavir at a dose of 1,250 mg twice daily. [AHFS Drug Information 1999; p 601; Agouron Pharmaceuticals Inc. Available at: http://www.agouron.com. Accessed: May 15, 2000.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Nelfinavir mesylate tablets and powder should be stored at 15-30 C (59-86 F). [PDR 1999; p 487] MANUFACTURERS 0000003726: Agouron Pharmaceuticals Inc 11095 Torreyana Rd San Diego, CA 92121 Contact: Carolyn Peterson (888)847-2237 MANUFACTURERS 0000003726: Agouron Pharmaceuticals Inc 11095 Torreyana Rd San Diego, CA 92121 Contact: Lisa Bauman (858)622-8031 REFERENCES MED/99380066. Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond MJ, Marcovina SM, Glauser MP, Nicod P, Darioloi R, Mooser V. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 1999 Aug 17;100(7):700-5. MED/99285296. Mann M, Piazza-Hepp T, Koller E, Struble K, Murray J. Unusual distributions of body fat in AIDS patients: a review of adverse events reported to the Food and Drug Administration. Aids Patient Care STDS 1999 May;13(5):287-95. Review. MED/99379713. Krogstad P, Wiznia A, Luzuriaga K, Dankner W, Nielsen K, Gersten M, Kerr B, Hendricks A, Boczany B, Rosenberg M, Jung D, Spector SA, Bryson Y. Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect Dis 1999 May;28(5):1109-18. MED/99254254. Barry M, Mulcahy F, Merry C, Gibbons S, Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999 Apr;36(4):289-304. Review. MED/99216866. Pai VB, Nahata MC. Nelfinavir mesylate: a protease inhibitor. Ann Pharmacother 1999 Mar;33(3):325-39. Review. MED/99180109. Malaty LI, Kuper JJ. Drug interactions of HIV protease inhibitors. Drug Saf 1999 Feb;20(2):147-69. Review. MED/99125808. Aweeka F, Jayewardene A, Staprans S, Bellibas SE, Kearney B, Lizak P, Novakovic-Agopian T, Price RW. Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1-infected patients with and without AIDS dementia complex. J Acquir Immune Defic Syndr Hum Retrovirol 1999 Jan 1;20(1):39-43. MED/99079498. Markus R, Brew BJ. HIV-1 peripheral neuropathy and combination antiretroviral therapy [letter]. Lancet 1998 Dec 12;352(9144):1906-7. MED/98327095. Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shetty BV, Lee CA. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 1998 Jul;26(7):609-16. MED/98268846. Markowitz M, Conant M, Hurley A, Schluger R, Duran M, Peterkin J, Chapman S, Patick A, Hendricks A, Yuen GJ, Hoskins W, Clendeninn N, Ho DD. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection. J Infect Dis 1998 Jun;177(6):1533-40. AIDS/98930323. Ramirez CM, Gottlieb MS, Becker M, Dubin JA. Viral suppression with nelfinavir in a protease experienced population. HIV Pathog Treat Conf 1998 Mar 13-19;:55 (abstract no. 2034). ENTRY MONTH 199612 LAST REVISION DATE 20000801 84 UNIQUE IDENTIFIER DRG-0262 NAME OF SUBSTANCE CI-1012 [Protocol ID: 97 I-032 ] REGISTRY NUMBER 2527-57-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzamide, 2,2'-dithiobis- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 278A PROTOCOL ID NUMBERS No longer recruiting FDA 278B PROTOCOL ID NUMBERS No longer recruiting CC 97 I-032 PHARMACOLOGICAL ACTION Zinc fingers are part of the viral nucleocapsid protein that envelops HIV RNA inside the virus. The zinc fingers are believed to play a vital role in two stages of the viral life cycle: (1) they bind to HIV RNA and package into anew virus budding out from the cell; and (2) they appear to stabilize the RNA during reverse transcription of HIV RNA into DNA. Compounds that eject the zinc from one of the zinc fingers may disrupt its bond with viral RNA and thus with either the maturation of new infectious virus or infection of the cell. C1-1012 targets NCp7, a highly conserved, multifunctional structural protein, and inhibits production of virions in HIV-infected cells in vitro. CI-1012 does not have direct virucidal effect since pretreated virions had similar level of infectivity as untreated virions. In vitro experiments indicate that CI-1012 inhibits an early stage of HIV infection. Comparison with other drugs such as AZT indicates that CI-1012 inhibits a step after the virus binds to cells. DNA PCR analysis of infected cells showed that the rate of full length DNA synthesis was slowed. Biochemical assay shows that CI-1012 can extrude zinc ions from HIV nucleocapsid protein. CI-1012 does not have any observable effect on genomic RNA packaging. In a rising, single-dose, placebo controlled clinical trial, oral doses of 25-, 50-, 100-, 150- and 250-mg CI-1012 were administered to 24 healthy subjects. Clinical labortory measurements, ECGs, and physical assessments were performed throughout the trial. Serial blood and urine samples were collected for CI-1012 assay. Plasma Cmax and AUC increased with increasing dose, tmax was observed 2 - 3 hours postdose, and the terminal elimination half-life averaged 33 hours. In summary, single oral doses of up to 250 mg CI-1012 demonstrated linera pharmacokinetic behavior and were well tolerated by healthy volunteers. [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 106 (abstrat no. 229).; Conf Retroviruses Opportunistic Infect 3rd Conf 1996; p 116; AmfAR Treat Dir 1997 Dec] DISEASES STUDIED/TREATED Under investigation for the treatment of primary HIV infections in asymptomatic HIV-1 infected patients. [Protocol ID: 97 I-032 ] CLASSIFICATION CODE Investigational - Zinc finger inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS CI-1012 wal well tolerated at all dose levels. The most frequently reported adverse event was headache, noted by approximately 33% of subjects who received CI-1012 and placebo. Abnormalities in clinical laboratory parameters were transient and appeared to be unrelated to CI-1012 dose. [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 106 (abstract no. 229).] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: CI-1012 is a novel benzamide-disulfide with antiviral activity against HIV-1, HIV-2, clinical isolates and AZT-resistant isolates. [Conf Retroviruses Opportunistic Infect 3rd Conf 1996; p 116] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration. [Protocol ID: 97 I-032 ] MANUFACTURERS 0000004009: Parke-Davis Pharmaceutical Research 2800 Plymouth Rd Ann Arbor, MI 48105 Contact: Dr J Tyler Martin (313)997-3556 REFERENCES MED/98049536. de Rocquiqny H, Petitjean P, Tanchou V, Decimo D, Drouot L, Delaunay T, Darlix JL, Roques BP. The zinc fingers of HIV nucleocapsid protein NCp7 direct interactions with the viral regulatory protein Vpr. J Biol Chem. 1997 Dec 5;272(49):30753-9. MED/97173291. Tummino PJ, Harvey PJ, McQuade T, Domagala J, Gogliotti R, Sanchez J, Song Y, Hupe D. The human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein Zinc ejection activity of disulfide benzamides and benzisothiazolones: correlation with anti-HIV and virucidal activities. Antimicrob Agents Chemother. 1997 Feb;41(2):394-400. AIDS/97926419. Shailer P, Brodfuehrer J, Sedman A, Vassos A. Single-dose safety, tolerance, and pharmacokinetics of CI-1012, a new HIV antiretroviral agent, in healthy volunteers. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:106(abstract no. 229). AIDS/97702501. Anonymous. Protease inhibitors and beyond. PI Perspect, 1997 Mar, No 21,15-6. MED/96323138. Turpin JA, Terpening SJ, Schaeffer CA, Yu G, Glover CJ, Felsted RL, Sausville EA, Rice WG. Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of gag precursors and result in the release of noninfectious virus particles. J Virol. 1996 Sep;70(9):6180-9. AIDS/97926098. Sharmeen L, Heldsinger A, Neorr B, McQuade T, Gracheck S, Gracheck S. Role of zinc coordinating amino acids of nucleocapsids in the HIV life cycle. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:141 (abstract no. 415). MED/96165501. Tummino PJ, Scholten JD, Harvey PJ, Holler TP, Maloney L, Gogliotti R, Domagala J, Hupe D. The in vitro ejection of zinc from human immunodeficiency virus (HIV) type 1 nucleocapsid protein by disulfide benzamides with cellular anti-HIV activity. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):969-73. AIDS/96920338. Domagala J, Gogliotti R, Sanchez J, Stier M, Tummino P, Gracheck S, Hupe D, Bader J, Schultz R, Rice W. Two novel classes of HIV-1 inhibitors which interact with 338 nucleocapsid protein P7NC: structure-activity relationships vs. antiviral activity and correlation with Zn ejection. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:116. AIDS/96920341. McQuade T, Heldsinger A, Domagala J, Gracheck S, Sharmeen L. Anti-viral activity of CI-1012 (PD 159206) and CI-1013 (PD 161374) : novel anti-HIV agents which function at early steps of virus replication. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:116. MED/96072970. Rice WG, Supko JG, Malspeis L, Buckheit RW Jr, Clanton D, Bu M, Graham L, Schaeffer CA, Turpin JA, et al. Inhibitors of HIV nucleocapsid protein zinc fingers as candidates for the treatment of AIDS. Science. 1995 Nov 17;270(5239):1194-7. MED/96015469. Yu X, Hathout Y, Fenselau C, Sowder RC 2nd, Henderson LE, Rice WG, Mendeleyev J, Kun E. Specific disulfide formation in the oxidation of HIV-1 zinc finger protein nucleocapsid p7. Chem Res Toxicol. 1995 Jun;8(4):586-90. ENTRY MONTH 199612 LAST REVISION DATE 20001106 85 UNIQUE IDENTIFIER DRG-0261 NAME OF SUBSTANCE LXR015-1 [Protocol ID: 258A ] PROTOCOL ID NUMBERS No longer recruiting FDA 258A DISEASES STUDIED/TREATED Under investigation for the treatment of primary HIV infections. [Protocol ID: 258A ] CLASSIFICATION CODE Investigational - Antiviral [Protocol ID: 258A ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules. [Protocol ID: 258A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration. [Protocol ID: 258A ] MANUFACTURERS 0000003660: LXR Biotechnology Inc 1401 Marina Way South Richmond, CA 948043746 Contact: Monica Phillips (510)412-9100 ENTRY MONTH 199611 LAST REVISION DATE 20000801 86 UNIQUE IDENTIFIER DRG-0260 NAME OF SUBSTANCE Testosterone enanthate [USPD 2000; p 700] REGISTRY NUMBER 315-37-7 [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus/. Accessed June 27, 2001.] STANDARD CHEMICAL NAME Androst-4-en-3-one, 17-((1-oxoheptyl)oxy)-, (17beta)- [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus/. Accessed June 27, 2001.] SYNONYMS Delatestryl [U.S. FDA. Electronic Orange Book. Available at http://www.fda.gov/cder/ob/default.htm. Accessed June 27, 2001.] PROTOCOL ID NUMBERS Complete NIAID ACTG 313 PHARMACOLOGICAL ACTION Testosterone is the principal endogenous androgen. Endogenous androgens are essential hormones that are responsible for a number of physical conditions, including alterations in body musculature and fat distribution. Hypogonadism is relatively common among HIV-infected patients. In addition, megestrol acetate, which is used to treat HIV-associated wasting, is known to cause a reduction in testosterone levels and may be a reason for the preferential increase in body fat versus lean muscle mass that is observed in patients taking this drug. Studies have shown that testosterone replacement in middle-aged men with mid-segment obesity decreases visceral fat, plasma glucose, and insulin levels, and also decreases blood pressure. Other studies have shown that testosterone replacement in androgen-deficient HIV-infected men decreases fat mass and augments lean body mass. While the pathophysiology of visceral obesity syndrome (visceral fat accumulation, insulin resistance, and hyperlipidemia) common to HIV-infection is multifactorial, it is possible that testosterone replacement in androgen-deficient individuals can impact favorably on this syndrome. It also is possible that testosterone replacement may substantially increase the amount of lean body mass accrued during treatment of wasting with megestrol acetate. Testosterone esters are less polar than free testosterone and, when suspended in oil and injected intramuscularly, are absorbed relatively slowly from the lipid phase. This allows for longer time intervals between doses (as much as 2 to 4 weeks for testosterone enanthate). Approximately 40 percent of circulating plasma testosterone binds to sex hormone-binding globulin (SHBG), 2 percent remains unbound (free), and the remainder binds to albumin and other proteins. The fraction bound to albumin dissociates easily and is presumed to be biologically active, whereas the SHBG fraction is not. Generally, the amount of SHBG in plasma, which varies significantly with age, determines the distribution of testosterone between free and bound forms, and free testosterone concentrations determine the drug's half-life. Testosterone half-life, however, is highly variable, with values of 10 to 100 minutes being reported in the literature. Testosterone is metabolized principally in the liver to various 17-ketosteroid metabolites, the most active of which are estradiol and dihydrotestosterone (DHT). Both testosterone and its metabolites are excreted in urine and feces (approximately 90 and 6 percent, respectively, of an intramuscular dose). [AHFS Drug Information 2000; p 2772-6; J Clin Endocrinol Metab 2000 Jan;85(1):35-41; Protocol ID: ACTG 313 ; Protocol ID: ACTG A5079 ; Protocol ID: ACTG 313 ; PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.; AHFS Drug Information 2000; p 2772-6] DISEASES STUDIED/TREATED Testosterone is included in HIV clinical trials to assess its efficacy in reducing adverse symptoms (e.g., decreased muscle mass and increased visceral fat) reported by androgen-deficient HIV-infected individuals. It also is investigated as a treatment for the testosterone deficiency that is induced by megestrol acetate in the treatment of HIV-associated wasting. [Protocol ID: ACTG A5079 ; Protocol ID: ACTG 313 ] CLASSIFICATION CODE Androgen [USP DI 2000; p 140] CLASSIFICATION CODE Antianemic [USP DI 2000; p 140] OTHER MAJOR USES Testosterone enanthate is indicated as replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone (congenital or acquired). In females who are 1 to 5 years postmenopausal, testosterone enanthate may be used for the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] SUBSTANCE INTERACTIONS Concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; these drugs should be combined with caution, particularly in patients with cardiac or hepatic disease. The use of testosterone by diabetic patients may result in decreased blood glucose levels and reduced insulin requirements; testosterone also may reduce anticoagulant requirements of patients taking oral anticoagulants. Patients should be monitored for excessive hypoglycemic or hypoprothrombinemic responses, respectively. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.; AHFS Drug Information 2000; p 2772-6] ADVERSE EFFECTS In males, adverse events associated with testosterone enanthate therapy include: hirsutism, male pattern baldness, seborrhea, and acne; gynecomastia, breast pain or tenderness, excessive frequency and duration of penile erections, abnormal ejaculation, oligospermia, prostate disorder (enlarged prostate, BPH, or elevated PSA results), testis disorder, dysuria, and urinary tract infection; retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates; nausea, diarrhea, cholestatic jaundice, and alterations in liver function tests; suppression of clotting factors II, V, VII, and X, leukopenia, and polycythemia; increased or decreased libido, headache, dizziness, asthenia, generalized paresthesia, and insomnia; anxiety, depression, personality disorder, and CNS stimulation; increased serum cholesterol; and abdominal or back pain, myalgia, and arthralgia. In females, adverse events include amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after testosterone is discontinued. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] CONTRAINDICATIONS Testosterone is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate. Testosterone is contraindicated in pregnant or lactating women. Testosterone enanthate also is contraindicated in patients with known hypersensitivity to the drug or other product ingredients. [AHFS Drug Information 2000; p 2772-6] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Testosterone enanthate is a derivative of the primary endogenous androgen, testosterone. Esterification of the 17-beta-hyroxy group of testosterone increases its duration of action. Once in the body, testosterone enanthate is hydrolyzed to the biologically active parent compound. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] CHEMICAL/PHYSICAL DATA Molecular Formula: C26-H40-O3 [ChemIDplus. Available at http://chem.sis.nlm.nih.gov/chemidplus/. Accessed June 27, 2001.] CHEMICAL/PHYSICAL DATA Molecular Weight: 400.59 [USPD 2000; p 700] CHEMICAL/PHYSICAL DATA Melting Point: 36-37.5 C [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA Elemental Comp: C79.12%, H9.78%, O11.09% (base) [Merck Index 1996; p 1569] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water; soluble in vegetable oils. [AHFS Drug Information 2000; p 2772-6] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Testosterone enanthate is a white or creamy white, crystalline powder that is odorless or has a faint odor characteristic of heptanoic acid. [AHFS Drug Information 2000; p 2772-6; PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Available in a strength of 200 mg/ml, supplied as 1 ml single dose syringes and 5 ml multiple dose vials. Chlorobutanol (chloral derivative) is included as a preservative. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection, generally administered every 2 to 4 weeks. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Testosterone enanthate injections should be stored at room temperature. A precipitate may form if the injections are stored at low temperature; warming the product between the palms of the hands facilitates dissolution. [PDR Online. Delatestryl monograph. Available at http://physician.pdr.net. Accessed June 27, 2001.] MANUFACTURERS 0000003659: Bio-Technology General Corp 70 Wood Ave South Iselin, NJ 08830 Contact: Herb Henney (908)632-8800 MANUFACTURERS 0000003659: Bio-Technology General Corp 70 Wood Ave South Iselin, NJ 08830 REFERENCES MED/21290983. Lo JC, Schambelan M. Reproductive function in human immunodeficiency virus infection. J Clin Endocrinol Metab 2001 Jun;86(6):2338-43. MED/21242786. Fairfield WP, Finkelstein JS, Klibanski A, Grinspoon SK. Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome. J Clin Endocrinol Metab 2001 May;86(5):2020-6. MED/21152732. Newshan G, Leon W. The use of anabolic agents in HIV disease. Int J STD AIDS 2001 Mar;12(3):141-4. MED/20513677. Hadigan C, Corcoran C, Piecuch S, Rodriguez W, Grinspoon S. Hyperandrogenemia in human immunodeficiency virus-infected women with the lipodystrophy syndrome. J Clin Endocrinol Metab 2000 Oct;85(10):3544-50. MED/20417627. Grinspoon S, Corcoran C, Parlman K, Costello M, Rosenthal D, Anderson E, Stanley T, Schoenfeld D, Burrows B, Hayden D, Basgoz N, Klibanski A. Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. A randomized, controlled trial. Ann Intern Med 2000 Sep 5;133(5):348-55. MED/20145260. Bhasin S, Storer TW, Javanbakht M, Berman N, Yarasheski KE, Phillips J, Dike M, Sinha-Hikim I, Shen R, Hays RD, Beall G. Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 2000 Feb 9;283(6):763-70. MED/20036233. Bhasin S, Javanbakht M. Can androgen therapy replete lean body mass and improve muscle function in wasting associated with human immunodeficiency virus infection? JPEN J Parenter Enteral Nutr 1999 Nov-Dec;23(6 Suppl):S195-201. MED/99208434. Grinspoon S, Corcoran C, Anderson E, Hubbard J, Stanley T, Basgoz N, Klibanski A. Sustained anabolic effects of long-term androgen administration in men with AIDS wasting. Clin Infect Dis 1999 Mar;28(3):634-6. MED/98299405. Grinspoon S, Corcoran C, Askari H, Schoenfeld D, Wolf L, Burrows B, Walsh M, Hayden D, Parlman K, Anderson E, Basgoz N, Klibanski A. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998 Jul 1;129(1):18-26. MED/98063664. Cofrancesco J Jr, Whalen JJ 3rd, Dobs AS. Testosterone replacement treatment options for HIV-infected men. J Acquir Immune Defic Syndr Hum Retrovirol 1997 Dec 1;16(4):254-65. ENTRY MONTH 199611 LAST REVISION DATE 20010627 87 UNIQUE IDENTIFIER DRG-0259 NAME OF SUBSTANCE Interleukin-12 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 325 PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS Recruiting CC 01 C-0067 PROTOCOL ID NUMBERS Recruiting CC 96 C-0113 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5049 PROTOCOL ID NUMBERS Recruiting NIAID DAIDS R001 PROTOCOL ID NUMBERS Terminated CC 98 I-0091 CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3322] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p. 3322] MANUFACTURERS 0000003658: Genetics Institute 87 CambridgePark Drive Cambridge, MA 02140 Contact: Celine Briscoe (617)498-8133 REFERENCES ICA11/96925477. Daftarian PM, Kumar A, Diaz-Mitoma F. Interleukin(IL)-12 induces IL-10 expression in peripheral blood mononuclear cells (PBMC) from HIV-infected individuals. Int Conf AIDS. 1996 Jul 7-12;11(2):442 (abstract no.Pub.A.1027). AIDS/97920698. Gomez KC, Laraque F, Cervia JS, Drago T, Sia C, Sypek J, He S, Noel GJ, Ho JL. Altered cellular immunity to HIV proteins and tetanus toxoid in HIV-infected children: in vitro restoration by interleukin-12. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;124(poster no.4). AIDS/96920472. Chehimi J, Zyad A, Ruby B, Trinchieri G, Starr S. Production and immunomodulatory effects of IL-12 in HIV-infected infants. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:141. AIDS/96920309. Jacobson MA, Hardy D, Connick E, Anderson R, Debruin M. Phase I trial of recombinant human interleukin 12 (rhIL-12) in 309 HIV-infected subjects. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:110. AIDS/96700677. Anonymous. Genetics Institute suspends phase II study of rhiL-12. J Int Assoc Physicians AIDS Care. 1995 Jun;1(5):34. AIDS/95920437. McFarland E, Harding PA, Schooley RT, Kuritzkes DR. Interleukin-12 (IL-12) enhances natural killer cell activity in peripheral blood mononuclear cells from HIV-infected infants and children. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:129. AIDS/95920535. Perales MA, Lieberman J. IL-12 induces HIV-1 replication in CD8-depleted PBMC from some seropositive donors. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:148. ENTRY MONTH 199611 LAST REVISION DATE 20000801 88 UNIQUE IDENTIFIER DRG-0258 NAME OF SUBSTANCE Amprenavir [Protocol ID: 94 I-202 ] REGISTRY NUMBER 161814-49-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Carbamic acid, ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methy- lpropyl)amino)-2-hydrox y-1-(phenylmethyl)propyl)-, (3S)-tetrahydro-3-furanyl ester [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed April 13, 2001] SYNONYMS Agenerase [USP DI 2000; p. 122] PROTOCOL ID NUMBERS Complete CC 00 I-0053 PROTOCOL ID NUMBERS Complete NIAID ACTG 347 PROTOCOL ID NUMBERS Complete NIAID ACTG 373 PROTOCOL ID NUMBERS No longer recruiting FDA 238J PROTOCOL ID NUMBERS No longer recruiting FDA 264A PROTOCOL ID NUMBERS No longer recruiting FDA 264B PROTOCOL ID NUMBERS No longer recruiting FDA 264C PROTOCOL ID NUMBERS No longer recruiting FDA 264D PROTOCOL ID NUMBERS No longer recruiting FDA 264E PROTOCOL ID NUMBERS No longer recruiting FDA 264F PROTOCOL ID NUMBERS No longer recruiting FDA 264G PROTOCOL ID NUMBERS No longer recruiting FDA 264H PROTOCOL ID NUMBERS No longer recruiting FDA 264J PROTOCOL ID NUMBERS No longer recruiting FDA 264K PROTOCOL ID NUMBERS No longer recruiting FDA 264L PROTOCOL ID NUMBERS No longer recruiting FDA 264M PROTOCOL ID NUMBERS No longer recruiting FDA 264N PROTOCOL ID NUMBERS No longer recruiting FDA 280C PROTOCOL ID NUMBERS No longer recruiting FDA 280D PROTOCOL ID NUMBERS No longer recruiting FDA 295B PROTOCOL ID NUMBERS No longer recruiting FDA 299A PROTOCOL ID NUMBERS No longer recruiting CC 94 I-202 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0147 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS Recruiting FDA 313A PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5043 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5061 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5072 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-04-008 PROTOCOL ID NUMBERS Terminated CC 99 I-0062 PHARMACOLOGICAL ACTION MODE OF ACTION: HIV encodes a homodimeric aspartyl protease that plays a role in viral replication. Inhibition of this enzyme blocks the cleavage of gag and gag-pol polyprotein precursors into key structural proteins and replication enzymes, and results in the production of morphologically altered, non-infectious virus particles. It is assumed that 141W94 inhibits the virally encoded protease and causes the resulting inability to process gag and gag-pol polyproteins. Antiviral activity of 141W94 is specific for HIV. In vitro no activity was observed against HSV-1, HSV-2, VZV, HCMV or a variety of other viruses. In a phase I study 150, 300, 600, 900 and 1,200 mg doses of 141W94. The terminal half-life of the substance remained relatively constant average plasma concentrations at 8 and 12 h after dosing were greater than 10 times the IC50. [Drugs Fut 1996; 21(4); p 347-50] DISEASES STUDIED/TREATED HIV infection. [Protocol ID: 94 I-202 ] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 119] CLASSIFICATION CODE Protease inhibitor [AHFS Drug Information 2000; p. 590] ADVERSE EFFECTS The lack of cytotoxicity of 141W94 was confirmed in several in vitro systems. Preclinical toxicity studies were done in mice and rats (p.o. and i.v. routes). The acute toxicity of 141W94 was low. The oral median lethal dose was greater than 3,000 mg/kg. The i.v. median lethal dose was greater than 300 mg/kg in mice. A human phase I trial showed 141W94 to be well tolerated when administered to HIV+ individuals at single doses up to 1,200 mg. No serious adverse experience or laboratory test abnormalities were found. [Drugs Fut 1996; 21(4); p 347-50] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: 141W94 is a peptomimetic with three asymmetric centers. It represents one of the smaller, less stereochemically complex of the protease inhibitors currently under development. [Drugs Fut 1996; 21(4); p 347] CHEMICAL/PHYSICAL DATA Molecular Formula: C25-H35-N3-O6-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules. [Drugs Fut 1996; 21(4); p 349] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Drugs Fut 1996; 21(4); p 349] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000003873: Vertex Pharmaceuticals Inc 130 Waverly Street Cambridge, MA 021394242 Contact: Jaime Hernandez (919)483-6300 REFERENCES MED/99312177. Amprenavir approved for HIV treatment. Am J Health Syst Pharm 1999 Jun 1;56(11):1057-8. MED/99318598. Sadler BM, Hanson CD, Chittick GE, Symonds WT, Roskell NS. Safety and pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus (HIV) type 1 protease inhibitor, following oral administration of single doses to HIV-infected adults. Antimicrob Agents Chemother 1999 Jul;43(7):1686-92. MED/99285299. Updated data on amprenavir. Aids Patient Care STDS 1999 May;13(5):307. MED/99169170. Murphy RL, Gulick RM, DeGruttola V, D'Aquila RT, Eron JJ, Sommadossi JP, Currier JS, Smeaton L, Frank I, Caliendo AM, Gerber JG, Tung R, Kuritzkes DR. Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infection. AIDS Clinical Trials Group 347 Study Team. J Infect Dis 1999 Apr;179(4):808-16. MED/99236556. Kaul DR, Cinti SK, Carver PL, Kazanjian PH. HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications. Pharmacotherapy 1999 Mar;19(3):281-98. Review. MED/98409695. Drusano GL, D'Argenio DZ, Symonds W, Bilello PA, McDowell J, Sadler B, Bye A, Bilello JA. Nucleoside analog 1592U89 and human immunodeficiency virus protease inhibitor 141W94 are synergistic in vitro. Antimicrob Agents Chemother 1998 Sep;42(9):2153-9. MED/98280592. Adkins JC, Faulds D. Amprenavir. Drugs 1998 Jun;55(6):837-42; discussion 843-4. Review. MED/98313372. Decker CJ, Laitinen LM, Bridson GW, Raybuck SA, Tung RD, Chaturvedi PR. Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 1998 Jul;87(7):803-7. Tisdale M, Myers RE, Harrigan PR, Larder BA. Analyses of HIV genotype and phentype during 4 weeks dose-escalating monotheraphy with the HIV protease inhibitor 141W94 in Hiv-infected patients with CD4 counts 150-400/mm3. AIDS/97926520. 4th Conf Retro and Opportun Infect 1997 Jan 22-26:174 (abstract no. 593). MED/96283736. St. Clair MH, Millard J, Rooney J, Tisdal M, Parry N, Sadler BM, Blum MR, Painter G. In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antiviral Res 1996 Jan;29(1):53-6. AIDS/95920638. Painter GR, St Clair MH, Demiranda P, Reynolds D, Ching S, Dornsife R, Livingston DJ, Pazhanisamy S, Tung R. An overview of the preclinical development of the HIV protease inhibitor VX-478 (141W94). Natl Conf Hum Retroviruses Relat Infect (2nd) 1995 Jan 29-Feb 2:167. ENTRY MONTH 199611 LAST REVISION DATE 20010420 89 UNIQUE IDENTIFIER DRG-0257 NAME OF SUBSTANCE Abacavir sulfate [USP DI 2000; p 3] REGISTRY NUMBER 188062-50-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-p- urin-9-yl]-2-cyclopente ne-1-methanol sulfate (salt) (2:1) [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] SYNONYMS component of Trizivir [Protocol ID: 308A ] SYNONYMS Ziagen [USP DI 2000; p 3] PROTOCOL ID NUMBERS Complete CC 00 I-0053 PROTOCOL ID NUMBERS Complete NIAID ACTG 330 PROTOCOL ID NUMBERS Complete NIAID ACTG 368 PROTOCOL ID NUMBERS No longer recruiting FDA 238A PROTOCOL ID NUMBERS No longer recruiting FDA 238B PROTOCOL ID NUMBERS No longer recruiting FDA 238C PROTOCOL ID NUMBERS No longer recruiting FDA 238D PROTOCOL ID NUMBERS No longer recruiting FDA 238E PROTOCOL ID NUMBERS No longer recruiting FDA 238F PROTOCOL ID NUMBERS No longer recruiting FDA 238G PROTOCOL ID NUMBERS No longer recruiting FDA 238H PROTOCOL ID NUMBERS No longer recruiting FDA 238J PROTOCOL ID NUMBERS No longer recruiting FDA 238K PROTOCOL ID NUMBERS No longer recruiting FDA 238L PROTOCOL ID NUMBERS No longer recruiting FDA 238M PROTOCOL ID NUMBERS No longer recruiting FDA 238R PROTOCOL ID NUMBERS No longer recruiting FDA 238T PROTOCOL ID NUMBERS No longer recruiting FDA 264B PROTOCOL ID NUMBERS No longer recruiting FDA 264F PROTOCOL ID NUMBERS No longer recruiting FDA 264H PROTOCOL ID NUMBERS No longer recruiting FDA 264K PROTOCOL ID NUMBERS No longer recruiting FDA 264L PROTOCOL ID NUMBERS No longer recruiting FDA 264M PROTOCOL ID NUMBERS No longer recruiting FDA 264N PROTOCOL ID NUMBERS No longer recruiting FDA 264P PROTOCOL ID NUMBERS No longer recruiting FDA 280B PROTOCOL ID NUMBERS No longer recruiting FDA 280C PROTOCOL ID NUMBERS No longer recruiting FDA 280D PROTOCOL ID NUMBERS No longer recruiting FDA 295B PROTOCOL ID NUMBERS No longer recruiting FDA 299A PROTOCOL ID NUMBERS No longer recruiting FDA 307A PROTOCOL ID NUMBERS No longer recruiting FDA 308A PROTOCOL ID NUMBERS No longer recruiting FDA 316A PROTOCOL ID NUMBERS No longer recruiting CC 94 I-202 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0147 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5014 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5064 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5105 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG P1018 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 316B PROTOCOL ID NUMBERS Recruiting NIAID ACTG 321 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 356 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5061 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5072 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5103 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-04-008 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended FDA 298B PROTOCOL ID NUMBERS Terminated CC 99 I-0062 PHARMACOLOGICAL ACTION Abacavir is a prodrug that is pharmacologically active only after conversion to carbovir triphosphate. This conversion depends on cellular rather than viral enzymes and occurs in both virus-infected and uninfected cells. Carbovir triphosphate is a structural analogue of deoxyguanosine-5'-triphosphate, which is the natural substrate for viral RNA-directed DNA polymerase (reverse transcriptase). The absence of a 3'-hydroxy group on carbovir triphosphate prevents formation of phosphodiester linkages that are needed for the elongation of DNA chains. Strains of HIV type 1 (HIV-1) with reduced susceptibility or resistance to abacavir have been recovered both in vitro and in vivo. Mutation of HIV reverse transcriptase appears to be the principal mechanism of resistance. Point mutations result in amino acid substitutions at positions K65R, L74V, Y115F, and M184V. Cross-resistance between abacavir and some deoxynucleoside reverse transcriptase inhibitors (didanosine, lamivudine, and zalcitabine) has been reported. Most strains of HIV-1 isolates that were resistant to multiple deoxynucleosides were also resistant to abacavir. Cross-resistance between abacavir and protease inhibitors is unlikely because the drugs target different enzymes; cross-resistance between abacavir and nonnucleoside reverse transcriptase inhibitors is also unlikely due to different binding sites and mechanisms of action. Abacavir sulfate is well absorbed following oral administration, with a bioavailability of approximately 83%. Systemic absorption is comparable following administration of tablets and oral solution. Peak plasma concentrations occur from 0.75 to 1.7 hours after a dose. Administration with food may decrease peak concentration but does not significantly affect bioavailability. Following intravenous administration of abacavir sulfate the apparent volume of distribution is 0.86 L/kg, suggesting distribution into the extravascular compartment. Concentrations in cerebrospinal fluid range from 27 to 33% of the corresponding plasma concentrations. Abacavir also readily distributes into erythrocytes. Protein binding is moderate (about 50%) and is independent of drug concentration. Abacavir sulfate is metabolized in the liver by alcohol dehydrogenase and glucuronosyltransferase. Metabolites lack antiviral activity. The elimination half-life following a single dose is approximately 1.5 hours. Limited information is available on the pharmacokinetics of abacavir in renal or hepatic impairment. [AHFS Drug Information 2000; p. 585-586; USP DI 2000; p. 1] DISEASES STUDIED/TREATED Abacavir sulfate is indicated, in combination with other agents, for treatment of human immunodeficiency virus (HIV) infection in adults and children. In initial clinical studies, abacavir was used in combination with 2 other nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine). The use of abacavir in combination with HIV protease inhibitors and/or nonnucleoside reverse transcriptase inhibitors is being evaluated. [USP DI 2000; p. 1; AHFS Drug Information 2000; p. 587] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 585] SUBSTANCE INTERACTIONS There are no significant effects of food on abacavir sulfate absorption and bioavailability. Alcohol ingested during treatment with abacavir may result in increased concentrations and half-life of the antiviral due to competition for common metabolic pathways. Abacavir is not significantly metabolized by cytochrome P450 (CYP) enzymes. Clinically important interactions between abacavir and drugs metabolized through these pathways are not expected. Concomitant administration of abacavir and the protease inhibitor amprenavir, which is metabolized principally by the 3A4 CYP isoenzyme, increases bioavailability and plasma concentrations of the latter. Dosage adjustment is not required according to the amprenavir manufacturer. Clinically significant pharmacokinetic interactions have not been observed in studies evaluating the combination of abacavir and the nucleoside reverse transcriptase inhibitors, lamivudine and zidovudine. Although specific studies have not been performed, clinically important drug interactions with nonnucleoside reverse transcriptase inhibitors are not expected. Finally, in vitro studies have demonstrated synergistic or additive antiviral effects against HIV-1 when abacavir is combined with amprenavir, lamivudine, zidovudine, and nevirapine. [USP DI 2000; p. 2] ADVERSE EFFECTS Abacavir is generally well tolerated; however, potentially life threatening hypersensitivity reactions have been reported in 5% of clinical trial patients receiving the drug in combination with lamivudine and zidovudine. Risk factors for these reactions have not been identified. Symptoms usually appear within the first six weeks of treatment with abacavir, although they may occur at any time. Multiple organ and body systems may be involved, and the condition may progress to anaphylaxis, hypotension, hepatic or renal failure, and death. The most frequent manifestations include fever, skin rash, fatigue, gastrointestinal symptoms, or respiratory symptoms such as pharyngitis, dyspnea, or cough. Other signs and symptoms include malaise, lethargy, myalgia, arthralgia, edema, paresthesia, lymphadenopathy, and mucous membrane lesions. Rash may or may not occur. Symptoms worsen with continued therapy but frequently resolve upon withdrawal of the drug. Abacavir should be discontinued permanently at the first sign of hypersensitivity, even if hypersensitivity cannot be confirmed and other causes are possible. Patients should not be rechallenged. The most severe hypersensitivity reactions appear to occurr with re-exposure to the drug. Hypersensitivity reactions should be reported to the Abacavir Hypersensitivity Registry, at 1-800-270-0425. When therapy with abacavir has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of therapy is under consideration, the reason for discontinuation should be unambiguous otherwise the drug should not be reintroduced. Other severe, but less frequent, reactions include hepatotoxicity, consisting of lactic acidosis and severe hepatomegaly with steatosis, and pancreatitis. Fatalities have occurred. Possible risk factors include female gender, obesity, and prolonged nucleoside exposure. Less serious side effects include nausea or vomiting, diarrhea, loss of appetite, headache, fatigue, and insomnia. [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.; U.S. FDA. MedWatch. Safety-Related Drug Labeling Changes. Available at: http://www.fda.gov/medwatch/safety/2000/jul00- .htm. Accessed 10/10/00.; USP DI 2000; p. 2; Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] CONTRAINDICATIONS Abacavir sulfate is contraindicated in patients with previously demonstrated hypersensitivity to the drug or any other components of the commercial product. [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Abacavir is a synthetic analogue of guanine, a naturally occurring purine nucleoside. It differs structurally from other reverse transcriptase inhibitors (didanosine, lamivudine, stavudine, zalcitabine, and zidovudine) in that it is a carbocyclic nucleoside rather than a dideoxynucleoside. [AHFS Drug Information 2000; p. 585] CHEMICAL/PHYSICAL DATA Molecular Formula: (C14-H18-N6-O)2-H2-S-O4 [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 670.76 [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Elemental Comp: C50.14%, H5.71%, N25.06%, O14.31%, S4.78% [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Abacavir sulfate is freely soluble in distilled water (77mg/ml at 25 C). [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Abacavir sulfate is a white to off-white solid. [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Abacavir sulfate is available as tablets equivalent to 300 mg of abacavir; oral solution contains 20 mg/ml abacavir. [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Glaxo Wellcome. Ziagen product information. Available at: http://www.ziagen.com/. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets and oral solution should be stored at controlled room temperature of 20 to 25 C. Oral solution may be refrigerated but should not be frozen. [USP DI 2000; p. 3] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 REFERENCES MED/99385798. Margolis D, Heredia A, Gaywee J, Oldach D, Drusano G, Redfield R. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr 1999 Aug 15;21(5):362-70. MED/99381767. Chittick GE, Gillotin C, McDowell JA, Lou Y, Edwards KD, Prince WT, Stein DS. Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food. Pharmacotherapy 1999 Aug;19(8):932-42. MED/99376541. Escaut L, Liotier JY, Albengres E, Cheminot N, Vittecoq D. Abacavir rechallenge has to be avoided in case of hypersensitivity reaction. AIDS 1999 Jul 30;13(11):1419-20. MED/99318602. Wang LH, Chittick GE, McDowell JA. Single-dose pharmacokinetics and safety of abacavir (1592U89), zidovudine, and lamivudine administered alone and in combination in adults with human immunodeficiency virus infection. Antimicrob Agents Chemother 1999 Jul;43(7):1708-15. MED/99246337. Deeks SG, Hellman NS, Grant RM, Parkin NT, Petropoulos CJ, Becker M, Symonds W, Chesney M, Volberding PA. Novel four-drug salvage treatment regimens after failure of a human immunodeficiency virus type 1 protease inhibitor-containing regimen: antiviral activity and correlation of baseline phenotypic drug susceptibility with virologic outcome. J Infect Dis 1999 Jul;179(6):1375-81. MED/99254254. Barry M, Mulcahy F, Merry C, Gibbons S, Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999 Apr;36(4):289-304. MED/99205493. Kline MW, Blanchard S, Fletcher CV, Shenep JL, McKinney RE Jr, Brundage RC, Culnane M, Van Dyke RB, Dankner WM, Kovacs A, Pearce G. A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team. Pediatrics 1999 Apr;103(4):e47. MED/99169762. Kumar PN, Sweet DE, McDowell JA, Symonds W, Lou Y, Hetherington S, LaFon S. Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 1999 Mar;43(3):603-8. MED/99049594. Saag MS, Sonnerborg A, Torres RA, Lancaster D, Gazzard BG, Schooley RT, Romero C, Kelleher D, Spreen W, LaFon S. Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV-infected adults. Abacavir Phase 2 Clinical Team. AIDS 1998 Nov 12;12(16):F203-9. ENTRY MONTH 199610 LAST REVISION DATE 20001010 90 UNIQUE IDENTIFIER DRG-0256 NAME OF SUBSTANCE Measles-Mumps-Rubella Vaccine (Live) [Protocol ID: ACTG 225 ] SYNONYMS M-M-R II [USP DI 2000; p 2052] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 225 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1024 PHARMACOLOGICAL ACTION M-M-R II is highly immunogenic and generally well tolerated. A single injection of the vaccine induced measles hemagglutination-inhibition (HI) antibodies in 95%, mumps neutralizing antibodies in 96%, and rubella HI antibodies in 99% of susceptible persons. Vaccine induced antibody levels following administration of M-M-R II have been shown to persist up to 11 years without substantial decline. [PDR 1997; p 1730] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 2047] OTHER MAJOR USES Immunization against measles (rubeola), mumps and rebella (German measles). [PDR 1997; p 1730] SUBSTANCE INTERACTIONS Measles virus vaccine live may temporarily suppress tuberculin skin sensitivity; therefore, skin test should be done before, simultaneously with, or 4-6 weeks after administration of the vaccine. Manufacturer states that administration of this vaccine should be separated by at least 1 month from administration of live virus vaccines other than poliovirus, rubella, or mumps. Patients receiving immunosuppressive agents may have a diminished response to this vaccine and replication of the virus may be potentiated. The interval between discontinuance of above therapy and regaining the ability to respond to live virus vaccines is estimated to vary from 3-12 months. Measles virus vaccine live should be deferred for at least 3 months following administration of hepatitis B immune globulin, tetanus immune globulin, IGIM used for preexposure or postexposure prophylaxis of hepatitis A infection, or red blood cells; for at least 4 months following administration of rabies immune globulin; for at least 5 months following administration of varicella-zoster immune globulin or IGIM used for measles prophylaxis in immunocompetent patients; for at least 6 months following use of IGIM for measles prophylaxis in immunodeficient patients or administration of packed red blood cells or whole blood; for at least 7 months following administration of plasma or platelet products; for at least 8 months following administration of IGIV for replacement therapy of immunodeficiencies; for at least 8-10 months following administration of IGIV for the treatment of idiopathic thrombocytopenic purpura (ITP); or for at least 11 months following administration of IGIV for Kawasaki syndrome. [AHFS Drug Information 1997; p 2613-4] ADVERSE EFFECTS Burning and/or stinging of short duration at the injection site and anaphylaxis and anaphylactoid reactions have been reported. The adverse clinical reactions associated with the use of M-M-R II are those expected to follow administration of the monovalent vaccines given separately. These may include malaise, sore throat, cough rhinitis, headache, dizziness, fever, rash, nausea, vomiting or diarrhea; mild local reactions such as erythema, induration, tenderness and regional lymphadenopathy; parotitis, orchitis, nerve deafness, thrombocytopenia and purpura; allergic reactions such as wheal and flare at the injection site or urticaria; polyneuritis; and arthralgia and/or arthritis (usually transient and rarely chronic). Vasculitis, otitis media, and conjunctivitis have also been reported. Moderate fever [101-102.9F (38.3-39.4C)] may occur occasionally, high fever [over 103F (39.4C)] occurs less commonly. On rare occasions, children developing fever may exhibit febrile convulsions. Afebrile convulsions or seizures; syncope; erythema multiforme; forms of opti neuritis, including retrobulbar neuritis, papillitis, and retinitis have been reported. [PDR 1997; p 1732] CONTRAINDICATIONS Contraindicated in patients with anaphylactic or anaphylactoid reactions to neomycin or eggs; patients with febrile respiratory illness or other active febrile infections; patients with active untreated tuberculosis; patients who are receiving immunosuppressive therapy; patients with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems; patients with primary and acquired immunodeficiency states, including patients who are immunosuppressed in association with AIDS or other clinical manisfectations of infection with human immunodeficiency viruses, cellular immune deficiencies, and hypogammaglobulinemic and dysgammaglobulinemic states; patients with a history of congenital or hereditary immunodeficiency. Do not give M-M-R II to pregnant females; if vaccination of postpubertal females is undertaken, pregnancy should be avoided for 3 months following vaccination. [PDR 1997; p 1731] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A sterile lyophilized preparation of (1) ATTENUVAX (Measles Virus Vaccine live), a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and grown in cell cultures of chick embryo; (2) MUMPSVAX (Mumps Virus Vaccine live), the Jeryl Lynn (B level) strain of mumps virus grown in cell culture of chick embryo; and (3) MERUVAX II (Rubella Virus Vaccine live), the Wistar RA 27/3 strain of live attenuated rubella virus grown in human diploid cell (WI-38) culture. [PDR 1997; p 1730] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lyophilized vaccine in vial of single dose, or 10 dose is supplied with a vial of diluent. When reconstituted as directed, the dose for injectin is 0.5ml and contains not less than the equivalent of 1,000 TCID 50 of the U.S. Reference mumps virus, and 1,000 TCID 50 of the U.S. Reference Rubella Virus. [PDR 1997; p 1732] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection preferably into the outer aspect of upper arm. [PDR 1997; p 1732] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Before reconstitution, store M-M-R II at 2-8 C (36-46 F) prot ected from light. Store reconstituted vaccine in the vaccine vial in a dark place at 2-8 C and discard if not used within 8 hours. [PDR 1997; p 1732] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES MED/96312573. Anonymous. Measles pneumonitis following measles-mumps-rubella vaccination of a patient with HIV infection, 1993. MMWR Morb Mortal Wkly Rep. 1996 Jul;45(28):603-6. ENTRY MONTH 199610 LAST REVISION DATE 20010417 91 UNIQUE IDENTIFIER DRG-0255 NAME OF SUBSTANCE Measles Virus Vaccine (Live) [PDR 1997; p 650] SYNONYMS Attenuvax [PDR 1997] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 225 PHARMACOLOGICAL ACTION MODE OF ACTION: Measles virus vaccine live stimulates active immunity to measles by inducing production of measles-specific immunoglobulin G (IgG) and M (IgM) antibodies (humoral immunity). The vaccine produces an inapparent or mild, noncommunicable infection. The antibody response to initial vaccination (primary response) resembles that caused by primary natural measles infection, with an initial transient increase in serum IgM titers and a subsequent increase in serum IgG titers, although the titers achieved with vaccination are lower. As with natural infection, IgG antibody titers decline slowly over time, but immunity is thought to persist for many years and possibly lifelong in most vaccines. Individuals who experience initial antigenic stimulation from either natural infection or vaccine generally exhibit and anamnestic (secondary) response to subsequent revaccination or exposure to natural measles. This anamnestic response generally is characterized by a rapid but often transient increase in serum IgG titers, but little or no detectable IgM production. [AHFS Drug Information 1997; p 2608] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 2043] OTHER MAJOR USES Immunization against measles (rubeola). [PDR 1997; p 1650] SUBSTANCE INTERACTIONS Measles virus vaccine live may temporarily suppress tuberculin skin sensitivity; therefore, skin test should be done before, simultaneously with, or 4-6 weeks after administration of the vaccine. Manufacturer states that administration of this vaccine should be separated by at least 1 month from administration of live virus vaccines other than poliovirus, rubellla, or mumps. Patients receiving immunosuppressive agents may have a diminished response to this vaccine and replication of the virus may be potentiated. Vaccination should be deferred until immunosuppressive agent is discontinued. The interval between discontinuance of above therapy and regaining the ability to respond to live virus vaccines is estimated to vary from 3-12 months. Measles virus vaccine live should be deferred for at least 3 months following administration of hepatitis B immune globulin, tetanus immune globulin, IGIM used for preexposure or postexposure prophylaxis of hepatitis A infection, or red blood cells; for at least 4 months following administration of rabies immune globulin; for at least 5 months following administration of varicella-zoster immune globulin or IGIM used for measles prophylaxis in immunocompetent patients; for at least 6 months following use of IGIM for measles prophylaxis in immunodeficient patients or administration of packed red blood cells or whole blood; for at least 7 months following administration of plasma or platelet products; for at least 8 months following administration of IGIV for replacement therapy of immunodeficiencies; for at least 8-10 months following administration of IGIV for the treatment of idiopathic thrombocytopenic purpura (ITP); or for at least 11 months following administration of IGIV for Kawasaki syndrome. [PDR 1997; p 2608] ADVERSE EFFECTS Burning and/or stinging of short duration at the injection site and anaphylaxis and anaphylactoid reactions have been reported. Occasionally, moderate fever [101-102.9F(38.3-39.4)], rash, or both may occur during the month after vaccination; cough, rhinitis, and Erythema multiforme have also been reported. High fever [over 103F(39.4C)] and lymphadenopathy have been reported but are less common. Rarely, allergic reactions such as wheal and flare at the injectin site or urticaria; diarrhea; febrile convulsions with children developing fever; afebrile convulsions or seizures; syncope; thrombocytopenia and purpura; vasculitis; forms of optic neuritis, including retrobulbar neuritis, papillistis, and retinitis. [PDR 1997; p 1650] CONTRAINDICATIONS Contraindicated in patients with anaphylactic or anaphylactoid reactions to neomycin or eggs; patients with febrile respiratory illness or other active febrile infections; patients with active untreated tuberculosis; patients who are receiving immunosuppressive therapy; patients with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems; patients with primary and acquired immunodeficiency states, including patients who are immunosuppressed in association with AIDS or other clinical manisfestations of infection with human immunodeficiency viruses, cellular immune deficiencies, and hypogammaglobulinemic and dysgammaglobulinemic states; patients with a history of congenital or hereditary immunodeficiency. Do not give Attenuvax to pregnant females; if vaccination of postpubertal females is undertaken, pregnancy should be avoided for 3 months following vaccination. [PDR 1997; p 1650] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A sterile lyophilized preparation of a more attenuated line of measles virus derived from Ender's attenuated Edmonston strain. [PDR 1997; p 1650] CHEMICAL/PHYSICAL DATA Stability: The expiration date of measles virus vaccine live is 1-2 years, depending on the manufacturer's data, after the date of issue from the manufacturer's cold storage (e.g., 1 year when the manufacturer's cold storage was -20C). [AHFS Drug Information 1997; p 2608] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lyophilized vaccine in vial of single dose, 10-dose, or 50-dose is supplied with a vial of diluent. When reconstituted as directed, the dose for injection is 0.5ml and contains not less than 1,000 TCID (tissue culture infectious doses) of the U.S. Referance virus. [PDR 1997; p 1651; AHFS Drug Information 1997; p 2614] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection preferably into the outer aspect of the upper arm. [PDR 1997; p 1651; AHFS Drug Information 1997; p 2614] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Before reconstitution, store Attenuvax at 2-8 C (36-46 F) protected from light. Store reconstituted vaccine in the vaccine vial in a dark place at 2-8 C and discard if not used within 8 hours. [PDR 1997; p 1651] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES ASHM8/97153700. Crowe S. vaccination for the person with HIV infection. Annu Conf Australas Soc HIV Med.1996 Nov 14-17;8:104(abstract no.119). ICA11/96923168. Angel JB, Snydman DR, Udem SA, Delellis RA, Walpita P, Lerch R, Sidhu MS, Noble JT. A fatal case of pneumonitis due to vaccine-strain measles virus in a man with acquired immunodeficiency syndrome. Int Conf AIDS.1996 Jul 7-12;11(2):17(abstract no.WeB.110). MED/96333977. Anonymous. National Advisory Committee on Immunization (NACI) Interim advisory on measles revaccination of persons with acquired immunodeficiency syndrome (AIDS). Can Commun Dis Rep. 1996 Jul;22(14):116-7. ICA11/96921368. Embree J, Nagelkerke N, Datta P, Njenga S, Ndinya-Achola Jo, Plummer FA. Int Conf AIDS.1996 Jul 7-12; 11(1):107(abstract no.Mo.B.1304). ENTRY MONTH 199610 LAST REVISION DATE 20000801 92 UNIQUE IDENTIFIER DRG-0254 NAME OF SUBSTANCE Bacteriophage phi X 174 [MeSH ] PROTOCOL ID NUMBERS Complete CC 96 I-58 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 402 CLASSIFICATION CODE Diagnostic aid - Immune system function [Protocol ID: 96 I-58 ] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/96351468. Szostak MP, Hensel A, Eko FO, Klein R, Auer T, Mader H, Haslberger A, Bunka S, Wanner G, Lubitz W. Bacterial ghosts: non-living candidate vaccines. J Biotechnol 1996. Jan 26;44(1-3):161-70. ENTRY MONTH 199610 LAST REVISION DATE 20000801 93 UNIQUE IDENTIFIER DRG-0253 NAME OF SUBSTANCE Hydroxyurea [USPD 2000; p 358] REGISTRY NUMBER 127-07-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Urea, hydroxy- [USPD 1998; p 365] SYNONYMS Droxia [USP DI 2000; p 1739] SYNONYMS Hydrea [USP DI 2000; p 1739] PROTOCOL ID NUMBERS Complete NIAID ACTG 307 PROTOCOL ID NUMBERS Complete NIAID ACTG A5039 PROTOCOL ID NUMBERS No longer recruiting FDA 238R PROTOCOL ID NUMBERS No longer recruiting FDA 244C PROTOCOL ID NUMBERS No longer recruiting FDA 244D PROTOCOL ID NUMBERS No longer recruiting FDA 292C PROTOCOL ID NUMBERS No longer recruiting FDA 296A PROTOCOL ID NUMBERS No longer recruiting FDA 304A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5069 PROTOCOL ID NUMBERS Recruiting CC 99 C-0118 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Terminated FDA 292D PROTOCOL ID NUMBERS Terminated FDA 292E PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PROTOCOL ID NUMBERS Terminated NIAID AIEDRP AI-03-001 PHARMACOLOGICAL ACTION Exactly how hydroxyurea produces its cytotoxic and cytoreproductive effects is unknown. In vitro studies support the theory that hydroxyurea produces its effects via inhibition of ribonucleotide reductase, a cellular enzyme responsible for the synthesis of deoxynucleoside triphosphates. The decrease in deoxynucleoside triphosphates, particularly dATP, results in inhibition of DNA synthesis. There is no effect on synthesis of RNA or protein. After oral administration, hydroxyurea is readily absorbed from the gastrointestinal tract and reaches peak serum concentration within 2 hours. Elimination is primarily via the kidneys. [USP DI 2000; p 1739; PDR 2000; p 861, 865] DISEASES STUDIED/TREATED Previous studies have shown that addition of hydroxyurea to some reverse transcriptase inhibitor treatment regimens results in increased antiviral effects. Further study is needed to evaluate the role of this drug as an adjunct to antiretroviral drug regimens. [AHFS Drug Information 2000; p 944] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1739] CLASSIFICATION CODE Sickle cell disease therapy agent [USP DI 2000; p 3204] OTHER MAJOR USES Hydroxyurea is FDA-approved for treatment of several forms of cancer, resistant chronic myelocytic leukemia, and sickle cell anemia. Also, hydroxyurea is used to treat essential thrombocytosis and polycythemia vera. [USP DI 2000; p 1739, 3204] SUBSTANCE INTERACTIONS There are no reported effects of food or other drugs on hydroxyurea. However, caution is recommended when the drug is used concurrently with other blood dyscrasia-causing medications or bone marrow depressants. Also, because hydroxyurea may suppress normal defense mechanisms, immunization of patients with a live virus vaccine should be undertaken only with extreme caution. [PDR 2000; p 865; USP DI 2000; p 1740] ADVERSE EFFECTS Adverse effects associated with the use of hydroxyurea include bone marrow depression (anemia, leukopenia, and thrombocytopenia). Leukopenia generally develops first, about 10 days after the start of therapy, and is most common. Stomatitis, nausea, anorexia, vomiting, and diarrhea also are reported. Dermatologic reactions, including atrophy, brittle nails, darkening or redness of the skin, and skin ulcers or rash, have been reported rarely in patients taking hydroxyurea daily for several years. In patients with severe renal function impairment, administration of hydroxyurea may result in visual and auditory hallucinations and pronounced hematologic toxicity. [USP DI 2000; p 1740; PDR 2000; p 865] CONTRAINDICATIONS This medication is contraindicated in patients with leukopenia (WBC <2,500), thrombocytopenia (platelets <100,000), or severe anemia. [PDR 2000; p 865] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Hydroxyurea is structurally similar to urea and acetohydroxamic acid and is also a urease inhibitor. [AHFS Drug Information 2000; p 941] CHEMICAL/PHYSICAL DATA Molecular Formula: C-H4-N2-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 76.05 [USP DI 2000; p 1739] CHEMICAL/PHYSICAL DATA Melting Point: 133-136 C [Merck Index 1996; p 833] CHEMICAL/PHYSICAL DATA Elemental Comp: C15.79%, H5.30%, N36.83%, O42.07% [Merck Index 1996; p 833] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water and hot alcohol [Merck Index 1996; p 833] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Tasteless, white crystalline powder [PDR 2000; p 865] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200, 300, 400, and 500 mg capsules [PDR 2000; p 866] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral [PDR 2000; p 866] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature, preferably 25 C (77 F); excursions permitted to 15-30 C (59-86 F). Keep container tightly closed. [PDR 2000; p 861, 865] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/20318458. Lori F, Lisziewicz J. Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug. Clin Infect Dis. 2000 Jun;30 Suppl 2:S193-7. MED/20318452. Zala C, Rouleau D, Montaner JS. Role of hydroxyurea in treatment of disease due to human immunodeficiency virus infection. Clin Infect Dis. 2000 Jun;30 Suppl 2:S143-50. MED/20188473. Lori F, Lisziewicz J. Hydroxyurea: mechanisms of HIV-1 inhibition. Antivir Ther. 1998;3 Suppl 4:25-33. MED/20132674. Gibbs MA, Sorensen SJ. Hydroxyurea in the treatment of HIV-1. Ann Pharmacother. 2000 Jan;34(1):89-93. Review. MED/20114806. Ravot E, Lisziewicz J, Lori F. New uses for old drugs in HIV infection: the role of hydroxyurea, cyclosporin and thalidomide. Drugs. 1999 Dec;58(6):953-63. Review. MED/20023410. Frank I. Clinical use of hydroxyurea in HIV-1 infected patients. J Biol Regul Homeost Agents. 1999 Jul-Sep;13(3):186-91. Review. MED/20023409. Maserati R. Hydroxyurea in the treatment of HIV-1 infection: toxicity and side effects. J Biol Regul Homeost Agents. 1999 Jul-Sep;13(3):181-5. Review. MED/20023408. Lori F, Lisziewicz J. Mechanisms of human immunodeficiency virus type 1 inhibition by hydroxyurea. J Biol Regul Homeost Agents. 1999 Jul-Sep;13(3):176-80. Review. MED/99443171. Lori F, Rosenberg E, Lieberman J, Foli A, Maserati R, Seminari E, Alberici F, Walker B, Lisziewicz J. Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters. AIDS Res Hum Retroviruses. 1999 Oct 10;15(15):1333-8. MED/98294595. Rutschmann OT, Opravil M, Iten A, Malinverni R, Vernazza PL, Bucher HC, Bernasconi E, Sudre P, Leduc D, Yerly S, Perrin LH, Hirschel B. A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study. AIDS. 1998 May 28;12(8):F71-7. MED/98254972. Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin Pharmacokinet. 1998 May;34(5):347-58. Review. MED/97240673. Montaner JS, Zala C, Conway B, Raboud J, Patenaude P, Rae S, O'Shaughnessy MV, Schechter MT. A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV trials network protocol 080. J Infect Dis. 1997 Apr;175(4):801-6. MED/97173302. Palmer S, Cox S. Increased activation of the combination of 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine in the presence of hydroxyurea. Antimicrob Agents Chemother. 1997 Feb;41(2):460-4. MED/96262016. Giacca M, Zanussi S, Comar M, Simonelli C, Vaccher E, de Paoli P, Tirelli U. Treatment of human immunodeficiency virus infection with hydroxyurea: virologic and clinical evaluation. J Infect Dis. 1996 Jul;174(1):204-9. ENTRY MONTH 199610 LAST REVISION DATE 20001011 94 UNIQUE IDENTIFIER DRG-0252 NAME OF SUBSTANCE Itraconazole-cyclodextrin [Protocol ID: 96 C-41 ] PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-41 DISEASES STUDIED/TREATED Oropharyngeal candidiasis. [Protocol ID: 96 C-41 ] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 319] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/97057727. Phillips P, Zemcov J, Mahmood W, Montaner JS, Craib K, Clarke AM. Itraconazole cyclodextrin solution for fluconazole-refractory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptiblity. AIDS. 1996 Oct;10(12):1369-76. ICA11/96920887. Moskovitz BL, Wilcox CM, Darouiche R, Wu J, Mallegol I. Itraconazole oral solution (IS) compared with fluconazole (F) for treatment of esophageal candidiasis (EC). Int Conf AIDS. 1996 Jul 7-12;11(1):17 (abstract no.Mo.B.116). ICA9/93336139. Cartledge JD, Midgley J, Youle M, Fisher M, Gazzard BG. The use of cyclodextrin solution formulation of itraconazole (ITR-SOL) to treat candidiasis unresponsive to other azole preparations in patients with AIDS. Int Conf AIDS. 1993 Jun 6-11;9(1):55 (abstract no. WS-B12-2). ICA10/94371567. Mahmood W, Hamann-Trou D, Phillips P, Zemcov SJ, Montaner JS, Clarke AM, Itraconazole solution for fluconazole-refratory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptibility. Int Conf AIDS. 1994 Aug 7-12;10(2):23 (abstract no. 386B). ENTRY MONTH 199609 LAST REVISION DATE 20000801 95 UNIQUE IDENTIFIER DRG-0251 NAME OF SUBSTANCE Peptide Construction 3, Synthetic [Protocol ID: 257A ] PROTOCOL ID NUMBERS No longer recruiting FDA 257A PHARMACOLOGICAL ACTION MODE OF ACTION: Data suggest that SPC3 prevents HIV-1 attachment to the surface of CD4- cells that express galactosylceramide, an alternative receptor for HIV-1 gp120. In CD4+ lymphocytes, SPC3 interferes with a post-binding step necessary for virus entry into the cell. [Proc Natl Acad Sci USA 1995 May 23;92(11); p 4867-71] DISEASES STUDIED/TREATED HIV infection. [Protocol ID: 257A ] CLASSIFICATION CODE Investigational - Antiviral [Protocol ID: 257A ] CONTRAINDICATIONS Contraindicated in women of reproductive potential. [Protocol ID: 257A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic multibranched peptide containing eight HIV-1 gp120 V3 loop GPGRAF motifs. [Biochemistry 1995 Jul 4;34(26); p 8294-8] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 257A ] MANUFACTURERS 0000003589: Columbia Research Laboratories Inc 100 North Village Ave / Suite 32 Rockville Centre, NY 11570 Contact: Dr Howard Levine (516)766-2660 REFERENCES MED/97121263. Delezay O, Hammache D, Fantini J, Yahi N. SPC3, a V3 loop-derived synthetic peptide inhibitor of HIV-1 infection, binds to cell surface glycosphingolipids. Biochemistry. 1996 Dec 10;35(49):15663-71. MED/95322380. Mabrouk K, Van Rietschoten J, Rochat H, Loret EP. Correlation of antiviral activity with beta-turn types for V3 synthetic multibranched peptides from HIV-1 gp120. Biochemistry. 1995 Jul 4;34(26):8294-8. MED/96172685. Sabatier JM, Baghdiguian S, Yahi N, Rochat H, Van Rietschoten J, Fantini J. SPC3, a nontoxic peptide inhibitor of HIV infection [letter]. In Vitro Cell Dev Biol Anim. 1995 Jun;31(6):415-8. MED/95281557. Yahi N, Fantini J, Baghdiguian S, Mabrouk K, Tamalet C, Rochat H, Van Rietschoten J, Sabatier JM. SPC3, a synthetic peptide derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120, inhibits HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4867-71. ENTRY MONTH 199608 LAST REVISION DATE 20000801 96 UNIQUE IDENTIFIER DRG-0250 NAME OF SUBSTANCE Ziconotide [USPD 2000 p. 768] REGISTRY NUMBER 107452-89-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME omega-Conotoxin M VIIA [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 256A PHARMACOLOGICAL ACTION MODE OF ACTION: In patients and animals with painful peripheral neuropathies, spontaneous ectopic discharge from injured primary afferents is hypothesized to maintain a central state of hyperexcitability that underlies hyperalgesia and allodynia. Temporary suppression of this discharge allows the central state to normalize, such that hyperalgesia and allodynia are absent or reduced. Ca++ channels are involved in the genesis of spontaneous discharge from injured afferents. SNX-111 and SNX-124, synthetic homologs of omega-conopeptides (MVIIA and GVIA) and potent blockers of neuronal N-type voltage-sensitive Ca++ channels, may be useful in treatment of the abnormal pains that occur after nerve injury. Pharmacokinetic studies of SNX-111 were conducted in rats and cynmolqus monkeys to determine the disposition of this compound when it is administered for 24 hr by continuous, constant-rate intraveneous infusion . In all cases apparent steady-state plasma SNX-111 concentration were achieved within 2-4 hrs. Steady-state volume of distribution values were approximately 40% of body weight, indicating extravascular dissemination of SNX-111 to both extracellular and intracellular fluids. Elimination curves contained two exponential components. The fast components (rat t1/2, alpha= 0.375 hr; monkey t1/2, alpha = 0.730 hr) accounted for approximately 97% of the unit impulse disposition function. The apparent terminal half-life ranged from 4.61 hr (rat) to 6.48 hr (monkey). [J Pharmacol Exp Ther 1995 Aug;274(2); p 666-72; Drug Metab Dispos 1997 Mar;25(3); p 379-83] DISEASES STUDIED/TREATED Pain related to HIV. [Protocol ID: 256A ] CLASSIFICATION CODE Analgesic [USPD 2000 p. 769] OTHER MAJOR USES Pain related to cancer. Areas of potential therapeutic utility include treatment of nociceptive and neuropathic pain and neuroprotection after ischemic brain injury. [Protocol ID: 256A ; J Cardiovasc Pharmacol 1997 Sep;30(3); p 400-3] SUBSTANCE INTERACTIONS [USP DI 1995; p 1279] CONTRAINDICATIONS Contraindicated in pregnant and nursing women. [Protocol ID: 256A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic homolog of omega-conopeptide. First neuronal N-type, voltage-sensitive calcium channel (VSCC) blocker to enter clinical drug development. [J Pharmacol Exp Ther 1995 Aug;274(2); p 666-72] CHEMICAL/PHYSICAL DATA Molecular Formula: C102-H172-N36-O32-S7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 2639.14 [USPD 2000 p. 768] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intrathecal. [Protocol ID: 256A ] MANUFACTURERS 0000003564: Neurex Corp 3760 Haven Ave Menlo Park, CA 94025 Contact: Unspecified (415)853-1500 REFERENCES MED/97445441. McGuire D, Bowersox S, Fellmann JD, Luther RR. Sympatholysis after neuron-specific, N-type, Voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans. J Cardivasc Pharmacol 1997 Sep;30(3):400-3. MED/97459785. Sato K, Raymond C, Martin-Moutot N, Sasaki T, Omori A, Ohtake A, Kim JI, Kohno T, Takahashi M, Seager M. Binding of chimeric analogs of omega-conotoxin MVIIA and MVIIC to the N- and P/Q-type calcium channels. FEBS Lett 1997 Sep 8;414(2):480-4. MED/97422167. MacLachlan LK, Middleton DA, Edwards AJ, Reid DG. A case history. NMR studies of the structure of a small protein, omega-conotoxin MVIIA. Methods Mol Biol 1997;60:337-62. MED/97335722. Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). Neurol Res 1997 Jun;19(3):334-9. MED/97227275. Bowersox SS, Mandeme J, Tarczy-Hornoch K, Miljanlch G, Luther RR. Pharmacokinetics of SNX-111, a selective N-type calcium channel blocker, in rats and cynomolgus monkeys. Drug Metab Dispos 1997 Mar;25(3):379-83. MED/97123098. Bowersox SS, Gadbois T, Singh T, Pettus M, Wang YX, Luther RR. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX111, produces spinal antinociception in rats models of acute, persistent and neuropathic pain. J Pharmacol Exp Ther 1996 Dec;279(3):1243-9. MED/97070382. Nielsen KJ, Thomas L, Lewis RJ, Alewood PF, Craik DJ. A consensus structure for omega-conotoxins with different selectivities for voltage-sensitive calcium channel subtypes: comparison of MVIIA, SVIB and SNX-202. J Mol Biol 1996 Oct 25;263(2):297-310. AIDS/97229579. Neurex launches phase III program for the treatment of chronic pain [news]. Aids Patients Care STDS. 1996 Oct;10(5):311-2. MED/95367555. Kohno T, Kim JI, Kobayashi K, Kodera T, Maeda T, Sato K. Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin MVIIA. Biochemistry 1995 Aug 15;34(32):10256-65. MED/95363679. Xiao WH, Bennett GJ. Synthetic omega-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats. J Pharmacol Exp Ther 1995 Aug;274(2):666-72. ENTRY MONTH 199608 LAST REVISION DATE 20001106 97 UNIQUE IDENTIFIER DRG-0249 NAME OF SUBSTANCE Nerve Growth Factor, Recombinant Human [Protocol ID: ACTG 291 ] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 291 PHARMACOLOGICAL ACTION MODE OF ACTION: The gene for human nerve growth factor (NGF) has been cloned into a mammalian cell line and large quantities of recombinant human NGF (rhNGF) can now be produce for clinical use, but little is known about the fate of rhNGF following delivery to the brain. In a study, polymer matrices containing 125I-labled rhNGF were implanted into the brains of adult rats and the spatial distribution of the released protein was measured for 8 weeks after implatation. For the first several days, the rate of NGF release from the polymer matrix was high (approximately 100 ng/day). At later times, the the release rate decreased (2-10 ng/day). NGF levels were always highest in the tissue closest to the polymer. The first 10-fold decrease occurred during the first ten days of study; a further 6 weeks was required to achieve the second 10-fold decrease. Comparsion of local rhNGF concentration profiles with a simple mathematical model indicated that rhNGF diffuses through the brain interstitial space and is elimanted with a half-life of approximately 45 min, although elimination appears to be substantially slower in white matter regions. This limited ability of NGF to penetrate and be retained within the brain tissue indicates that NGF will need to be delivered almost directly to the target tissue for efficacy. A study evaluating the safety of a single intravenous or subcutaneous doses of rhNGF in healthy human volunteers at doses ranging from 0.03 to 1 micrograms/kg showed no life-threatening adverse events at any dose. Antibodies to rhNGF were not detected in any subject. These results indicate to systemically administered rhNGF experts a characteristic and reproducible biological effect in healthy subjects at very low doses and in a dose-dependent manner. In another study, following mulitiple dosing, some peripheral neuropathic patients reported an improvement in clinical symptoms, which in some case correlated with improvements in neurological examinations. [Neurotoxicology 1996 Fall-Winter; 17(3-4); p 865-70; Brain Res 1996 Jul 15; 727(1-2); p 169-81; Ann Neurol 1994 Aug;36(2); p 244-6] DISEASES STUDIED/TREATED HIV-related peripheral neuropathy. [Protocol ID: ACTG 291 ] CLASSIFICATION CODE Growth hormone [Protocol ID: ACTG 291 ] OTHER MAJOR USES Diabetic peripheral neuropathy. [Protocol ID: ACTG 291 ] ADVERSE EFFECTS Adverse effects with intravenous administration have included mild to moderate pain with swallowing, pain in the masseter muscles, pain in the throat, and painful muscles in other areas. Adverse effects with subcutaneous administration have included moderate diffuse muscle pain and injection site hyperalgesia, described as increased sensitivity to touch or heat around the injection site. Adverse effects with intravenous administration have included mild to moderate pain with swallowing, pain in the masseter muscles, pain in the throat, and painful muscle in other areas. Averse effects with subcutaneous admininistration have included moderate diffuse muscle pain and injection site hyperalgesia, described as increased sensitivity to touch or heat around the injection site. Results from recent preclinical studies indicated no safety findings which would preclude the chronic administration of rhNGF in clinical trials in humans. [Protocol ID: ACTG 291 ; Ann Neurol 1994 Aug;36(2); p 244-6; Neurotoxicology 1996 Fall-Winter; 17(3-4); p 865-70] CONTRAINDICATIONS Contraindicated in pregnant and nursing women. [Protocol ID: ACTG 291 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Homodimer consisting of predominately a 118-amino acid residue monomer. [Protocol ID: ACTG 291 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Clear, colorless liquid. [Protocol ID: ACTG 291 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 2 mg/ml in 0.5 ml vials. [Protocol ID: ACTG 291 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous, intravenous. [Protocol ID: ACTG 291 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (35-46 F). Do not freeze. [Protocol ID: ACTG 291 ] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 REFERENCES MED/97435009. Mrak RE, Griffin WS. The role of chronic self-propagating glial responses in neurodegeneration: implications for long-lived survivors of human immunodeficiency virus. J Neurovirol 1997 Aug;3(4):241-6. MED/97327439. Day-Lollini PA, Stewart GR, Taylor MJ, Johnson RM, Chellman GJ. Hyperplastic changes within the leptomeninges of the rat and monkey in responses to chronic intracerbroventricular infusion of nerve growth factor. Exp Neurol 1997 May;145(1):24-37. MED/97241110. Roger BC. Development of recombinant human nerve growth factor (rhNGF) as a treatment for periperal neuopathic disease. Neurotoxicology 1996 Fall-Winter;17(3-4):865-70. MED/97116619. Krewson CE, Dause R, Mak M, Saltzman WM. Stabilization of nerve growth factor in controlled release polymers and in tissue. J Biomater Sci Polym Ed 1996;8(2):103-17. MED/97001854. De Young LR, Burton LE, Liu J, Powell MF, Schmelzer CH, Skelton NJ. RhNGF slow unfolding is not due to proline isomerization: possibility of a cystine knot loop-threading mechanism. Protein Sci 1996 Aug;5(8):1554-66. MED/96309670. Emmet CJ, Stewart GR, Johnson RM, Aswani SP, Chan RL, Jakeman LB. Distribution of radioiodinated recombinant human nerve growth factor in primate brain following intracerebroventricular infusion. Exp Neurol 1996 Aug;140(2):151-60. MED/96440084. Krewson CE, Saltzman WM. Transport and elimination of recombinant human NGF during long-termed delivery to the brain. Brain Res 1996 Jul;15727(1-2):169-81. MED/96295126. Knepp VM, Whatley JL, Muchnik A, Calderwood TS. Identification of antioxidants of peroxide-mediated oxidation of recombinant human ciliary neurotrophic factor and recombinant human growth factor. PDA J Pharm Sci Technol 1996 May-Jun;50(3):163-71. MED/95330310. Emmett CJ, Aswani SP, Stewart GR, Fairchild D, Johnson RM. Dose-response comparison of recombinant human nerve growth factor and recombinant human basic fibroblast growth factor in the fimbria fornix model of acute cholinergic degeneration. Brain Res 1996 Mar;673(2):199-207. MED/95010541. Forander P, Bjorklund L , Stromberg I. Dose-dependent effects of recombinant human NGF on grated adult adrenal medullary tissue. Exp Neurol 1994 Apr;126(2):168-77. MED/94330699. Petty BG, Cornblath DR, Adornato BT, Chaudhry V, Flexner C, Wachsman M, Sinicropi D, Burton LE, Peroutka SJ. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994 Aug;36(2):244-6. ENTRY MONTH 199607 LAST REVISION DATE 20000801 98 UNIQUE IDENTIFIER DRG-0248 NAME OF SUBSTANCE Varicella Virus Vaccine (Live) [Merck & Co Inc 1996 June] SYNONYMS Varivax [Physicians GenRx 1996; p 2090] PROTOCOL ID NUMBERS Recruiting NIAID ACTG 265 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 391 PHARMACOLOGICAL ACTION MODE OF ACTION: Induces both humoral and cell-mediated responses, although the role and relative contribution of each type of response to long-term immunity against varicella has not been fully determined. Responses elicited by Varivax appear to be less than those elicited by natural infection with wild-type varicella-zoster virus. In some individuals, especially healthy adults and immunocompromised children, the vaccine provides partial immunity and modification of varicella infection rather than complete protection. Continued long-term studies are necessary to determine the extent and duration of protection against varicella provided by primary immunization with the vaccine. Seroconversion following administration of varicella virus vaccine live does not result in complete protection for individuals and breakthrough varicella infections may occur despite seroconversion. [AHFS Drug Information 1997; p 2653-4] DISEASES STUDIED/TREATED Prevention of varicella (chickenpox) in HIV-infected patients. [Protocol ID: ACTG 265 ] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 3107] OTHER MAJOR USES Indicated for vaccination against varicella virus infection (chickenpox, herpes, zoster, shingles) in individuals 12 months of age and older. FDA approved March 1995. [Physicians GenRx 1996; p 2090] SUBSTANCE INTERACTIONS Vaccination should be deferred for at least 5 months following blood or plasma transfusion, or administration of immune globulin or varicella zoster immune globulin. Following administration of varicella virus vaccine live, any immune globulin should not be given for 2 months. Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination, as Reye's Syndrome has been reported following the use of salicylates during natural varicella infection. The varicella vaccine can be administered concomitantly with M-M-R II (Measles, Mumps, and Rubella Vaccine Live), and witrh DTap (diphtheria, tetanus, acelluar pertussis) and PedvaxHIB, using separate sites and syringes. [PDR 1997; p 1809] ADVERSE EFFECTS Generally well tolerated. Primary adverse effects include pain, soreness, swelling, redness, or itching at the injection site or generalized rash. Other adverse effects may include respiratory illness, cough, irritability/ nervousness, fatigue, headache, teething (in children), Malaise, Adominal pain, nausea, eye complaints, chills, lymphadenopathy, myalgia,allergic reactions, stiff neck, heat rash or prickly heat, arthralgia, eczema, dry skin, dermatitis, constipation, and, rarely, febrile seizures in children aged 1-12. Several case of herpes zoster (shingles) have been reported in children and adults in clinical trials. The long term effect of varicella vaccine on the incidence of herpes zoster; particularly in those vaccinees exposed to natural varicella, is unknown. [Physicians GenRx 1996; p 2091; PDR 1997; p 1809] CONTRAINDICATIONS Contraindicated in patients with blood dyscrasias, leukemia, lymphoma, or other malignant neoplasms affecting the bone marrow or lymphatic system. Also contraindicated in patients with hypersensitivity to vaccine components, prior anaphylactoid reaction to neomycin, active untreated tuberculosis, immunosuppression, family history of congenital or hereditary immunodeficiency unless the disorder has been ruled out in the patient, or febrile respiratory disease or other active febrile infection. Contraindicated in pregnant women and in patients who are receiving immunosuppressive therapy, including recent immunoglobulin therapy or chronic aspirin therapy. Use with caution in patients who have direct contact with immunocompromised individuals, newborns, or pregnant women. Safety and efficacy of the varicella virus vaccine live in children and adults with HIV infections have not been established. In general HIV+ individuals should not receive live viral vaccines. [AHFS Drug Information 1997; p 2654] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Preparation of Oka/Merck strain of live, attenuated varicella virus, initially obtained from a child with natural varicella and propagated in embryonic guinea pig cell culture and finally propagated in human diploid cell culture. [Physicians GenRx 1996; p 2090] CHEMICAL/PHYSICAL DATA Stability: To maintain potency, the lyophilized vaccine must be kept frozen at an average temperature of -15 C (+5F) or colder and must be used before expiration date. [PDR 1997; p 1808] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vaccine is administered in 0.5 mL doses. When the vaccine is administered within 30 minutes following reconstitution as specific, each 0.5 mL dose contains at least 1350 plaque-forming units (PFU) of Oka/Merck virus. Children 12 months to 12 years should receive a single 0.5 mL dose subcutaneously. Adolescents and adults 13 years and older should receive a 0.5 mL dose subcutaneously at elected date and a second 0.5 mL dose 4 to 8 weeks later. [AHFS Drug Information 1997; p 2655; PDR 1997; p 1810] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. (WARNING: Should NOT be administered IV). [Physicians GenRx 1996; p 2092] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store frozen at -15 C (5 F)or colder. Protect from light. Use within 30 minutes following reconstitution. Discard it reconstituted vaccine is not used within 30 minutes [Physicians GenRx 1996; p 2092; PDR 1997; p 1810] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES MED/97383801. Reuman PD, Sawyer MH, Kuter BJ, Matthews H. Safety and immunogenicity of concurrent administration of measles- mumps-rubella-varicella vaccine and PedvaxHIB vaccines in healthy children twelve to eighteen months old. The MMRV Study Group. Pediatr Infect Dis J 1997 Jul;16(7):662-7. MED/97333504. Arvin AM. The varicella vaccine. Curr Clin Top Infect Dis 1997;17:110-46. MED/97331799. Arvin AM. Live attenuated varicella vaccine. Pediatr Ann 1997 Jun;26(6):384-8. MED/97282937. Gerecitano J, Friedman-Kien A, Chazen GD. Allergic reaction to varicella vaccine [letter]. Ann Intern Med 1997 May 15;126(10):833-4. MED/97329657. Pepose JS. The potential impact of the varicella vaccine and new antivirals on ocular disease related to varicella-zoster virus. Am J Ophthamol 1997 Feb;123(2):243-51. MED/97194089. Krah DL, Cho I, Schofield RW, Ellis RW. Comparison of gpELISA and neutralizing antibody responses to Oka/Merck live varicella vaccine (Varivax) in children and adults. Vaccine 1997 Jan;15(1):61-4. MED/97061030. Arvin AM, Gershon AA. Live attenauted varicella vaccine. Annu Rev Microbiol 1996;50:59-100. MED/97051904. LaRussa P, Steinberg S, Gershon AA. Varicella vaccine for immunocompromised children: results of collaborative studies in the United States and Canada. J Infect Dis 1996. Nov;174 Suppl 3:S320-3. MED/97056005. Schouten JW. Effects of the varicella vaccine on long-term immunity [letter] Am Fam Physician 1996 Nov 1;54(6):1894-6. MED/97009248. Gershon AA, LaRusssa P, Steinberg S. The varicella vaccine. Clinical trials in immunocompromised individuals. Infect Dis Clin North Am 1996 Sep;10(3):583-94. ENTRY MONTH 199607 LAST REVISION DATE 20000801 99 UNIQUE IDENTIFIER DRG-0247 NAME OF SUBSTANCE HIV-1 Immunogen [Protocol ID: 092 ] SYNONYMS Remune [Protocol ID: ACTG A5046s ] PROTOCOL ID NUMBERS No longer recruiting FDA 092 PROTOCOL ID NUMBERS No longer recruiting FDA 093 PROTOCOL ID NUMBERS No longer recruiting FDA 094 PROTOCOL ID NUMBERS No longer recruiting CC 95 C-172 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5046s PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5058s PROTOCOL ID NUMBERS No longer recruiting FDA B008 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5057 PROTOCOL ID NUMBERS Recruiting FDA B009 PROTOCOL ID NUMBERS Terminated NIAID AIEDRP AI-05-006 PHARMACOLOGICAL ACTION HIV-1 Immunogen has been shown to be safe and well tolerated in clinical studies. Results from these studies have demonstrated improvements in both immunologic and virologic parameters in HIV-infected persons receiving serial injections of this vaccine. The lymphocyte proliferation response to HIV antigens was cross-clade-specific and was as large as, or larger than, that observed in many long-term non-progressors. The vaccine also has been shown to produce the following effects: improvements in percentage of CD4+ cells and HIV-1 DNA in peripheral blood mononuclear cells; greater delayed-type hypersensitivity reactivity to HIV-1 antigen; increased HIV-1 antigen-stimulated interferon gamma, beta-chemokine, and RANTES production; increased titers of antibodies to p24; increased levels of HIV-specific CD8+ T cells in subjects cotreated with HAART; and decreases in viral load. Study 806 is a multicenter, double-blind, placebo-controlled, randomized clinical trial, which was terminated following an independent Data and Safety Monitoring Board recommendation. The basis for the recommendation was the lack of difference in event rates between the treatment groups. There were 53 clinical events in each group, with no difference in time to clinical progression or death. Similarly, there was no difference in number of deaths without progression to a specific clinical event. There were no statistically significant differences between the groups with respect to changes in HIV RNA, CD4+ percentage, or body weight. However, there was a small, but statistically significant, increase in average CD4+ cell count in the vaccine group compared with the control group. [Protocol ID: ACTG A5057 ; JAMA 2000 Nov 1;284(17):2193-202] DISEASES STUDIED/TREATED HIV-1 Immunogen is an investigational therapeutic vaccine. It is being studied in clinical trials to determine whether it can induce or enhance HIV-specific cell-mediated immune responses in HIV-infected individuals. [Agouron Pharmaceuticals Inc. Frequently Asked Questions. Available at: http://www.agouron.com/Pages/immuneBased/it_F- aqs.html#Question 04. Accessed November 1, 2000.] CLASSIFICATION CODE Vaccine [Protocol ID: 092 ] ADVERSE EFFECTS Side effects most frequently reported in clinical trials studying HIV-1 Immunogen administration with antiretroviral drugs are local pain, soreness, and redness at the site of injection; muscle aches; fatigue; and headache. Side effects were generally mild and transient. [Agouron Pharmaceuticals Inc. Frequently Asked Questions. Available at: http://www.agouron.com/Pages/immuneBased/it_F- aqs.html#Question 04. Accessed November 1, 2000.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: HIV-1 Immunogen is a gp120-depleted, inactivated, whole-virus vaccine. Virus particles are obtained from a cell line derived from the parent HuT-78 and a virus isolate (HZ321) subtype M. The virus particles are emulsified in Incomplete Freund's Adjuvant (IFA), which is an immunologic adjuvant. Western blot analyses indicate that all HIV proteins and glycoproteins are present in the vaccine, although gp160 and gp120 are present in trace amounts only. Because of the absence of the highly variable gp120, this vaccine is thought to present the more conserved viral core antigens. Therefore, even though it contains a clade A envelope and clade G gag, HIV-1 Immunogen vaccine exhibits broad immune cross-reactivity with multiple clades of virus. [Protocol ID: ACTG A5057 ] CHEMICAL/PHYSICAL DATA Stability: The contents of the syringe should be inspected to ensure emulsion integrity. A small amount of layering (clear oil on top of the emulsion) is acceptable. If the material is discolored or separated into 2 large distinct phases, the product should be discarded. [Protocol ID: ACTG A5057 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Off-white, viscous, opaque, water-in-oil emulsion [Protocol ID: ACTG A5057 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The HIV-1 Immunogen vaccine is supplied in unit-dose syringes containing approximately 10 mcg/ml p24 antigen (approximately equal to 100 mcg of total protein). [Protocol ID: ACTG A5057 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The unit-dose syringe should be allowed to warm to room temperature for at least 45 minutes prior to injection. The entire contents of the syringe are administered intramuscularly with a 22-gauge, 1.5-inch needle into the deltoid muscle. [Protocol ID: ACTG A5057 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The vaccine should be stored at 2-8 C (35-46 F). Unit-dose syringes may be left at room temperature for up to 4 hours prior to administration. [Protocol ID: ACTG A5057 ] MANUFACTURERS 0000003541: Immune Response Corp 5935 Darwin Ct Carlsbad, CA 92008 Contact: Trial Information (800)684-8624 MANUFACTURERS 0000003541: Immune Response Corp 5935 Darwin Ct Carlsbad, CA 92008 Contact: Carolyn Peterson (888)847-2237 MANUFACTURERS 0000003726: Agouron Pharmaceuticals Inc 11095 Torreyana Rd San Diego, CA 92121 Contact: Lisa Bauman (858)622-8031 REFERENCES Kahn JO, Cherng DW, Mayer K, Murray H, Lagakos S. Evaluation of HIV-1 Immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 10(6)/L CD4 cell counts. JAMA. 2000 Nov 1;284(17):2193-202. MED/20236902. Maino VC, Suni MA, Wormsley SB, Carlo DJ, Wallace MR, Moss RB. Enhancement of HIV type 1 antigen-specific CD4+ T cell memory in subjects with chronic HIV type 1 infection receiving an HIV type 1 immunogen. AIDS Res Hum Retroviruses. 2000 Apr 10;16(6):539-47. MED/20234839. Moss RB, Giermakowska WK, Diveley JP, Savary JR, Wallace MR, Maigetter RZ, Jensen FC, Carlo DJ. CXCR4 and CCR5 expression on CD4+ T cells in vivo and HIV-1 antigen beta-chemokine production in vitro after treatment with HIV-1 Immunogen (REMUNE). J Hum Virol. 2000 Jan-Feb;3(1):44-9. MED/99437259. Patterson BK, Carlo DJ, Kaplan MH, Marecki M, Pawha S, Moss RB. Cell-associated HIV-1 messenger RNA and DNA in T-helper cell and monocytes in asymptomatic HIV-1-infected subjects on HAART plus an inactivated HIV-1 immunogen. AIDS. 1999 Sep 10;13(13):1607-11. MED/99367568. Moss RB, Wallace MR, Giermakowska WK, Webb E, Savary J, Chamberlin-Brandt C, Theofan G, Musil R, Richieri SP, Jensen FC, Carlo DJ. Phenotypic analysis of human immunodeficiency virus (HIV) type 1 cell-mediated immune responses after treatment with an HIV-1 immunogen. J Infect Dis. 1999 Sep;180(3):641-8. MED/98394557. Churdboonchart V, Moss RB, Sirawaraporn W, Smutharaks B, Sutthent R, Jensen FC, Vacharak P, Grimes J, Theofan G, Carlo DJ. Effect of HIV-specific immune-based therapy in subjects infected with HIV-1 subtype E in Thailand. AIDS. 1998 Aug 20;12(12):1521-7. MED/98335956. Moss RB, Giermakowska WK, Savary JR, Theofan G, Daigle AE, Richieri SP, Jensen FC, Carlo DJ. A primer on HIV type 1-specific immune function and REMUNE. AIDS Res Hum Retroviruses. 1998 Jun;14 Suppl 2:S167-75. Review. MED/98132495. Moss RB, Giermakowska W, Lanza P, Turner JL, Wallace MR, Jensen FC, Theofan G, Richieri SP, Carlo DJ. Cross-clade immune responses after immunization with a whole-killed gp120-depleted human immunodeficiency virus type-1 immunogen in incomplete Freund's adjuvant (HIV-1 Immunogen, REMUNE) in human immunodeficiency virus type-1 seropositive subjects. Viral Immunol. 1997;10(4):221-8. MED/96183598. Levine AM, Groshen S, Allen J, Munson KM, Carlo DJ, Daigle AE, Ferre F, Jensen FC, Richieri SP, Trauger RJ, Parker JW, Salk PL, Salk J. Initial studies on active immunization of HIV-1 infected subjects using a gp120-depleted HIV-1 immunogen: long-term follow-up. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Apr 1;11(4):351-64. MED/87229054. Salk J. Prospects for the control of AIDS by immunizing seropositive individuals. Nature. 1987 Jun 11-17;327(6122):473-6. ENTRY MONTH 199606 LAST REVISION DATE 20001109 100 UNIQUE IDENTIFIER DRG-0246 NAME OF SUBSTANCE Lodenosine [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 110143-10-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting CC 95 C-0192 PROTOCOL ID NUMBERS No longer recruiting CC 97 C-0119 PHARMACOLOGICAL ACTION MODE OF ACTION: Similar to dideoxyadenosine (ddA), except that a fluorine atom is introduced into the 2'-position of the glycon. Like ddA and its metabolite ddI, beta-F-ddA is metabolized intracellularly to a triphosphate moiety that acts as a reverse transcriptase inhibitor. Because of the fluorine substitution, beta-F-ddA is expected to be absorbed better than didanosine because the fluorinated molecules become more stable to acid conditions. beta-F-ddA has demonstrated anti-HIV activity in vitro. beta-F-ddA does not appear to have cross resistance with ddI or other nucleoside analogues, and is even active against strains of HIV that have multi-dideoxynucleoside resistance associated with a mutation at codon 151 of reverse transcriptase. In comparison with zalcitabine, beta-F-ddA is 22000 times less potent in suppressing cellular mitochondrial DNA synthesis, while anti-HIV potency is only modestly less compared to the unfluorinated compound. Inhibition of mitochondrial DNA could be responsible for the delayed clinical toxicity sometimes observed with dideoxynucleosides. [Protocol ID: 95 C-192 ; Biochem Pharmacol 1994 Oct 7;48(7); p 1477-81] DISEASES STUDIED/TREATED HIV infection. [Protocol ID: 95 C-192 ] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Has shown cardiotoxicity in rats. [Fundam Appl Toxicol 1995 Sep;27(2); p 167-76] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fluorinated analogue of didanosine; a purine dideoxynucleoside. [Protocol ID: 95 C-192 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H12-F-N5-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 253.24 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 95 C-192 ] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES ICA11/96921146. Johns DG, Driscoll J. 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA): a new anti-HIV clinical drug candidate. Int Conf AIDS. 1996 Jul 7-12;11(1):68 (abstract no.Mo.A.1076). AIDS/96095608. Pommier Y. Inhibition of HIV-1 integrase by mono- and oligonucleotides. Abstr Meet Groups Stud Struct AIDS Relat Syst Their Appl Target Drug Des. 1995 Jun 5-7;:9 (unnumbered abstract). MED/95032193. Tsai CH, Doong SL, Johns DG, Driscoll JS, Cheng YC. Effect of anti-HIV 2'-beta-fluoro-2',3'-dideoxynucleoside analogues on the cellular content of mitochondrial DNA and on lactate production. Biochem Pharmacol. 1994 Oct 7;48(7):1477-81. ENTRY MONTH 199606 LAST REVISION DATE 20000801 101 UNIQUE IDENTIFIER DRG-0245 NAME OF SUBSTANCE Levamisole hydrochloride [USPD 1998; p. 414] REGISTRY NUMBER 16595-80-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Imidazo(2,1-b)thiazole, 2,3,5,6-tetrahydro-6-phenyl-, monohydrochloride, (S)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Ergamisol [USP DI 2000; p. 1960] PROTOCOL ID NUMBERS No longer recruiting CC 95 C-184 PHARMACOLOGICAL ACTION MODE OF ACTION: Appears to act as an immunorestorative agent in the presence of immunosuppression resulting from recent surgery and chemotherapy, but does not stimulate the immune response to above normal levels. May be related to T-cell activation and proliferation, augmentation of monocyte and macrophage activity, and increases in neutrophil mobility, adherence, and chemotaxis. Does not have cytotoxic effects. Rapidly absorbed from the gastrointestinal tract. The plasma half-life is between 3-4 hours for levamisole and 16 hours for its metabolites. It is extensively metabolized by the liver and the metabolites excreted mainly by the kidneys. [USP DI 1997; p 1860; Physicians GenRx 1996; p II-1233] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection. [Physicians GenRx 1996; p II-1233] CLASSIFICATION CODE Antineoplastic adjunct [USP DI 2000; p. 1958] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p. 1958] OTHER MAJOR USES Indicated, in combination with fluorouracil, for treatment of Dukes C adenocarinoma of the colon following complete resection of primary tumor. [USP DI 1997; p 1860] SUBSTANCE INTERACTIONS Has been reported to produce Antabuse-like side effects when given with alcohol. Concomitant administration of phenytoin and levamisole plus fluorouracil has led to increased plasma levels of phenytoin. Concurrent use of levamisole and warfarin sodium (or other coumarin-like drugs) may cause prolongation of prothrombin time beyond the therapeutic range. [PDR 1997; p 1340] ADVERSE EFFECTS Adverse effects (in combination with fluorouracil) may include nausea, vomiting, diarrhea, stomatitis, anorexia, rash, pruritus, flu-like symptoms, fever, chills, dizziness, ataxia, depression, confusion, memory loss, weakness, inability to concentrate, headache, reversible neutropenia, sepsis, thrombocytopenia, and hyperbilirubinemia. Adverse effects when administered alone may include rash, arthralgia/myalgia, fever, neutropenia, urinary infection, and cough. Other adverse effects reported in worldwide experience with levamisole hydrochloride include exfoliative dermatitis, periorbital edema, vaginal bleeding, anaphylaxis, convulsions, hallucinations, renal failure, hyperlipidemia, elevated serum creatinine, and increased alkaline phosphatase. [Physicians GenRx 1996; p II-1234; PDR 1997; p 1340-1] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to the drug or its components. [Physicians GenRx 1996; p II-1234; PDR 1997; p 1340] CHEMICAL/PHYSICAL DATA Molecular Formula: C11-H12-N2-S.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 240.76 [USPD 1998; p. 414] CHEMICAL/PHYSICAL DATA Melting Point: 227-229 C [Merck Index 1996; p. 932] CHEMICAL/PHYSICAL DATA Elemental Comp: C64.67%, H5.92%, N13.71%, S15.70% (base) [Merck Index 1996; p. 932] CHEMICAL/PHYSICAL DATA Stability: Soluble in water. Stable in acid aqueous media. [Merck Index 1996; p 932] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to pale cream colored crystalline powder that is almost odorless. [PDR 1997; p 1340] SUBSTANCE DELIVERY DATA DOSAGE FORM: 50 mg tablets. [PDR 1997; p 1341] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Physicians GenRx 1996; p II-1233] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). Protect from moisture. [Physicians GenRx 1996; p II-1235] MANUFACTURERS 0000001070: Janssen Pharmaceutica Inc 1125 Trenton-Harbourton Rd / PO Box 200 Titusville, NJ 085600200 Contact: Dr Richard Meibach (908)730-3135 MANUFACTURERS 0000001070: Janssen Pharmaceutica Inc 1125 Trenton-Harbourton Rd / PO Box 200 Titusville, NJ 085600200 Contact: Unspecified (800)526-7736 REFERENCES AIDS/97220424. Salhany JM, Stevenson M. Hypothesis: potential utility of pyridoxal 5'-phosphate (vitamin B6) and levamisole in immune modulation and HIV-1 infection. AIDS Patient Care STDS. 1996 Dec;10(6):353-6. MED/96152477. De Brabander M, Vandebroek J, Wassenaar H, De Cree J, Baisier A, Demoen B, De Ridder R, Jagers E, Roels V, Vogels O, et al. Immunological alterations induced by adjuvant treatment of postoperative colon carinoma Duke's B or C with levamisole in combination with 5-FU. Anticancer Res. 1995 Sep-Oct;15(5B):2271-7. MED/95319356. Wigginton JM. Reversal of ferritin-mediated immunosuppression by levamisole: a rationale for its application to management of the acquired immune deficiency syndrome (AIDS). Med Hypotheses. 1995 Feb;44(2):85-8. MED/95161644. Bourinbaiar AS, Lee-Huang S, Krasinski K, Borkowasky W. Anti-HIV effect of immunomodulating agent, levamisole, in vitro. Biomed Pharmacother. 1994;48(7):327-30. MED/94323613. Fleming TR, Prentice RL, Pepe MS, Glidden D. Surrogate and auxiliary endpoints in clinical trials, with potential application in cancer and AIDS research. Stat Med. 1994 May 15;13(9):955-68 MED/94322276. Sun A, Chiang CP, Chiou PS, Wang JT, Liu By, Wu YC. Immunomodulation by levamisole in patients with recurrent aphthous ulcers or oral lichen planus. J Oral Pathol Med. 1994 Apr;23(4):172-7. MED/93140467. Matondo P, Kalima P. Levamisole for HIV- infected children in Zambia (letter; comment). Lancet. 1993 Jan 16;341(8838):178-9. MED/92317522. Glick M, Muzyka BC. Alternative therapies for major aphthous ulcers in AIDs patients. J Am Dent Assoc. 1992 Jul;123(7);61-5. ICA8/92401191. Laane H, Eussen R, Graafmans J. The effects of levamisole on HIV-infected patients. Int Conf AIDS. 1992 Jul 19-24;8(2):B163 (abstract no. PoB 3456) ENTRY MONTH 199605 LAST REVISION DATE 20001107 102 UNIQUE IDENTIFIER DRG-0244 NAME OF SUBSTANCE Ritonavir [USPD 1998; p. 640] REGISTRY NUMBER 155213-67-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1- -methylethyl) -4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl- )-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)] [PDR 1999; p 464] SYNONYMS Norvir [USP DI 2000; p. 3493] PROTOCOL ID NUMBERS Complete CC 00 I-0053 PROTOCOL ID NUMBERS Complete NIAID ACTG 223 PROTOCOL ID NUMBERS Complete NIAID ACTG 246/946 PROTOCOL ID NUMBERS Complete NIAID ACTG 315 PROTOCOL ID NUMBERS Complete NIAID ACTG 359 PROTOCOL ID NUMBERS Complete NIAID ACTG 378 PROTOCOL ID NUMBERS Complete NIAID ACTG 401 PROTOCOL ID NUMBERS Complete NIAID ACTG A5047 PROTOCOL ID NUMBERS No longer recruiting FDA 229G PROTOCOL ID NUMBERS No longer recruiting FDA 229H PROTOCOL ID NUMBERS No longer recruiting FDA 229J PROTOCOL ID NUMBERS No longer recruiting FDA 229R PROTOCOL ID NUMBERS No longer recruiting FDA 229S PROTOCOL ID NUMBERS No longer recruiting FDA 238J PROTOCOL ID NUMBERS No longer recruiting FDA 245C PROTOCOL ID NUMBERS No longer recruiting FDA 245D PROTOCOL ID NUMBERS No longer recruiting FDA 245E PROTOCOL ID NUMBERS No longer recruiting FDA 246S PROTOCOL ID NUMBERS No longer recruiting FDA 264N PROTOCOL ID NUMBERS No longer recruiting FDA 295B PROTOCOL ID NUMBERS No longer recruiting FDA 312A PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-0003G PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-63 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0147 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 338 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 354 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 377 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 397 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 403 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 042 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 057 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 228H PROTOCOL ID NUMBERS Recruiting FDA 246T PROTOCOL ID NUMBERS Recruiting FDA 246U PROTOCOL ID NUMBERS Recruiting FDA 246V PROTOCOL ID NUMBERS Recruiting FDA 285F PROTOCOL ID NUMBERS Recruiting FDA 302B PROTOCOL ID NUMBERS Recruiting FDA 313A PROTOCOL ID NUMBERS Recruiting FDA 316B PROTOCOL ID NUMBERS Recruiting CC 98 C-0041 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 345 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 386 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5043 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5055 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5061 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5072 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5093 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1013 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Terminated NIAID AIEDRP AI-03-001 PHARMACOLOGICAL ACTION MODE OF ACTION: Ritonavir is a selective, competitive inhibitor of HIV protease. This enzyme plays an essential role in the HIV replication cycle and the formation of infectious virus. By interfering with the formation of essential proteins and enzymes, ritonavir blocks the maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions. The antiviral activity of ritonavir does not depend on intracellular conversion to an active metabolite. HIV protease inhibitors, including ritonavir, act at different stages of the HIV replication cycle than the dideoxynucleoside and nonnucleoside reverse transcriptase inhibitors. Ritonavir exhibits cytotoxic properties at concentrations at least 1000x greater than those required for antiretroviral activity. Resistance to ritonavir has been produced in vitro, with mutation of HIV protease seeming to be the principle mechanism of resistance. Some HIV mutations were also found in patient groups on ritonavir monotherapy. The antiretroviral effects of ritonavir and other agents such as dideoxynucleosides are additive or synergistic against HIV-1. Cross-resistance between ritonavir and dideoxynucleoside or nonnucleoside transcriptase inhibitors is highly unlikely because these drugs have different target enzymes. Ritonavir is well absorbed following oral administration; peak plasma concentrations come within 2-4 hours. The drug does not appear to be metabolized on first pass through the liver. Ritonavir is 98-99% plasma bound. The drug is metabolized in the liver; five metabolites have been identified in urine and feces. Some 86.4% of a 600-mg dose is eliminated through the feces, both as unchanged drug (33.8%) and as metabolites, and 11.3% is excreted in the urine (3.5% as unchanged drug). [AHFS Drug Information 1999; p 604-6] DISEASES STUDIED/TREATED The FDA has approved ritonavir soft gel capsules and oral solution use in combination with other antiretroviral agents for the treatment of HIV infection. Ritonavir has also been approved by the FDA for use in children between the ages of 2 and 16 based on safety and pharmacokinetic data. [Abbott Laboratories. Available at: http://www.rxabbott.com. Accessed: May 15, 2000.; 1999 Jul 1] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 2698] CLASSIFICATION CODE Protease inhibitor [AHFS Drug Information 2000; p. 640] SUBSTANCE INTERACTIONS Drug interactions may occur when ritonavir is coadministered with a wide variety of other drugs mostly because of pharmacokinetic interactions. Ritonavir is metabolized by isoforms of the cytochrome P-450 enzyme system. When it is administered with other drugs that are extensively metabolized by these isoenzymes, competition for the isoenzymes may occur, there may be decreased metabolism of these drugs, and their plasma concentration may be elevated. Ritonavir is expected to increase plasma levels of the following drugs (among others): amiodarone, astemizole, bepridil, bupropion, cisapride, clozapine, erythromycin, meperidine, methylphenidate, phenothiazines, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, terfenadine and warfarin. This may lead to an increased risk of arrhythmias, hematological complications, seizures and other serious adverse effects. Coadministration of ritonavir and ergotamine or dihydroergotamine has been associated with acute ergot toxicity. Ritonavir may produce a decrease in the plasma levels of the following drugs: atovaquone, clofibrate, daunorubicin, diphenoxylate, metoclopramide, and sedatives/hypnotics. Coadministration of ritonavir with the following drugs may cause extreme sedation and respiratory depression: alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, and zolpidem. [AHFS Drug Information 1999; p 610] ADVERSE EFFECTS Adverse effects most frequently reported include asthenia, nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias. Less common adverse effects include fever, headache, malaise, vasodilation, constipation, dyspepsia, flatulence, local throat irritation, increase in creatine phosphokinase, hyperlipidemia, myalgia, dizziness, insomnia, somnolence, abnormal thinking, pharyngitis, rash, and sweating. Other adverse events reported occurred in less than 2% of the patients studied; these included cardiovascular, GI, endocrine, CNS, hematological and lymphatic systems, and dermatological reactions. Ritonavir has also been associated with alterations in triglyceride, AST, ALT, GGT, CPK, and uric acid laboratory test values. [PDR 1999; p 468; Abbott Laboratories. Available at: http://www.rxabbott.com. Accessed: May 15, 2000.; 1999 Jul 1] CONTRAINDICATIONS Because ritonavir is principally metabolized by the liver, it needs to be used with caution in patients with impaired liver functions. There have been reports of increased bleeding when patients with type A or type B hemophilia were treated with protease inhibitors. A causal relationship has not been established. It is not known whether the drug crosses the placenta. However, the drug should be used in pregnant women only if clearly needed. It is also not known whether ritonavir is distributed into human milk but the CDC advises HIV-positive women in general not to breast-feed, in order to avoid virus transmission to their infants. The evaluation of ritonavir as an antiviral drug in pediatric HIV patients is ongoing. [PDR 1999; p 466-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic peptidomimetic HIV protease inhibitor. Chemical structure was designed based on structure of HIV protease. Symmetric nature of ritonavir results in a highly selective, potent inhibitor of HIV protease. [AmfAR Treat Dir 1999 Summer;10(1); p 35] CHEMICAL/PHYSICAL DATA Molecular Formula: C37-H48-N6-O5-S2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 720.96 [USPD 1998; p. 640] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.64%, H6.71%, N11.66%, O11.10%, S8.90% [Merck Index 1996; p. 1418] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in methanol and ethanol; soluble in isopropanol; practically insoluble in water. [PDR 1999; p 464] CHEMICAL/PHYSICAL DATA Stability: The oral solution is stable for 30 days when kept at 25 C (77F). [PDR 1999; p 469] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to light tan powder with bitter metallic taste. [PDR 1999; p 464] SUBSTANCE DELIVERY DATA DOSAGE FORM: 100-mg soft gelatin capsules and 8-oz bottles of 80 mg/ml oral solution. [Abbott Laboratories. Available at: http://www.rxabbott.com. Accessed: May 15, 2000.; 1999 Jul 1] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 469] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store capsules at 2-8 C (36-46 F) and protect from light. Store oral solution at 2-8 C (36-46 F) and avoid exposure to excessive heat. Refrigerated storage of soft gelatin capsules by patients is recommended, but not required if used within 30 days and stored below 25 C (77 F). [PDR 1999; p 469; Abbott Laboratories. Available at: http://www.rxabbott.com. Accessed: May 15, 2000.; 1999 Jul 1] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/99420236. Rublein JC, Eron JJ Jr, Butts JD, Raasch RH. Discontinuation rates for protease inhibitor regimens containing ritonavir 600 mg versus ritonavir 400 mg plus saquinavir 400 mg. Ann Pharmacother 1999 Sep;33(9):899-905. MED/99385799. Kravcik S, Gallicano K, Roth V, Cassol S, Hawley-Foss N, Badley A, Cameron DW. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr 1999 Aug 15;21(5):371-5. MED/99394828. Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother 1999 Jul-Aug;33(7-8):859-63. MED/99246406. Sleasman JW, Nelson RP, Goodenow MM, Wilfret D, Hutson A, Baseler M, Zuckerman J, Pizzo PA, Mueller BU. Immunoreconstitution after ritonavir therapy in children with human immunodeficiency virus infection involves multiple lymphocyte lineages. J Pediatr 1999 May;134(5):597-606. MED/99217477. Cameron DW, Japour AJ, Xu Y, Hsu A, Mellors J, Farthing C, Cohen C, Poretz D, Markowitz M, Follansbee S, Angel JB, McMahon D, Ho D, Devanarayan V, Rode R, Salgo M, Kempf DJ, Granneman R, Leonard JM, Sun E. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1999 Feb 4;13(2):213-24. MED/99223946. Kirk O, Katzenstein TL, Gerstoft J, Mathiesen L, Nielsen H, Pedersen C, Lundgren JD. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999 Jan 14;13(1):F9-16. MED/99030026. Mueller BU, Zeichner SL, Kuznetsov VA, Heath-Chiozzi M, Pizzo PA, Dimitrov DS. Individual prognoses of long-term responses to antiretroviral treatment based on virological, immunological and pharmacological parameters measured during the first week under therapy. AIDS 1998 Oct 22;12(15):F191-6. MED/99135017. Ren S, Lien EJ. Development of HIV protease inhibitors: a survey. Prog Drug Res 1998;51:1-31. MED/98153719. Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, Sun E, Henry D, Rode R, Potthoff A, Leonard J. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998 Feb 21;351(9102):543-9. MED/96067436. Markowitz M, Saag M, Powderly WG, Hurley AM, Hsu A, Valdes JM, Henry D, Sattler F, La Marca A, Leonard JM, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995 Dec 7;333(23):1534-9. ENTRY MONTH 199604 LAST REVISION DATE 20000801 103 UNIQUE IDENTIFIER DRG-0243 NAME OF SUBSTANCE ALVAC-HIV MN120TMGNP (vCP300) [Protocol ID: AVEG 026 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 026 PHARMACOLOGICAL ACTION ALVAC vaccines are recombinant live vector vaccines that are utilized primarily to induce cellular immune responses, but they also can elicit humoral responses. In addition, when ALVAC is used as a primary immunization, the antibody response can be augmented substantially by subsequent boost with recombinant subunit protein vaccines. The ALVAC line of vaccines is based on the canarypox vector. Canarypox is a member of the pox virus family, of which vaccinia (cowpox) is also a member. The canarypox virus, which originates in birds, is considered safer than vaccinia because it does not reproduce in humans. Another advantage of the canarypox virus is its ability to transport large amounts of foreign genes. Various HIV genes have been inserted into this vector. The genes originate from the clade B virus, which is the predominant subtype of HIV-1 found in the US and Europe. After administration of ALVAC vCP300 vaccine, HIV-1 genes are expressed in the host cell. The gag gene expresses a polyprotein that matures into core proteins (p24, p17, and p15). The pol gene expresses the protease enzyme, which catalyzes the partition of p15 into p9 and p6. The nef and pol genes also encode for peptides that contain multiple CTL epitopes. The proteins form virus-like particles that are enveloped by the products of env gene expression. The viral particles bud from the cell membrane and are similar to HIV virions in their appearance and structure, but not infectivity. Studies have demonstrated that these pseudovirions are indeed immunogenic. Neutralizing antibodies are detected in 20% of volunteers receiving ALVAC vCP300 alone and in up to 100% of volunteers receiving an additional gp120 boost. Cytotoxic activity, including an enlarged nef and pol CTL response (relative to older ALVAC vaccines), is observed in over 60% of volunteers. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.; AIDS Vaccine Evaluation Group (AVEG). Listing of candidate HIV vaccines used in AVEG studies. Available at: http://www.scharp.org/public/index.htm. Accessed August 7, 2000.; Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] DISEASES STUDIED/TREATED ALVAC vaccines are investigated as preventative vaccines for HIV infection. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 026 ] ADVERSE EFFECTS The canarypox virus does not replicate in the human host; therefore, recombinants are unlikely to cause disease in recipients or be transmitted to unvaccinated contacts. Adverse reactions reported after ALVAC vaccine administration are similar to those observed in healthy adults who have received marketed vaccines. Local and systemic side effects are mild to moderate and usually resolve within 72 hours after immunization. Local effects include transient pain, tenderness, redness, and swelling at the site of injection. Less common systemic effects include headache, malaise, fever, dizziness, and nausea. No severe adverse reactions have been reported. [Protocol ID: AVEG 202 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ALVAC vCP300 is a recombinant canarypox vaccine that expresses a part of the env gene product, gag and protease gene proteins, and nef and pol gene products containing multiple CTL epitopes. The env gene expresses the glycoprotein (gp) 120 of the HIV-1 MN strain and the transmembrane (TM) gp41 of the HIV-1 LAI strain. The other proteins expressed are of the HIV-1 LAI strain. ALVAC vCP300 is cultivated in specific pathogen-free chick embryo fibroblasts. The recombinant virus is suspended in a serum- and antibiotic-free culture medium to which a virus stabilizer is added. The solution is then lyophilized. [Protocol ID: AVEG 026 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: The lyophilized product is a white to pink powder. The reconstituted product is a slightly opalescent, pink to purplish-blue liquid. [Protocol ID: AVEG 026 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The vaccine is supplied as single-dose vials of sterile lyophilized product containing 10(6.3) of tissue culture 50% infective doses (TCID50) of ALVAC vCP300. Sterile water for injection that is adjusted to a pH of 5.0 to 7.0 is supplied as the diluent. [Protocol ID: AVEG 026 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The product should be thawed at room temperature for approximately 30 minutes. The contents of the vial are reconstituted with 1 ml of the supplied diluent. The vaccine is administered intramuscularly with a 22-gauge, 1.5-inch needle into the deltoid muscle. [Protocol ID: AVEG 026 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powder should be stored at -20 C. The product should be thawed at room temperature for approximately 30 minutes. Once reconstituted, the vaccine should be kept refrigerated (3-5 C) and used within two hours. Freezing of the reconstituted vaccine should be avoided. [Protocol ID: AVEG 026 ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 REFERENCES Kaslow RA, Rivers C, Goepfert P, Tang J, El Habib R, Weinhold K, Mulligan MJ. Association of HLA class I alleles with cytotoxic T-lymphocyte (CTL) responses to gag and env in recipients of ALVAC-HIV canarypox vaccines. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 818). Larsson M, Engelmayer J, Lee M, Cox W, Steinman R, Bhardwaj N. Dendritic cells infected with recombinant canarypox virus induce potent anti-HIV cytolytic and helper T cell responses from chronically infected individuals. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 830). Ignatius R, Lewis M, Cox WI, Frankel S, Mascola J, Villamide L, Mehlhop E, Steinman RM, Pope M. In vivo T cell priming in rhesus macaques by reinjected immature and mature dendritic cells bearing soluble or recombinant viral vector-encoded antigens. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 434). MED/20048108. Gorse GJ, Patel GB, Mandava MD, Belshe RB. Vaccine-induced cytotoxic T lymphocytes against human immunodeficiency virus type 1 using two complementary in vitro stimulation strategies. Vaccine. 1999 Dec 10;18(9-10):835-49. AIDS/20710224. Evans TG; Keefer MC; Belshe RB; Schwartz D; Graham BS; Corey L; Mulligan MJ; Stablein D. Rates and determinants of positive HIV screening test results in uninfected participants in phase I/II trials of candidate HIV-1 vaccines. Natl HIV Prev Conf. 1999 Aug 29-Sep 1; (abstract no. 293). MED/99326725. Evans TG, Keefer MC, Weinhold KJ, Wolff M, Montefiori D, Gorse GJ, Graham BS, McElrath MJ, Clements-Mann ML, Mulligan MJ, Fast P, Walker MC, Excler JL, Duliege AM, Tartaglia J. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J Infect Dis. 1999 Aug;180(2):290-8. AIDS/20711288. John R; Castillo R; Arango-Jaramillo S; Turner B; Iyengar S; Schwartz D. Induction of in vitro resistance to R4 and R5 HIV-1 by vaccination with ALVAC vCP300 canarypox vector containing env, gag, pol, and nef gene segments. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:75 (abstract no. 45). MED/97454417. Ferrari G, Berend C, Ottinger J, Dodge R, Bartlett J, Toso J, Moody D, Tartaglia J, Cox WI, Paoletti E, Weinhold KJ. Replication-defective canarypox (ALVAC) vectors effectively activate anti-human immunodeficiency virus-1 cytotoxic T lymphocytes present in infected patients: implications for antigen-specific immunotherapy. Blood. 1997 Sep 15;90(6):2406-16. AIDS/97927175. Finkielsztejn L, Salmon-Ceron D, Excler JL, Zak Dit Zbar O, Raux M, Gomard E, Gluckman JC, Blondeau C, Sicard D. Safety and immunogenicity of a live, recombinant canarypox virus expressing gp120TM-MN/gag/protease-LAI and CTL domains of nef and pol- LAI (alvac-HIV vCP300) in HIV-negative volunteers. Conf Adv AIDS Vaccine Dev. 1997 May 4-7;:211 (poster 106). AIDS/97927172. Carruth LM, Castro MG, Crone SN, Ferris RL, Siliciano RF. Induction of HIV-1 specific CTL by canarypox vectors in phase I vaccine trials. Conf Adv AIDS Vaccine Dev. 1997 May 4-7;:208 (Poster 103). AIDS/97926030. Corey L, Weinhold K, Montefiori D, McElrath J, Excler JL, Duliege AM, Stablein D. Combination candidate HIV vaccines using a canarypox vector (vCP205) followed by boosting with gp120(SF-2). 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:209 (abstract no. LB18). MED/97030197. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11349-53. Review. MED/95341166. Perkus ME, Tartaglia J, Paoletti E. Poxvirus-based vaccine candidates for cancer, AIDS, and other infectious diseases. J Leukoc Biol. 1995 Jul;58(1):1-13. Review. MED/95317468. Plotkin SA, Cadoz M, Meignier B, Meric C, Leroy O, Excler JL, Tartaglia J, Paoletti E, Gonczol E, Chappuis G. The safety and use of canarypox vectored vaccines. Dev Biol Stand. 1995;84:165-70. ENTRY MONTH 199602 LAST REVISION DATE 20000921 104 UNIQUE IDENTIFIER DRG-0242 NAME OF SUBSTANCE Nitazoxanide [USPD 1998; p. 513] REGISTRY NUMBER 55981-09-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N-(5-Nitro-2-thiazolyl)salicylamide acetate (ester) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 336 PROTOCOL ID NUMBERS No longer recruiting FDA 253A PROTOCOL ID NUMBERS Recruiting FDA 253B PROTOCOL ID NUMBERS Terminated FDA 253C DISEASES STUDIED/TREATED AIDS-related cryptosporidiosis. [Protocol ID: 253B ] CLASSIFICATION CODE Antiparasitic [USP DI 2000; p. 3316] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H9-N3-O5-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 307.29 [USPD 1998; p. 513] SUBSTANCE DELIVERY DATA DOSAGE FORM: 500 mg tablets. [Protocol ID: 253B ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 253B ] MANUFACTURERS 0000003497: Unimed Pharmaceuticals Inc 4 Parkway North 2nd floor Deerfield, IL 60015 Contact: Lauren Boswell (800)864-6330 REFERENCES AIDS/96701490. Anonymous. NTZ qualifies for orphan drug status. Positiv Aware. 1996 May/June; 7(3):6. AIDS/96700966. Smart T. NTZ trials for cryptosporidiosis. GMHC Treat Issues. 1995 Sep; 9(9):14. ENTRY MONTH 199602 LAST REVISION DATE 20001107 105 UNIQUE IDENTIFIER DRG-0241 NAME OF SUBSTANCE HBY 097 [Protocol ID: 252A ] STANDARD CHEMICAL NAME (S)-3,4-dihydro-7-methoxy-2((methylthio)-meth- yl)- 3-thioxo-1(2H)-quinoxalinecarboxylic acid-1-methylethylester [Protocol ID: 252A ] PROTOCOL ID NUMBERS No longer recruiting FDA 252A PHARMACOLOGICAL ACTION MODE OF ACTION: Non-nucleoside reverse transcriptase inhibitor specific for HIV-1. HBY-097 was given orally at doses of 125, 250, 375, 500 and 750 mg tid for 7 days and 14 days (750 mg dose only) to asymptomatic and mildly symptomatic HIV-positive subjects with CD4 counts between 200 and 500 cells/mm3. HBY-097 was rapidly absorbed following PO doses. The considerable overlap in Cmax and AUC values between the dose levels indicated high interindividual variability. Following the 250, 500, and 750 mg doses, trough concentrations ranged from 206-720 micrograms/L, 364-1226 micrograms/L and 461-2116 micrograms/L, respectively. Based on the IC90 range of clinical isolates, and the high protein binding (greater than 95%), it was predicted that these trough concentrations would be clinically relevant. Two of 3 subjects who completed 750 mg tid x 14 days treatment showed greater than one log reduction in the viral load after 14 days of treatment; the third subject had very low viral load at baseline which reached 0 after 14 days of treatment. The data indicated that HBY-097 is reasonably well tolerated and exhibits promising antiviral properties. Another study designed to characterize viral load and viral characteristics during a 14-day treatment of HIV-1 positive individuals with HBY-097, showed that all viruses before and after therapy were of the non-cytopathogenic phenotype with moderate or low replication capacity. Genotypic analysis of viral RNA from serum of cultured viruses and of proviral DNA showed no induction of a relevant non-nucleoside reverse transcriptase inhibitor-resistance mutation. [Int Conf AIDS 1996 Jul 7-12;11(1); p 111 (abstract no.Mo.B.1326); Int Conf AIDS 1996 Jul 7-12;11(1); p 72 (abstract no.Mo.A.1102)] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: 252A ] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS HBY-097 was safe and reasonably well tolerated with no consistent dose-related adverse event or laboratory abnormalities. Two subjects in the 750 mg tid x 14 day treatment group discontinued study medication due to a generalized maculopapular rash which emerged on Day 10. [Int Conf AIDS 1996 Jul 7-12;11(1); p 111 (abstract no.Mo.B.1326)] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Quinoxaline derivative. [Natl Conf Hum Retrv Rela Inf (2nd) 1995; p 70] CHEMICAL/PHYSICAL DATA Molecular Formula: C15-H20-N2-O3-S2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 340.47 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg tablets. [Protocol ID: 252A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 252A ] MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 REFERENCES ICA11/96921390. Shah A, Kumor K, Sullivan J, Amand R, Cole S, Agarwal V, Krol G, Huguenel E, Suarez JR, Heller AH. Safety, tolerability and pharmacokinetics (PK) of HBY-097 in asymptomatic and mildly symptomatic HIV-positive patients. Int Conf AIDS. 1996 Jul 7-12;11(1):111 (abstract no.Mo.B.1326). ICA11/96921172. Rubsamen-Waigmann H, Wainberg MA, Huguenel E, Shah A, Paessens A, Kleim JP, Rosner M. Antiviral profile of HBY097, a nonnucleoside inhibitor of HIV-1 RT in a phase I study. Int Conf AIDS. 1996 Jul 7-12;11(1):72 (abstract no.Mo.A.1102). MED/96133872. Kleim JP, Rosner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnold E, Riess G. Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants. Proc Natl Acad Sci USA. 1996 Jan 9;93(1):34-8. MED/96109422. Kleim JP, Bender R, Kirsch R, Meichsner C, Paessens A, Rosner M, Rubsamen-Waigmann H, Kaiser R, Wichers M, Schneweis KE, et al. Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1995 Oct;39(10):2253-7. AIDS/95920498. Kleim JP, Paessens A, Bender R, Kirsch R, Meichsner C, Rosner M, Winkler I, Riess G. Evaluation of in vitro resistance development against the quinoxaline HBY 097 reveals novel patterns of mutations within the HIV-1 gene encoding the reverse transcriptase. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2:141. AIDS/95920118. Paessens A, Blunck M, Kleim JP, Meichsner C, Riess G, Rosner M, Rubsamen HW, Winkler I. HBY 097, in vitro antiviral profile against HIV-1 in acute and persistent infection systems: combined drug interaction with different inhibitors of HIV-1 or other viruses. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2:70. AIDS/95920117. Rosner M, Bender R, Billhardt UM, Dienst K, Kirsch R, Kleim JP, Meichsner C, Paessens A, Riess G, Winkler I. HBY 097, a new quinoxaline derivative with highly potent and selective anti-HIV-1 activity. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2:70. AIDS/96701081. New type of HIV drug. Treat Rev. 1995 Nov;(no 20):4. AIDS/96700963. Pieribone V. Overcoming resistance to reverse transcriptase inhibitors. GMHC Treat Issues. 1995 Sep;9(9):8-9. MED/95229100. [New substance against AIDS in clinical trial (news)]. Fortschr Med. 1995 Feb 10;113(4):58. ENTRY MONTH 199511 LAST REVISION DATE 20000801 106 UNIQUE IDENTIFIER DRG-0240 NAME OF SUBSTANCE Pneumococcal Conjugate Vaccine, Heptavalent [Protocol ID: ACTG 292 ] SYNONYMS Prevnar [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/efoi/approve.htm. Accessed 03/28/01.] PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 292 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1024 PHARMACOLOGICAL ACTION MODE OF ACTION: The chemical and immunologic properties of a heptavalent vaccine composed of high-molecular-weight polymers of the lipopolysaccharide (LPS) O polysaccharides representative of the most common clinical isolates of Pseudomonas aeruginosa were investigated; and the serum antibody response to nonvaccine strains aeruginosa, including strains expressing structural variants (subtype strains) of the O side chain of the vaccine strains were evaluated. Mouse and rabbit immune sera showed different patterns of opsonic activity against subtype strains, indicating that different epitopes on these antigens are immunodominant in the representatives of these two animal species tested. The polyvalent vaccine was effective at eliciting antibodies to vaccine components in mice and rabbits, but it remains to be determined if the current heptavalent formulation contains sufficient components to provoke human antibodies reactive with a majority of clinical strains of P. aeruginosa. [Infect Immun 1994 Sep;62(9); p 3608-16] DISEASES STUDIED/TREATED HIV-associated pneumococcal disease. [Protocol ID: ACTG 292 ] CLASSIFICATION CODE Vaccine [Protocol ID: ACTG 292 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Pneumococcal capsular saccharides from serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F bound to a diphtheria toxin mutant (CRM197) carrier protein. [Protocol ID: ACTG 292 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular. [Protocol ID: ACTG 292 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (35-46 F). Do not freeze. [Protocol ID: ACTG 292 ] MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Unspecified (610)647-9452 MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 REFERENCES MED/97005606. King JC Jr, Vink PE, Farley JJ, Parks M, Smilie M, Madore D, Lichenstein R, Malinoski F. Comparison of the safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide vaccine in human immunodeficiency virus and non-human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1996 Mar;15(3):192-6. MED/96217731. Rodriguez-Barradas MC, Groover JE, Lacke CE, Gump DW, Lahart CJ, Pandey JP, Musher DM. IgG antibody to pneumococcal capsular polysaccharide in human immunodeficiency virus-infected subjects: persistence of antibody in responders, revaccination in nonresponders, and relationship of immunoglobulin allotype to reponse. J Infect Dis. 1996 Jun;173(6):1347-53. MED/96196149. Swiatlo E, Benton K, Briles DE. Pneumococcal vaccine response in human immunodeficiency virus-infected patients [letter]. J Infect Dis. 1996 Mar;173(3):777-8. MED/96132467. Ahmed F, Steinhoff MC, Rodriguez-Barradas MC, Hamilton RG, Musher DM, Nelson KE. Effect of human immunodeficiency virus type 1 infection on the antibody response to a glycoprotein conjugate pneumococcal vaccine: results from a randomized trial. J Infect Dis. 1996 Jan;173(1):83-90. MED/95245225. Jain A, Jain S, Gant V. Should patients positive for HIV infection receive pneumococcal vaccine? [see comments]. BMJ. 1995 Apr 22;310(6986):1060-2. MED/95367899. McDonald P, Lighton L, Anderson R. Pneumococcal vaccine for HIV patients. Patients with HIV infection should be immunised...[letter; comment]. BMJ. 1995 Aug 5;311(7001):387-8. MED/95263074. Willocks LJ, Vithayathil K, Tang A, Noone A. Pneumococcal vaccine and HIV infection:report of a vaccine failure and reappraisal of its value in clinical practice. Genitourin Med.1995 Apr;71(2):71-2. MED/95158135. Peters VB, Diamant EP, Hodes DS, Cimino CO. Impaired immunity to pneumococcal polysaccharide antigens in children with human immunodeficiency virus infection immunized with pneumococcal vaccine. Pediatr Infect Dis J. 1994 Oct;13(10):933-4. MED/94341860. Hatano K, Boisot S, DesJardins D, Wright DC, Brisker J, Pier GB. Immunogenic and antigenic properties of a heptavalent high-molecular-weight O-polysaccharide vaccine derived from Pseudomonas aeruginosa. Infect Immun 1994 Sep;62(9):3608-16. MED/94069234. Requejo HI. Polyvalent pneumococcal polysaccharide vaccines; a review of the literature. Rev Hosp Clin Fac Med Sao Paulo. 1993 May-Jun;48(3):130-8. ENTRY MONTH 199511 LAST REVISION DATE 20000801 107 UNIQUE IDENTIFIER DRG-0239 NAME OF SUBSTANCE Pneumococcal Vaccine, Polyvalent (23-valent) [Protocol ID: ACTG 292 ] SYNONYMS Pnu-Imune 23 [USP DI 2000; p 2500] SYNONYMS Pneumovax 23 PROTOCOL ID NUMBERS Complete NIAID ACTG 340 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 292 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1024 DISEASES STUDIED/TREATED HIV-associated pneumococcal disease. [Protocol ID: ACTG 292 ] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 2497] OTHER MAJOR USES Immunization against infections caused by the 23 most prevalent types of streptococcus pneumoniae (pneumococci) included in the vaccine. [PDR 1997; p 1437] SUBSTANCE INTERACTIONS Patients with impaired immune responsiveness whether due to the use of immunosuppresive therapy, a genetic defect, HIV infection, or other causes may have a reduced antibody response to active immunization procedures. Patients who have received extensive chemotherapy and/or splenectomy for the treatment of Hodgkin's disease have been shown to have an impaired serum antibody response to pneumococcal vaccine. In one study, administration of the vaccine to patients on immunosuppressive drugs and/or irradiation for Hodgkin's disease resulted in reduction of preexisting antibody levels in several patients. It is unclear whether this effect was due to the vaccine or to the effects of irradiation and/or chemotherapy. [PDR 1997; p 1438] ADVERSE EFFECTS Incidence of adverse reactions is relatively low, of short duration, and not serious. Patients may experience local reaction characterized by soreness at the injection site within 3 days after immunization, low grade fever and mild myalgia within 24 hours after immunization. Rash, urticaria, arthritis, arthralgia, and adenitis have been reported rarely. [PDR 1997; p 1438] CONTRAINDICATIONS Hypersensitivity to any component of the vaccine, including thimerosal, a mercury derivative, is a contraindication to the use of this product. The occurrence of any type of neurological symptoms or signs following administration of this product is a contraindication to future use. The vaccine should not be administered to persons with acute febrile illness until their temporary symptoms and/or signs have abated. This product should not be used in children under 2 years of age. This product is not recommended for use in pregnant or nursing women. [PDR 1997; p 1438] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Purified capsular polysaccharide antigens of 23 types of Streptococcus pneumoniae (Danish types 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F). [MMWR 1989 Feb 10;38(5); p 64-68, 73-76] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Clear and colorless liquid. [PDR 1997; p 1437] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile solution is formulated to contain 25 ug of each of the 23 purified polysaccharide types per 0.5 ml dose of vaccine: 2.5 ml/vial (for use with syringe only): 5 x 0.5 ml (one dose) LEDERJECT (disposable syringes). [PDR 1997; p 1438] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular or subcutaneous. [Protocol ID: ACTG 292 ; PDR 1997; p 1437] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (35-46 F). Do not freeze. [Protocol ID: ACTG 292 ; PDR 1997; p 1438] MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr Amy Baim (914)732-2147 MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Dr John Riefler (914)732-2035 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (610)647-9452 REFERENCES MED/96217731. Rodriguez-Barradas MC, Groover JE, Lacke CE, Gump DW, Lahart CJ, Pandey JP, Musher DM. IgG antibody to pneumococcal capsular polysaccharide in human immunodeficiency virus-infected subjects: persistence of antibody in responders, revaccination in nonresponders, and relationship of immunoglobulin allotype to reponse. J Infect Dis. 1996 Jun;173(6):1347-53. MED/97005606. King JC Jr, Vink PE, Farley JJ, Parks M, Smilie M, Madore D, Lichenstein R, Malinoksi F. Comparison of the safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide vaccine in human immunodeficiency virus and non-human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1996 Mar;15(3):192-6. MED/96132467. Ahmed F, Steinhoff MC, Rodriguez-Barradas MC, Hamilton RG, Musher DM, Nelson KE. Effect of human immunodeficiency virus type 1 infection on the antibody response to a glycoprotein conjugate pneumococcal vaccine: results from a randomized trial. J Infect Dis. 1996 Jan;173(1):83-90. MED/96128450. Loeliger AE, Rijkers GT, Aerts P, Been-Tiktak A, Hoepelman AI, van Dijk H, Borleffs JC. Deficient antipneumococcal polysaccharide responses in HIV-seropositive patients. FEMS Immunol Med Microbiol. 1995 Sep;12(1):33-41. MED/96002832. Keller DW, Breiman RF. Preventing bacterial respiratory tract infections among persons infected with human immunodeficiency virus. Clin Infect Dis. 1995 Aug;21 Suppl 1:S77-83. MED/95271058. Weiss PJ, Wallace MR, Oldfield EC 3rd, O'Brien J, Janoff EN. Response of recent human immunodeficiency virus seroconverters to the pneumococcal polysaccharide vaccine and Haemophilus influenzae type b conjugate vaccine. J Infect Dis. 1995 May;171(5):1217-22. MED/95263074. Willocks LJ, Vithayathil K, Tang A, Noone A. Pneumococcal vaccine and HIV infection: report of a vaccine failure and reappraisal of its value in clinical practice. Genitourin Med. 1995 Apr;71(2):71-2. AIDS/95920708. Peters V, Hodes D, Cimino C. Antibody responses to pneumococcal polysaccharides (PnPS) in HIV-infected children immunized with pneumococcal vaccine (PV). Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:34. MED/93139380. Sanders LA, Rijkers GT, Kuis W, Tenbergen-Meekes AJ, de Graeff-Meeder BR, Hiemstra I, Zegers BJ. Defective antipneumococcal polysaccharide antibody response in children with recurrent respiratory tract infections. J Allergy Clin Immunol. 1993 Jan;91(1 Pt 1):110-9. MED/92166439. Rodriguez-Barradas MC, Musher DM, Lahart C, Lacke C, Groover J, Watson D, Baughn R, Cate T, Crofoot G. Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine. J Infect Dis. 1992 Mar;165(3):553-6. ENTRY MONTH 199511 LAST REVISION DATE 20010328 108 UNIQUE IDENTIFIER DRG-0238 NAME OF SUBSTANCE A-007 [Protocol ID: 247A ] STANDARD CHEMICAL NAME 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylh- ydrazone [Protocol ID: 247A ] PROTOCOL ID NUMBERS No longer recruiting FDA 247A DISEASES STUDIED/TREATED Cutaneous lesions from Kaposi's sarcoma and lymphoproliferative disorders. [Protocol ID: 247A ] CLASSIFICATION CODE Antineoplastic [Protocol ID: 247A ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.25% gel. [Protocol ID: 247A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical. [Protocol ID: 247A ] MANUFACTURERS 0000003466: DEKK - TEC Inc 3839 Ulloa St New Orleans, LA 70119 Contact: Dr Lee Roy Morgan (504)488-5415 ENTRY MONTH 199511 LAST REVISION DATE 20000801 109 UNIQUE IDENTIFIER DRG-0237 NAME OF SUBSTANCE Selegiline hydrochloride [USPD 2000; p 643] REGISTRY NUMBER 14611-52-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzeneethanamine, N,alpha-dimethyl-N-2-propynyl-, hydrochloride, (R)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Eldepryl [USP DI 2000; p 2758] PROTOCOL ID NUMBERS No longer recruiting FDA 250A PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5090 PHARMACOLOGICAL ACTION MODE OF ACTION: Irreversibly inhibits monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria, by acting as a suicide substrate for the enzyme, i.e., it is converted by MAO to an active moiety that combines irreversibly with the active site and/or the enzyme's essential FAD cofactor. [PDR 1997; p 2729] DISEASES STUDIED/TREATED HIV-associated dementia. [Protocol ID: ACTG A5090 ] CLASSIFICATION CODE Antidyskinetic [USP DI 2000; p. 2756] OTHER MAJOR USES Management of Parkinson's disease in patients who experience deterioration on levodopa/carbidopa therapy. [USP DI 2000; p 2756] SUBSTANCE INTERACTIONS Interacts with meperidine. [PDR 1997; p 2730] ADVERSE EFFECTS Adverse effects may include nausea, hallucinations, confusion, depression, loss of balance, insomnia, orthostatic hypotension, increased akinetic involuntary movements, agitation, arrhythmia, bradykinesia, chorea, delusion, hypertension, new or increased angina pectoris and syncope, headache, leg pain, back pain, tinnitus, migraine, supraorbital pain, burning throat, chills, numbness in fingers and toes, taste disturbance, constipation, weight loss, anorexia, dysphagia, diarrhea, rectal bleeding, slow urination, urinary frequency, increased sweating, diaphoresis, facial hair, hair loss, hematoma, rash, and photosensitivity. [PDR 1997; p 2730] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to the drug and in those receiving meperidine and other opioids. [PDR 1997; p 2730; Physicians GenRx 1997; p II-1872] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Levorotatory acetylenic derivative of phenethylamine. [Somerset Pharmaceuticals. Eldepryl product labeling. Available at http://www.somersetpharm.com/products/product- _labeling.html. Accessed 03/15/01.] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H17-N.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 223.74 [USPD 2000; p 643] CHEMICAL/PHYSICAL DATA Melting Point: 141-142 [Merck Index 1996; p. 1448] CHEMICAL/PHYSICAL DATA Elemental Comp: C83.37%, H9.15%, N7.48% (base) [Merck Index 1996; p. 1448] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water, chloroform, and methanol. [Somerset Pharmaceuticals. Eldepryl product labeling. Available at http://www.somersetpharm.com/products/product- _labeling.html. Accessed 03/15/01.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to near white crystalline powder. [Somerset Pharmaceuticals. Eldepryl product labeling. Available at http://www.somersetpharm.com/products/product- _labeling.html. Accessed 03/15/01.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 5 mg capsules and tablets; [USP DI 2000; p 2758; Protocol ID: ACTG A5090 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2731; Protocol ID: ACTG A5090 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). [USP DI 2000; p 2758; Protocol ID: ACTG A5090 ] MANUFACTURERS 0000003463: Somerset Pharmaceuticals Inc 5215 West Laurel St Tampa, FL 330671729 Contact: Unspecified (813)288-0040 MANUFACTURERS 0000003463: Somerset Pharmaceuticals Inc 5215 West Laurel St Tampa, FL 330671729 REFERENCES MED/20100112. Sacktor N, Schifitto G, McDermott MP, Marder K, McArthur JC, Kieburtz K. Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study. Neurology 2000 Jan 11;54(1):233-5. MED/97471837. Rohatagi S, Barrett JS, DeWitt KE, Morales RJ. Integrated pharmacokinetic and metabolic modeling of selegiline and metabolites after transdermal administration. Biopharm Drug Dispos 1997 Oct;18(7):567-84. MED/97406630. Mahmood I. Clinical pharmacokinetics and pharmacodynamics of selegiline. An update. Clin Pharmacokinet 1997 Aug;33(2):91-102. MED/97166343. Wilfried K, Muller T, Kruger R, Horst P. Selegiline stimulates biosynthesis of cytokines interleukin-1 beta and interleukin-6. Neuroreport. 1996 Nov 25;7(18):2847-8. MED/97142238. Kuhn W, Muller T. The clinical potential of Deprenyl in neurologic and psychiatric disorders. J Neural Transm Suppl. 1996;48:85-93. MED/97142236. Yasar S, Goldberg JP, Goldberg SR. Are metabolites of 1-deprenyl (selegiline) useful or harmful? Indications from preclinical research. J Neural Transm Suppl. 1996;48:61-73. MED/97142235. Tatton WG, Wadia JS, Ju WY, Chalmers-Redman RM, Tatton NA. (-)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. J Neural Trasm Suppl. 1996;48:45-59. MED/97142234. Magyar K, Szende B, Lengyel J, Tekes K. The pharmacology of B-type selective monoamine oxidase inhibitors; milestones in (-)-deprenyl research. J Neural Transm Suppl. 1996;29-43. MED/97256338. Deprenyl--past and future. Proceedings of a symposium. Lake Starnberg, Bavaria, 1995, J Neural Transm Suppl. 1996;48:1-112. MED/97165376. Thomas CE, Huber EW, Ohlweiler DF. Hydroxyl and peroxyl radical trapping by the monoamine oxidase-B inhibitors deprenyl and MDL 72, 974A:implications for protection of biologic substrates. Free Radic Biol Med. 1997;22(4):733-7. ENTRY MONTH 199511 LAST REVISION DATE 20010315 110 UNIQUE IDENTIFIER DRG-0236 NAME OF SUBSTANCE Thioctic acid [USPD 1998; p. 727] REGISTRY NUMBER 62-46-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,2-Dithiolane-3-valeric acid [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 250A PHARMACOLOGICAL ACTION MODE OF ACTION: Enhances the free radical scavenging mechanisms of vitamin E. Free radicals can damage brain cells. It is believed that HIV-infected patients have a compromised antioxidant defense system. Blood antioxidants are decreased and peroxidation products of lipids and proteins are increased. Such patients may benefit from antioxidant supplementation therapy. Short-term effects of the natural antioxidant thioctic acid on blood antioxidants and peroxidation products were investigated in HIV positive patients. In the majority of patients thioctic acid increased plasma ascorbate (9 of 10 patients), total glutathione (7 of 7 patients), total plasma thiol groups (8 of 9 patients);T helper lymphocytes and T helper/suppressor cell ratio (6 of 10 patients), while the lipid peroxidation products malondialdehyde (8 of 9 patients) and 4-hydroxynonenal (7 of 9 patients) were decreased. Gene expression of human immunodeficiency virus (HIV) depends on a host of cellular transcription factors including nuclear factor-kappaB (NF-kappaB). The involvement of reactive oxygen intermediates has been implicated as intracellular messengers in the inducible activation of NF-kappaB. A study, compared the efficacy of two antioxidants, thioctic acid and N-acetylcysteine (NAC), which are widely recognized NF-kappaB inhibitors. Thioctic acid has a more potent activity in inhibiting NF-kappaB-mediated gene expression. It was also found that 0.2 mM thioctic acid could cause 40% reduction in the HIV-1 expression from the TNF-alpha-stimulated OM 10.1, a cell line latently infected with HIV-1. These findings confirm the involvement of reactive oxygen intermediates in NF-kappaB-mediated HIV gene expression as well as the efficacy of thioctic acid as a therapeutic regimen for HIV infection and AIDS. [Protocol ID: 250A ; Arzneimittelforschung 1993 Dec;43(12); p 1359-62; FEBS Lett 1996 Sep 23;394(1); p 9-13] DISEASES STUDIED/TREATED HIV-associated dementia. [Protocol ID: 250A ] CLASSIFICATION CODE Antioxidant [Arzneimittelforschung 1993 Dec;43(12); p 1359] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Enzymatic cofactor. [Protocol ID: 250A ] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H14-O2-S2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 206.33 [USPD 1998; p. 727] CHEMICAL/PHYSICAL DATA Elemental Comp: C46.57%, H6.84%, O15.51%, S31.08% [Merck Index 1996; p. 1591] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200 mg tablets. [Protocol ID: 250A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 250A ] MANUFACTURERS 0000003464: ASTA Medica AG Weismullerstrasse 45 Frankfurt, REFERENCES MED/97074193. Merin JP, Matsuyama M, Kira T, Baba M, Okamoto T. Alpha-lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants. FEBS Lett. 1996 Sep 23;394(1):9-13. MED/96150853. Teichert J, Preiss R. Determination of lipoic acid in human plasma by high-performance liquid chromatography with electrochemical detection. J Chromatogr B Biomed Appl 1995 Oct 20;672(2):277-81. MED/95392479. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med. 1995 Aug;19(2):227-50. MED/95392479. Suzuki YJ, Mizuno M, Tritschler HJ, Packer L. Redox regulation of NF-kappa B DNA binding activity by dihydrolipoate. Biochem Mol Biol Int. 1995 Jun;36(2):241-6. MED/95160683. Han D, Tritschler HJ, Packer L. Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line. Biochem Biophys Res Commun. 1995 Feb 6;207(1):258-64. MED/95091847. Shoji S, Furuishi K, Misumi S, Miyazaki T, Kino M, Yamataka K. Thiamine disulfide as a potent inhibitor of human immunodeficiency virus (type-1) production. Biochem Biophys Res Commun. 1994 Nov 30;205(1):967-75. ICA10/94371739. Suzuki YJ, Packer L. Inhibition of NF-kappa B DNA binding by alpha-lipoic acid. Int Conf AIDS. 1994 Aug 7-12;10(2):27 (abstract no. 401A). ICA10/94371058. Shoji S, Furuishi K, Misumi S, Miyazaki T, Kino M, Yamataka K, Matsuoka H, Tachibana K. Anti-HIV effects of redox reagents on HIV-1 infected cell lines. Int Conf AIDS. 1994 Aug 7-12;10(2):114 (abstract no.PA0336). MED/94190328. Fuchs J, Schofer H, Milbradt R, Buhl R, Siems W, Grune T. Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients. Arzneimittelforschung. 1993 Dec;43(12):1359-62. MED/92177673. Baur A, Harrer T, Peukert M, Jahn G, Kalden JR, Fleckenstein B. Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. Klin Wochenschr. 1991 Oct 2;69(15):722-4. ENTRY MONTH 199511 LAST REVISION DATE 20001107 111 UNIQUE IDENTIFIER DRG-0235 NAME OF SUBSTANCE Lobucavir [USPD 1998; p. 425] REGISTRY NUMBER 127759-89-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 6H-Purin-6-one, 2-amino-9-(2,3-bis(hydroxymethyl)cyclobutyl)-- 1,9-dihydro-, (1R-(1alpha,2beta,3alpha))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 248A PHARMACOLOGICAL ACTION MODE OF ACTION: Two newly synthesized carbocyclic oxetanocin analogs, (+/-)-9-[(1 beta, 2 alpha, 3 beta)-2,3-bis (hydroxymethyl)-1-cyclobutyl]adenine (cyclobut-A) and (+/-)-9-[(1 beta, 2 alpha, 3 beta)-2,3-bis (hydroxymethyl)-1-cyclobutyl]guanine (cyclobut-G) were tested for activity against the infectivity of human immunodeficiency virus (HIV) in vitro. Both compounds protected CD4+ ATH8 cells against the infectivity and cytopathic effects of HIV type 1 (HIV-1) and suppressed proviral DNA synthesis in ATH8 cells exposed to HIV-1 vitro at concentrations of 50 to 100 microM. These compounds also inhibited the in vitro infectivity of HIV-2. Both compounds completely suppresed the replication of a monocytotropic strain of HIV-1 in monocytes and macrophages at concentrations as low as 0.5 microM as assessed by inhibition of HIV-1 p24 gag protein production. 2'-Deoxyguanosine readily reversed the antiretroviral activity of cyclobut-G in our system. Both cyclobut-A and cyclobut-G appear to have a certain level of in vitro toxicity. [Antimicrob Agents Chemother 1990 Feb;34(2); p 287-94] DISEASES STUDIED/TREATED Cytomegalovirus (CMV) infections; HIV infection; Herpes infection. [Protocol ID: 248A ; AmfAR Treat Dir 1997;8(3); p 69] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Molecular Formula: C11-H15-N5-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 265.27 [USPD 1998; p. 425] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 248A ] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 REFERENCES MED/90225763. Hayashi S, Norbeck DW, Rosenbrook W, Fine RL, Matsukura M, Plattner JJ, Broder S, Mitsuya H. Cyclobut-A and cyclobut-G, carbocyclic oxetanocin analogs that inhibit the replication of human immunodeficiency virus in T cells and monocytes and macrophages in vitro. Antimicrob Agents Chemother. 1990 Feb;34(2):287-94. MED/97125604. Katlama C. Consequences for the management of cytomegalovirus. AIDS. 1996 Nov;10 Suppl 1:S43-6. ASHM6/95291740. Mills J. Prophylaxis and treatment of opportunistic viral infections in patients with HIV infection. Annu Conf Australas Soc HIV Med. 1994 Nov 3-6;6:134 (unnumbered abstract). MED/94012339. De Clercq E. Antivirals for the treatment of herpesvirus infections. J Antimicrob Chemother. 1993 Jul;32 Suppl A:121-32. MED/93158382. De Clercq E. Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact. Adv Virus Res. 1993;42:1-55. MED/90230227. Norbeck DW, Kern E, Hayashi S, Rosenbrook W, Sham H, Herrin T, Plattner JJ, Erickson J, Clement J, Swanson R, et al. Cyclobut-A and cyclobut-G: broad-spectrum antiviral agents with potential utility for the therapy of AIDS. J Med Chem. 1990 May;33(5):1281-5. ENTRY MONTH 199511 LAST REVISION DATE 20001107 112 UNIQUE IDENTIFIER DRG-0234 NAME OF SUBSTANCE Fomivirsen sodium [USPD 1998; p. 325] REGISTRY NUMBER 160369-77-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Deoxyribonucleic acid d(P-thio)(G-C-G-T-T-T-G-C-T-C-T-T-C-T-T-C-T-T- -G-C-G), eicosasodium salt [USPD 1998; p. 325] SYNONYMS Vitravene [USP DI 2000; p. 1599] PROTOCOL ID NUMBERS No longer recruiting FDA 251A PROTOCOL ID NUMBERS No longer recruiting FDA 251B PROTOCOL ID NUMBERS No longer recruiting FDA 251C PROTOCOL ID NUMBERS No longer recruiting FDA 251D DISEASES STUDIED/TREATED FDA approved on August 26, 1998 for the local treatment of cytomegalovirus (CMV) retinitis in patients with AIDS who are intolerant of or have a contraindication to other treatment(s) for CMV retinitis or who were insufficiently responsive to previous treatment(s) for CMV retinitis. [Int Conf AIDS 1994 Aug 7-12;10(2); p 10 (abstract no. 332B)] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1599] OTHER MAJOR USES CMV retinitis. [USAN 1997; p 318] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Phosphorothioate oligonucleotide [USP DI 2000; p. 1600] CHEMICAL/PHYSICAL DATA Molecular Formula: C204-H263-N63-O114-P20-S20.20Na [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 7122.16 [USPD 1998; p. 325] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravitreal. [Int Conf AIDS 1994 Aug 7-12;10(2); p 10 (abstract no. 332B)] MANUFACTURERS 0000003440: Isis Pharmaceuticals Inc Carlsbad Research Ctr / 2292 Faraday Ave Carlsbad, CA 92008 Contact: Jack Bogaev (760)603-2353 MANUFACTURERS 0000005294: CIBA Vision Corporation 11460 Johns Creek Parkway Duluth, GA 300971556 REFERENCES AIDS/96701616. Anonymous. Isis presents data on safety and effectiveness of antisense CMV retinitis compound. J Int Assoc Physicians AIDS Care. 1996 May;2(5):50. AIDS/96701668. Anonymous. Anti-CMV drug trials back on-line. GMHC Treat Issues. 1996 May;10(5):9. AIDS/95700311. Anonymous. New drug for CMV in trials. Treat Review. 1995 Jan;: no 16(3). MED/96126403. Azad RF, Brown-Driver V, Buckheit RW Jr, Anderson KP. Antiviral activity of a phosphorothioate oligonucleotide complementary to human cytomegalovirus RNA when used in combination with antiviral nucleoside analogs. Antiviral Res. 1995 Oct;28(2):101-11. MED/94058190. Azad RF, Driver VB, Tanaka K, Crooke RM, Anderson KP. Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region. Antimicrob Agents Chemother 1993 Sep;37(9):1945-54. ICA10/94370996. Palestine AG, Cantrill HL, Luckie AP, Ai E. Intravitreal treatment of CMV retinitis with an antisense oligonucleotide, ISIS 2922. Int Conf AIDS 1994 Aug 7-12;10(2):10 (abstract no. 332B). ENTRY MONTH 199510 LAST REVISION DATE 20000801 113 UNIQUE IDENTIFIER DRG-0233 NAME OF SUBSTANCE Indinavir sulfate [USPD 1998; p. 376] REGISTRY NUMBER 157810-81-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME [1(1S,2R),5(S)]-2,3,5-Trideoxy-N-(2,3-dihydro- -2-hydroxy-1H-inden-1-y l)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-- 4- (3-pyridinylmethyl)-1-piperazinyl]-2-(phenylm- ethyl)-D-erythro-penton amide sulfate. [PDR 1999; p 1762] SYNONYMS Crixivan [USP DI 2000; p. 3439] PROTOCOL ID NUMBERS Complete FDA 246A PROTOCOL ID NUMBERS Complete FDA 246G PROTOCOL ID NUMBERS Complete CC 91 CC-0019 PROTOCOL ID NUMBERS Complete NIAID ACTG 223 PROTOCOL ID NUMBERS Complete NIAID ACTG 320 PROTOCOL ID NUMBERS Complete NIAID ACTG 333 PROTOCOL ID NUMBERS Complete NIAID ACTG 343 PROTOCOL ID NUMBERS Complete NIAID ACTG 368 PROTOCOL ID NUMBERS Complete NIAID ACTG 373 PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS No longer recruiting FDA 075-00 MERCK PROTOCOL ID NUMBERS No longer recruiting FDA 225C PROTOCOL ID NUMBERS No longer recruiting FDA 228C PROTOCOL ID NUMBERS No longer recruiting FDA 228F PROTOCOL ID NUMBERS No longer recruiting FDA 228G PROTOCOL ID NUMBERS No longer recruiting FDA 232D PROTOCOL ID NUMBERS No longer recruiting FDA 238J PROTOCOL ID NUMBERS No longer recruiting FDA 238K PROTOCOL ID NUMBERS No longer recruiting FDA 244B PROTOCOL ID NUMBERS No longer recruiting FDA 245E PROTOCOL ID NUMBERS No longer recruiting FDA 246B PROTOCOL ID NUMBERS No longer recruiting FDA 246D PROTOCOL ID NUMBERS No longer recruiting FDA 246E PROTOCOL ID NUMBERS No longer recruiting FDA 246F PROTOCOL ID NUMBERS No longer recruiting FDA 246H PROTOCOL ID NUMBERS No longer recruiting FDA 246J PROTOCOL ID NUMBERS No longer recruiting FDA 246K PROTOCOL ID NUMBERS No longer recruiting FDA 246M PROTOCOL ID NUMBERS No longer recruiting FDA 246N PROTOCOL ID NUMBERS No longer recruiting FDA 246P PROTOCOL ID NUMBERS No longer recruiting FDA 246R PROTOCOL ID NUMBERS No longer recruiting FDA 246S PROTOCOL ID NUMBERS No longer recruiting FDA 259G PROTOCOL ID NUMBERS No longer recruiting FDA 260A PROTOCOL ID NUMBERS No longer recruiting FDA 260B PROTOCOL ID NUMBERS No longer recruiting FDA 264A PROTOCOL ID NUMBERS No longer recruiting FDA 264E PROTOCOL ID NUMBERS No longer recruiting FDA 264K PROTOCOL ID NUMBERS No longer recruiting FDA 264M PROTOCOL ID NUMBERS No longer recruiting FDA 281A PROTOCOL ID NUMBERS No longer recruiting FDA 281B PROTOCOL ID NUMBERS No longer recruiting FDA 300A PROTOCOL ID NUMBERS No longer recruiting FDA 312A PROTOCOL ID NUMBERS No longer recruiting CC 94 I-202 PROTOCOL ID NUMBERS No longer recruiting NCI 95 C-163 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 328 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 338 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 365 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 370 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 388 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 395 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5041 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5051 PROTOCOL ID NUMBERS No longer recruiting FDA ATLANTIC STUDY PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 042 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 057 PROTOCOL ID NUMBERS No longer recruiting NIAID L DRUG PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 228H PROTOCOL ID NUMBERS Recruiting FDA 246T PROTOCOL ID NUMBERS Recruiting FDA 246U PROTOCOL ID NUMBERS Recruiting FDA 246V PROTOCOL ID NUMBERS Recruiting CC 97 I-082 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 358 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5043 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5055 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5093 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1013 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-08-002 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended FDA 300B PROTOCOL ID NUMBERS Terminated CC 99 I-0062 PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PROTOCOL ID NUMBERS Terminated NIAID AIEDRP AI-03-001 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 041 PHARMACOLOGICAL ACTION MODE OF ACTION: Indinavir is a selective, competitive, reversible inhibitor of HIV protease. This enzyme plays an essential role in the HIV replication cycle and the formation of infectious virus. The drug inhibits the function of the enzyme, blocks maturation of the virus and causes the formation of immature, noninfectious virions. Indinavir is active in both acutely and chronically infected cells. The latter are not affected by dideoxynucleoside reverse transcriptase inhibitors. Indinavir does not affect early stages of the HIV replication cycle. Indinavir's antiviral activity does not depend on intracellular conversion to an active metabolite. Mutation of HIV protease appears to be the principal mechanism of resistance to indinavir. In vitro studies indicate that the antiretroviral effects of HIV protease inhibitors and some dideoxynucleoside agents or nonnucleoside agents may be additive. Recent clinical evidence shows that a regimen using two dideoxynucleoside reverse transcriptase inhibitors and an HIV protease inhibitor can suppress HIV replication to levels that cannot be detected by standard tests. Some degree of cross-resistance between various HIV protease inhibitors can occur. Thus some strains of indinavir-resistant HIV are cross-resistant to ritonavir, but not all ritonavir-resistant strains are resistant to indinavir. Cross-resistance between indinavir and dideoxynucleoside or nonnucleoside reverse transcriptase inhibitors is unlikely because these drugs have different target enzymes. Indinavir is rapidly absorbed from the GI tract with peak plasma concentration being reached in 0.8 hours. Presence of food in the GI tract can decrease the extent of indinavir absorption. Indinavir is about 60% bound to plasma proteins. The drug is metabolized in the liver. The plasma half-life of the drug averages 1.8 hours. Indinavir is metabolized to at least 7 metabolites, including one glucuronide and 6 oxidative metabolites. Indinavir is excreted primarily in the feces both as unabsorbed drug and as metabolites. Some 19% of the drug (in one study) is eliminated through the urine. [AHFS Drug Information 1999; 585-6] DISEASES STUDIED/TREATED Indinavir in combination with antiretroviral agents is indicated for the treatment of HIV infection. This indication is based on 2 clinical trials of approximately 1 year duration that demonstrated: (1) a reduction in the risk of AIDS-defining illness or death; (2) a prolonged suppression of HIV-RNA. [Merck & Company. Available at: http://www.merck.com. Accessed: May 15, 2000.] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1767] CLASSIFICATION CODE Protease inhibitor [AHFS Drug Information 2000; p. 617] SUBSTANCE INTERACTIONS Metabolism of indinavir is mediated by the P-450 isoenzyme CYP3A4, and the possibility exists that drugs that induce this isoenzyme may reduce plasma indinavir concentrations. Conversely, concomitant administration of indinavir with drugs that increase concentration of that isoenzyme may increase plasma indinavir concentration. Concomitant use of indinavir with astemizole, cisapride, ergot alkaloids, and derivatives of midazolam, terfenadine, or triazolam is contraindicated because competition for the CYP3A4 isoenzyme may result in decreased metabolism and increased plasma levels of these drugs, creating the potential for serious, or life-threatening adverse effects. Rifampin should not be coadministered with indinavir. The nucleoside analog antiretroviral agents do not require dosage adjustments when given with indinavir. Concurrent use of clarithromycin, ketoconazole, quinidine and zidovudine can increase indinavir blood levels. Didanosine, fluconazole, rifampin, and rifabutin have produced decreases in indinavir blood levels. Coadministration of indinavir has resulted in increased blood levels of oral contraceptives. Administration of indinavir with grapefruit juice resulted in a decrease in indinavar concentration (AUC). When administered with trimethoprim/sulfamethoxazole, trimethoprim levels increased but the sulfa levels were unaffected. Administration with isoniazid resulted in increased levels of the antitubercular. The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including indinavir, are used in combination with HMG-CoA reducatase inhibitors that are metabolized by the CYP3A4 pathway (e.g., atorvastatin, cerivastatin, lovastatin, or simvastatin). [AHFS Drug Information 1999; p 589-90] ADVERSE EFFECTS Adverse effects include changes in hematologic and hepatic function tests, nephrolithiasis (kidney stones), abdominal pain, asthenia/fatigue, diarrhea, headache, dizziness, insomnia, nausea, back and side pain, rash, vomiting, acid regurgitation (backflow of stomach acid to the esophagus), and taste perversion. Indirect hyperbilirubinemia has occurred frequently with indinavir administration and has sometimes been associated with increases in serum transaminases. Both hyperbilirubinemia and nephrolithiasis occurred more frequently at doses exceeding 2.4 g/day compared to doses = 2.4 g/day. Adequate hydration is recommended in all patients treated with indinavir. Some HIV-1-infected patients on indinavir treatment accumulate intra-abdominal fat that may cause abdominal symptoms. Recent evidence suggests that other HIV-1 protease inhibitors may be associated with changes in body-fat distribution. [PDR 1999; p 1765-6; Merck & Company. Available at: http://www.merck.com. Accessed: May 15, 2000.; Lancet 1998 Mar 21;351:9106; p 871] CONTRAINDICATIONS The possibility of spontaneous bleeding may increase in hemophilia patients receiving HIV protease inhibitors. Hyperglycemia or new-onset diabetes mellitus may occur when patients are put on indinavir. Preexisting diabetes mellitus may be exacerbated in patients on indinavir. Modification of the usual dosage of indinavir may be necessary in patients with mild or moderate hepatic impairment. The drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Indinavir is distributed into milk in rats. It is not known whether the drug is also distributed into milk in humans. However, in general, HIV-infected women should not breast-feed infants. [AHFS Drug Information 1999; 588-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Indinavir is a peptidomimetic protease inhibitor. A peptidomimetic compound contains amino acids like a peptide but is structurally altered to resist rapid degradation in the body. [AmfAR Treat Dir 1998;9(2); 1998;9(2); P 24] CHEMICAL/PHYSICAL DATA Molecular Formula: C36-H47-N5-O4.H2-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 711.88 [USPD 1998; p. 376] CHEMICAL/PHYSICAL DATA Melting Point: 150-153 C [Merck Index 1996; p. 850] CHEMICAL/PHYSICAL DATA Elemental Comp: C70.45%, H7.72%, N11.41%, O10.43% (base) [Merck Index 1996; p. 850] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water. [Merck Index 1996; p 850] CHEMICAL/PHYSICAL DATA Stability: Store in a tightly closed container at room temperature, 15-30 C (59-86 F). Indinavir capsules are sensitive to moisture and should be dispensed and stored in the original container with a desiccant. [PDR 1999; p 1766] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Indinavir sulfate is a white to off-white, hygroscopic, crystalline powder. [PDR 1999; p 1762] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200-mg and 400-mg capsules. [PDR 1999; p 1766] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 1762] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). Protect from moisture. [PDR 1999; p 1766] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES MED/99367570. Hirsch M, Steigbigel R, Staszewski S, Mellors J, Scerpella E, Hirschel B, Lange J, Squires K, Rawlins S, Meibohm A, Leavitt R. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy. J Infect Dis 1999 Sep;180(3):659-65. MED/99404407. Roberts AD, Muesing RA, Parenti DM, Hsia J, Wasserman AG, Simon GL. Alterations in serum levels of lipids and lipoproteins with indinavir therapy for human immunodeficiency virus-infected patients. Clin Infect Dis 1999 Aug;29(2):441-3. MED/99413513. Pradier C, Pesce A, Carrieri P, Cottalorda J, Boyer P, Senesi C, Fuzibet JG, Dellamonica P, Cassuto JP. Effect of indinavir and higher CD4+ T-cell count on viral load response after 6 months of highly active antiretroviral therapy. Clin Ther 1999 Aug;21(8):1313-20. MED/99342916. Martin C, Sonnerborg A, Svensson JO, Stahle L. Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS 1999 Jul 9;13(10):1227-32. MED/99285296. Mann M, Piazza-Hepp T, Koller E, Struble K, Murray J. Unusual distributions of body fat in AIDS patients: a review of adverse events reported to the Food and Drug Administration. Aids Patient Care STDS 1999 May;13(5):287-95. Review. MED/99000298. Havlir DV, Marschner IC, Hirsch MS, Collier AC, Tebas P, Bassett RL, Ionnaidis JP, Holohan MK, Leavitt R, Boone G, Richman DD. Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med 1998 Oct 29;339(18):1261-8. MED/99000299. Pialoux G, Raffi F, Brun-Vezinet F, Meiffredy V, Flandre P, Gastaut JA, Dellamonica P, Yeni P, Delfraissy JF, Aboulker JP. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indianvir in previously untreated HIV-1 infected patients. Trilege (Agence Nationale de Recherches sure le SIDA 072) Study Team. N Engl J Med 1998 Oct 29;339(18):1269-76. MED/99049703. Evans TG, Bonnez W, Soucier HR, Fitzgerald T, Gibbons DC, Reichman RC. Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells. Antiviral Res 1998 Oct;29(3):163-73. MED/98139022. Yeh KC, Deutsch PJ, Haddix H, Hesney M, Hoagland V, Ju WD, Justice SJ, Osborne B, Sterrett AT, Stone JA, Woolf E, Waldman S. Single-dose pharmacokinetics of indinavir and the effect of food. Antimicrob Agents Chemother 1998 Feb;42(2):332-8. MED/99135017. Ren S, Lien EJ. Development of HIV protease inhibitors: a survey. Prog Drug Res 1998;51:1-31. ENTRY MONTH 199510 LAST REVISION DATE 20000801 114 UNIQUE IDENTIFIER DRG-0232 NAME OF SUBSTANCE P3C541b Lipopeptide [Protocol ID: 090 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 021 PROTOCOL ID NUMBERS No longer recruiting FDA 090 PHARMACOLOGICAL ACTION MODE OF ACTION: Lipopeptide analogues of bacterial lipoproteins activate macrophages and B-lymphocytes. The products formed by coupling these lipopeptides to low molecular mass antigens can be used to induce antigen-specific antibodies in mice. Immunization with synthetic peptides is used to induce cytotoxic T cell (CTL) responses in vivo. However, CTL peptide vaccines require the use of multiple peptides to overcome genetic diversity associated with MHC restriction, and prior epitope identification from the chosen protein template. [Biol Chem Hoppe Seyler 1990 Oct;371(10); p 967-75; Vaccine 1996 Dec;14(17-18); p 1664-70] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: 090 ] CLASSIFICATION CODE Vaccine [Protocol ID: 090 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lipopeptide. [Protocol ID: 090 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. [Protocol ID: 090 ] MANUFACTURERS 0000002563: United Biomedical Inc 25 Davids Drive Happauge, NY 11788 Contact: Dr Bruce Forrest (516)273-2828 REFERENCES MED/97185156. Kuebler PJ, Nixon DF. Cytotoxic T cell induction with ratchet peptide libraries. Vaccine. 1996 Dec;14(17-18):1664-70. MED/97005302. Loleit M, Ihlenfeldt HG, Brunjes J, Jung G, Muller B, Hoffmann P, Bessler WG, Pierres M, Haas G. Synthetic peptides coupled to the lipotripeptide P3CSS induce in vivo B and T-helper cell responses to HIV-1 reverse transcriptase. Immunobiology. 1996 Jan;195(1):61-76. MED/96155144. Sauzet JP, Deprez B, Martinon F, Guillet JG, Gras-Masse H, Gomard E. Long-lasting anti-viral cytotoxic T lymphocytes induced in vivo with chimeric-multirestricted lipopeptides. Vaccine. 1995 Oct;13(14):1339-45. MED/96329200. Deprez B, Sauzet JP, Boutillon C, Martinon F, Tartar A, Sergheraert C, Guillet JG, Gomard E, Gras-Masse H. Comparative efficiency of simple lipopeptide constructs for in vivo induction of virus-specific CTL. Vaccine.1996 Apr;14(5)375-82. AIDS/96700666. Boston: important trial of treatment vaccine, CD4 over 500. AIDS Treat News. 1995 Aug 4;(no 228):4-5. MED/91166747. Loleit M, Troger W, Wiesmuller KH, Jung G, Strecker M, Bessler WG. Conjugates of synthetic lymphocyte-activating lipopeptides with segments from HIV proteins induce protein-specific antibody formation. Biol Chem Hoppe Seyler. 1990 Oct;371(10):967-75. ENTRY MONTH 199508 LAST REVISION DATE 20000801 115 UNIQUE IDENTIFIER DRG-0231 NAME OF SUBSTANCE PCLUS [AIDS Therapies 1995 Sep] PROTOCOL ID NUMBERS No longer recruiting CC 94 C-0159 PHARMACOLOGICAL ACTION MODE OF ACTION: Induction of cytotoxic T lymphocytes and neutralizing antibodies. Induction of virus-specific cytotoxic T lymphocytes (CTL) is an important part of vaccine strategy. CTL induction in vivo by two hepatitis C virus (HCV) peptides containing CTL epitopes, one from the NS5 region (P17) and one from the core (C7), was compared. P17 required covalent attachment of a helper peptide (PCLUS3 containing a cluster of epitopes from the human immunodeficiency virus envelope protein), whereas C7 did not. The helper cells induced by PCLUS3-17 or by C7 were shown to be CD4+ and to produce interleukin-2 (IL-2). Thus, help can be supplied by a natural helper epitope intrinsic to the CTL peptide, as in C7, or by attaching a helper epitope from another protein, as in the case of P17. The cluster peptides may be useful promiscuous helper peptides for a variety of CTL epitopes from diverse pathogens. [J Immunol 1994 Jan 15;152(2); p 549-56; J Infect Dis 1996 Jan;173(1); p 24-31] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: 94 C-159 ] CLASSIFICATION CODE Vaccine [Protocol ID: 94 C-159 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Multiple peptide sequences from the HIV-1 MN envelope protein that are recognized by multiple human and murine major histocompatibility complex (MHC) types. These sequences contain peptide 18. The peptide clusters are held together in Montanide Incomplete Seppic Adjuvant (ISA). [AIDS Therapies 1995 Sep] MANUFACTURERS 0000003418: Peninsula Laboratories Inc 601 Taylor Way San Carlos, CA 94070 Contact: Dr Phalen (800)650-4442 REFERENCES MED/96132459. Shirai M, Chen M, Arichi T, Masaki T, Nishioka M, Newman M, Nakazawa T, Feinstone SM, Berzofsky JA. Use of intrinsic and extrinsic helper epitopes for in vivo induction of anti-hepatitis C virus cytotoxic T lymphocytes (CTL) with CTL epitope peptide vaccines. J Infect Dis. 1996 Jan;173(1): 24-31. MED/95169519. Johnson RP, Hammond SA, Trocha A, Siliciano RF, Walker BD. Epitope specificity of MHC restricted cytotoxic T lymphocytes induced by candidate HIV-1 vaccine. AIDS Res Hum Retroviruses. 1994;10 Suppl 2:S73-5. MED/94110609. Shirai M, Pendleton CD, Ahlers J, Takeshita T, Newman M, Berzofsky JA. Helper-cytotoxic T lymphocyte (CTL) determinant linkage required for priming of anti-HIV CD8+ CTL in vivo with peptide vaccine constructs. J Immunol. 1994 Jan 15;152(2):549-56. MED/94039374. Bergmann C, Stohlmann SA, McMillan M. An endogenously synthesized decamer peptide efficiently primes cytotoxic T cells specific for the HIV-1 envelope glycoprotein. Eur J Immunol. 1993 Nov;23(11):2777-81. MED/93378321. Berzofsky JA. Epitope selection and design of synthetic vaccines. Molecular approaches to enhancing immunogenicity and cross-reactivity of engineered vaccines. Ann N Y Acad Sci. 1993 Aug 12;690:256-64. MED/93371734. Venet A, Walker BD. Cytotoxic T-cell epitopes in HIV/SIV infection. AIDS. 1993;7 Suppl 1:S117-26. MED/93271830. Johnson RP, Walker BD. Indentification of HIV-1 cytotoxic T-lymphocyte epitopes and implications for vaccine development. Biotechnol Ther. 1991;2(1-2):137-46. MED/93271829. Berzofsky JA. Progress toward an artificial vaccine for HIV: identification of helper and cytotoxic T-cell epitopes and methods of immunization. Biotechnol Ther. 1991;2(1-2):123-35. MED/91358746. Berzofsky JA, Pendleton CD, Clerici M, Ahlers J, Lucey DR, Putney SD, Shearer GM. Construction of peptides encompassing multideterminant clusters of human immunodeficiency virus envelope to induce in vitro T cell responses in mice and humans of multiple MHC types. J Clin Invest. 1991 Sep;88(3):876-84. MED/92113420. Cease KB. Peptide component vaccine engineering: targeting the AIDS virus. Int Rev Immunol. 1990;7(1):85-107. ENTRY MONTH 199508 LAST REVISION DATE 20000801 116 UNIQUE IDENTIFIER DRG-0230 NAME OF SUBSTANCE ALVAC-HIV MN120TMG (vCP205) [Protocol ID: AVEG 022 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 022 PROTOCOL ID NUMBERS Complete NIAID AVEG 022A PROTOCOL ID NUMBERS Complete NIAID AVEG 029 PROTOCOL ID NUMBERS Complete NIAID AVEG 033 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 027 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 032 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 034 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 038 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 202 PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 007 PROTOCOL ID NUMBERS No longer recruiting FDA RV124 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 326 PROTOCOL ID NUMBERS Recruiting FDA B011 PHARMACOLOGICAL ACTION ALVAC vaccines are recombinant live vector vaccines that are utilized primarily to induce cellular immune responses, but they also can elicit humoral responses. In addition, when ALVAC is used as a primary immunization, the antibody response can be augmented substantially by subsequent boost with recombinant subunit protein vaccines. The ALVAC line of vaccines is based on the canarypox vector. Canarypox is a member of the pox virus family, of which vaccinia (cowpox) is also a member. The canarypox virus, which originates in birds, is considered safer than vaccinia because it does not reproduce in humans. Another advantage of the canarypox virus is its ability to transport large amounts of foreign genes. Various HIV genes have been inserted into this vector. The genes originate from the clade B virus, which is the predominant subtype of HIV-1 found in the US and Europe. After administration of ALVAC vCP205 and penetration into the host cell, HIV-1 genes are expressed. The gag gene expresses a polyprotein that matures into core proteins (p24, p17, and p15). The pol gene expresses the protease enzyme, which catalyzes the partition of p15 into p9 and p6. These proteins form virus-like particles that are enveloped by the products of env gene expression. The viral particles bud from the cell membrane and are similar to HIV virions in their appearance and structure, but not infectivity. Studies have demonstrated that these pseudovirions are indeed immunogenic. Depending on the dose of the vaccine and the type of boost administered, neutralizing antibodies have been induced in the majority of vaccine recipients and cytotoxic activity is noted in over half of the recipients. In addition, some CTLs have shown cross-recognition of cells infected by primary isolates from clades A, C, D, and E. Trials investigating mucosal delivery (oral, intranasal, intrarectal, intravaginal) or use of novel adjuvants (e.g., granulocyte-macrophage colony-stimulating factor, GM-CSF) are under way. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.; AIDS Vaccine Evaluation Group (AVEG). Listing of candidate HIV vaccines used in AVEG studies. Available at: http://www.scharp.org/public/index.htm. Accessed August 7, 2000.; Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] DISEASES STUDIED/TREATED ALVAC vaccines are investigated as preventative vaccines for HIV infection. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 022 ] ADVERSE EFFECTS The canarypox virus does not replicate in the human host; therefore, recombinants are unlikely to cause disease in recipients or be transmitted to unvaccinated contacts. Adverse reactions reported after ALVAC vaccine administration are similar to those observed in healthy adults who have received marketed vaccines. Local and systemic side effects are mild to moderate and usually resolve within 72 hours after immunization. Local effects include transient pain, tenderness, redness, and swelling at the site of injection. Less common systemic effects include headache, malaise, fever, dizziness, and nausea. No severe adverse reactions have been reported. [Protocol ID: AVEG 202 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ALVAC vCP205 is a recombinant canarypox vaccine that expresses the gag, protease, and a part of the env gene proteins. The env gene expresses the glycoprotein (gp) 120 of the HIV-1 MN strain and the transmembrane (TM) gp41 of the HIV-1 LAI strain. The gag and protease proteins are of the HIV-1 LAI strain. ALVAC vCP205 is cultivated in specific pathogen-free chick embryo fibroblasts. The recombinant virus is suspended in a serum- and antibiotic-free culture medium to which a virus stabilizer is added. The solution is then lyophilized. [Protocol ID: AVEG 202 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: The lyophilized product is a pale yellow powder. The reconstituted product is a pale pink liquid. [Protocol ID: HIVNET 007 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The vaccine is supplied as single-dose vials of sterile lyophilized product containing various strengths of tissue culture 50% infective doses (TCID50) of ALVAC vCP205. Sterile water for injection that is adjusted to a pH of 5.0 to 7.0 is supplied as the diluent. [Protocol ID: AVEG 202 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The contents of the vial are reconstituted with 1 ml of the supplied diluent. The vial should be swirled gently for 10 seconds just prior to administration. The vaccine is administered intramuscularly with a 22-gauge, 1.5-inch needle into the deltoid muscle. The vaccine is also under investigation for administration by various mucosal routes, including oral, intranasal, intrarectal, and intravaginal routes. The dose is 1 ml of reconstituted vaccine for all routes of administration. [Protocol ID: AVEG 202 ; Protocol ID: AVEG 027 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powder should be refrigerated (2-8 C). Once reconstituted, the vaccine should be refrigerated and used within two hours. Freezing of both forms should be avoided. [Protocol ID: AVEG 202 ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 REFERENCES MED/20481642. Verrier F, Burda S, Belshe R, Duliege AM, Excler JL, Klein M, Zolla-Pazner S. A human immunodeficiency virus prime-boost immunization regimen in humans induces antibodies that show interclade cross-reactivity and neutralize several X4-, R5-, and dualtropic clade B and C primary isolates. J Virol. 2000 Nov;74(21):10025-33. Novak RM, Baum L, Spear G, Nog P, Tim G, Hanson C. Absence of antibodies with neutralizing or antibody-dependent cellular cytotoxic activity in vaginal secretions after parenteral vaccination with ALVAC vCP205 and rgp120 in high risk women in the U.S. Int Conf AIDS. 2000 Jul 9-14;13 (abstract no. WePeA4100). Lambert J, Johnson D, McFarland E, McNamara J, Muresan P, Curd J, El Habib R, Caudrelier P, Fenton T. A phase 1 study of the safety and immunogenicity of an HIV-1 ALVAC vaccine in children born to HIV infected mothers: preliminary results. Int Conf AIDS. 2000 Jul 9-14;13 (abstract no. WeOrC558). Musey LK, Ha R, Galloway C, Tabet S, Ding Y, Belshe R, Celum C, McElrath MJ. Systemic and mucosal immunity in HIV-1 vaccine recipients. Int Conf AIDS. 2000 Jul 9-14;13 (abstract no. WeOrC554). John R, Arango-Jaramillo S, Castillo RC, Weinhold K, Schwartz D. Correlation of vaccine-induced cross-tropic in vitro resistance to HIV-1(baL) with CTL activity. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 819). Kaslow RA, Rivers C, Goepfert P, Tang J, El Habib R, Weinhold K, Mulligan MJ. Association of HLA class I alleles with cytotoxic T-lymphocyte (CTL) responses to gag and env in recipients of ALVAC-HIV canarypox vaccines. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 818). MED/20094484. Arp J, Rovinski B, Sambhara S, Tartaglia J, Dekaban G. Human immunodeficiency virus type 1 envelope-specific cytotoxic T lymphocytes response dynamics after prime-boost vaccine regimens with human immunodeficiency virus type 1 canarypox and pseudovirions. Viral Immunol. 1999;12(4):281-96. Larsson M, Engelmayer J, Lee M, Cox W, Steinman R, Bhardwaj N. Dendritic cells infected with recombinant canarypox virus induce potent anti-HIV cytolytic and helper T cell responses from chronically infected individuals. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 830). Ignatius R, Lewis M, Cox WI, Frankel S, Mascola J, Villamide L, Mehlhop E, Steinman RM, Pope M. In vivo T cell priming in rhesus macaques by reinjected immature and mature dendritic cells bearing soluble or recombinant viral vector-encoded antigens. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 434). MED/99408833. Fang ZY, Kuli-Zade I, Spearman P. Efficient human immunodeficiency virus (HIV)-1 Gag-Env pseudovirion formation elicited from mammalian cells by a canarypox HIV vaccine candidate. J Infect Dis. 1999 Oct;180(4):1122-32. AIDS/20710224. Evans TG; Keefer MC; Belshe RB; Schwartz D; Graham BS; Corey L; Mulligan MJ; Stablein D. Rates and determinants of positive HIV screening test results in uninfected participants in phase I/II trials of candidate HIV-1 vaccines. Natl HIV Prev Conf. 1999 Aug 29-Sep 1; (abstract no. 293). MED/99260285. Salmon-Ceron D, Excler JL, Finkielsztejn L, Autran B, Gluckman JC, Sicard D, Matthews TJ, Meignier B, Valentin C, El Habib R, Blondeau C, Raux M, Moog C, Tartaglia J, Chong P, Klein M, Milcamps B, Heshmati F, Plotkin S. Safety and immunogenicity of a live recombinant canarypox virus expressing HIV type 1 gp120 MN MN tm/gag/protease LAI (ALVAC-HIV, vCP205) followed by a p24E-V3 MN synthetic peptide (CLTB-36) administered in healthy volunteers at low risk for HIV infection. AGIS Group and L'Agence Nationale de Recherches sur Le Sida. AIDS Res Hum Retroviruses. 1999 May 1;15(7):633-45. MED/99090756. Belshe RB, Gorse GJ, Mulligan MJ, Evans TG, Keefer MC, Excler JL, Duliege AM, Tartaglia J, Cox WI, McNamara J, Hwang KL, Bradney A, Montefiori D, Weinhold KJ. Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine Evaluation Group. AIDS. 1998 Dec 24;12(18):2407-15. MED/97454417. Ferrari G, Berend C, Ottinger J, Dodge R, Bartlett J, Toso J, Moody D, Tartaglia J, Cox WI, Paoletti E, et al. Replication-defective canarypox (ALVAC) vectors effectively activate anti-human immunodeficiency virus-1 cytotoxic T lymphocytes present in infected patients: implications for antigen-specific immunotherapy. Blood. 1997 Sep 15;90(6):2406-16. MED/97030197. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11349-53. Review. MED/95341166. Perkus ME, Tartaglia J, Paoletti E. Poxvirus-based vaccine candidates for cancer, AIDS, and other infectious diseases. J Leukoc Biol. 1995 Jul;58(1):1-13. Review. MED/95317468. Plotkin SA, Cadoz M, Meignier B, Meric C, Leroy O, Excler JL, Tartaglia J, Paoletti E, Gonczol E, Chappuis G. The safety and use of canarypox vectored vaccines. Dev Biol Stand. 1995;84:165-70. ENTRY MONTH 199508 LAST REVISION DATE 20001107 117 UNIQUE IDENTIFIER DRG-0229 NAME OF SUBSTANCE Interleukin-10 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 130068-27-8 STANDARD CHEMICAL NAME Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced) [CHEMLINE ] PROTOCOL ID NUMBERS Complete CC 95 I-125 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0026 PHARMACOLOGICAL ACTION MODE OF ACTION: Suppresses cytokine production from macrophages and T cells; also, exerts complex regulatory effects on CD8+ T cells, natural killer cells, vascular endothelial cells, and B lymphocytes. Levels of IL-10 are elevated in HIV-infected individuals, suggesting that this cytokine may play a role in the suppression of T cell and monocyte/macrophage function typical of HIV disease. IL-10 has blocked HIV-induced tumor necrosis factor alpha and IL-6 secretion and inhibited HIV replication in monocyte-derived macrophages. [AIDS Res Hum Retroviruses 1994 Oct;10(10); p 1199-206; J Clin Invest 1994 Feb;93(2); p 768-775; Blood 1994 Jun 15;83(12); p 3591-99] DISEASES STUDIED/TREATED Enhancement of immune response and inhibition of tumor necrosis factor production in HIV infection. [Protocol ID: 95 I-125 ] CLASSIFICATION CODE Immunomodulator [Protocol ID: 95 I-125 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Factor that is coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [CHEMLINE ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 95 I-125 ] MANUFACTURERS 0000001199: Schering - Plough Research 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Professional Information (800)526-4099 REFERENCES MED/96146742. Ludewig B, Gelderblom HR, Becker Y, Schafer A, Pauli G. Transmission of HIV-1 from productively infected mature Langerhans cells to primary CD4+ T lymphocytes results in altered T cell responses with enhanced production of IFN-gamma and IL-10. Virology. 1996 Jan 1;215(1):51-60. MED/96133016. Finnegan A, Roebuck KA, Nakai BE, Gu DS, Rabbi MF, Song S, Landay AL. IL-10 cooperates with TNF-alpha to activate HIV-1 latently and acutely infected cells of monocyte/macrophage lineage. J Immunol. 1996 Jan 15;156(2):841-51. MED/96141091. Huhn RD, Radwanski E, O'Connell SM, Sturgill MG, Clarke L, Cody RP, Affrime MB, Culter DL. Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers. Blood 1996 Jan 15;87(2):699-705. MED/96096449. Estaquier J, Idziorek T, Zou W, Emilie D, Farber CM, Bourez JM, Ameisen JC. T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med. 1995 Dec 1;182(6):1759-67. MED/96022650. Katsikis PD, Cohen SB, Londei M, Feldmann M. Are CD4+ Th1 cells pro-inflammatory or anti-inflammatory? The ratio of IL-10 to IFN-gamma or IL-2 determines their function. Int Immunol. 1995 Aug;7(8):1287-94. MED/96005824. Cohen SB. IL-10 and IL-3 synergize to cause proliferation of human T cells. Immunology; VOL 85,ISS 3,1995,P351-6. MED/95151356. Weissman D, Poli G, Fauci AS. Interleukin 10 blocks HIV replication in macrophages by inhibiting the autocrine loop of tumor necrosis factor alpha and interleukin 6 induction of virus. AIDS Res Hum Retroviruses. 1994 Oct;10(10):1199-206. MED/94157097. Clerici M, Wynn TA, Berzofsky JA, Blatt SP, Hendrix CW, Sher A, Coffman RL, Shearer GM. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest. 1994 Feb;93(2):768-75. ENTRY MONTH 199508 LAST REVISION DATE 20000801 118 UNIQUE IDENTIFIER DRG-0228 NAME OF SUBSTANCE APL 400-003 [Protocol ID: 089 ] PROTOCOL ID NUMBERS No longer recruiting FDA 004 PROTOCOL ID NUMBERS No longer recruiting FDA 005 PROTOCOL ID NUMBERS No longer recruiting FDA 089 PROTOCOL ID NUMBERS No longer recruiting CC 96 I-50 PHARMACOLOGICAL ACTION MODE OF ACTION: Facilitated DNA inoculation involves direct injection of noninfectious HIV genes into a patient's muscle, along with agents that promote uptake of the genes into host cells. Host cells that have taken up these genes then produce viral proteins in a form that elicits immune responses in the form of antibodies (which eradicate free virus in the bloodstream), killer T-cells (which destroy infected cells), and helper T-cells (which expand the overall immune response). The immune response is directed against multiple sites and proteins of the virus, giving the immune system many targets for attacking the virus. The vaccine does not use a viral vector. Genes are taken up by the host cells but are not integrated into the host chromosomes; thus, there are no permanent changes in the host's genetic material. 15 HIV-infected subjects given the vaccine in a dose-ranging study. Subjects with CD4 cell counts greater than or equal to 500 recieved 3 intramuscular vaccine doses at 10 week intervals with follow-up for 36 weeks None of the subjects developed antinuclear or anti-DNA antibodies. CD4 counts rose greater than or equal to 20% in 2, and fell in 4; CD8 increased greater than or equal to 20% in 3, and fell in 4. Viral load increased by greater than or equal to 0.5 log in 1, and fell by greater than or equal to 0.5 in 1. Doses-related rises in anti-env antibody occured, as did time-dependent CTL responses to env-expressing target cells. The vaccine appears safe and capable of inducing specific immune responses to HIV antigens. [U of Pennsylvania Press Release 1995 June 16; Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 142] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: 089 ] CLASSIFICATION CODE Vaccine [Protocol ID: 089 ] ADVERSE EFFECTS In a clinical trial of the vaccine, all subjects were without evidence of local or systemic clinical toxicity. Neither have CBC, urinalysis, serum creatinine, aldolase, or liver chemistries changed. [Conf Retroviruses Opportunistic Infect 4th 1997 Jan 22-26; p 142] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Segment of DNA -- called a cassette -- that incorporates different parts of the HIV genome, including genes for the envelope protein and a regulatory gene of the virus. [U of Pennsylvania Press Release 1995 June 16] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular. [Protocol ID: 089 ] MANUFACTURERS 0000002865: Wyeth - Ayerst Research PO Box 8299 Philadelphia, PA 19101 Contact: General Information (610)688-4400 REFERENCES ICA11/97926859. Boyer JD, Ugen KE, Wang B, Bagarazzi M, Chattergoon M, Javadian A, Ciccareli R, Weiner DB, Carrano RA. Induction of protection from HIV-1 challenge in chimpanzees by DNA vaccination. Int Conf AIDS. 1996 Jul 7-12;11 (Program Supplement):18 (abstract no. Th.A.923). MED/97362802. Kim JJ, Bagarazzi ML, Trivedi N, Hu Y, Kazahaya K, Wilson DM, Ciccarelli R, Chattergoon MA, Dang K, Mahalingam S. et al. Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes. Natl Biotechnol. 1997 Jul;15(7):641-6. MED/97378953. Ugen KE, Boyer JD, Wang B, Bagarazzi M, Javadian A, Frost P, Merva MM, Agadjanyan MG, Nyland S, Williams WV. et al. Nucleic acid immunization of chimpanzees as a prophylactic immunotherapeutic vaccination model for HIV-1: prelude to a clinicla trial. Vaccine. 1997 Jun; 15(8):927-30. MED/97378927. Wang B, Dang K, Agadjanyan MG, Srikantan V, Li F, Ugen KE, Boyer J, Merva M, Williams WV, Weiner DB. Mucosal immunization with a DNA induces immune responses against HIV-1 at a mucosal site. Vaccine. 1997 Jun;15(8):821-5. MED/97378941. Kim JJ, Ayyavoo V, Bagarazzi ML. Chattergoon M, Boyer JD, Wang B, Weiner DB. Development of a multicomponet candidate vaccine foe HIV-1. Vaccine. 1997 Jun;15(8):879-83. MED/97378942. Shiver JW, Davies ME, Yasutomi Y, Perry HC, Freed DC, Letvin NL, Liu MA. Anti-HIV env immunities elicited by nucleic acid vaccines. Vaccine. 1997 Jun;15(8):884-7. MED/97378952. Fuller DH, Corb MM, Barnett S, Steimer K, Haynes JR. Enhancement of immunodeficiency virus-specific immune responses in DNA-immunized rhesus macaques. Vaccine. 1997 Jun;15(8):924-6. AIDS/97927032. Bagarazzi ML, Boyer JD, Dang K, Chattergonn M, Javadian MA, Wang B, Weiner DB. HIV-1 DNA vaccination of pregnant chimpanzees induces cellular and humoral immune responses including placental transfer of antibodies and specific IgA antibodies in breast milk. Conf Adv AIDS Vaccine Dev. 1997 May 4-7;:48. AIDS/97926164. MacGregor R, Gluckman S, Lacy K, Wang B, Ugen K, Chattergoon M, Bagarazzi J, Williams W, Ginsberg R, Higgins T, et al. A DNA plasmid vaccine for HIV-1: experience in the first human trial indicates humoral and cell-immune responses. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:142 (abstract no. 421). ENTRY MONTH 199508 LAST REVISION DATE 20000801 119 UNIQUE IDENTIFIER DRG-0227 NAME OF SUBSTANCE Prednisone [USPD 1998; p. 599] REGISTRY NUMBER 53-03-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 17,21-dihydroxy-pregna-1,4-diene-3,11,20-trio- ne, [Merck Index 1996; p 1326] SYNONYMS Deltasone [USP DI 2000; p. 1058] PROTOCOL ID NUMBERS Complete NIAID ACTG 271 PROTOCOL ID NUMBERS No longer recruiting CC 95 I-0133 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 349 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PHARMACOLOGICAL ACTION MODE OF ACTION: Pharmacology of the corticosteroids is complex and the drugs affect almost all body systems. Maximum pharmacologic activity lags behind peak blood concentrations, suggesting that most effects of the drugs result from modification of enzyme activity rather than from direct actions by the drugs. In pharmacologic doses, systemically administered glucocorticoids suppress release of corticotropins from the pituitary; thus the adrenal cortex ceases secretion of endogenous corticosteriods (secondary adrenocortical insufficiency). The duration of anti-inflammatory activity of glucocorticoids approximately equals the duration of hypothalamic-pituitary-adrenal (HPA) axis suppression. The duration of HPA-axis of prednisone is 1.25-1.5 days after a single 50 mg oral dose. Most glucocorticoids appear to be readily absorbed when administered orally. Prednisone is rapidly converted to prednisolone, but much of cortisone is inactivated before it can be converted to hydrocortisone. Pharmacologically active glucocorticoids are metabolized primarily in the liver, to biologically inactive compounds. Inactive metabolites are excreted by the kidneys. Small amounts of unmetabolized drugs are also excreted in urine. [AHFS Drug Information 1997; p 2234-5] DISEASES STUDIED/TREATED HIV-associated nephropathy; HIV-associated idiopathic esophageal ulcer. [Am J Med 1994 Aug;97(2); p 145-51; Am J Gastroenterol 1994 Dec;89(12); p 2163-7] CLASSIFICATION CODE Anti-inflammatory [USP DI 2000; p. 1037] CLASSIFICATION CODE Antiemetic [USP DI 2000; p. 1037] CLASSIFICATION CODE Corticosteroid [USP DI 2000; p. 1037] CLASSIFICATION CODE Immunosuppressant [USP DI 2000; p. 1037] OTHER MAJOR USES Considered the glucocorticoid of choice for anti-inflammatory or immunosuppressant effects, used in concomitant therapy with a mineralocorticoid in the treatment of the following diseases: adrenocortical insufficiency; adrenogenital syndrome; hypercalcemia due to sarcoidosis or vitamin D intoxication; granulomatous thyroiditis; symptomatic relief of inflammation and symptoms of rheumatic disorders, collagen diseases, selected ocular inflammations, hematologic disorders, cancer chemotherapy-induced nausea and vomiting, cerebral edema, myasthenia gravis, nephrotic syndrome, and dermatologic, respiratory, gastrointestinal, neoplastic, or liver diseases. [AHFS Drug Information 1997; p 2367, 2345-9] SUBSTANCE INTERACTIONS Interact with drugs that induce hepatic enzymes, such as barbiturates, phenytoin, and rifampin; estrogens; nonsteroidal anti-inflammatory agents, such as indomethacin and aspirin; potassium-depleting drugs, such as thiazides, furosemide, ethacrynic acid, and amphotericin B; anticholinesterase agents, such as ambenonium, neostigmine, and pyridostigmine; vaccines and toxoids; oral anticoagulants; and cyclosporine. [AHFS Drug Information 1997; p 2351-2] ADVERSE EFFECTS Short-term administration of glucocorticoids, even in massive dosages, is unlikely to produce harmful effects. When the drugs are used for longer than brief periods, however, they can produce a variety of adverse effects including the following, adrenocortical insufficiency; musculoskeletal effects: protein catabolism manifested as muscle wasting, muscle pain or weakness, delayed wound healing, and atrophy of the protein matrix of the bone resulting in osteoporosis, vertebral compression fractures, aseptic necrosis of femoral or humoral heads or pathologic fractures of long bones; increased susceptibility to infection; fluid and electrolyte disturbances: sodium retention with resultant edema, potassium loss, hypokalemic alkalosis, and hypotension, and congestive heart failure; ocular effects: posterior subcapsular cataracts (particularly in children), exophthalmos, or increased intraocular pressure which may result in glaucoma or may occasionally damage the optic nerve; endocrine effects: hypercorticism (cushingoid state), amenorrhea or other menstrual difficulities, glucose intolerance resulting in hyperglycemia, aggravation of precipitation of diabetes mellitus, decrease in sperm motility and sperm number in some men; gastrointestinal effects: nausea, vomiting, anorexia which may result in weight loss, increased appetite which my result in weight gain, diarrhea or constipation, abdominal distension, pancreatitis, gastric irritation, ulcerative esophagitis, and development, reactivation, perforation, hemorrhage and delayed healing of peptic ulcers; nervous system effects: headache, vertigo, insomnia, restlessness and increased motor activity, ischemic neuropathy, EEG abnormalities, seizures, precipitation of mental disturbances ranging from euphoria, mood swings, depression and anxiety, personality changes to frank psychosis; dermatologic effects: impaired wound healing, skin atrophy and thinning, acne, increased sweating, hirsutism, facial erythema, striae, petechiae, ecchymoses, easy bruising, hives and/or allergic dermatitis, urticaria, and angioedema. Abrupt withdrawal of glucocorticoids may result in anorexia, nausea and vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. [AHFS Drug Information 1997; p 2349-50] CONTRAINDICATIONS Contraindicated in patients with systemic fungal infections and with known hypersensitivity to drug components. Contraindicated in patients with known hypersensitivity to any of the other corticosteroids. Contraindicated in women who are either pregnant or nursing. Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of the drug. Drug should not be used in patients with peptic ulcer, and viral infections or bacterial infections not controlled by anti-infectives except in life-threatening situations. Should be used with extreme caution in patients with a known history of drug allergy, those after recent myocardial infarction, hypothyroidism, cirrhosis, diverticulitis, nonspecific ulcerative colitis, or those with recent intestinal anastomosis, psychotic patients with hypertension or congestic heart failure, patients with myasthenia gravis receiving anticholinesterase therapy, thromboembolic disorders, seizure disorders, renal insufficiency, osteoporosis, and herpes simplex infections of the eye. Long-term administration of pharmacologic dosages of the drug to children should be avoided if possible, since the drug may retard bone growth. [Physicians GenRx 1997; p II-1744; AHFS Drug Information 1997; p 2367, 2345-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic anti-inflammatory glucocorticoid (adrenocortical steroid) derived from cortisone. [AHFS Drug Information 1997; p 2367] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H26-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 358.44 [USPD 1998; p. 599] CHEMICAL/PHYSICAL DATA Elemental Comp: C70.37%, H7.31%, O22.32% [Merck Index 1996; p. 1326] CHEMICAL/PHYSICAL DATA Solubility: Very slightly soluble in water; slightly soluble in alcohol. [AHFS Drug Information 1997; p 2367] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to practically white, odorless, crystalline powder. [AHFS Drug Information 1997; p 2367] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral solution (5mg/5ml), syrup (5mg/5ml), solution concentrate (5mg/ml), tablets (1, 2.5, 5, 10, 20, 25, 50 mg), film-coated tablets (5mg). [AHFS Drug Information 1997; p 2368] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration. [AHFS Drug Information 1997; p 2367] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Prednisone tablets should be stored in well-closed containers at a temperature less than 40 C, preferrably between 15-30 C. Syrup should be stored in tight containers. Oral solution and oral solution concentrate should be stored in a tight container at 15-30 C. [AHFS Drug Information 1997; p 2368] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 REFERENCES MED/97254645. Watterson MK, Detwiler RK, Bolin P Jr. Clinical response to prolonged corticosteroids in a patient with human immunodeficiency virus-associated nephropathy. Am J Kidney Dis. 1997 Apr;29(4):624-6. AIDS/97926700. Craven DE, Duncan R, Jhamb K, Hirschhorn L, Steger K, Stram JR. Medical treatment of benign lymphoepithelial parotid cysts (BLPC) in patients with human immunodeficiency virus (HIV) infection. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:197 (abstract no. 717). MED/97118364. Zanussi S, Simonelli C, D'Andrea M, Comar M, Bidoli E, Giacca M, Tirelli U, Vaccher E, De Paoli P. The effects of antineoplastic chemotherapy on HIV disease. AIDS Res Hum Retroviruses. 1996 Dec 10;12(18):1703-7. MED/97120054. Bradley WG, Verma A. Painful vasculitic neuropathy in HIV-1 infection: relief of pain with prednisone therapy. Neurology. 1996 Dec;47(6):1446-51. MED/96438596. Briggs WA, Tanawattanacharoen S, Choi MJ, Scheel PJ Jr, Nadasdy T, Racusen L. Clinicopathologic correlates of prednisone treatment of human immunodeficiency virus-associated nephropathy. Am J Kidney Dis. 1996 Oct;28(4):618-21. ICA11/96921434. Graves M, Salvato P, Thompson C. MAIC and the effect of prednisone on disease progression in AIDS patients. Int Conf AIDS. 1996 Jul 7-12;11(1):119 (abstract no. Mo.B.1371). ICA11/96922077. Beardsell AD, Coker K, Woodfall B, Conway B. Cotrimoxazole (TMP-SMX) desensitization using adjunctive steroid therapy in HIV/AIDS patients. Int Conf AIDS. 1996 Jul 7-12;11(1):237 (abstract no. Tu.B.414). ICA11/96922580. Nemechek P, Whal D, Sackuvich L. Evidence of subclinical adrenal insufficiency in patients with AIDS, CDC class III. Int Conf AIDS. 1996 Jul 7-12;11(1):331 (abstract no. Tu.B.2378). ICA11/96921327. Karmochkine M, Oksenhendler E, Martinez F, Beaufils H, Valantin MA, Coutellier A, Idatte JM, Herson S. Effectiveness and side-effects of steroid therapy in renal disease associated with HIV infection. Int Conf AIDS, 1996 Jul 7-12;11(1):100 (abstract no. Mo.B.1263). MED/96006293. de Asis ML, Bernstein LJ, Schliozberg J. Treatment of resistant oral aphthous ulcers in children with acquired immunodeficiency syndrome. J Pediatr. 1995 Oct;127(4):663-5. ENTRY MONTH 199507 LAST REVISION DATE 20000801 120 UNIQUE IDENTIFIER DRG-0226 NAME OF SUBSTANCE OPC 14117 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 103233-65-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Piperazineacetamide, N-(2,3-dihydro-7-hydroxy-2,2,4,6- tetramethyl-1H-inden-1-yl)-4-(3-methoxyphenyl- )- [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting FDA 242A PHARMACOLOGICAL ACTION MODE OF ACTION: Has both a brain function-activating effect and protective effect against cerebral ischemia. Acts by inhibiting oxygen free radicals. Oxygen free radicals generated by leukocytes may contribute to tissue injury after central nervous system (CNS) focal ischemia or trauma. In vitro studies using stimulated polymorphonuclear (PMN) leukocytes and monocytes demonstrated that OPC 14117 significantly reduces PMN hydrogen peroxide production, with the 100 microM concentration of the drug significantly more effective than the 10 microM concentration. [J Neurol Sci 1992 May;109(1); p 107-10; MeSH ] DISEASES STUDIED/TREATED HIV-related cognitive dysfunction. [Protocol ID: 242A ] CLASSIFICATION CODE Antioxidant [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Formula: C26-H35-N3-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 60 mg tablets. [Protocol ID: 242A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 242A ] MANUFACTURERS 0000005360: Otsuka America Pharmaceutical Inc 2440 Research Boulevard Rockville, MD 20850 Contact: Jodi Andrews (415)424-1290 MANUFACTURERS 0000003364: Otsuka America Pharmaceutical Inc 1290 Page Mill Rd / Suite 200 Palo Alto, CA 94304 REFERENCES AIDS/96700633. Anonymous. Vitamin E drug. Treat Rev. 1995 May;:no 18(1). MED/92388919. Fisher M and Arpano MM. Inhibition of stimulated human leukocyte hydrogen peroxide generation by a novel antioxidant, OPC-14117. J Neurol Sci 1992 May;109(1):107-10. MED/97365345. Safety and tolerability of the antioxidant OPC-14117 in HIV-associated cognitive impairment. The Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Neurology. 1997 Jul;49(1):142-6. ENTRY MONTH 199507 LAST REVISION DATE 20000801 121 UNIQUE IDENTIFIER DRG-0225 NAME OF SUBSTANCE Clavulanate potassium [USPD 1998; p. 175] REGISTRY NUMBER 61177-45-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Oxa-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3-(2-hydroxyethylidene)-7-oxo-, monopotassium salt, (2R-(2alpha,3Z,5alpha))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS (component of) Augmentin [USP DI 2000; p. 2412] SYNONYMS (component of) Timentin [USP DI 2000; p. 2412] PROTOCOL ID NUMBERS Complete FDA 243A PHARMACOLOGICAL ACTION MODE OF ACTION: Clavulanic acid, which is produced by fermentation of Streptomyces clavulgerus, possesses the ability to inactivate a wide variety of betalactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important blasmid mediated beta-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. Clavulanate potassium is well absorbed from the gastrointestinal tract after oral administration. It is approximately 25% bound to human serum. [PDR 1997; p 2637] DISEASES STUDIED/TREATED AIDS-associated sinusitis. [Protocol ID: 243A ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2412] CLASSIFICATION CODE Beta-lactamase Inhibitor [USP DI 2000; p. 2412] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Potassium salt of clavulanic acid, which is a beta-lactam structurally related to the penicillins. [PDR 1997; p 2367] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H8-N-O5.K [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 237.25 [USPD 1998; p. 175] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2637] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 REFERENCES MED/96098371. Salvemini JN, Baldwin HE. Botryomycosis in a patient with acquired immunodeficiency syndrome. Cutis. 1995 Sep;56(3):158-60. ENTRY MONTH 199506 LAST REVISION DATE 20001107 122 UNIQUE IDENTIFIER DRG-0224 NAME OF SUBSTANCE HIV-1 C4-V3 Polyvalent Peptide Vaccine [Protocol ID: DATRI 010 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 020 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 010 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5049 PHARMACOLOGICAL ACTION MODE OF ACTION: Potential induction of cross-reactive antibody responses. The vaccine is composed of selected gp120 epitopes T1, SP10, and A. The peptide sequences represent the minimally sufficient epitopes necessary to generate neutralizing antibody, MHC class I-restricted cytotoxic T-lymphocyte (CTL), and helper cell responses. The SP10(A) portions of gp120 are amino acids 303-327, representing V3 loop epitopes important for neutralizing antibodies, and the T1 portion is amino acids 428-443, a helper T-cell epitope. The section of SP10(A) composed of amino acids 304-313 is an important epitope for MHC class I-restricted CTL responses in individuals with HLA-B7 phenotype. The HIV-1 C4-V3 polyvalent peptide vaccine not only utilizes epitopes from gp120 but also is a prototype multivalent immunogen containing the amino acid sequences for selected epitopes from four of the most common HIV isolates in the United States and Europe -- EV91, MN, RF, and CAN0 -- which are predicted to represent 50-90% of the HIV isolates in the United States. The HIV env-encoded synthetic peptide T1-SP1OMN(A) contains immunodominant epitopes of the C4/V3 regions of gp120. The mucosal immunogenicity of this peptide in various vaccine preparations was first tested in rabbits using chronically isolated Thiry-Vella (T-V) ileal loops. Intestinal and serum samples collected from rabbits immunized via T-V loops demonstrated secretory IgA (S-Iga) and IgG anti-T1-SP1OMN(A), respectively, when assayed by ELISA. Intranasal delivery of the peptide supplemented with cholera toxin (CT) resulted in serum IgG and S-Iga anti-T1-=SP1OMN(A) in vaginal and nasal secretions. This study further demonstrates the relationship between nasal immunization and vaginal immunity. [AIDS Res Hum Retroviruses 1997 Jul;13(10):881-9; p 881-9; Protocol ID: DATRI 010 ] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: DATRI 010 ] CLASSIFICATION CODE Vaccine [Protocol ID: DATRI 010 ] ADVERSE EFFECTS Anticipated adverse effects include local reactions at the injection site, such as discomfort, pain, tenderness, swelling, itching, skin discoloration, and drainage of clear fluid. Also, fever, fatigue, or body aches (flu-like symptoms) may occur. [Protocol ID: DATRI 010 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic polyvalent peptide vaccine. [Protocol ID: DATRI 010 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. [Protocol ID: DATRI 010 ] MANUFACTURERS 0000002865: Wyeth - Ayerst Research PO Box 8299 Philadelphia, PA 19101 Contact: General Information (610)688-4400 REFERENCES MED/97340908. Winchell JM, Van Kruiningen HJ, Silbart LK. Mucosal immune response to an HIV C4/V3 peptide following nasal or intestinal immunization of rabbits. AIDS Res Hum Retroviruses. 1997 Jul 1;13(10):881-9. MED/95260530. Haynes BF, Moody MA, Heinley CS, Kober B, Millard WA, Scearce RM. HIV type 1 V3 region primer-induced antibody supression is overcome by administration of C4-V3 peptide as a polyvalent immunogen. AIDS Res Hum Retroviruses. 1995 Feb;11(2):211-21. MED/95132652. Zaghouani H, Anderson SA, Sperber KE, Daian C, Kennedy RC, Mayer L, Bona CA. Induction of antibodies to the human immunodeficiency virus type 1 by immunization of baboons with immunoglobulin molecules carrying the principal neutralizing determinant of the envelope protein. Proc Natl Acad Sci USA. 1995 Jan 17;92(2):631-5. ICA10/94371080. Sia C, Chong P, Matthews T, Bolognesi D, Klein M. Improved construction of synthetic HIV vaccine candidates. Int Conf AIDS. 1994 Aug 7-12;10(2):119 (abstract no. PA0357). MED/94202302. Johnson RP, Hammond SA, Trocha A, Siliciano RF, Walker BD. Induction of a major histocomatibility complex class I-restricted cytotoxic T-lymphocyte response to a highly conserved region of human immunodeficiency virus type 1 (HIV-1) gp120 in seronegative humans immunized with a candidate HIV-1 vaccine. J Virol. 1994 May;68(5):3145-53. ENTRY MONTH 199506 LAST REVISION DATE 20000801 123 UNIQUE IDENTIFIER DRG-0223 NAME OF SUBSTANCE Mitoguazone [USPD 1998; p. 480] REGISTRY NUMBER 459-86-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Hydrazinecarboximidamide, 2,2'-(1-methyl-1,2-ethanediylidene)bis-, dihydrochloride [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting FDA 241A PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits biosynthesis of polyamines, which play an important role in regulation of cell proliferation, differentiation, and functional stimulation of terminally differentiated cells. MGBG crosses the blood brain barrier and appears to work in patients with inanition (a condition characterized by marked weakness, extreme weight loss, and decreased metabolism). In vitro studies with HeLa cells treated with MGBG showed a marked depression in levels of the cellular polyamines putrescine, spermidine, and spermine. Other studies indicate that MGBG diminishes the respiratory burst activity of macrophages induced by lipopolysaccharides and interferon gamma; this inhibitory effect of MGBG was concentration-dependent and could be reversed by spermine, which is the final product of polyamine biosynthesis. [Cancer Lett 1993 Aug 16;72(1-2); p 83-90; Ann Oncol 1994 Jul;5(6); p 487-93; J Leukoc Biol 1992 Dec;52(6); p 585-7] DISEASES STUDIED/TREATED Under investigation for the treatment of AIDS-related non-Hodgkin's lymphoma. [AmfAR Treat Dir 1997;8(3); p 75] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3314] OTHER MAJOR USES Non-small cell lung cancer, Hodgkin's disease. [Invest New Drugs 1993 Feb;11(1); p 91-2; Ann Oncol 1994 Jul;5(6); p 487-93] ADVERSE EFFECTS Adverse effects have included flushing, tingling, euphoria, or somnolence during infusion. Other adverse effects have included mild nausea, vomiting, fatigue, and neutropenia. [Proc Annu Meet Am Soc Clin Oncol 1994;13; A11] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Structural analog of spermidine. [Biochem Pharmacol 1993 Sep 14;46(6); p 969-74] CHEMICAL/PHYSICAL DATA Molecular Formula: C5-H12-N8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 184.20 [USPD 1998; p. 480] CHEMICAL/PHYSICAL DATA Elemental Comp: C32.60%, H6.7%, N60.83% [Merck Index 1996; p. 1063] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 241A ] MANUFACTURERS 0000003329: ILEX Oncology Inc 14785 Omicron Dr / Suite 100 San Antonio, TX 782453217 Contact: Susan Smith (800)243-7645 REFERENCES MED/97213861. Levine AM, Tulpule A, Tessman D, Kaplan L, Giles F, Luskey BD, Scadden DT, Northfelt DW, Silverberg I, Wernz J, et al. Mitoguazone therapy in patients with refactory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial. J Clin Oncol. 1997 Mar;15(3):1094-103. ICA11/96924266. Levine A, Tulpule A, Espina BM, Von Hoff D, Tessman D. Mitoguazone (MGBG) with radiation therapy in AIDS-related primary CNS-lymphoma. Int Conf AIDS. 1996 Jul 7-12: 11(2):222 (abstract no. Th.B.184). MED/97070920. Rizzo J, Levine AM, Weiss GR, Pearce T, Kraynak M, Mueck R, Smith S, Von Hoff DD, Kuhn JG. Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkins lymphoma. Invest New Drugs. 1996; 14(2):227-34. AIDS/96701139. Mascolini M. Lymphoma: MGBG new studies, compassionate use in earlier disease. AIDS Treat News. 1995 Dec 22;:no 237,4. AIDS/96700645. Mascolini M. Oncologists scout new directions for KS and lymphoma therapies. J Int Assoc Physicians AIDS Care. 1995 Jun;1(5):10-4. MED/96015008. Ferme C, Bastion Y, Lepage E, Berger F, Brice P, Morel P, Gabarre J, Nedellec G, Reman O, Cheron N, et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin's disease [see comments]. Ann Oncol. 1995 Jul;6(6):543-9. ICDB/96614424. Lim SW, Look RM, Bick AB, Hamburg SI, Lawrence GN, Fuerst MP, Kusuanco DA, Kessler CE, Giles FJ. MGBG therapy of relapsed extralymphatic HIV-associated non-Hodgkin's lymphoma (HIV NHL) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol; 14:A1274 1995. MED/95001580. Von Hoff, DD. MGBG: teaching an old drug new tricks. Ann Oncol. 1994 Jul;5(6):487-93. MED/84288336. Knight WA 3d, Fabian C, Costanzi JJ, Jones SE, Coltrman CA Jr. Methylglyoxal bis guanylhydrazone (methyl-GAG, MGBG) in lymphoma and Hodgkin's disease. A Phase II trial of the Southwest Oncology Group. Invest New Drugs. 1983;1(3):235-7. MED/82227522. Kelsen DP, Yagoda A, Warrell R, Chapman R, Whittes R, Gralla RJ, Casper E, Young CW. Phase II trials of methylglyoxal-bis (guanylhydrazone). Am J Clin Oncol. 1982 Apr;5(2):221-5. ENTRY MONTH 199505 LAST REVISION DATE 20000801 124 UNIQUE IDENTIFIER DRG-0222 NAME OF SUBSTANCE HIV p17/p24:Ty-VLP [AIDS 1993 Oct;7(10); p 1315-23] PROTOCOL ID NUMBERS Complete NIAID AVEG 019 PHARMACOLOGICAL ACTION MODE OF ACTION: Vaccine delivery system with the potential for inducing broadly cross-reactive CD8+ cytotoxic T-lymphocyte (CTL) responses to p17 and p24. A previous study indicated that hybrid p17/p24:Ty-VLP was capable of inducing both cellular and humoral immunity to HIV-1 gag p17 and p24 components. [AIDS 1993 Oct;7(10); p 1315-23; Protocol ID: AVEG 019 ] DISEASES STUDIED/TREATED Prevention of HIV infection. [Protocol ID: AVEG 019 ] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 019 ] ADVERSE EFFECTS Adverse effects of the intramuscular injection may include pain, soreness, redness, and swelling at the injection site. Other adverse effects may include fever, chills, rash, aches, pains, nausea, headache, and fatigue. Side effects after rectal administration of the vaccine may include local discomfort, crampy abdominal pain, or watery diarrhea immediately following injection. [Protocol ID: AVEG 019 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fusion product of the gag gene of HIV-1 IIIB and a gene from the yeast retrotransposon. Retrotransposons are transposable elements (transposons) that involve a retrovirus-like process of reverse transcription. The TYA-gag fusion gene produces a protein that retains the self-assembly properties of the retrotransposon and thereby expresses the HIV-1 gag gene products p17 and p24 in a virus-like particle (VLP). The fusion protein contains amino acids 1-381 of yeast protein p1, 33 C-terminal amino acids of p17, and 177 amino acids of p24 (not including the 48 C-terminal amino acids of p24). Together the p17 and p24 components comprise 30% of the mass. [Protocol ID: AVEG 019 ] CHEMICAL/PHYSICAL DATA Stability: Virus-like particles (VLPs) adjuvanted with aluminum hydroxide (alum) are stable at 4 C for at least 30 months. [Protocol ID: AVEG 019 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Adjuvanted with alum or unadjuvanted. [Protocol ID: AVEG 019 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular; oral; rectal. [Protocol ID: AVEG 019 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store adjuvanted formulation at 4 C. Store unadjuvanted formulation at -70 C. [Protocol ID: AVEG 019 ] MANUFACTURERS 0000003327: British Biotech PLC Watlington Rd / Cowley Oxford, Contact: Annapolis, MD office (410)266-7909 REFERENCES MED/97229917. Klein MR, Veenstra J, Holwerda AM, Roos MT, Gow I, Patou G, Coutinho RA, De Wolf F, Miedema F. Gag-specific immune responses after immunization with p17/p24:Ty virus-like particles in HIV type 1-seropositive individuals. AIDS Res Hum Retroviruses. 1997 Mar 20;13(5):393-9. MED/97000088. Veenstra J, Williams IG, Colebunders R, Dorrell L, Tchamouroff SE, Patou G, Lange JM, Weller IV, Goeman J, Uthayakumar S, et.al. Immunization with recombinant p17/p24:Ty virus-like particles in human immunodeficiency virus-infected persons. J Infect Dis. 1996 Oct;174(4):862-6. MED/96066231. Weber J, Cheinsong-Popov R, Callow D, Adams S, Patou G, Hodgkin K, Martin S, Gotch F, Kingsman A. Immunogenicity of the yeast recombinant p17/p24:Ty virus-like particles (p24-VLP) in healthy volunteers. Vaccine. 1995 Jun;13(9):831-4. MED/95407117. Brookman JL, Stott AJ, Cheeseman PJ, Adamson CS, Holmes D, Cole J, Burns NR. Analysis of TYA protein regions necessary for formation of the Ty1 virus-like particle structure. Virology; VOL 212,ISS 1,1995,P69-76. MED/95065695. Luo L, Li Y, Dales S, Kang CY. Mapping of functional domains for HIV-2 gag assembly into virus-like particles. Virology; VOL 205,ISS 2,1994,P496-502. MED/94092369. Martin SJ, Vyakarnam A, Cheingsong-Popov R, Callow D, Jones KL, Senior JM, Adams SE, Kingsman AJ, Matear P, Gotch FM, et al. Immunization of human HIV-seronegative volunteers with recombinant p17/p24:Ty virus-like particles elicits HIV-1 p24-specific cellular and humoral immune responses. AIDS 1993 Oct;7(10):1315-23. ENTRY MONTH 199505 LAST REVISION DATE 20000801 125 UNIQUE IDENTIFIER DRG-0221 NAME OF SUBSTANCE CI-0694 [Protocol ID: 95 I-126 ] STANDARD CHEMICAL NAME 5-(Sulfamethoxazoyl)-glutaryl-dexamine [Protocol ID: 95 I-126 ] PROTOCOL ID NUMBERS No longer recruiting CC 95 I-126 PHARMACOLOGICAL ACTION MODE OF ACTION: Therapeutic suppression of IgG antibody response to SMX, probably by acting at the level of B cells with receptor specificity for SMX. [Protocol ID: 95 I-126 ] DISEASES STUDIED/TREATED Possible prevention or reversal of sensitivity to SMX in patients with HIV infection and SMX intolerance. [Protocol ID: 95 I-126 ] CLASSIFICATION CODE Immunomodulator [Protocol ID: 95 I-126 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Dextran backbone to which 20-50 sulfamethoxazole (SMX) molecules are covalently attached. [Protocol ID: 95 I-126 ] CHEMICAL/PHYSICAL DATA Molecular Weight: 28 +/- 8 kg/mole [Protocol ID: 95 I-126 ] CHEMICAL/PHYSICAL DATA Solubility: Readily soluble in water or saline. [Protocol ID: 95 I-126 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Lyophilized powder. [Protocol ID: 95 I-126 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 120 mg vials. [Protocol ID: 95 I-126 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. [Protocol ID: 95 I-126 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C. [Protocol ID: 95 I-126 ] MANUFACTURERS 0000003325: Cortech Inc 7000 North Broadway Denver, CO 80221 Contact: Unspecified (303)650-1200 ENTRY MONTH 199505 LAST REVISION DATE 20000801 126 UNIQUE IDENTIFIER DRG-0220 NAME OF SUBSTANCE Magnesium sulfate [USPD 1998; p. 437] REGISTRY NUMBER 10034-99-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Sulfuric acid magnesium salt (1:1), heptahydrate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 020J PHARMACOLOGICAL ACTION MODE OF ACTION: Parenterally in doses sufficient to produce hypermagnesemia (magnesium conc. > 2.5 mEq/L), magnesium sulfate may depress the CNS and block peripheral neuromuscular transmission producing anticonvulsant effects. Excess magnesium appears to decrease the amount of acetylcholine liberated by the motor nerve impulse. Magnesium also acts peripherally producing vasodilation. Magnesium readily crosses the placenta and is distributed into milk. Magnesium sulfate is excreted by the kidney. When magnesium sulfate is administered intravenously, the onset of action is immediate and the duration is about 30 minutes. Following intramuscular administration of the drug, the onset of the action occurs in about 1 hour and the duration of action is 3-4 hours. As an anticonvulsant, effective serum concentrations of magnesium have been reported to range from 2.5-7.5 m Eq/L. [AHFS Drug Information 1997; p 1661] DISEASES STUDIED/TREATED Alleviation or elimination of hypocalcemia and hypomagnesemia associated with foscarnet infusion. [Protocol ID: 020J ] CLASSIFICATION CODE Electrolyte replenisher [USP DI 2000; p. 2016] OTHER MAJOR USES Magnesium sulfate is mainly used as an anticonvulsant for the prevention and control of seizures in severe preclampsia or in eclampsia. It is also used to inhibit uterine contraction in preterm labor; to control seizures associated with epilepsy, glomerulonephritis, or hypothyroidism; to treat acute magnesium deficiency which may be associated with clinical conditions including malabsorption syndromes, alcoholism, cirrhosis of the liver, acute pancreatitis, or prolonged intravenous therapy with magnesium-free fluids; to counteract intense muscle stimulating effects of barium poisoning; to prevent magnesium deficiency in patients receiving total parenteral nutrition. [AHFS Drug Information 1997; p 1661-2] SUBSTANCE INTERACTIONS Concomitant administration with CNS depressants such as barbiturates, opiates, or general anesthetics must be done with careful adjustment of these agents to prevent additive central depressant effects. Concomitant administration of neuromuscular blocking agents should be done with caution. Magnesium sulfate should be administered with extreme caution in digitalized patients because serious changes in cardia conduction, which can result in heart block, may occur if calcium administration is required to treat magnesium toxicity. [AHFS Drug Information 1997; p 1663] ADVERSE EFFECTS Signs of magnesium intoxication which may begin at serum concentration of 4 mEq/L, include flushing, sweating, hypotension, depression of reflexes, flaccid paralysis, hypothermia, circulatory collapse, depression of cardiac function, and CNS depression. These symptoms can proceed to fatal respiratory paralysis. Hypocalcemia with signs of tetany secondary to magnesium sulfate therapy for eclampsia has been reported. [AHFS Drug Information 1997; p 1662] CONTRAINDICATIONS Should be administered with caution to patients with impaired renal functions. Magnesium sulfate is contraindicated in patients with heart blockage or myocardial damage. [AHFS Drug Information 1997; p 1662] CHEMICAL/PHYSICAL DATA Molecular Formula: Mg-S-O4.7H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 246.48 [USPD 1998; p. 437] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water; slightly soluble in alcohol. [Merck Index 1996; p 971] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Efflorescent crystals or powder; bitter, saline, cooling taste. [Merck Index 1996; p 971] SUBSTANCE DELIVERY DATA DOSAGE FORM: Parenteral injection solutions (10, 12.5, or 50%); parenteral injection solutions (4 or 8%) for intravenous use only; parenteral injection solutions (1 or 2%) in 5% dextrose for intravenous use only. [AHFS Drug Information 1997; p 1663] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous or intramuscular injections. [AHFS Drug Information 1997; p 1663] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Magnesium sulfate injection solutions should be stored at a temperature less than 40 C, preferrably between 15-30 C; freezing should be avoided. [AHFS Drug Information 1997; p 1660] MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Cheryl Karol (508)366-1100 REFERENCES MED/97417851. Bruner JP, Bruner TA, Sarno AP. Long-term intravenous tocolytic therapy. Mil Med. 1997 Aug;162(8):555-9. MED/97412548. Lilley LL, Guanci R. Magnesium Sulfate: is that the right dose? Am J Nurs. 1997 Aug;97(8):12-4. MED/97374579. Verduyn SC, Vos MA, van der Zande J, van der Hulst FF, Wellens HJ. Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by mangesium. Cardoivasc Res. 1997 Jun;34(3):453-63. MED/97403929. Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz B. Acute myocardial infarction without thrombolytic therapy: beneficial effects of magnesium sulfate. Herz. 1997 Jun;22 Suppl 1:73-6. MED/97331259. Hebert P, Mehta N, Wang J, Hindmarsh T, Jones G, Cardinal P. Functional magnesium deficiency in critically ill patients using a magnesium-loading test. Crit Care Med. 1997 May;25(5):749-55. MED/97391038. Theophanides T. Biological implications of magnesium salts at the molecular level. Magnes Res. 1996 Dec; 9(4):259-62. ICA10/94369690. Stroud S, Salvato P, Thompson C. Magnesium level and peripheral neuropathy. Int Conf AIDS. 1994 Aug 7-12;10(1):202 (abstract no. PB0235). ENTRY MONTH 199504 LAST REVISION DATE 20001107 127 UNIQUE IDENTIFIER DRG-0219 NAME OF SUBSTANCE Kynostatin 272 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 147318-81-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Thiazolidinecarboxamide, N-(1,1-dimethylethyl)-3-(2-hydroxy-3- ((2-(((5-isoquinolinyloxy)acetyl)amino)-3- (methylthio)-1-oxopropyl)amino)-1-oxo-4-pheny- lbutyl)-, (4R-(3(2S*,3S*(R*)),4R*)) [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting NCI 94 C-147 PROTOCOL ID NUMBERS No longer recruiting NCI 94 C-40 PHARMACOLOGICAL ACTION MODE OF ACTION: Highly potent against HIV protease with little inhibition of other aspartic proteases in a wide spectrum of HIV strains in vitro. In one study, IC50s of KNI-272 against HIV type 1 LAI, RF, and MN, and HIV type 2 ROD were 0.1, 0.02, 0.04 and 0.1 microM, respectively, when tested in target CD4+ ATH8 cells. Ratio of 50% cytotoxic concentration to IC50 was > 4000, as assessed in peripheral blood mononuclear cells. KNI-272 blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in HIV-1 infected cells. Data from a later study suggest that decreased virus sensitivity to KNI-272 may develop. Detailed studies of protein binding suggest that in human plasma binding of KNI-272 occurs predominantly to alpha 1-acid glycoprotein. These studies further suggest that KNI-272 is extensively (98-99%) protein bound at concentrations likely to be achieved in the circulation. [Antimicrob Agents Chemother 1993 Apr;37(4); p 810-7; Int Conf AIDS 1994 Aug 7-12;10(2); (abstract no. 516B) p 60; Antimicrob Agents Chemother 1994 May;38(5); p 1107-11] DISEASES STUDIED/TREATED Primary HIV infection. [Int Conf AIDS 1994 Aug 7-12;10(2); (abstract no. 516B) p 60] CLASSIFICATION CODE Investigational - Protease inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Adverse effects experienced by patients thus far include fatigue, parotitis (inflammation of salivary gland), elevated liver function tests, and elevated amylase without evidence of pancreatitis. [Protocol ID: 94 C-40 ] CONTRAINDICATIONS Contraindicated in pregnant women. [Protocol ID: 94 C-40 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Transition-state mimetic tripeptide HIV protease inhibitor containing allophenylnorstatine with a hydroxymethylcarbonyl isostere. [Int Conf AIDS 1994 Aug 7-12;10(2); (abstract no. 516B) p 60] CHEMICAL/PHYSICAL DATA Molecular Formula: C33-H41-N5-O6-S2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 667.85 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Extremely low aqueous solubility (4 mcg/ml). [J Pharm Sci 1994 Aug;83(8); p 1142-6] SUBSTANCE DELIVERY DATA DOSAGE FORM: Liquid, capsules, or tablets. [Protocol ID: 94 C-40 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous; oral. [Protocol ID: 94 C-40 ] MANUFACTURERS 0000003301: Natl Cancer Institute / Japan Energy Corp 9000 Rockville Pike / Clinical Ctr Bethesda, MD 20892 Contact: (800)772-5464 REFERENCES MED/97291248. Humphrey RW, Ohagen A, Davis DA, Fukazawa T, Hayashi H, Hoglund S, Mitsuya H, Yarchoan R. Removal of human immunodeficiency virus type 1 (HIV-1) protease inhibitors from preparations of immature HIV-1 virions does not result in an increase of infectivity or the appearance of mature morphology. Antimocrob Agents Chemother. 1997 May; 41(5):1017-23. AIDS/97926492. Yusa K, Kavlick MF, Mitsuya H. HIV-1 acquires resistance to multiple classes of antiviral drugs through recombination. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:173 (abstract no. 585). MED/97123278. Kiriyama A, Nishiura T, Ishino M, Yamamoto Y, Ogita I, Kiso Y, Takada K. Binding characteristics of KNI-272 to plasma proteins, a new potent tripeptide HIV protease inhibitor. Biopharm Drug Dispos. 1996 Dec;17(9):739-51. AIDS/97229611. Kynostatin 272. Pediatr AIDS HIV Infect. 1996 Apr;7(2):132-4. MED/97063852. Kiriyama A, Sugahara M, Yoshikawa Y, Kiso Y, Takada K. The bioavailability of oral dosage forms of a new HIV-1 protease inhibitor, KNI-272, in beagle dogs. Biopharm Drugs Dispos. 1996 Mar;17(2):125-34. MED/96232640. Kiso Y. Design and synthesis of substrate-based peptidomimetic human immunodeficiency virus protease inhibitors containing the hydroxymethylcarbonyl isostere. Biopolymers. 1996;40(2):235-44. MED/96105495. Chokekijchai S, Shirasaka T, Weinstein JN, Mitsuya H. In vitro anti-HIV-1 activity of HIV protease inhibitor KNI-272 in resting and activated cells: implications for its combined use with AZT or ddI. Antiviral Res. 1995 Sep;28(1):25-38. MED/95352609. Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson B, Mitsuya H, Erickson JW. Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry. 1995 Jul 25;34(29):9282-7. AIDS/95920125. Humphrey RW, Mitsuya H, Yarchoan R. HIV protease inhibitors do not prevent cell death during single-cycle HIV infection of CEM-ss cells in vitro. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:71. AIDS/95920128. Anderson B, Kageyama S, Ueno T, Shirasaka T, Liu B, Gulnick S, Erickson J, Mitsuya H. In vitro induction HIV-1 with reduced sensitivity to HIV protease inhibitors, KNI-227 and KNI-272. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:72. ENTRY MONTH 199502 LAST REVISION DATE 20000801 128 UNIQUE IDENTIFIER DRG-0218 NAME OF SUBSTANCE Acitretin [USPD 1998; p. 21] REGISTRY NUMBER 55079-83-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4,6,8-Nonatetraenoic acid, 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimet- hyl-, (all-E)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Soriatane [USP DI 2000; p. 25] PROTOCOL ID NUMBERS No longer recruiting FDA 239A PHARMACOLOGICAL ACTION MODE OF ACTION: Certain retinoids have been shown in rats and mice to induce hepatic cytochrome P-50 enzyme. Acitretin, the active primary metabolite of etretinate (another retinoid used in treatment of psoriasis) may induce its own metabolism. Acitretin is eliminated far more rapidly from the human body than is etretinate. Re-esterification (in the body) of acitretin to etretinate results in a loss of the metabolic advantage of the former. Retinoids (including acitretin) contribute potentially to cancer chemotherapy and chemoprevention. They induce cell differentiation, inhibit cell proliferation, suppress expression of viral oncogenesis, and inhibit angiogenesis necessary for tumor growth. [J Am Acad Dermatol 1992 Dec;27(6 Pt 2); p S19-22; J Pharm Sci 1994 May;83(5); p 662-67; J Cell Biochem 1994 Dec;56(4); p 427-35] DISEASES STUDIED/TREATED Treatment of psoriasis in HIV-positive patients. [Protocol ID: 239A ] CLASSIFICATION CODE Antipsoriatic [USP DI 2000; p. 20] CLASSIFICATION CODE Keratinization stabilizer [USP DI 2000; p. 20] OTHER MAJOR USES Various dermatoses. [Dermatologica 1998;176(4); p 182-90] ADVERSE EFFECTS Adverse reactions are dose-related and typical of hypervitaminosis A. They include alopecia, cheilitis and drying of the mucous membranes, hypertriglyceridemia, and elevation of cholesterol levels. Acitretin has teratogenic potential. It appears to be connected to higher occurrence of vulvo-vaginal candidiasis. Extensive extraspinal hyperostosis after long-term oral retinoid (acitretin) therapy was noted in one patient. [Drugs 1992 Apr;43(4); p 597-627; J Clin Epidemiol 1995 Aug;48(8); p 991-97; J Am Acad Dermatol 1995 Feb;32(2 Pt 2); p 322-25] CONTRAINDICATIONS Contraindicated in women of childbearing potential because of teratogenicity. [Protocol ID: 239A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic retinoid; free acid form and major metabolite of etretinate. [Merck Index 1996; p 20] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H26-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 326.44 [USPD 1998; p. 21] CHEMICAL/PHYSICAL DATA Melting Point: 228-230 C [Merck Index 1996; p. 20] CHEMICAL/PHYSICAL DATA Elemental Comp: C77.27%, H8.03%, O14.70% [Merck Index 1996; p. 20] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules 10 and 25 mg. [USP DI 1997; p 3027] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 239A ] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES MED/97341497. Buccheri L, Katchen BR, Karter AJ, Cohen SR. Acitretin therapy is effective for psoriasis associated with human immunodeficiency virus infection. Arch Dermatol. 1997 Jun;133(6):711-5. MED/97247353. Herrmann G, Jungblut RM, Goerz G. Skeletal changes after long-term therapy with synthetic retinoids [letter]. Br J Dermatol. 1997 Mar;136(3):275-8. MED/97221704. van de Kerkhof PC, de Rooij MJ. Multiple squamous cell carcinomas in a psoriatic patient following high-dose photochemotherapy and cyclosporin treatment: response to long-term acitretin maintenance. Br J Dermatol 1997 Feb;136(2):275-8. MED/97129195. Koo J, Nguyen Q, Gambla C. Advances in psoriasis therapy. Adv Dermatol 1997;12:47-72;discussion 73. MED/97183845. Kuijpers AL, van Dooren-Greebe JV, van de Kerkhof PC. Failure of combination therapy with acitretin and cyclosporin A in 3 patients with erythrodermic psoriasis [letter] REVIEW ARTICLE:11 REFS. Dermatology. 1997;194(1):88-90. MED/97137029. Zachariae H, Heickendorff L, Bjerring P. Plasma endothelin in psoriasis: possible relations to therapy and toxicity. Acta Derm Venereol. 1996 Nov;76(6):442-3. MED/97028471. Maier H, Honigsmann H. Concentration of etretinate in plasma and subcutaneous fat after long-term acitretin [letter] Lancet. 1996 Oct 19;348(9034):1107. MED/96287795. Mork NJ, Kolbenstvedt A, Austad J. Skeletal side-effects of 5 years' acitretin treatment [letter] Br J Dermatol. 1996 Jun;134(6):1156-7. MED/96297444. Lister RK, Lecky BR, Lewis-Jones MS, Young CA. Acitretin-induced myopathy [letter] Br J Dermatol. 1996 May; 134(5):989-90. MED/97010279. Armstrong DK, Irvine A, Walsh MY, Mayne EE, Burrows D. Multiple dermatofibromas in a patient with HIV infection. Clin Exp Dermatol. 1995 Nov;20(6):474-6. ENTRY MONTH 199411 LAST REVISION DATE 20001107 129 UNIQUE IDENTIFIER DRG-0217 NAME OF SUBSTANCE Tecogalan sodium [USPD 1998; p. 712] REGISTRY NUMBER 134633-29-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME D-gluco-D-galactan sulfate [Protocol ID: 088A ] PROTOCOL ID NUMBERS No longer recruiting FDA 088A PROTOCOL ID NUMBERS No longer recruiting FDA 088B PROTOCOL ID NUMBERS No longer recruiting FDA 088C PROTOCOL ID NUMBERS No longer recruiting FDA 088D PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibitory effect of tecogalan sodium on endothelial cell migration and proliferation is thought to be mediated by the inhibition of the binding of fibroblast growth factor to endothelial cells. Tecogalan sodium has shown potent and selective inhibition of HIV-1 replication in vitro. SP-PG (tecogalan sodium) controlled the in vitro growth of AIDS-associated Kaposi's sarcoma (KS)-derived spindle-shaped cells at noncytotoxic concentrations. SP-PG also inhibited the vascular hyperpermeability response and the angiogenesis associated with the induction of KS-like lesions. The anti-tumor effect of tecogalan is thought to be mediated by the inhibition of the binding of fibroblast growth factors to cell receptors. Pharmacokinetic studies (in phase I trial) show that the peak plasma concentration correlates with the peak activated partial thromboplastin time and that little of the drug is excreted in the urine. [Proc Annu Meet Am Soc Clin Oncol 1994;13; p A23; Science 1992 Mar 13:255(5050); p 1437-40; Proc Annu Meet Am Assoc Cancer Res 1995;36; p A628] DISEASES STUDIED/TREATED Inhibitor of Kaposi's sarcoma. [AmfAR Treat Dir 1995;7(4); p 70] CLASSIFICATION CODE Antineoplastic adjunct [USPD 2000 p. 691] OTHER MAJOR USES Treatment of solid tumors. [Proc Annu Meet Am Soc Clin Oncol 1994;13; p A23] ADVERSE EFFECTS Adverse effects include prolongation of activated partial thromboplastin time (with peak times being 1.0-4.0 x the upper limit of normal), fever, and chills. Toxicities in a phase I study with 17 patients were transient and include fevers in 16, chills in 12, headaches in 10, rigors in 7, tachycardia in 5, and nausea in 5 patients. Neutropenia and anemia were rare and there were no instances of thrombocytopenia. [Proc Annu Meet Am Soc Clin Oncol 1994;13; p A23; Blood 1994 84(10, Suppl 1); p 240a] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fermentation product of Arthrobacter sp. AT-25, and composed of sulfated polysaccharide and small amounts of peptidoglycan and phosphorous. [USAN 1997; p 695] CHEMICAL/PHYSICAL DATA Molecular Weight: 29,000 [USPD 1998; p. 712] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 088A ] MANUFACTURERS 0000003236: Daiichi Pharmaceutical Corp 11 Philips Parkway Montvale, NJ 07645 Contact: Tom Boersig (201)944-4333 REFERENCES MED/96437090. Eckhardt SG, Burris HA, Eckardt JR, Weiss G, Rodriguez G, Rothenberg M, Rinaldi D, Barrington R, Kuhn JG, et al. A phase I clinical and pharmacokinetic study of the angiogenesis inhibitor, tecogalan sodium [see comments in: Ann Oncol. 1996 Jul; 7(5):441-4]. Ann Oncol. 1996 Jul; 7(5): 491-6. MED/96249989. Murata T, Ishibashi T, Yoshikawa H, Khalil A, Inomata H. Tecogalan sodium inhibits corneal neovascularization induced by basic fibroblast growth factor. Ophthalmic Res. 1995; 27(6): 330-4. ICDB/95608407. Eckardt SG, Eckardt JR, Weiss G, Rinaldi D, Rodriguez G, Fields S, Kuhn J, Smetzer L, Higashi L, Von Hoff DD, et al. Results of a phase I trial of the novel angiogenesis inhibitor, tecogalan sodium (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res; 36:A628 1995. MED/95247403. Sakamoto T, Ishibashi T, Kimura H, Yoshikawa H, Spee C, Harris MS, Hinton DR, Ryan SJ. Effect of tecogalan sodium on angiogenesis in vitro by choroidal endothelial cells. Invest Ophthalmol Vis Sci 1995 May;36(6):1076-83. MED/94339000. Bicknell R. Vascular targeting and the inhibition of angiogenesis. Ann Oncol. 1994;5 Suppl 4:45-50. MED/94324941. Chleboun JO, Sellers P, Muir G, Chew P, Martins RN. The effect of tecogalan sodium on the development of the collateral circulation after acute arterial occlusion. Biochem Biophys Res Commun.1994 Jul 29;202(2):1149-55. ICDB/95606242. Krown SE. AIDS-related Kaposi's sarcoma: clinical aspects (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res;35:659-60 1994. ICDB/94600020. Eckhardt SG, Burris HA, Eckardt JR, Weiss G, Rinaldi D, Barrington R, Smith L, Fields S, Kuhn J, Smith S, et al. Phase I assessment of the novel angiogenesis inhibitor DS4152 (Tecogalan Sodium) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol. 1994;13:A23. MED/94280703. Baba M, Shigeta S, Ikeuchi T, Korenaga H, Osada Y. Anti-angiogenesis agent DS-4152 is a potent and selective inhibitor of HIV-1 replication in vitro. AIDS. 1994 Jan;8(1):43-8. ICDB/96615859. Tulpule A, Snyder JC, Espina BM, Higashi L, Satomi M, Lombardy EE, Gill PS. A phase I study of tecogalan, a novel angiogenesis inhibitor in the treatment of AIDS-related Kaposi's sarcoma and solid tumors (Meeting abstract). Blood; 84(10, Suppl 1): 248a 1994. ENTRY MONTH 199409 LAST REVISION DATE 20000801 130 UNIQUE IDENTIFIER DRG-0216 NAME OF SUBSTANCE Telinavir [USPD 1998; p. 714] REGISTRY NUMBER 143224-34-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Butanediamide, N1-(3-((((1,1-dimethylethyl)amino)carbonyl)(2- -methylpropyl)amino)-2- hydroxy-1-(phenylmethyl)propyl)-2-((2-quinoli- nylcarbonyl)amino)-, (1S-(1R*,(R*),2S*))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 282 PHARMACOLOGICAL ACTION MODE OF ACTION: HIV-infected cells produce large polyproteins which are precursors to the individual components of HIV. Protease, which is also produced by HIV-infected cells, cleaves the large precursor proteins, thereby separating the final viral elements (e.g., p 24 and reverse transcriptase) in preparation for viral assembly. If the precursor proteins are not processed by the protease enzyme, nonfunctioning non-infectious virons are formed. The three dimensional structure of the HIV protease has been fully determined; researchers are therefore able to rationally design compounds (i.e., protease inhibitors) to inhibit it. Selectively inhibited HIV protease in vitro and demonstrated antiviral activity against HIV-1, HIV-2, SIV, and zidovudine-resistant strains of HIV-1 in vitro. After treatment of HIV-infected CEM cells with SC-52151, the virus core of infectious extracellular virus particles was absent. A four-arm, phase I/II clinical study using the highest previously tested daily dose of SC-52151, 2250 mg, was conducted in 49 patients. One patient developed hypertriglyceridemia, and one had fever and dyspnea. Although SC-52151 was well tolerated and one formulation used resulted in plasma concentrations above the IC90 for viral replication, no antiviral activity was produced. The manufacturer has announced that development of their two protease inhibitors, SC-52151 & SC-55389A, has ceased. [Protocol ID: ACTG 282 ; AmfAR Treat Dir 1995;7(4); p 54-6; J Acquir Immune Defic Syndr Hum Retrovirol 1997 May 1;15(1); p 28-34] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: ACTG 282 ] CLASSIFICATION CODE Investigational - Protease inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CONTRAINDICATIONS Contraindicated in pregnant or nursing women, since safety has not been determined. [Protocol ID: ACTG 282 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Urea-based peptidomimetic. [Protocol ID: ACTG 282 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C33-H44-N6-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 604.75 [USPD 1998; p. 714] SUBSTANCE DELIVERY DATA DOSAGE FORM: 175 ml amber glass bottles of elixir or SEDDS (self-emulsifying drug delivery system) formulation. [Protocol ID: ACTG 282 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 282 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature. [Protocol ID: ACTG 282 ] MANUFACTURERS 0000001201: G D Searle & Co 5200 Old Orchard Road Skokie, IL 60077 Contact: Dr Richard Aspinall (708)982-8651 REFERENCES MED/97323587. Yuan JH, Stolzenbach JC, Salamon CM, Snook SS, Schoenhard GL. Improvement of bioavailability of the HIV protease inhibitor SC-52151 in the beagle dog by coadministration of the CYP3A4 inhibitor, ketoconazole. Xenobiotica. 1997 May; 27(5): 489-97. MED/97358555. Fischl MA, Richman DD, Flexner C, Para MF, Haubrich R, Karim A, Yeramian P, Holden-Wiltse J, Meehan PM. Phase I/II study of the toxicity, pharmacokinetics, and activity of the HIV protease inhibitor SC-52151. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 May 1; 15(1): 28-34. MED/97275173. Lazdins JK, Mestan J, Goutte G, Walker MR, Bold G, Capraro HG, Klimkait T. In vitro effect of alpha1-acid glycoprotein on the anti-human immunodeficiency virus (HIV) activity of the protease relevant HIV protease inhibitors. J Infect Dis. 1997 May; 175(5): 1063-70. MED/96202332. Rose RE, Gong YF, Greytok JA, Bechtold CM, Terry BJ, Robinson BS, Alam M, Colonno RJ, Lin PF. Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors. Proc Natl Acad Sci U S A. 1996 Feb 20: 93(4): 1648-53. MED/96109417. Bryant M, Getman D, Smidt M, Marr J, Clare M, Dillard R, Lansky D, DeCrescenzo G, Heintz R, Houseman K, et al. SC-52151, a novel inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1995 Oct; 39(10): 2229-34. MED/96234098. Moutouh L, Corbeil J, Richmann DD. Recombination leads to the rapid emergence of HIV-1 dually resistant mutants under selective drug pressure. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6106-11. AIDS/96920156. Potts KE, Smid ML, Tucker SP, Stiebel TR, McDonald JJ, Stegman RA, Stallings WC, Wiegand RC. Characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylurea isostere containing protease inhibitors in vitro. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:81. AIDS/95920218. Fischl MA, Richman DD, Flexner C, Meehan P, Para MF, Haubrich R, Cook J, Wood K, Karim A. Phase I study of two formulations and dose schedules of SC-521151, a protease inhibitor. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:88. MED/93140133. Getman DP, DeCrescenzo GA, Heintz RM, Reed KL, Talley JJ, Bryant ML, Clare M, Houseman KA, Marr JJ, Mueller RA, et al. Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem. 1993 Jan 22;36(2):288-91. ENTRY MONTH 199408 LAST REVISION DATE 20001107 131 UNIQUE IDENTIFIER DRG-0215 NAME OF SUBSTANCE Raluridine [USPD 1998; p. 627] REGISTRY NUMBER 119644-22-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Uridine, 5-chloro-2', 3'-dideoxy-3'-fluoro- [Antimicrob Agents Chemother 1994 July;38(7); p 1590-1603] PROTOCOL ID NUMBERS No longer recruiting FDA 237A PHARMACOLOGICAL ACTION MODE OF ACTION: 935U83 (also called BW935U83) is a nucleoside reverse transcriptase inhibitor. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV-1 obtained from patients naive to AZT, 935U83 inhibited virus growth with an average 50% inhibitory concentration. Importantly, 935U83 retained activity against HIV strains that were resistant to AZT, ddI, or ddc. Testers were unable to generate virus which was resistant to 935U83 by passaging either HXB2 (AZT-sensitive) or RTMC (AZT-resistant) strains in the presence of high concentrations of 935U83. The anabolic profile of 935U83 was similar to that of AZT, and 935U83 triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. Pharmacokinetic evaluation showed good oral bioavailability (86% in mice and 60% in monkeys) and less extensive metabolism to the glucuronide relative to AZT. 935U83 showed low toxicity. In monkeys dosed orally with up to 700 mg/kg/day for 1 and 6 months, the only possible treatment-related finding was cataracts in 1 of 12 animals given the intermediate dose of 225 mg/kg/day. At the highest doses in mice and monkeys, maximal concentrations in plasma were more than 100-fold the anti-HIV IC50s against clinical isolates. This safety profile in animals compares very favorably with that of any of the anti-HIV drugs approved to date (i.e., 1994). A phase I trial of a single dose of 935U83 revealed excellent tolerance, oral bioavailability, and a half-life of 1.2 hours. [Antimicrob Agents Chemother 1994 July;38(7); p 1590-603; Prog Abst Intersci Conf Antimicrob Agents Chemother 1994 Oct; p 133] DISEASES STUDIED/TREATED Primary HIV infection. Drug development discontinued per company. [Protocol ID: 237A ; Glaxo Wellcome Inc 1996 April] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CONTRAINDICATIONS Contraindicated in pregnant women. [Protocol ID: 237A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A 3'-fluoropyrimidine nucleoside. [Antimicrob Agents Chemother 1994 July;38(7); p 1590-1603] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H10-Cl-F-N2-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 264.64 [USPD 1998; p. 627] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 237A ] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 REFERENCES AIDS/95920300. Bartlett JA, McMahon D. A phase I trial of BW935U83 in HIV infected persons. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:104. AIDS/95920790. Joyner SS, Novak P, Dornsife RE, Dev IK. Molecular basis for the increased hematopoietic toxicity of FLT compared to AZT and 935U83. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:93. AIDS/95920848. Bartlett JA, Fife KH. A phase I trial of BW935U83 in HIV infected persons. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:133. MED/95070022. Daluge SM, Purifoy DJ, Savina PM, St Clair MH, Parry NR, Dev IK, Novak P, Ayers KM, Reardon JE, Roberts GB, et al. 5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile. Antimicrob Agents Chemother. 1994 Jul;38(7):1590-603. AIDS/9592600. Riddler SA, McMahon DK, Bartlett JA, Savina PM, Wang LH, Dunn JA, Mellors JW. A phase I single-dose trial to evaluate the safety and pharmacokinetics (PK) of 5-chloro-2'3'-dideoxy-3'fluorouridine (935U83). Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:160. ENTRY MONTH 199408 LAST REVISION DATE 20000801 132 UNIQUE IDENTIFIER DRG-0214 NAME OF SUBSTANCE Sulfadiazine [USPD 1998; p. 692] REGISTRY NUMBER 68-35-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzenesulfonamide, 4-amino-N-2-pyrimidinyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 237 PROTOCOL ID NUMBERS No longer recruiting CC 98 I-0153 PHARMACOLOGICAL ACTION MODE OF ACTION: Sulfonamides are broad-spectrum, bacteriostatic, anti-infectives. They are structural analogs of para-aminobenzoic acid (PABA) and competitively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of PABA into dihydrofolic acid, the immediate precursor of folic acid. This blocks the synthesis of dihydrofolic acid and decreases the amount of metabolically active tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA. Susceptible bacteria are those that must synthesize folic acid. Sulfadiazine is readily absorbed from the GI tract. After a single 2-gram dose, peak plasma concentrations of 60 microgram/mL were reached within 4 hours. Sulfadiazine is distributed into most body tissues; the drug appears to cross cell membranes freely. The drug is excreted largely in the urine. Urinary sulfadiazine concentrations usually are 10-25 times those attained in serum. About 15-40% of the sulfadiazine in the urine is in the N-4 acetylated form; about 43-60% is excreted unchanged. [USP DI 1997; p 2693; AHFS Drug Information 1997; p 620] DISEASES STUDIED/TREATED Toxoplasmic encephalitis. [Protocol ID: ACTG 237 ; AHFS Drug Information 1997; p 620] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2851] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2851] OTHER MAJOR USES Gram positive and gram negative infections, excluding urinary tract infections, unless other sulfonamides have failed. Toxoplasmosis, as an adjunct to pyrimethamine therapy, malaria, trachoma, nocardiosis and chancroid. [PDR 1995; p 988; USP DI 1997; p 2696] SUBSTANCE INTERACTIONS The effects of oral anticoagulants (coumarin or indanedione derivatives) and methotrexate may be increased by sulfadiazine. Sulfonylurea hypoglycemic agents, thiazide diuretics and uricosuric agents may be potentiated. Agents such as indomethacin, probenecid, and salicylates may displace the sulfa from plasma albumin and increase the concentrations of free drug in the plasma. Interactions have also been reported with hemolytics, hepatotoxic medications and methenamine. [PDR 1995; p 988] ADVERSE EFFECTS Adverse effects include crystalluria (crystals in the urine), hematuria, kidney stones, kidney failure, hypersensitivity reactions, and anemia. [Protocol ID: ACTG 237 ; PDR 1995; p 988; AHFS Drug Information 1997; p 617-8] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to sulfonamides, in infants less than 2 months of age and in pregnant women at term and during nursing. [PDR 1995; p 988; AHFS Drug Information 1997; p 618-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Dihydrofolate synthetase inhibitor; a synthetic derivative of p-amino-benzenesulfonamide. [Protocol ID: ACTG 237 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H10-N4-O2-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 250.28 [USPD 1998; p. 692] CHEMICAL/PHYSICAL DATA Melting Point: 252-256 C [Merck Index 1996; p. 1521] CHEMICAL/PHYSICAL DATA Elemental Comp: C47.99%, H4.03%, N22.39%, O12.79%, S12.81% [Merck Index 1996; p. 1521] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in water at 37 C and in alcohol or acetone. Soluble at 1 g/620 ml human serum at 37 C. Freely soluble in dilute mineral acids and in solutions of potassium and sodium hydroxides and in ammonia water. [Merck Index 1996; p 1521] CHEMICAL/PHYSICAL DATA Stability: Stable in air but darkens on exposure to light. [AHFS Drug Information 1997; p 620] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: A white or slightly yellow, odorless or nearly odorless powder. [AHFS Drug Information 1997; P 620] SUBSTANCE DELIVERY DATA DOSAGE FORM: 500 mg tablets. [Protocol ID: ACTG 237 ; PDR 1995; p 988] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 237 ; PDR 1995; p 988] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C. Protect from light. [Protocol ID: ACTG 237 ; PDR 1995; p 988] MANUFACTURERS 0000003408: EON Labs Manufacturing 227-15 North Conduit Ave Laurelton, NY 11413 Contact: Drug Information (800)366-1595 REFERENCES MED/96320354. Becker K, Jablonowski H, Haussinger D. Sulfadiazine-associated nephrotoxicity in patients with the acquired immunodeficiency syndrome. Medicine (Baltimore). 1996 Jul;75(4):185-94. MED/96303152. Wei ME, Campbell SH, Taylor C. Precipitous visual loss secondary to optic nerve toxoplasmosis as an unusual presentation of AIDS. Aust N Z J Ophthalmol. 1996 Feb;24(1):75-7. MED/96369158. Diaz F, Collazos J, Mayo J, Martinez E. Sulfadiazine-induced multiple urolithiasis and acute renal failure in a patient with AIDS and Toxoplasma encephalitis. Ann Pharmacother. 1996 Jan;30(1):41-2. AIDS/96343499. Kamaurulzaman A, Hoy J. Effect of folinic acid on haematological toxicity during treatment of cerebral toxoplasmosis in patients with AIDS. Annu Conf Australs Soc HIV Med. 1995 Nov 16-19;768 (abstract no. 68). AIDS/96343496. Marriott DJ, Miliken S, Harkness JL, Brew B, Maitland D, Canning E, Kench J, Field A. Myositis in an HIV-infected patient caused by new microsporidian species. Annu Conf Australas Soc HIV Med 1995 Nov 16-19;7:67 (abstract no. 65). MED/97278534. de Diego JA, Penin P, Arribas JR, Vazquez E, Vazquez JJ. A clinical-parasitological monotherapy cure in the treatment of experimental infection by a highly virulent strain of Toxoplasma gondii. Folia Microbiol (Praha). 1996; 41(6): 513-6. MED/97196897. Mir N, O'Farrell N, Creagh TA, Knowles C. Obstructive renal failure requiring surgical intervention in an AIDS patient being treated with sulphadiazine. Int J STD AIDS. 1997 Jan;8(1):61-2. MED/97138637. Ebrahimzadeh A, Bottone EJ. Persistent diarrhea caused by Isospora belli: therapeutic response to pyrimethamine and sulfadiazine. Diagn Microbiol Infect Dis. 1996 Oct; 26(2): 87-9. MED/97030415. Laing RB, Flegg PJ, Brettle RP, Leen CL, Burns SM. Clinical features, outcome and survival from cerebral toxoplasmosis in Edingburgh AIDS patients. Int J STD AIDS. 1996 Jul; 7(4): 258-64. MED/97106847. de Sequera P, Albalate M, Hernandez J, Vazquez A, Abad J, Ramiro E, Fernandez Guerrero M, Caramelo C, Casado S, Ortiz A, Acute renal failure due to sulphadiazine crystalluria in AIDS patients. Postgrad Med J. 1996 Sep; 72(851): 557-58. ENTRY MONTH 199408 LAST REVISION DATE 20001107 133 UNIQUE IDENTIFIER DRG-0213 NAME OF SUBSTANCE Isotretinoin [USPD 1998; p. 399] REGISTRY NUMBER 4759-48-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Retinoic acid, 13-cis- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Accutane [USP DI 2000; p. 1867] PROTOCOL ID NUMBERS Complete NIAID ACTG 216 PROTOCOL ID NUMBERS Complete NIAID ACTG 293 PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits sebaceous gland function and keratinization. Isotretinoin is 99% bound in human plasma almost exclusively to albumin. Terminal elimination half-life ranges from 10 to 20 hours from oral administration of 80 mg (capsules). The major identifiable metabolite in blood is 4-oxo-isotretinoin, which has a mean elimination half-life of 25 hours (range 17-50 hours). Oral absorption of isotretinoin increases when taken with food or milk. [PDR 1997; p 2252] DISEASES STUDIED/TREATED Treatment of anal neoplasia secondary to anogenital human papillomavirus infection. [Protocol ID: ACTG 216 ; AmfAR Treat Dir 1997;8(3); p 73] CLASSIFICATION CODE Keratinization stabilizer [USP DI 2000; p. 1862] OTHER MAJOR USES Treatment of acne vulgaris, cystic acne, and several other skin diseases. [AHFS Drug Information 1997; p 2771; PDR 1997; p 2252] SUBSTANCE INTERACTIONS Concurrent use of etretinate, tretinoin or vitamin A may result in additive toxic effects; concurrent tetracyclines may increase the potential for the development of pseudotumor cerebri. [USP DI 1997; p 1771] ADVERSE EFFECTS Adverse effects include major fetal abnormalities, cheilitis, conjunctivitis, pseudotumor cerebri (benign intracranial hypertension), skeletal hyperostosis, musculoskeletal symptoms including arthralgia, decreased night vision, corneal opacities, inflammatory bowel disease, changes in serum lipid levels, hepatotoxicity, transient chest pain, rash, and thinning of hair. Less frequent adverse effects include peeling of palms and soles, skin infections, nonspecific urogenital findings and gastrointestinal symptoms, fatigue, headache, depression, and increased susceptibility to sunburn. CNS reactions (seizures, emotional instability, dizziness, nervousness, drowsiness, malaise, etc.) have been reported but may not be related to therapy. [PDR 1997; o 2253] CONTRAINDICATIONS Strongly contraindicated in pregnant and nursing women and in those who may become pregnant while on therapy. Also contraindicated in patients with sensitivity to parabens, to vitamin A, and to other retinoids. [PDR 1997; p 2252-3; AHFS Drug Information 1997; p 2773] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Isotretinoin, a synthetic retinoid, is the 13-cis-isomer of naturally occurring all-trans-retinoic acid (tretinoin). [AHFS Drug Information 1997; p 2769] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H28-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 300.44 [USPD 1998; p. 399] CHEMICAL/PHYSICAL DATA Melting Point: 174-175 C [Merck Index 1996; p. 1404] CHEMICAL/PHYSICAL DATA Elemental Comp: C79.96%, H9.39%, O10.65% [Merck Index 1996; p. 1404] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water, sparingly soluble in alcohol. [AHFS Drug Information 1997; p 2770] CHEMICAL/PHYSICAL DATA Stability: Photosensitive and degrades when exposed to light; capsules are stable for two years. [AHFS Drug Information 1997; p 2770] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow-orange to orange crystalline powder. [PDR 1997; p 2252] SUBSTANCE DELIVERY DATA DOSAGE FORM: 10, 20, and 40 mg soft gelatin capsules. [PDR 1997; p 2253] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2253] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). Protect from light. [PDR 1997; p 2253] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES MED/96087477. Sass JO, Masgrau E, Saurat JH, Nau H. Metabolism of oral 9-cis-retinoic acid in the human. Identification of 9-cis-retinoyl-beta-glucuronide and 9-cis-4-oxo-retinoyl-beta-glucuronide as urinary metabolites. Drug Metab Dispos 1995 Sep;23(9):887-91. MED/95390704. Otley CC, Avram MR, Johnson RA. Isotretinoin treatment of human immunodeficiency virus-associated eosinophilic folliculitis. Results of an open, pilot trial. Arch Dermatol. 1995 Sep:131(9):1047-50. ICDB/95613987. Lewi D, Reboredo G, Jauregui Rueda H, Monticelli A, Losso M, Vujacich C, Litovska S, Marantz A, De la Torre A, Politi P. Phase II trial of 13-cis-retinoic acid (CRA) in AIDS-related Kaposi's sarcoma (KS) (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res;14:A835 1995. MED/94265797. Markowska J, Nowak M, Niecewicz R, Breborowicz J, Wiese E, Zengteler G. Results of topical treatment of HPV infection in the uterine cervix using interferon beta, 13-cis-retinoic acid and TFX. Eur J Gynaecol Oncol. 1994;15(1):65-9. MED/94305011. Birley HD, Luzzi GA, Walker MM, Ryait B, Taylor-Robinson D, Renton AM. The association of human papillomavirus infection with balanoposthitis: a description of five cases with proposals for treatment. Int J STD AIDS. 1994 Mar-Apr;5(2):139-41. Digiovanna JJ. Therapy of skin cancer, psoriasis, keratinization disorders, and cystic acne. Crisp Data Base National Institutes of Health. MED/94355255. Lippman SM, Hong WK. 13-cis-retinoic acid plus interferon-alpha in solid tumors: keeping the cart behind the horse [editorial]. Ann Oncol. 1994 May;5(5):391-3. MED/97359623. Yen A, Sanchez RL, Raimer SS. Papular mucinosis associated with AIDS: response to isotretinoin. J Am Acad Dermatol. 1997 Jul; 37(1): 127-8. MED/96308893. Kellock DJ, Parslew R, Mendelsohn SS, O'Mahony CP. Non-specific urethritis--possible association with isotretinoin therapy. Int J STD AIDS. 1996 Mar-Apr; 7(2): 135-6. MED/96258893. Maeda Y, Miyatake J, Sono H, Matsuda M, Tatsumi Y, Horiuchi F, Irimajiri K, Horiuchi A. 13-cis retinoic acid inhibits growth of adult T cell leukemia cells and causes apoptosis; possible new indication for retinoid therapy [see comments]. Intern Med. 1996 Mar; 35(3): 180-4. MED/96315407. Bergbrant IM. Seborrheic dermatitis and Pithyrosporum yeasts. Curr Top Med Mycol. 1995; 6: 95-112. ENTRY MONTH 199407 LAST REVISION DATE 20001107 134 UNIQUE IDENTIFIER DRG-0212 NAME OF SUBSTANCE HIV-1 Peptide Vaccine, Microparticulate Monovalent [Protocol ID: AVEG 018 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 018 PROTOCOL ID NUMBERS Complete NIAID AVEG 023 PROTOCOL ID NUMBERS No longer recruiting FDA 091 PHARMACOLOGICAL ACTION MODE OF ACTION: Consists of eight PND-derived peptides attached to a lysine core to form radial-octamers. The PND peptides are the immunogenic portion of the multiple antigen peptide; the lysine core matrix is not immunogenic. The antigen is entrapped in biodegradable microparticles that may protect it from acid and proteolytic digestion in the gastrointestinal tract. Microparticles are taken up into the Peyer's patches following oral administration, phagocytosed by macrophages, and degraded over time, thus inducing both mucosal and systemic immunity. [Protocol ID: AVEG 018 ] DISEASES STUDIED/TREATED Prevention of HIV infection. [Protocol ID: AVEG 018 ] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 018 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: HIV-1 MN branched peptide entrapped in polymeric microparticles. [Protocol ID: AVEG 018 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Freeze-dried white powder entrapped in microparticles prepared from polymers. [Protocol ID: AVEG 018 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Biodegradable microparticles. [Protocol ID: AVEG 018 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: AVEG 018 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (35.6-46.4 F). [Protocol ID: AVEG 018 ] MANUFACTURERS 0000002563: United Biomedical Inc 25 Davids Drive Happauge, NY 11788 Contact: Dr Bruce Forrest (516)273-2828 REFERENCES MED/97304082. Cleland JL. Protein delivery from biodegradable microspheres. Pharm Biotechnol. 1997;10:1-43. MED/97410431. Ben-Yedidia T, Arnon R. Design of peptide and polypeptide vaccines. Curr Opin Biotechnol. 1997Aug;8(4):442-8. AIDS/97920735. Burnett PR, VanCott TC, van Hamont JE, Loomis-Price LD, Cox JH, Mascola JR, Birx DL. Immunogenicity of parenterally administered microencapsulated HIV-1 gp160. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:161[Poster 41]. MED/95120365. Wassef NM, Alving CR, Richards RL. Liposomes as carriers for vaccines. Immunomethods. 1994 Jun;4(3):217-22. AIDS/95921127. Grek V, Zgoulli S, Zinner S, Thonart P. Microencapsulation of antigens using a spray-drying technique: potential application to HIV vaccines. Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:72. ENTRY MONTH 199407 LAST REVISION DATE 20000801 135 UNIQUE IDENTIFIER DRG-0211 NAME OF SUBSTANCE Levocarnitine [USPD 1998; p. 416] REGISTRY NUMBER 541-15-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Propanaminium, 3-carboxy-2-hydroxy-N,N,N-trimethyl-, hydroxide, inner salt, (R)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Carnitor [USP DI 2000; p. 1963] PROTOCOL ID NUMBERS Complete NIAID ACTG 359 PROTOCOL ID NUMBERS No longer recruiting FDA 232D PROTOCOL ID NUMBERS No longer recruiting FDA 232E PROTOCOL ID NUMBERS No longer recruiting FDA 232G PROTOCOL ID NUMBERS No longer recruiting FDA 232H PROTOCOL ID NUMBERS No longer recruiting FDA 246N PROTOCOL ID NUMBERS No longer recruiting CC 93 N-30 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 039 PHARMACOLOGICAL ACTION MODE OF ACTION: Carrier molecule in the transport of long chain fatty acids across the inner mitochondria, delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. The mean distribution half-life for a 20 mg/kg IV dose was 0.585 h and the mean apparent terminal elimination half-life of total levocarnitine was 17.4 h. Mean body clearance was about 4.0 L/h. [PDR 1997; p 2623] DISEASES STUDIED/TREATED Zidovudine-induced myopathy resulting from carnitine deficiency. [Protocol ID: 93 N-30 ] CLASSIFICATION CODE Carnitine deficiency therapy agent [USP DI 2000; p. 1962] OTHER MAJOR USES Acute and chronic treatment of inborn errors of metabolism that result in carnitine deficiency. [PDR 1997; p 2623] SUBSTANCE INTERACTIONS Levocarnitine can be competitively inhibited by D,L-carnitine; requirements for levocarnitine may be increased in patients receiving valproic acid. [Drug Evaluations Annual 1992; p 2190] ADVERSE EFFECTS Adverse effects include mild gastrointestinal complaints, including transient nausea and vomiting, abdominal cramps, and diarrhea; and drug-related body odor. [PDR 1997; p 2623] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Naturally occurring essential cofactor of fatty acid metabolism. Used as a nutritional supplement for treatment of primary or secondary carnitine deficiencies. [Drug Evaluations Annual 1992; p 2190] CHEMICAL/PHYSICAL DATA Molecular Formula: C7-H15-N-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 161.20 [USPD 1998; p. 416] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, hot alcohol. Practically insoluble in acetone, ether, benzene. [Merck Index 1996; p 303] CHEMICAL/PHYSICAL DATA Stability: Very hygroscopic solid. [Merck Index 1996; p 303] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White powder. [PDR 1997; p 2624] SUBSTANCE DELIVERY DATA DOSAGE FORM: 330 mg tablets; oral solution, 5 ml ampuls (1 g/5 ml) for intravenous injection. [PDR 1997; p 2623-4] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous. [PDR 1997; p 2623-4] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets, injections and oral solutions; store at 25 C (77 F). Protect ampules from light. [PDR 1997; p 2623] MANUFACTURERS 0000005223: Sigma-Tau Pharmaceuticals 800 South Frederick Avenue Gaithersburg, MD 20877 Contact: Unspecified (800)447-0169 MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/97222555. Di Marzio L, Alesse E, Roncaioli P, Muzi P, Moretti S, Marcellini S, Amicosante G, De simone C, Cifone MG. Influence of L-carnitine on CD95 cross-lining-induced apoptosis and ceramide generation in human cell lines: correlation with its effects on purified acidic and neutral sphingomyelinases in vitro. Pro Assoc Am Physicians. 1997 Mar; 109(2): 154-63. MED/97222554. Cifone MG, Alesse E, Di Marzio L, Ruggeri B, Zazzeroni F, Moretti S, Famularo G, Steinberg SM, Vullo E, De Simone C. Effect of L-carnitine treatment in vivo on apoptosis and ceramide generation in peripheral blood lymphocytes from AIDS patients. Proc Assoc Am Physicians. 1997 Mar; 109(2): -53. MED/96347288. Virmani MA, Biselli R, Spadoni A, Rossi S, Corsico N, Calvani M, Fattorossi A, De Simone C, Arrigoni-Martelli E. Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacol Res. 1995 Dec; 32(6): 383-9. MED/96155690. Mintz M. Carnitine in human immunodeficiency virus type 1 infection/acquired immune deficiency syndrome. J Child Neurol. 1995 Nov;10 Suppl 2:S40-4. MED/95298176. Famularo G, De Simone C. A new era for carnitine? Immunol Today. 1995 May;16(5):211-3. MED/96049855. Vitale G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21(4):157-9. MED/94315860. Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. Part I: L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest. 1994 Jul;71(1):102-12. MED/95057042. Semino-Mora MC, Leon-Monzon ME, Dalakas MC. The effect of L-carnitine on the AZT-induced destruction of human myotubes. Part II: Treatment with L-carnitine improves the AZT-induced changes and prevents further destruction. Lab Invest. 1994 Nov;71(5):773-81. MED/94338602. De Simone C, Famularo G, Tzantzoglou S, Trinchieri V, Moretti S, Sorice F. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS. 1994 May;8(5):655-60. MED/94206021. Dalakas MC, Leon-Monzon ME, Bernardini I, Gahl WA, Jay CA. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol. 1994 Apr;35(4):482-7. MED/93195254. De Simone C, Tzantzoglou S, Famularo G, Moretti S, Paoletti F, Vullo V, Delia S. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol. 1993 Jan;15(1):1-12. MED/93113914. Grau JM, Casademont J, Pedrol E, Fernandez-Sola J, Cardellach F, Barros N, Urbano-Marquez A. Chronic fatigue syndrome: studies on skeletal muscle. Clin Neuropathol. 1992 Nov-Dec;11(6):329-32. MED/92215480. De Simone C, Tzantzoglou S, Jirillo E, Marzo A, Vullo V, Martelli EA. L-carnitine deficiency in AIDS patients. AIDS. 1992 Feb;6(2):203-5. ENTRY MONTH 199405 LAST REVISION DATE 20001107 136 UNIQUE IDENTIFIER DRG-0210 NAME OF SUBSTANCE Vesnarinone [USPD 1998; p. 777] REGISTRY NUMBER 81840-15-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Piperazine, 1-(3,4-dimethoxybenzoyl)-4-(1,2,3,4-tetrahydr- o-2-oxo-6-quinolinyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 234A PROTOCOL ID NUMBERS No longer recruiting FDA 234B PROTOCOL ID NUMBERS No longer recruiting FDA 234C PROTOCOL ID NUMBERS No longer recruiting FDA 234D PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits both nucleoside and nucleobase transport in mammalian cells. Inhibits replication of HIV-1 in a peripheral blood lymphocytes model and in chronically infected macrophages at clinically achieved concentrations. Vesnarinone has no direct inhibitory activity against the reverse transcriptase of HIV-1, syncytium formation in short term assays, or retroviral protease. In addition, vesnarinone inhibits production of TNF-alpha and IL-6 by human peripheral blood mononucleated cells stimulated with lipopolysaccharide (LPS). Preliminary results from a phase I clinical trial in asymptomatic HIV+ patients treat with 60 or 90 mg vesnarione daily showed no significant effect on plasma RNA viremia,CD4 or CD8 counts, TNF, IL-6, or beta-2-microglobulin. [Biochem Biophys Res Commun 1993 Sep 30;195(3); p 1264-71; Life Sci 1995 Jun 30;57(6); p 75-81; AmfAR Treat Dir 1997;8(3); p 61] DISEASES STUDIED/TREATED Under investigation in the US as a treatment for HIV and Kaposi's sarcoma. [Protocol ID: 234A ; AmfAR Treat Dir 1997;8(3); p 82] CLASSIFICATION CODE Cardiotonic [USPD 2000 p. 755] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Used in Japan as a treatment for mild to moderate congestive heart failure. [Biochem Biophys Res Commun 1993 Sep 30;195(3); p 1264-71; AmfAR Treat Dir 1997;8(3); p 61] SUBSTANCE INTERACTIONS Possibly interacts with nucleoside analog antiretroviral agents such as AZT, ddI, and ddC. [Protocol ID: 234A ] ADVERSE EFFECTS In patients with heart failure, neutropenia and agranulocytosis have been reported. [AmfAR Treat Dir 1997;8(3); p 61] CONTRAINDICATIONS Contraindicated in pregnant women. [Protocol ID: 234A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthesized quinolinone derivative. An inotropic phosphodiesterase inhibitor. [Circulation 1994 Mar;89(3); p 955-8] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H25-N3-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 395.46 [USPD 1998; p. 777] CHEMICAL/PHYSICAL DATA Melting Point: 238.1-239.5 C [Merck Index 1996; p. 1700] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.82%, H6.37%, N10.63%, O16.18% [Merck Index 1996; p. 1700] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water; slightly soluble in glacial acetic acid, chloroform, benzyl alcohol. [Merck Index 1996; p 1700] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets. [Protocol ID: 234A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 234A ] MANUFACTURERS 0000005360: Otsuka America Pharmaceutical Inc 2440 Research Boulevard Rockville, MD 20850 Contact: Jodi Andrews (415)424-1290 MANUFACTURERS 0000003364: Otsuka America Pharmaceutical Inc 1290 Page Mill Rd / Suite 200 Palo Alto, CA 94304 REFERENCES ICA11/96923453. Kaneko H, Sekigawa I, Takeda N, Neoh LP, Ogasawara H, Yamaguchi K, Hishikawa T, Takasaki Y, Iida N, Hashimoto H, et al. Vesnarinone inhibits TNF-alpha-mediated T cell activation induced by HIV-1 gp120-bound macrophage. Int Conf AIDS. 1996 Jul 7-12;11(2):72 (abstract no. We.A.3091). MED/96203800. Oyaizu N, McCloskey TW, Than S, Pahwa S. Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion. Blood. 1996 Mar 15;87(6):2361-8. AIDS/96920138. Kiat R, Tirawatnapong S, Ubolyam S, Suthapinthu P, Nookhai S, Aihara K, Ohi H, Adachi M, Phanuphak. A Phase I trial of vesnarinone in HIV-infected persons with CD4+ cells counts greater than 200 cells/microliter. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:78. MED/95387276. Zhan X, Yin G, Liu S. Kinetic study on the photostability of solid vesnarinone and the equivalent relationship between daylight and lamplight. J Pharm Sci 1995 May;84(5):624-6. MED/95349329. Kumakura T, Takase K, Terada N, Gelfand EW. Vesnarinone inhibits nucleoside and nucleobase transport. Life Sci. 1995;57(6):PL75-81. ICA10/94370922. Mitsuyasu R, Bort L, Miles SA, Hardy WD, Petit RG. Preliminary results of a phase I study of vesnarinone (OPC-8212) in HIV-infected persons with CD4 > 300 cells/MM3. Int Conf AIDS. 1994 Aug 7-12;10(1):8 (abstract no. 005B). ICA10/94369695. Maruyama Y, Kobayachi N, Maruyama I, Osame M. Vesnarinone; a preliminary therapeutic approach to HIV-1 infection. Int Conf AIDS. 1994 Aug 7-12;10(1):203 (abstract no. PBO241). ICA10/94371029. Maruyama I, Nakajima T, Kitajima I, Osame M, Zhao JQ, Chen IS, Aihara K, Nakai S, Ikeda M, Adachi M. Vesnarionone, a quinolinone derivative, inhibits the replication of HIV-1 in cultured cells. Int Conf AIDS. 1994 Aug7-12;10(2):107 (abstract no. PA0307). ICA10/943689543. Petit RG, Miles S, Magpantay L, Mitsuyasu R. Vesnarinone inhibits AIDS-KS cells in culture. Inf Conf AIDS. 1994 Aug 7-12;10(1):169 (abstract no. PB0104). MED/94029956. Maruyama I, Maruyama Y, Nakajima T, Kitajima I, Osame M, Zhao JQ, Chen IS, Nakai S, Ikeda M, Yabu-uchi Y, et al. Vesnarinone inhibits production of HIV-1 in cultured cells. Biochem Biophys Res Commun. 1993 Sep 30;195(3):1264-71. ENTRY MONTH 199405 LAST REVISION DATE 20001107 137 UNIQUE IDENTIFIER DRG-0209 NAME OF SUBSTANCE Adefovir dipivoxil [USPD 1998; p. 24] STANDARD CHEMICAL NAME 9-[2-(bispivaloyloxymethyl)phosphonylmethoxye- thyl]-adenine [Protocol ID: 232A ] SYNONYMS Preveon [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 310 PROTOCOL ID NUMBERS Complete NIAID ACTG 359 PROTOCOL ID NUMBERS No longer recruiting FDA 075-00 MERCK PROTOCOL ID NUMBERS No longer recruiting FDA 232A PROTOCOL ID NUMBERS No longer recruiting FDA 232B PROTOCOL ID NUMBERS No longer recruiting FDA 232C PROTOCOL ID NUMBERS No longer recruiting FDA 232D PROTOCOL ID NUMBERS No longer recruiting FDA 232E PROTOCOL ID NUMBERS No longer recruiting FDA 232F PROTOCOL ID NUMBERS No longer recruiting FDA 232G PROTOCOL ID NUMBERS No longer recruiting FDA 232H PROTOCOL ID NUMBERS No longer recruiting FDA 232J PROTOCOL ID NUMBERS No longer recruiting FDA 232K PROTOCOL ID NUMBERS No longer recruiting FDA 246N PROTOCOL ID NUMBERS No longer recruiting FDA 299A PROTOCOL ID NUMBERS No longer recruiting NCI 95 C-83 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 039 PHARMACOLOGICAL ACTION MODE OF ACTION: bis-POM PMEA exhibited in vitro antiviral activity against HIV and HCMV that was equipotent with the parent compound, PMEA. Metabolic studies of both compounds suggested a > 100-fold increase in the cellular uptake of the bis-POM derivative and formation of active diphosphorylated metabolite; however, bis-POM derivatives were chemically unstable and highly susceptible to serum-mediated hydrolysis, factors that limit their potential utility for intracellular drug delivery. In human trials, bioavailability of adefovir dipivoxil was 45.10 percent, 39.10 percent, and 36.50 percent with daily oral doses of 125, 250, and 500 mg, respectively, based on renal excretion. A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil was conducted in 36 HIV+ subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Median decreases in serum p24 antigen of 31% and 30% occurred in each drug-treated group, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups, compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at 125 mg daily, the lowest dosage studied. [Antiviral Res 1992 Sep;19(3); p 267-73; Antimicrob Agents Chemother 1993 Oct;37(10); p 2247-50; J Infect Dis 1997 Aug;176(2); p 406-13] DISEASES STUDIED/TREATED In November 1999, Gilead Sciences presented evidence to an FDA Advisory Committee on the safety and efficacy of a 60-mg dose of adefovir dipivoxil for HIV-infected patients. The committee recommended against accelerated approval of adefovir based on available data. The committee suggested the manufacturer re-submit the application with clear evidence for the efficacy of the 60-mg dose. However, in December 1999, Gilead Sciences announced the termination of its U.S. adefovir development program. [Gilead Sciences. Available at: http://www.gilead.com. Accessed: May 15, 2000.; 1999 Dec 3; U.S. Food and Drug Administration. Available at: http://www.fda.gov Accessed May 15; 1999 Nov 1, Antiviral Drugs Advisory Committee Meeting.] CLASSIFICATION CODE Investigational - Acyclic nucleoside phosphonate analog [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Adverse effects in adults have included grade 2 nausea, anorexia, vomiting, diarrhea, transaminase increase, and abdominal discomfort, primarily at daily doses of 250 and 500 mg. [Protocol ID: ACTG 310 ] CONTRAINDICATIONS Contraindicated in pregnant and lactating women. [Protocol ID: 232A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The bis(pivaloyloxymethyl) derivative of the nucleotide analog PMEA; ester prodrug of PMEA acetylated with chloromethyl pivalate. [Antiviral Res 1992 Sep;19(3); p 267-73] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H32-N5-O8-P [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 501.48 [USPD 1998; p. 24] CHEMICAL/PHYSICAL DATA Solubility: Low aqueous solubility. [Pharm Res 1994 Jun;11(6); p 839] SUBSTANCE DELIVERY DATA DOSAGE FORM: Granules. [Protocol ID: 232A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 232A ] MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: James Rooney (415)572-6597 MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: Medical Information (650)574-3000 REFERENCES MED/97379383. Barditch-Crovo P, Toole J, Hendrix CW, Cundy KC, Ebeling D, Jaffe HS, Lietman PS. Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmetho- xyethyl]adenine) in HIV-infected patients. J Infect Dis. 1997 Aug;176(2):406-13. AIDS/97290233. Hepatitis B and adefovir depivoxil. AIDS Patient Care STDS. 1997 Apr;11(2):103. AIDS/97926548. Cherrington JM, Fuller MF, Lalezari JP, Miner R, Chen MS, Drew WL. In vitro antiviral susceptibilities of isolates from CMV retinitis patients receiving first or second line cidofovir therapy: relationship to clinical outcome. 4th Conf Retro and Opportun Infect.1997 Jan 22-26;:120 (abstract no. 304). AIDS/97926544. Cherrington JM, Mulato AS, Lamy PL, Hellmann NS, Chen MS. Genotypic characterization of HIV-1 variants isolated from AIDS patients treated with adefovir dipivoxil (bis-POM PMEA). 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:104 (abstract no. 216). AIDS/97702375. James JS. GS 840 (adefovir dipivoxil): broad-spectrum antiviral trial, CD4 count under 100. AIDS Treat News. 1997 Feb 7;(No 264):4-5. AIDS/96920632. McKinney RE Jr. Ongoing and future trials of antiretroviral therapy in the pediatric AIDS clinical trials group (PACTG). 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:173. MED/96139529. Cundy KC, Barditch-Crovo P, Walker RE, Collier AC, Ebeling D, Toole J, Jaffe HS. Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother. 1995 Nov;39(11):2401-5. MED/95174749. Robbins BL, Connelly MC, Marshall DR, Srinivas RV, Fridland A. A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent. Mol Pharmacol. 1995 Feb;47(2)391-7. AIDS/95920519. Barditch-Crovo PA, Cundy KC, Wachsman M, Toole J, Burgee H, Ebeling D. Pharmacokinetic profile of 9-[2-(bispivaloyloxy-methyl) phosphonylmethoxy]adenine (bis-POM PMEA), an orally bioavailable prodrug of the antiviral nucleotide, PMEA. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:145. MED/94293304. Starrett JE Jr, Tortolani DR, Russell J, Hitchcock MJ, Whiterock V, Martin JC, Mansuri MM. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). J Med Chem. 1994 Jun 10;37(12):1857-64. ENTRY MONTH 199405 LAST REVISION DATE 20000801 138 UNIQUE IDENTIFIER DRG-0208 NAME OF SUBSTANCE Emtricitabine [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 143491-57-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2(1H)-Pyrimidinone, 4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxa- thiolan-5-yl)-, (2R-cis)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Coviracil [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 233A PROTOCOL ID NUMBERS No longer recruiting FDA 298A PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG P1021 PROTOCOL ID NUMBERS Recruiting FDA 298C PROTOCOL ID NUMBERS Recruiting FDA 298D PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5015 PROTOCOL ID NUMBERS Suspended FDA 298B PHARMACOLOGICAL ACTION MODE OF ACTION: Emtricitabine is nucleoside reverse transcriptase inhibitor with a chemical structure similar to 3TC but with an in vitro potency 4-10 times greater than 3TC. In one trial emtricitabine was rapidly and well absorbed. Plasma emtricitabine levels reach levels well above the in vitro IC90 over the entire dosing interval. Preliminary estimates show a mean half-life of approx. 7 hours. At a daily dose of 200 mg or more, HIV-1 RNA load suppression ranged from 1.72 - 1.92 log10. Plasma and intracellular kinetics as well as viral suppression supports once-daily dosing. Emtricitabine is excreted primarily through the kidneys. While food intake slightly decreased the rate of absorption, it did not affect overall oral bioavailability. Sequencing analysis of amplified RT from several patients who had received 3TC therapy demostrated that virus obtained from these patients was highly resistant to emtricitabine and 3TC. [Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 53 (abstract no. 12208); BETA 1998 Jul:38; Natl Conf Hum Retrv Rela Inf (1st) 1993 Dec 12-16; p 136] DISEASES STUDIED/TREATED Antiviral nucleoside analog drug currently in development. Structurally, emtricitabine is similar to 3TC (lamivudine), but in vitro, it appears to be much more potent against HIV than 3TC. Now in phase II/III clinical trials in HIV-infected patients. [BETA 1998 Jul:38; Triangle Pharmaceuticals 1999 Jan 26] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Active against hepatitis B Virus [Antimicrob Agents Chemother 1992;36; p 2686-92] SUBSTANCE INTERACTIONS Laboratory studies showed that combinations of AZT with emtricitabine, 3TC, ddC, and ddI produced synergistic interactions. Synergistic interactions were also found with AZT and emtricitabine or ddC in cells bearing AZT-resistant HIV. [Natl Conf Hum Retrv Rela Inf (1st) 1993 Dec 12-16; p 136] ADVERSE EFFECTS Emtricitabine was well tolerated with no serious or severe adverse events attributed to the drug. In one study, nausea occurred in a few cases and there were reports of headaches. Adverse events did not seem to be dose related. [Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 53 (abstract no. 12208)] CONTRAINDICATIONS Contraindicated in pregnant or nursing women. [Protocol ID: 233A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Nucleoside reverse transcriptase inhibitor. [Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 53 (abstract no. 12208)] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H10-F-N3-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 247.25 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200 mg once a day. [Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 53 (abstract no. 12208)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Int Conf AIDS 1998 12:347-8 (abstract no. 22417); p 53 (abstract no. 12208)] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004441: Triangle Pharmaceuticals Inc 4 Univ Place / 4611 Univ Dr Durham, NC 27707 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004441: Triangle Pharmaceuticals Inc 4 Univ Place / 4611 Univ Dr Durham, NC 27707 Contact: Jaime Hernandez (919)483-6300 REFERENCES AIDS/99703970. Hanna L. FTC: Antiretroviral in development. BETA. 1998 Jul:38. AIDS/98930144. Hill E. Taylor N, Borroto-Esoda K, Furman P, Moxham C, Painter G. In vitro synergy studies with MKC-442 a non-nucleoside HIV-1 reverse transcriptase inhibitor. Antiviral Res. 1998 Mar;37(3):A54 (abstract no. 49). AIDS/98703779. Cadman J. Looking down the drug pipeline. GMHC Treat Issues. 1998 Mar;12(3):5-9. AIDS/98929699. Pottage J, Thompson M, Kahn J, Delehanty J, McCreedy B, Rousseau F. Potent antiretroviral efficacy of low dose FTC, initial results from a phase I/II clinical trial. 5th Conf Retrovir Oppor Infect. 1998 Feb 1-5:224 (abstract no. LB9). ICA12/98386983. Delehanty J, Kahn J, Thompson M, Mildvan D, Pottage J, Shepp D, van der Horst C. Selection of FTC dose based on viral kinetics and pharmacokinetics in an accelerated clinical trial design. Int Conf AIDS. 1998;12:53 (abstract no. 12208). MED/99092537. Ladner SK, Miller TJ, Otto MJ, King RW. The hepatitis B virus M539V polymerase variation responsible for 3TC resistance also confers cross-resistance to other nucleoside analogues. Antivir Chem Chemother. 1998 Jan;9(1):65-72. MED/97472158. Cullen JM, Smith SL, Davis MG, Dunn SE, Botteron C, Cecchi A, Linsey D, Linzey D, Frick L, Paff MT, et al. In vivo antiviral activity and pharmacokinetics of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxa- thiolan-5-yl]cytosine in woodchuck hepatitis virus-infected woodchucks. Antimicrob Agents Chemother. 1997 Oct;41(10):2076-82. AIDS/98928024. Schinazi RF. New approaches to hepatitis B virus therapy. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18:321 (abstract no. S115). MED/96431833. Condreay LD, Condreay JP, Jansen RW, Paff MT, Averett DR. (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxa- thiolan-5-yl]cytosine (524W91) inhibits hepatitis B virus replication in primary human hepatocytes. Antimicrob Agents Chemother. 1996 Feb;40(2):520-3. MED/95209293. Frick LW, Lambe CU, St John L, Taylor LC, Nelson DJ. Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-- 1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus. Antimicrob Agents Chemother. 1994 Dec;38(12):2722-9. ENTRY MONTH 199405 LAST REVISION DATE 20001106 139 UNIQUE IDENTIFIER DRG-0207 NAME OF SUBSTANCE Ifosfamide [USPD 1998; p. 370] REGISTRY NUMBER 3778-73-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis(2-chloroethyl)tetrahydro-, 2-oxide [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Ifex [USP DI 2000; p. 1753] PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-207 PHARMACOLOGICAL ACTION MODE OF ACTION: Ifosfamide, like cyclophosphamide, requires transformation in the liver by mixed-function oxidases (cytochrome P-450 system) before it can exert its cytotoxic effect. After conversion to active metabolites, ifosfamide functions as an alkylating agent, interfering with DNA replication and transcription of RNA, and ultimately resulting in disruption of nucleic acid functions. Ifosfamide is cycle-phase nonspecific. Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8-5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6-2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours. Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6-2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present. Small quantities (nmole/ml) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide have been shown to interact with DNA. [PDR 1997; p 706; AHFS Drug Information 1997; p 770-5] DISEASES STUDIED/TREATED Treatment of AIDS-related non-Hodgkin's lymphoma. [Protocol ID: 93 C-207 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1749] OTHER MAJOR USES Germ cell testicular cancer. [PDR 1997; p 706] SUBSTANCE INTERACTIONS Precautions should be observed if coadministered with bone marrow depressants, live virus vaccines, radiation therapy or drugs affecting microsomal enzymes. [USP DI 1997; p 1623] ADVERSE EFFECTS In patients receiving ifosfamide as a single agent, the dose-limiting toxicities are myeleosuppression and urotoxicity. Alopecia occurred in many of the patients treated. Nausea and vomiting also were common occurrences in patients receiving ifosfamide (Ifex). Hematuria occurred in 6% to 92% of patients treated with Ifex. CNS side effects most commonly seen were somnolence, confusion, depressive psychosis, and hallucinations. Other adverse reactions observed in less than 1% of patients include stomatitis, salivation, pulmonary symptoms, polyneuropathy, malaise, hypotension, hypertension, fatigue, diarrhea, dermatitis, constipation, coagulopathy, cardiotoxicity, anorexia, allergic reaction, fever, phlebitis, and liver dysfunction and infections. [PDR 1997; p 706-7] CONTRAINDICATIONS Continued use of ifosfamide is contraindicated in patients with severely depressed bone marrow function and in patients who have demonstrated a previous hypersensitivity to it. [PDR 1997; p 706] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: 'lkylating agent that is chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide. [PDR 1997; p 706] CHEMICAL/PHYSICAL DATA Molecular Formula: C7-H15-Cl2-N2-O2-P [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 261.09 [USPD 1998; p. 370] CHEMICAL/PHYSICAL DATA Melting Point: 39-41 C [Merck Index 1996; p. 842] CHEMICAL/PHYSICAL DATA Elemental Comp: C32.20%, H5.79%, Cl27.16%, N10.73%, O12.26%, P11.86% [Merck Index 1996; p. 841] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water. [PDR 1997; p 706] CHEMICAL/PHYSICAL DATA Stability: Constituted or constituted and further diluted solutions of IFEX (Ifosfamide for intravenous use) should be refrigerated and used within 24 hours. [PDR 1997; p 707] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: A white crystalline powder. [PDR 1997; p 706] SUBSTANCE DELIVERY DATA DOSAGE FORM: 1 and 3 g single dose vials; available in combination packages with the uroprotective agent mesna. [PDR 1997; p 707] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [PDR 1997; p 706-7] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The dry powder may be stored at room temperature, preferably between 15-30 C. Storage above 40 C should be avoided. [PDR 1995; p 667; USP DI 1997; p 1625-6] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/97418078. Joqueviel C, Gilard V, Martino R, Malet-Martino M, Niemeyer U. Urinary stability of carboxycyclophosphamide and carboxyifosfamide, two major metabolites of the anticancer drugs cyclophosphamide and ifosfamide. Cancer Chemother Pharmacol 1997;40(5):391-9. MED/97418075. Goren MP, McKenna LM, Goodman TL. Combined intravenous and oral mesna in outpatients treated with ifosfamide. Cancer Chemother Pharmacol 1997;40(5):371-5. MED/97341808. Rossi R. Nephrotoxicity of ifosfamide--moving towards understanding the molecular mechanisms [editorial]. Nephrol Dial Transplant 1997 Jun;12(6):1091-2. MED/96087018. Dincol D, Icli F, Karaoguz H, Cay F, Arican A, Demirkazik A, Akbulut H. Mesna/ifosfamide, mitoxantrone, etoposide, bleomycin, vincristine, prednisone (MINE-BOP) combination chemotherapy in the treatment of refractory and relapsed non-Hodgkin's lymphoma. Acta Oncol 1995;34(7):937-40. MED/95222325. De Lena M, Ditonno P, Lorusso V, Brandi M, Timurian A, Marzullo F, Ventrella V, Pellecchia A. CEOP-B alternated with VIMB in intermediate-grade and high-grade non-Hodgkin's lymphoma: a pilot study. J Clin Oncol 1995 Apr;13(4):953-60. ICA9/93335239. Hentrich M, Brack N, Sander R, Lutz L, Jager H, Hartenstein R. Testicular germ cell tumors (GCT) and HIV infection: 2 case reports. Int Conf AIDS. 1993 Jun 6-11;9(1):412 (abstract no. PO-B15-1660). MED/93089742. Quezado ZM, Wilson WH, Cunnion RE, Parker MM, Reda D, Bryant G, Ognibene FP. High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med. 1993 Jan 1;118(1):31-6. ICDB/94695626. Gisselbrecht C, Lepage E, Tirelli U, Oksenhendler E, Gabarre J, Farcet JP, Gastaldi R, Coiffier B, Thyss A, Rapahel M, et al. Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol; 12:A1227 1993. TOXBIB/93/030841. Cabanillas F. Non-Hodgkin's lymphomas: a review of the M.D. Anderson experience. Semin Oncol. 1992 Feb;19(1 Suppl 1):11-3. TOXBIB/93/134390. Goss PE. New perspectives in the treatment of non-Hodgkin's lymphoma. Semin Oncol. 1992 Dec;19(6 Suppl 12):23-9. ICA7/3237091. Northfelt DW, Kahn JO, Volberding PA, Kaplan LD. Ifosfamide/etoposide for AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Int Conf AIDS. 1991 Jun 16-21;7(2):274 (abstract no. W.B.2370). ICDB/93689059. Cabanillas F. Malignant lymphomas. Hematology; 14:299-334 1991. ENTRY MONTH 199404 LAST REVISION DATE 20001107 140 UNIQUE IDENTIFIER DRG-0206 NAME OF SUBSTANCE TBC-3B Vaccine [Protocol ID: AVEG 014 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 014A/B PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 014C PHARMACOLOGICAL ACTION MODE OF ACTION: Insertion of the HIV-1 (strain IIIB) env, gag, and pol genes, each under the transcriptional direction of a vaccinia promoter element, into the genome of this parental virus resulted in the generation of a multivalent recombinant virus that efficiently expresses fully processed, authentically configured HIV-1 polypeptides encoded by those genes. In animal studies, this vaccine presented multiple conserved and variable HIV-1 epitopes to the immune system, and elicits both humoral and cell mediated immune responses to the expressed polypeptides. [Protocol ID: AVEG 014 ] DISEASES STUDIED/TREATED Prevention of HIV infection. [Protocol ID: AVEG 014 ] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 014 ] ADVERSE EFFECTS Adverse effects include possible tenderness, redness, and swelling at site of vaccination. [Protocol ID: AVEG 014 ] CONTRAINDICATIONS Contraindicated in pregnant and lactating women. [Protocol ID: AVEG 014 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Live recombinant vaccinia virus that expresses the env, gag, and pol genes of HIV-1 (IIIB strain). [Protocol ID: AVEG 014 ] CHEMICAL/PHYSICAL DATA Stability: Stable for 12 months at -75 to -85 C. [Protocol ID: AVEG 014 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 3 billion PFU/ml. [Protocol ID: AVEG 014 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Scarification by bifurcated needle. [Protocol ID: AVEG 014 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Freeze at -75 to -85 C. Can remain thawed at 4 C for 4 days. [Protocol ID: AVEG 014 ] MANUFACTURERS 0000002947: Therion Biologics Corp 76 Rogers St Cambridge, MA 02142 Contact: Dr Dennis Panicali (617)876-7779 REFERENCES AIDS/97927089. Richmond JF, Mustafa F, Lu S, Fenyo EM, Hurwitz JL, Montefiori DC, Robinson HL. Screening of HIV-1 env glycoproteins for the ability to raise neutralizing antibody using DNA immunization and recombinant vaccinia virus boosting. Conf Adv AIDS Vaccine Dev. 1997 May 4-7;:125 (Poster 20). MED/97288304. Richmond JF, Mustafa F, Lu S, Santoro JC, Weng J, O'Connell M, Fenyo EM, Hurwitz JL, Montefiori DC, Robinson HL. Screening of HIV-1 Env glycoproteins for the ability to raise neutralizing antibody using DNA immunization and recombinant vaccinia virus boosting. Virology. 1997 Apr 14;230(2):265-74. MED/97227578. Rencher SD, Lockey TD, Srinivas RV, Owens RJ, Hurwitz JL. Eliciting HIV-1 envelope-specific antibodies with mixed vaccinia virus recombinants. Vaccine. 1997 Feb;15(3):265-72. MED/96071441. Abimiku AG, Franchini G, Tartaglia J, Aldrich K, Myagkikh M, Markham PD, Chong P, Klein M, Kieny MP, Paoletti E, et al. HIV-1 recombinant poxvirus vaccine induces cross-protection against HIV-2 challenge in rhesus macaques [see comments]. Nat Med. 1995 Apr;1(4):321-9. MED/95376334. Perales MA, Schwartz DH, Fabry JA, Lieberman J. A vaccinia-gp160-based vaccine but not a gp160 protein vaccine elicits anti-gp160 cytotoxic T lymphocytes in some HIV-1 seronegative vaccines. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Sep 1;10(1):27-35. MED/95016023. Graham BS, Gorse GJ, Schwartz DH, Keefer MC, McElrath MJ, Matthews TJ, Wright PF, Belshe RB, Clements ML, Dolin R, et al. Determinants of antibody response after recombinant gp160 boosting in vaccinia-naive volunteers primed with gp160-recombinant vaccinia virus. The National Institute of Allergy and Infectious Disease AIDS Vaccine Clinical Trials Network. J Infect Dis. 1994 Oct;170(4):782-6. ICA8/92400000. Hesselton RM, Mazzara GP, Panicali D, Sullivan JL. HIV-specific immune responses in rabbits immunized with HIV-like particles and recombinant vaccinia virus. Int Conf AIDS. 1992 Jul 19-25;8(1):Mo13 (abstract no. MoA 0045). ENTRY MONTH 199404 LAST REVISION DATE 20000801 141 UNIQUE IDENTIFIER DRG-0205 NAME OF SUBSTANCE HIV-1 Peptide Immunogen, Multivalent [Protocol ID: AVEG 017 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 017 PROTOCOL ID NUMBERS Complete NIAID AVEG 023 PHARMACOLOGICAL ACTION MODE OF ACTION: The antigenic principal neutralizing determinant (PND) peptides are the major immunogenic portion of this multiple antigen peptide. Evaluation of the safety and immunogenicity of a formulation of HIV-1 gp120 principal neutralizing domain branched synthetic peptides (in alum) from 15 different viral strains representing diverse worldwide isolates given to healthy, seronegative adult volunteers showed that almost all vaccine recipients developed active lymphocyte proliferation was seen in the placebo group. After three vaccinations, gamma interferon could be detected in 4 day supernatants from one of five vaccinees, but no antigen-specific interleukin 4 (IL4) was seen. Il4 production to phytohemagglutinin (PHA) was occasionally detectable at this time. No antigen-specific cytokine production was seen at baseline in subjects. LPA responses did not predict the cytokine pattern seen. By utilizing restimulation protocols to allow for memory cells which secrete IL4 to develop. TH1/TH2 (acquired immune) responses can be seen following vaccination which may be missed using shorter in vitro culture techniques. Another series of studies showed that for including HIV-1 specific immunity, immunization with DNA vaccine followed by VCI (macromolecular multicomponet peptide vaccine) boosting produces better results than immunizing with either vaccine alone. [Protocol ID: AVEG 017 ; Conf Retroviruses Opportunistic Infect 3rd Conf 1996; p 141; Vaccine 1997 Jul;15(10); p 1049-56] DISEASES STUDIED/TREATED Prevention of HIV infection. [Protocol ID: AVEG 017 ] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 017 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Mixture of HIV-1 gp120 principal neutralizing domain (PND) branched synthetic peptides from 15 viral strains formulated in alum. Each strain component of the vaccine consists of eight homologous PND-derived peptides attached to a lysine core to form radial-octamers. [Protocol ID: AVEG 017 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.5 ml vials. [Protocol ID: AVEG 017 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular. [Protocol ID: AVEG 017 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store vials at 2-8 C. Storage above or below the recommended temperature may reduce potency. Do not freeze since freezing may destroy potency. [Protocol ID: AVEG 017 ] MANUFACTURERS 0000002563: United Biomedical Inc 25 Davids Drive Happauge, NY 11788 Contact: Dr Bruce Forrest (516)273-2828 REFERENCES MED/97414189. Okuda K, Xin KO, Tsuji T, Bukawa H, Tanaka S, Koff WC, Okunda K, Honma K, Kawamoto S. et al. DNA vaccination followed by macromolecular multicomponet peptide vaccination against HIV-1 induces strong antigen-specific immunity. Vaccine. 1997 July;15(10):1049-56. AIDS/97926165. Evans TG, Keefer MC, Wolff M, Weinhold K, Excler Jl, Duliege AM, McNamara J, McElrath JM, Graham BJ, Clements ML. et al. Immunization of HIV-1 non-infected volunteers with a canarypox recombinant containing HIV-1 env, gag, pol, and nef genes (vCP 300) given simultaneously or followed by recombinant HIV-1 SF2 gp120. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:204 (abstract no. 754). AIDS/96920471. Evans TG, Fitzgerald T, Demeter L, Keefer M, Koff W. Cytokine response to vaccination of HIV seronegative volunteers with a multivalent HIV-1 peptide immunogen. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:141. MED/94338751. Okuda K, Kaneko T, Shigematsu T, Yamakawa T, Tanaka S, Yamamoto A, Hamajima K, Nakajima K, Kawamoto S, Phanuphak P. Strong immunogenicity of a multicomponent peptide vaccine develope with the branched lysine oligopeptide method for human immunodeficiency virus infection. J Mol Recognit, 1993 Sep;6(3):101-9. ENTRY MONTH 199403 LAST REVISION DATE 20000801 142 UNIQUE IDENTIFIER DRG-0204 NAME OF SUBSTANCE WF10 [Protocol ID: 222A ] PROTOCOL ID NUMBERS No longer recruiting FDA 222A PROTOCOL ID NUMBERS No longer recruiting FDA 222B PROTOCOL ID NUMBERS No longer recruiting FDA 222C PHARMACOLOGICAL ACTION MODE OF ACTION: WF10 modifies the function of the monocyte/macrophage system by stimulating phagocytosis in macrophages and oxidative burst in monocytes. WF10 appears to concurrently enhance macrophage phagocytosis and reduce inappropriate immunologic activation. Although WF10 does not directly inhibit replication of HIV, the infectivity of cell-free HIV particles is decreased by WF10 in a concentration- and time-dependent manner. In one early clinical study, administration of WF10 in four treatment cycles over a 3-month period was associated with a decrease in opportunistic infections and hospitalizations and an increase in survival relative to the control group. [Int Conf AIDS 1998 12:347-8 (abstract no. 22417); AIDS 1993 7:1205-1212; Infection 1998 July/August;26(4):201-206] DISEASES STUDIED/TREATED WF10 is thought to enhance immune function in late stage HIV infection. It is intravenously administered and targets macrophage function. Even HAART (highly active antiretroviral therapy) does not appear effective against the latent HIV surviving in macrophages, a known reservoir of the virus in AIDS patients. [PR Newswire 1993 Jan 7; Infection 1998 July/August;26(4):201-206] CLASSIFICATION CODE Macrophage regulator [Protocol ID: 222A ] OTHER MAJOR USES Promotion of wound healing, including ulcer wounds. [Lancet 1986 Apr 12; Vol 1; p 825-28; Martindale: The Extra Pharmacopoeia 1993; p 1746] ADVERSE EFFECTS The most frequent adverse events considered related to WF10 are asthenia (weakness), injection site reaction, and injection site pain. The local reaction can be minimized by administration over a period of at least 90 minutes. Diarrhea, dizziness, headache, leukocytosis, anemia, nausea, photophobia, and taste perversion have been reported as possibly or probably related to WF10. [OXO Chemie Inc ] CONTRAINDICATIONS Contraindicated in individuals with known hypersensitivity to WF10 or any of its components. [OXO Chemie Inc ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: WF10, an aqueous solution of chemically stabilized chlorite matrix. [OXO Chemie Inc ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Colorless, odorless or nearly odorless liquid. [OXO Chemie Inc ] SUBSTANCE DELIVERY DATA DOSAGE FORM: WF10 is provided in 20-mL glass vials as a sterile, colorless, limpid, odorless, isotonic aqueous solution. [OXO Chemie Inc ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 222A ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store protected from light at normal room temperature (15-30 C). [OXO Chemie Inc ] MANUFACTURERS 0000004897: OXO Chemie 601 Gateway Blvd South San Francisco, CA 94080 Contact: Cecile Gauffrant (650)246-2200 REFERENCES MED/99082867. McGrath, M.S., Benike, C., Kuehne, F.-W. and Engleman, E. Effect of WF10 (TCDO) on antigen presentation. Transplant. Proc. 30, 4200-4204 (1998). AIDS/99704217. (CATIE). An American study of WF10 looks promising. CATIE TreatmentUpdate 91, 1998 September - Volume 10 Issue 7. MED/98383421. Raffanti SP, Schaffner W, Federspiel CF, Blackwell RB, Ching OA, Kuhne FW. Randomized, double-blind, placebo-controlled trial of the immune modulator WF10 in patients with advanced AIDS. Infection. 1998 Jul- Aug;26(4):202-7. (PRn) Dimethaid Announces World AIDS Conference Accepts Two WF10 Abstracts PR Newswire; Wednesday May 13, 1998. AIDS/98930335. Engleman E, Benike C, Kuehne F, McGrath M. WF10 (TCDO) inhibition of antigen presentation and its potential role in modulating HIV disease. Pathog Treat Conf. 1998 Mar 13-19;:58 (abstract no. 2046). (BW) (DIMETHAID-RESEARCH) (DMX.) Dimethaid Announces Presentation of New Results Validating WF10. BUSINESS WIRE; Thursday, March 12, 1998, 6:25 am PST. ICA12/98392560. Kahn JO, McGrath MS, Ching OM, Kuhne FW. A single center, phase 2 study evaluating the effects of WF10. Int Conf AIDS. 1998;12:349 (abstract no. 22423). ICA12/98392554. Herndier B, Lull R, Ah Ching O, Brosz M, Kuhne FW, Kahn J. Immunological parameters modified in HIV disease by the macrophage activity immunomodulator WF10 (a phase II pathogenesis study). Int Conf AIDS. 1998;12:347-348 (abstract no. 22417). ICA10/94369698. Busch HW, Christensen S, Reichelt D, Jahn S, Zidek W. Treatment of HIV-infected patients with advanced symptomatic disease with WF10 solution (TCDO). Int Conf AIDS. 1994 Aug 7-12;10(1):204 (abstract no. PB0245). MED/98361186. Perno CF, Newcomb FM, Davis DA, et al. Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with Human Immunodeficiency Virus. Journal of Infectious Diseases 1998;178:413-422. ENTRY MONTH 199403 LAST REVISION DATE 20010108 143 UNIQUE IDENTIFIER DRG-0203 NAME OF SUBSTANCE Diethylhomospermine [AmfAR Treat Dir 1995;7(4); p 64] REGISTRY NUMBER 119422-08-1 STANDARD CHEMICAL NAME 1,4-Butanediamine, N,N'-bis(4-(ethylamino)butyl)- [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting FDA 223A PHARMACOLOGICAL ACTION MODE OF ACTION: In a previous experiment to determine the antiproliferative effects of diethylhomospermine in human transitional cell carcinoma lines, the drug suppressed the activity of the biosynthetic enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase. The substantial antiproliferative activity of this polyamine analog was believed to result from mechanisms other than polyamine depletion. However, other experiments using HeLa cells demonstrated that diethylhomospermine depleted polyamines. [J Urol 1993;150; p 1293-7; Biochemistry 1993;32; p 4073-6] DISEASES STUDIED/TREATED Under investigation for refractory AIDS-related diarrhea. [AmfAR Treat Dir 1997;8(3); p 136] CLASSIFICATION CODE Antidiarrheal [AmfAR Treat Dir 1995;7(4); p 64] OTHER MAJOR USES Inhibited growth of tumor cells in culture. [Biochemistry 1993;32; p 4073-6] ADVERSE EFFECTS Constipation. [AmfAR Treat Dir 1995;7(4); p 64] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic polyamine analog. [AmfAR Treat Dir 1995;7(4); p 64] CHEMICAL/PHYSICAL DATA Molecular Formula: C16H38N4 [CHEMLINE ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 223A ] MANUFACTURERS 0000002926: Gainesville Veterans Administration Med Ctr Gastroenterology Section 111-C Gainesville, FL 32608 Contact: Dr Charles A Sninsky (904)374-6055 REFERENCES MED/95361048. Bergeron CJ, Basu HS, Marton LJ, Deen DF, Pellarin M, Feuerstein BG. Two polyamine analogs(BE-4-4-4 and BE-4-4-4-4) directly affect growth, survival, and cell cycle progression in two human brain tumor cell lines. Cancer Chemother Pharmacol 1995;36(5)411-7. MED/95152339. Fernandez CO, Frydman B, Samejima K. Interactions between polyamine analogs with antiproliferative effects and tRNA: a 15N NMR analysis. Cell Mol Biol (Noisy-le-grand) 1994 Nov;40(7):933-44. MED/97133458. Bergeron RJ, Weimar WR, Wu Q, Feng Y, McManis JS, Polyamine analogue regulation of NMDA MK-801 binding: a structure-activity study. J Med Chem 1996 Dec 20;39(26):5257-66. MED/96265145. Bergeron RJ, Yao GW, Yao H, Weimar WR, Sninsky CA, Raisler B, Feng Y, Wu Q, Gao F. Metabolically programmed polyamine analogue antidiarrheals. J Med Chem 1996 Jun 21;39(13):2461-71. MED/96417634. Bergeron RJ, Weimar WR, Luchetta G, Sninsky CA, Wiegand J, Metabolism and pharmacokinetics of N1,N14-diethylhomospermine. Drug Metab Dispos 1996 Mar;24(3):334-43. MED/96120801. Bergeron RJ, Wiegand J, Sninsky CA, Katovich MJ. The impact of polyamine analogues on the blood pressure of normotensive and hypertensive rats. Clin Exp Hypertens 1995 Nov;17(8):1197-217. ENTRY MONTH 199403 LAST REVISION DATE 20000801 144 UNIQUE IDENTIFIER DRG-0202 NAME OF SUBSTANCE Celgosivir hydrochloride [USPD 1998; p. 147] REGISTRY NUMBER 141117-12-6 [USPD 1998] STANDARD CHEMICAL NAME Butanoic acid, octahydro-1,7,8-trihydroxy-6-indolizinyl ester, (1S-(1alpha,6beta,7alpha,8beta,8abeta))- [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting FDA 221A PROTOCOL ID NUMBERS No longer recruiting FDA 221B PROTOCOL ID NUMBERS No longer recruiting FDA 221C PHARMACOLOGICAL ACTION MODE OF ACTION: Demonstrates inhibitory effect on glucosidases and has antiviral activity against HIV-1 and against Moloney murine leukemia virus (MOLV). In previous studies, MDL 28574 had an IC50 of 0.3 mcg/ml against HIV-induced syncytial formation in HeLa T4+ cells and an IC50 of 0.15 mcg/ml against productive infection in JM cells infected with HIV-1. In both cases, MDL 28574 was more potent than castanospermine. The IC50 was 0.05 mcg/ml against MOLV. MDL 28574 also showed equivalent activity to AZT and was more potent than castanospermine in inhibiting FLV-induced splenomegaly in mice. MDL 28574 was tested alone or in combination with AZT orally in groups of AIDS patients with CD4+ counts between 100 and 500 cells/microliter. Preliminary efficacy measures showed good results for about one third of the patients, stable results for a third, and rather poor results for another third of the patients. [Ann N Y Acad Sci 1990;616; p 90-6; Biochem Biophys Res Commun 1995 Mar 8;208(1); p 267-73; Int Conf AIDS 1996 Jul 7-12;11(1):18; p 75 (abstract no Mo.B.1121)] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: 221A ] CLASSIFICATION CODE Investigational - Glycosylation inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Bloody diarrhea and flatulence are the primary dose-limiting toxicities reported in one phase I and two phase II studies. [AmfAR Treat Dir 1997;8(3); p 50] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Analogue of the glucosidase I inhibitor, castanospermine. [Ann N Y Acad Sci 1990;616; p 90-6] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H21-N-O5.H-Cl [USPD 1998; p. 147] CHEMICAL/PHYSICAL DATA Molecular Weight: 295.76 [USPD 1998; p. 147] SUBSTANCE DELIVERY DATA DOSAGE FORM: Solution. [Protocol ID: 221A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 221A ] MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 REFERENCES ICA11/96921187. Arasteh K, Czerwinska R, Scholote F, Fatkenheuer G, Jessen H, Moll A, Gehring P, Ulmer A, Hamedani P, McPherson M. A randomized, double-blind, dose-ranging phase II European study of the safety and efficacy of chornically administered butanoyl-castanospermine (MDL 28,574A) HIV-infected patients. Int Conf AIDS. 1996 Jul 7-12;11(1):75 (abstract no. Mo.B.1121). ICA11/96922324. Roth H, McPherson M, Hamedani P, Herrmann WM, Sidarous E, Frampton M, Maddern J, Dieterich A. Phase I tolerance and pharmockinetics of a new castanospermine derivative, MDL 28,574A. Int Conf AIDS. 1996 Jul 7-12;11(1):284. (abstract no. Tu.B.2117). ICA11/96921393. Stoltz ML, McPherson M, Frampton M, Sidarous E, Jacobs M, Roth H. Pharmacokinetics of castanospermine in asymptomatic HIV-positive patients treated with MDL 28,574A during phase I trials. Int Conf AIDS. 1996 Jul 7-12;11(1):112 (abstract no. Mo.B.1329). ICA11/96921211. Richmond GJ, Zolnouni P, Stall J, McPherson M, Hamedani P, Cross V, Sidarous E, Stoltz M. Efficacy and safety of MDL 28,574A in HIV-positive patients with baseline CD4 values of 301-500. Int Conf AIDS. 1996 Jul 7-12;11(1):80 (abstract no. Mo.B.1145). ICA11/96921204. Zolnouni P, Berger DS, Perez G, Hamedani P, Frampton M, Gibson C, Sidarous E, Stoltz M. Efficacy and safety of MDL 28,574A in HIV-positive patients with baseline CD4 values of 100-300. Int Conf AIDS. 1996 Jul 7-12;11(1):78 (abstract no. Mo.B.1138). MED/96285861. Kang MS. Uptake and metabolism of BuCast: a glycoprotein processing inhibitor and potential anti-HIV drug. Glycobiology. 1996 Mar;6(2):209-16. MED/95328860. Brennan TM, Taylor DL, Bridges CG, Leyda JP, Tyms AS. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in combination with other anti-HIV compounds. Antiviral Res. 1995 Mar;26(2):173-87. MED/95299228. Bridges CG, Taylor DL, Kang MS, Brennan TM, Tyms AS. Treatment with the alpha-glucosidase 1 inhibitor 6-O-butanoyl castanospermine reduces the detection of LFA-1 (CD18/CD11a) by monoclonal antibodies. Glycobiology. 1995 Mar;5(2):243-7. MED/95299229. Bridges CG, Ahmed SP, Kang MS, Nash RJ, Porter EA, Tyms AS. The effect of oral treatment with 6-0-butanoyl castanospermine (MDL 28,574) in the murine zosteriform model of HSV-1 infection. Glycobiology 1995 Mar;5(2):249-53. MED/95194418. Ahmed SP, Nash RJ, Bridges CG, Taylor DL, Kang MS, Porter EA, Tyms AS. Antiviral activity and metabolism of the castanospermine derivative MDL 28,574, in cells infected with herpes simplex virus type 2. Biochem Biophys Res Commun 1995 Mar 8;208(1):267-73. ENTRY MONTH 199403 LAST REVISION DATE 20000801 145 UNIQUE IDENTIFIER DRG-0201 NAME OF SUBSTANCE Streptomycin sulfate [USPD 1998; p. 686] REGISTRY NUMBER 3810-74-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME D-Streptamine, O-2-deoxy-2-(methylamino)-alpha-L-glucopyrano- syl-(1->2)-O-5-deoxy-3- C-formyl-alpha-L-lyxofuranosyl-(1->4)-N,N'-bi- s(aminoiminomethyl)-, sulfate (2:3) (salt) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PHARMACOLOGICAL ACTION MODE OF ACTION: The pharmacokinetics of streptomycin are similar to those of the other aminoglycosides. Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. Following intramuscular administration of streptomycin in adults with normal renal functions, peak plasma concentrations are attained within 1-2 hours and are reported to range from 25-50 ug/ml after a single 1-g dose. Streptomycin is distributed into most body tissues and fluids except the brain. Substantial amounts of the drug reportedly are found in pleural fluid and tuberculous cavities. The drug crosses placenta; serum concentrations in cord blood are similar to maternal serum concentrations. Small amounts of streptomycin are distributed into milk. The plasma elimination half-life of streptomycin is usually 2-3 hours in adults with normal renal functions. In adults with normal renal function, approximately 30-90% of a single intramuscular dose of streptomycin is excreted unchanged by glomerular filtration within 24 hours with the major portion being excreted within the first 12 hours. [AHFS Drug Information 1997; p 71, 56] DISEASES STUDIED/TREATED Treatment of HIV-associated multi-drug resistant pulmonary tuberculosis. [Protocol ID: ACTG 238 ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 79] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 79] OTHER MAJOR USES Streptomycin is indicated for the treatment of individuals with moderate to severe infections caused by susceptible strains of microorganisms in the specific conditions listed below: Mycobacterium tuberculosis, non-tuberculosis infections with Pasteurella pestis (plague), Francisella tularensis (tularemia), Brucella, Calymmatobacterium granulomatis (donovanosis, granuloma inguinale), H. ducreyi (chancroid), H. influenzae (in respiratory, endocardial, and meningeal infections-concomitantly with another antibacterial agent), K. pneumonia (concomitantly with another antibacterial agent), E. coli, Ptoteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections, Streptococcus viridans, Enterococcus faecalis (in endocardial infections-concomitantly with penicillin). [PDR 1997; p 2032] SUBSTANCE INTERACTIONS Ototoxic effects are potentiated by ethacrynic acid, furosemide, mannitol and possibly other diuretics. [PDR 1997; p 2032] ADVERSE EFFECTS Common adverse reactions include vestibular ototoxicity (nausea, vomiting and vertigo), paresthesia of face, rash, fever, urticaria, angioneurotic edema, and eosinophilia. Less frequent adverse effects include cochlear ototoxicity (deafness), exfoliative dermatitis, anaphylaxis, azotemia, leucopenia, thrombocytopenia, pancytopenia, hemolytic anemia, muscular weakness and amblyopia. [PDR 1997; p 2032] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to streptomycin or to other aminoglycosides. [PDR 1997; p 2032] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Aminoglycoside antibiotic obtained from cultures of Streptomycin griseus. [AHFS Drug Information 1997; p 71] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H39-N7-O12.3/2(H2-O4-S) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 1457.41 [USPD 1998; p. 686] CHEMICAL/PHYSICAL DATA Elemental Comp: C43.37%, H6.76%, N16.86%, O33.01% (base) [Merck Index 1996; p. 1507] CHEMICAL/PHYSICAL DATA Solubility: Very soluble in water, but almost insoluble in alcohol, chloroform, or ether. [Merck Index 1996; p 1507] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to light gray or pale buff powder with faint amine-like odor. [Merck Index 1996; p 1507] SUBSTANCE DELIVERY DATA DOSAGE FORM: Ampules containing streptomycin sulfate equivalent to 1-g of streptomycin in 2.5 ml. [PDR 1997; p 2032] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [PDR 1997; p 2031] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store under refrigeration at 2 to 8 C (36 to 46 F). [PDR 1997; p 2032] MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Professional Information (800)438-1985 REFERENCES MED/94328758. Heym B, Honore N, Truffot-Pernot C, Banerjee A, Schurra C, Jacobs WR Jr. van Embden JD, Grosset JH, Cole ST. Implications of multidrug resistance for the future of short-course chemotherapy of tuberculosis: a molecular study {see comments}. Lancet. 1994 Jul 30; 344(8918):293-8. MED/94305146. Luo C, Chintu C, Bhal G, Ravigliont M, Diwan V, DuPont HL, Zumla A. Human immunodeficiency virus type-1 infection in Zambian children with tuberculosis: changing seroprevalence and evaluation of a thioacetazone-free regimen. Tuber Lung Dis. 1994 Apr;75(2):110-5. MED/97221882. Peloquin CA. Mycobacterium avium complex infection. Pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes. Clin Pharmacokinet. 1997 Feb; 32:2, 132-44. MED/97215051. Pozniak A. Tuberculous meningitis [letter]. Int J STD AIDS. 1997 Feb; 8:2, 139-40. MED/97015631. Espinal MA, Reingold AL, Perez G, Camilo E, Soto S, Cruz E, Matos N, Gonzalez G. Human immunodeficiency virus infection in children with tuberculosis in Santo Domingo, Dominican Republic: prevalence, clinical findings, and response to antituberculosis treatment. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Oct 1; 13:2, 155-9. MED/97048231. Humma LM. Prevention and treatment of drug resistant tuberculosis. Am J Health Syst Pharm. 1996 Oct 1; 53:19, 2291-8; quiz 2335-6. MED/96423967. Guay DR. Nontuberculous mycobacterial infections. Ann Pharmacother. 1996 Jul-Aug; 30:7-8, 819-30. MED/96341176. Grosset J. Current problems with tuberculosis treatment. Res Microbiol. 1996 Jan-Feb; 147:1-2, 10-6. MED/95165491. Elliott AM, Halwiindi B, Hayes RJ, Luo N, Mwinga AG, Tembo G, Machiels L, Teenburgen G, Pobee JO, Nunn PP, et al. The impact of human immunodeficiency virus in response to treatment and recurrence rate in patients treated for tuberculosis: two-year follow-up of a cohort in Lusaka, Zambia. J Trop Med Hyg. 1995 Feb; 98:1, 9-21. MED/95266133. Elliot AM, Halwiindi B, Hayes RJ, Luo N, Mwinga AG, Tembo G, Machiels L, Steenbergen G, Pobee JO, Nunn P. The impact of human immunodeficiency virus on mortality of patients treated for tuberculosis in a cohort study in Zambia [see comments]. Trans R Soc Trop Med Hyg. 1995 Jan-Feb; 89:1, 78-82. ENTRY MONTH 199403 LAST REVISION DATE 20000801 146 UNIQUE IDENTIFIER DRG-0200 NAME OF SUBSTANCE Aminosalicylic acid [USPD 1998; p. 48] REGISTRY NUMBER 65-49-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Amino-2-hydroxybenzoic acid [Merck Index 1996; P 83] SYNONYMS Paser [USP DI 2000; p. 3193] SYNONYMS Paser Granules [USP DI 2000; p. 3193] PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PHARMACOLOGICAL ACTION MODE OF ACTION: Bacteriostatic in action. Mechanism of action is similar to that of sulfonamides. Prevents the synthesis of folic acid in susceptible organisms by competitively blocking the conversion of aminobenzoic acid to dihydrofolic acid. The activity of aminosalicylic acid is partially blocked by aminobenzoic acid. Active only against M. tuberculosis. Resistant strains of initially susceptible organisms develop rapidly if aminosalicylic acid is used alone in the treatment of clinical tuberculosis. This can be delayed or prevented by concurrent treatment with other antituberculosis drugs. Inhibits the onset of resistance to streptomycin and isoniazid. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Following administration with food of a single 4-g oral dose of the drug as enteric-coated granules in healthy adults, peak serum concentration of 2 ug/ml was achieved in 2 hours and maintained for an average of 7.9 hours. The drug is distributed into various tissues and fluids in concentrations approximately equal to plasma concentrations of the drug. The drug is 50-73% bound to plasma proteins. The plasma half-life of aminosalicylic acid is approximately 1 hour. The drug is inactivated in the intestinal mucosa and liver primarily by acetylation. Aminosalicyclic acid and its metabolites are excreted in urine by glomerular filtration and tubular secretion. Aminosalicylic acid and its acetyl metabolite accumulate in patients with severe renal disease. [AHFS Drug Information 1997; p 415] DISEASES STUDIED/TREATED Treatment of multi-drug resistant pulmonary tuberculosis. [Protocol ID: ACTG 238 ] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 3193] OTHER MAJOR USES Aminosalicyclic acid is indicated for the treatment of tuberculosis in combination with other active agents. It is most commonly used in patients with Multi-drug Resistant tuberculosis or in situations when therapy with isoniazid and rifampin is not possible due to a combination of resistance and/or intolerance. [PDR 1997; p 1333] SUBSTANCE INTERACTIONS Aminosalicylic acid has been reported to interact with probenecid, diphenhydramine, digoxin, oral anticoagulants, ammonium chloride, and isoniazid; therefore, concurrent administration of aminosalicylic acid and these drugs should be avoided. [AHFS Drug Information 1997; p 416] ADVERSE EFFECTS Adverse effects include the following, gastrointestinal system (most common): nausea, vomiting, diarrhea, and abdominal pain; hypersensitivity reactions: fever, skin eruptions of various types including exfoliative dermatitis, infectious mononucleosis-like or lymphoma-like syndrome, leukopenia, agranulocytosis, thrombocytopenia, Coombs' positive hemolytic anemia, jaundice, hepatitis, pericarditis, hypoglycemia, optic neuritis, encephalopathy, Leofflers's syndrome, and vasculitis, and a reduction in prothrombin. Other adverse reaction includes crystalluria. [PDR 1997; p 1334] CONTRAINDICATIONS Contraindicated in patients with impaired renal or hepatic functions and in patients with gastric ulcers. Also contraindicated in patients who are hypersensitive to aminosalicylic acid and its congeners. [AHFS Drug Information 1997; p 416] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic analog of aminobenzoic acid. [AHFS Drug Information 1997; p 415] CHEMICAL/PHYSICAL DATA Molecular Formula: C7-H7-N-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 153.14 [USPD 1998; p. 48] CHEMICAL/PHYSICAL DATA Melting Point: 150-151 C [Merck Index 1996; p. 83] CHEMICAL/PHYSICAL DATA Elemental Comp: C54.90%, H4.61%, N9.15%, O31.34% [Merck Index 1996; p. 83] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, alcohol, dilute nitric acid, dilute sodium hydroxide. Slightly soluble in ether. Practically insoluble in benzene. [Merck Index 1996; p 83] CHEMICAL/PHYSICAL DATA Stability: With heat, aminosalicylic acid is decarboxylated to produce CO2 and m-aminophenol. It is also rapidly degraded in acid media. [PDR 1997; p 1333] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Off-white tan colored granules with an average diameter of 1.5 mm. [PDR 1997; P 1333] SUBSTANCE DELIVERY DATA DOSAGE FORM: 4 g packets. [PDR 1997; p 1334] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1333] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store below 15 C (59 F) in a refrigerator or freezer. Avoid excessive heat. [PDR 1997; p 1334] MANUFACTURERS 0000001019: Jacobus Pharmaceutical Co 37 Cleveland Lane / PO Box 5290 Princeton, NJ 08540 Contact: Dr David Jacobus (609)921-7447 MANUFACTURERS 0000001019: Jacobus Pharmaceutical Co 37 Cleveland Lane / PO Box 5290 Princeton, NJ 08540 Contact: Dr Neil Lewis (609)921-7447 MANUFACTURERS 0000001019: Jacobus Pharmaceutical Co 37 Cleveland Lane / PO Box 5290 Princeton, NJ 08540 Contact: Unspecified (609)921-7447 REFERENCES MED/97048231. Humma LM. Prevention and treatment of drug-resistant tuberculosis. Am J Health Syst Pharm. 1996 Oct 1; 53:19, 2291-8; quiz 2335-6. ICA11/96923717. Arbulu MM; Weisburd G; Biglione J; Terrazzino JC. Multidrug resistant tuberculosis in AIDS patients in the infectious diseases service - Sala 1-Pol.I. Carrasco-Rosario-Argentina. Int Conf AIDS. 1996 Jul 7-12; 11:2, 121 (abstract no. We.B.3368). MED/96341176. Grosset J. Current problems with tuberculosis treatment. Res Microbiol. 1996 Jan-Feb; 147:1-2, 10-6. MED/95277953. Chaloner C, Segal I, Hassan H, McIntosh J, Gut A, Rahme M, Braganza JM. A preliminary report on urinary BT-PABA/PAS excretion index, serum pancreatic isoamylase and faecal chymotrypsin tests of pancreatic dysfunction in Sowetan Africans. Clin Chim Acta. 1995 Jan 16; 233(1-2):89-99. MED/94211681. Peloquin CA, Henshaw TL, Huitt GA, Berning SE, Nitta AT, James GT. Pharmacokinetic evaluation of para-aminosalicylic acid granules. Pharmacotherapy. 1994 Jan-Feb; 14(1):40-6. MED/95063425. Heifets LB. Antimycobacterial drugs. Semin Respir Infect. 1994 Jun; 9(2):84-103. MED/94048413. Peloquin CA. Pharmacology of the antimycobacterial drugs. Med Clin North Am. 1993 Nov; 77(6):1253-62. MED/92266347. el-Chaar GM, Schwenk MH, Bardini J, Caliendo G, Frank C, Profeta LM, Talbot KA, Cohen H. New drugs on the horizon. Clin Podiatr Med Surg. 1992 Apr; 9(2):481-501. ENTRY MONTH 199403 LAST REVISION DATE 20000801 147 UNIQUE IDENTIFIER DRG-0199 NAME OF SUBSTANCE Capreomycin sulfate [USPD 1998; p. 128] REGISTRY NUMBER 1405-37-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Capreomycin sulfate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Capastat [USP DI 2000; p. 772] PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PHARMACOLOGICAL ACTION MODE OF ACTION: Active against strains of Mycobacterium tuberculosis found in humans. Not absorbed in significant quantities from the gastrointestinal tract and must be administered parenterally. In previous studies using 1 g capreomycin (IM), peak serum concentrations were achieved 1 to 2 hours after administration, and average peak levels reached were 28 and 32 mcg/ml, respectively. Frequent cross-resistance occurs between capreomycin and viomycin. No cross-resistance has been observed between capreomycin and isoniazid, aminosalicylic acid, cycloserine, streptomycin, ethionamide, or ethambutol. The plasma half-life of capreomycin in patients with normal renal function is 4-6 hours. Plasma concentrations of capreomycin are higher and the half-life is prolonged in patients with impaired renal function. Capreomycin is excreted mainly unchanged in urine by glomerular filtration. Following a single 1-g intramuscular dose of the drug in adults with normal renal funcion, approximately 57% of the dose is excreted in urine within 24 hours. [PDR 1997; p 968-9; AHFS Drug Information 1997; p 417] DISEASES STUDIED/TREATED Used as second-line therapy in combination with other antituberculosis drugs for pulmonary tuberculosis. [PDR 1997; p 969] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 771] OTHER MAJOR USES Capreomycin is to be used concomitantly with other appropriate antituberculosis agents, is indicated in pulmonary infection caused by capreomycin-susceptible strains of Mycobacterium tuberculosis when the primary agents (isoniazid, rifampin, ethambutol, aminosalicyclic acid and streptomycin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli. [PDR 1997; p 969] SUBSTANCE INTERACTIONS Since there is some evidence that nephrotoxic and/or ototoxic effects may be additive, the concurrent or sequential use of capreomycin and other nephrotoxic and/or ototoxic drugs including aminoglycosides, colistin, polymyxin B, and vancomycin should be avoided. [AHFS Drug Information 1997; p 418] ADVERSE EFFECTS Adverse effects include the following, nephrotoxicity: elevation of BUN above 20 mg/ml, depression of PSP excretion, abnormal urine sediment; ototoxicity: subclinical auditory loss, clinically apparent hearing loss, tinnitus, and vertigo; Liver: decrease in BSP excretion without change in AST (SGOT) or ALT(SGPT) in preexisting liver disease patients, abnormal results in liver function tests in patients receiving capreomycin concurrently with other antituberculosis agents known to cause changes in hepatic function; blood: leukocytosis, leukopenia, pain and induration at the injection site, excessive bleeding at the injection site, sterile abscesses, thrombocytopenia rarely; hypersensitivity; urticaria, maculopapular skin rashes associated in some cases with febrile reactions in cases when capreomycin and other antituberculosis drugs were given concomitantly. [PDR 1997; p 969] CONTRAINDICATIONS Should be used with extreme caution in patients with renal insufficiency or auditory impairment. Contraindicated in patients who are hypersensitive to capreomycin. Safe use in children has not been established. Should be used in pregnant women only if the potential benefits outweigh the potential risk to the fetus. [AHFS Drug Information 1997; p 418] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Cyclic peptide antibiotic similar to viomycin; produced by Streptomyces capreolus; complex of four microbiologically active components which have been characterized in part. [Merck Index 1996; p 286] CHEMICAL/PHYSICAL DATA Molecular Formula: H2-O4-S.W99 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water. [AHFS Drug Information 1997; p 417] CHEMICAL/PHYSICAL DATA Stability: Reconstituted capreomycin sulfate solutions are stable for 48 hours at room temperature or 14 days at 2-8 C. Solutions may develop a pale straw color and darken; however this does not affect potency. [AHFS Drug Information 1997; p 417] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White or practically white, amorphous powder. [AHFS Drug Information 1997; p 417] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile capreomycin sulfate equivalent to 1g of capreomycin activity supplied in 10 ml-size vials. [PDR 1997; p 970] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [PDR 1997; p 969] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature 15-30 C (59-86 F) prior to reconstitution. [PDR 1997; p 970] MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 REFERENCES MED/97048231. Humma LM. Prevention and treatment of drug-resistant tuberculosis. Am J Health Syst Pharm. 1996 Oct 1; 53:19, 2291-8; quiz 2335-6. ICA11/96923714. Breaux K; Graviss E; Lahart C, Is there a potential benefit of intermittent antimycobacterial use in HIV-infected patients at risk for DMAC? Int Conf AIDS. 1996 Jul 7-12; 11:2 120 (abstract no. We.B.3365). MED/96144260. Thiara AS, Cundliffe E. Analysis of two capreomycin-resistance determinants from Streptomyces capreolus and characterization of the action of their products. Gene 1995 Dec 29;167(1-2):121-6. AIDS/95920152. Bonomo RA, Briggs JM, Graham RG, Ward AL, Hassan M. Mycobacterium celatum sp. nov. infection in the acquired immunodeficiency syndrome (AIDS): description of a new opportunistic pathogen. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:76. MED/94166069. Wank H, Rogers J, Davies J, Schroeder R. Peptide antibiotics of the tuberactinomycin family as inhibitors of group I intron RNA splicing. J Mol Biol 1994 Mar 4;236(4):1001-10 MED/94139393. Nolan CM, Sandblom RE, Thummel KE, Slattery JT, Nelson SD. Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest 1995 Feb;105(2):408-11. MED/95031533. Weltman AC, Rose DN. Tuberculosis susceptibility patterns, predictors of multidrug resistance, and implications for initial therapeutic regimens at a New York City hospital. Arch Intern Med. 1994 Oct 10;154(19):2161-7. MED/94048413. Peloquin CA. Pharmacology of the antimycobacterial drugs. Med Clin North Am. 1993 Nov;77(6):1253-62. MED/93160311. Cowling P, Glover S, Reeves DS. Mycobacterium malmoense type II bacteraemia contributing to death in a patient with AIDS. Int J STD AIDS. 1992 Nov-Dec;3(6):445-6. MED/90024999. Heifets L, Lindholm-Levy P. Comparison of bactericidal activities of streptomycin, amikacin, kanamycin, and capreomycin against Mycobacterium avium and M. tuberculosis. Antimicrob Agents Chemother. 1989 Aug;33(8):1298-301. ENTRY MONTH 199403 LAST REVISION DATE 20001107 148 UNIQUE IDENTIFIER DRG-0198 NAME OF SUBSTANCE Benztropine mesylate [USPD 1998; p. 91] REGISTRY NUMBER 132-17-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3-(diphenylmethoxy)-8-methyl-, 8-azabicyclo(3.2.1) octane, methanesulfonate [Merck Index 1996; p 88] SYNONYMS Cogentin [USP DI 2000; p. 316] PROTOCOL ID NUMBERS Complete NIAID ACTG 242 PHARMACOLOGICAL ACTION MODE OF ACTION: The anticholinergic activity of benztropine is about equal to that of atropine. The antihistaminic activity is similar to that of pyrilamine maleate. Benztropine does not produce as much central stimulation as does trihexyphenidyl. Benztropine effects are cumulative and may not be evident until 2 or 3 days after start of treatment. [AHFS Drug Information 1997; p 909] DISEASES STUDIED/TREATED As an active placebo to mimic the side effects of study drugs. [Protocol ID: ACTG 242 ] CLASSIFICATION CODE Antidyskinetic [USP DI 2000; p. 314] OTHER MAJOR USES Adjunct in therapy for parkinsonism; useful in control of extrapyramidal disorders (except tardive dyskinesia) due to neuroleptic drugs. [PDR 1997; p 1661] SUBSTANCE INTERACTIONS Interacts with antipsychotic drugs such as phenothiazines or haloperidol, and with tricyclic antidepressants. [PDR 1997; p 1661] ADVERSE EFFECTS The adverse effects within the following category are listed in order of decreasing severity, cardiovascular effects: tachycardia; digestive system: paralytic ileus, constipation, vomiting, nausea, dry mouth; nervous system: toxic psychosis including confusion, disorientation, memory impairment, visual hallucinations, exacerbation of preexisting psychotic symptoms, nervousness, depression, listlessness, numbness of fingers; special senses: blurred vision, dilated pupils; urogenital: urinary retention, dysuria; metabolic/immune or skin effects: occasionally, an allergic reaction, e.g., skin rash, develops. Other adverse effects may include heat stroke, hyperthermia, and fever. [AHFS Drug Information 1997; p 421] CONTRAINDICATIONS Contraindicated in children under 3 years of age and in patients with hypersensitivity to the drug or to any compenent of the injection solution. Use with caution in older children. [PDR 1997; p 1661] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic tertiary amine containing sturctural features found in atropine and diphenydramine. [PDR 1997; p 1661] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H25-N-O.C-H4-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 403.55 [USPD 1998; p. 91] CHEMICAL/PHYSICAL DATA Melting Point: 143 C [Merck Index 1996; p. 189] CHEMICAL/PHYSICAL DATA Elemental Comp: C65.48%, H7.24%, N3.47%, O15.86%, S7.95% [Merck Index 1996; p. 188] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water. [Merck Index 1996; p 188] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystalline white powder, odorless, slightly hygroscopic. [PDR 1997; p 1661; AHFS Drug Information 1997; p 909] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.5, 1, and 2 mg tablets; 1 mg/ml sterile solution for injection. [PDR 1997; p 1662] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous; intramuscular. [PDR 1997; p 1661] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets and injection solution should be stored at a temperature less than 40 C, preferably between 15-30 C; freezing of the injection solution should be avoided. Tablets should be stored in well-closed containers. [AHFS Drug Information 1997; p 909] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 REFERENCES ICA5/00258889. Holmes VF. Rapid progression of organic delusional syndrome to dementia in AIDS. Int Conf AIDS. 1989 Jun 4-9;5:499 (abstract no. B.611). ENTRY MONTH 199403 LAST REVISION DATE 20000801 149 UNIQUE IDENTIFIER DRG-0197 NAME OF SUBSTANCE Mexiletine hydrochloride [USPD 1998; p. 471] REGISTRY NUMBER 5370-01-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2-Propanamine, 1-(2,6-dimethylphenoxy)-, hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Mexitil [USP DI 2000; p. 3484] PROTOCOL ID NUMBERS Complete NIAID ACTG 242 PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine hydrochloride is well absorbed (approximately 90%) from the gastrointestinal tract. Its first-pass metabolism is low. Peak blood levels are reached in 2-3 hours. In normal subjects, plasma elimination half-life is 10-12 hours. The drug is 50-60% bound to plasma protein, with a volume of distribution of 5-7 liters/kg. Mexiletine hydrochoride is metabolized by the liver, and approximately 10% is excreted unchanged by the kidney. Acidification accelerates the rate of excretion of the drug, and alkalinization retards it. Mexiletine plasma levels of at least 0.5 mcg/ml are generally required for therapeutic response. [PDR 1997; p 684] DISEASES STUDIED/TREATED Relief or reduction of pain in HIV-associated peripheral neuropathy. [Protocol ID: ACTG 242 ] CLASSIFICATION CODE Antiarrhythmic [USP DI 2000; p. 2136] OTHER MAJOR USES Treatment of documented ventricular tachycardia that are life threatening. [PDR 1997; p 684] SUBSTANCE INTERACTIONS No interactions were observed with commonly employed antianginal, antihypertensives, and anticoagulant drugs. Lowered mexiletine plasma levels were reported for concurrent use with some hepatic enzyme inducers such as rifampin, phenytoin, or phenobarbital. Concurrent use with theophylline may increase plasma theophylline levels. Concurrent administration of dimetidine and mexiletine has been reported to increase, decrease, or leave unchanged mexiletine plasma levels. [PDR 1997; p 685] ADVERSE EFFECTS Commonly produces reversible gastrointestinal and nervous system adverse reactions but is otherwise well tolerated. Adverse effects may include gastrointestinal distress, dizziness or lightheadedness, tremor, and coordination difficulties. [PDR 1997; p 685] CONTRAINDICATIONS Contraindicated in cardiogenic shock, or pre-existing second or third degree AV block (if no pacemaker is present). Should be used with caution in patients with structural heart disease hypotension and severe congestive heart failure, liver diseases, and patients with known seizure disorder. [PDR 1997; p 684] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Class 1B antiarrhythmic compound, with electrophysiologic properties in man similar to lidocaine. [PDR 1997; p 684] CHEMICAL/PHYSICAL DATA Molecular Formula: C11-H17-N-O.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 215.72 [USPD 1998; p. 471] CHEMICAL/PHYSICAL DATA Melting Point: 203-205 C [Merck Index 1996; p. 1054] CHEMICAL/PHYSICAL DATA Elemental Comp: C73.70%, H9.56%, N7.81%, O8.93% (base) [Merck Index 1996; p. 1054] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water and in alcohol. [PDR 1997; p 684] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder with slightly bitter taste. [PDR 1997; p 684] SUBSTANCE DELIVERY DATA DOSAGE FORM: 150, 200, and 250 mg gelatin capsules. [PDR 1997; p 686] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 684] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature 20-25 C (68-77 F). [PDR 1997; p 686] MANUFACTURERS 0000002793: Boehringer Ingelheim Pharmaceuticals Inc 900 Ridgebury Rd / PO Box 368 Ridgefield, CT 068770368 Contact: Dr Pedro Urquilla (203)791-6438 MANUFACTURERS 0000002866: Boehringer Ingelheim Pharmaceuticals Inc 900 Ridgebury Rd / PO Box 368 Ridgefield, CT 068770368 Contact: General Information (800)595-5494 REFERENCES MED/96132021. Kwok DW, Kerr CR, McErlane KM. Pharmacokinetics of mexiletine enantiomers in healthy human subjects. A study of the in vivo serum protein binding, salivary excretion and red blood cell distribution of the enantiomers. Xenobiotica 1995 Nov;25(10):1127-42. MED/95386737. Morita H, Hirabayashi K, Nozaki S, Ohmori K, Yoshikawa K, Matsuo H. Chronic effect of oral mexiletine administration on left ventricular contractility in patients with congestive heart failure: a study based on mitral regurgitant flow velocity measured by continuous-wave Doppler echocardiography. J Clin Pharmacol 1995 May;35(5);478-83. AIDS/95700461. Lein B. Potential therapy for painful neuropathy. PI Perspect. 1995 May;(no 16):11. MED/95272094. Murakawa Y, Inoue H, Kuo TT, Sezaki K, Nakajima T, Usui M, Yamashita T, Ajika K, Oikawa N, Sugimoto T, et al. Prolongation of intraventricular conduction time associated with fatal [correction of fetal] impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents. J Cardiovasc Pharmacol 1995 Feb;25(2):194-9. AIDS/95920655. Kemper CA, Ganer A, Kent G, Deresinski S. Double-blind placebo(P)-controlled cross-over study fails to show benefit of mexiletine (MX) in painful neuropathy. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29- Feb 2;:171. MED/95123881. Kempton J, Manoukian A, Levine B, Smialek J. A mexiletine intoxication. J Anal Toxicol 1994 Oct;18(6):346-7. MED/95123883. Rohrig TP, Harty LE. Postmortem distribution of mexiletine in a fatal overdose. J Anal Toxicol 1994 Oct;18(6):354-6. MED/92197862. Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology. 1992 Apr;76(4):513-7. MED/93105769. Stracke H, Meyer UE, Schumacher HE, Federlin K. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care. 1992 Nov;15(11):1550-5. ICA7/1206891. Kent GP, Ganer A, Deresinski SC. The safety and efficacy of mexiletine in HIV-associated painful peripheral neuropathy (PPN). Int Conf AIDS. 1991 Jun 16-21;7(1):199 (abstract no. M.B.2068). ENTRY MONTH 199403 LAST REVISION DATE 20001107 150 UNIQUE IDENTIFIER DRG-0196 NAME OF SUBSTANCE Ethionamide [USPD 1998; p. 288] REGISTRY NUMBER 536-33-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2-Ethyl-4-pyridinecarbothioamide [Merck Index 1996; p 638] SYNONYMS Trecator-SC [USP DI 2000; p. 1486] PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PHARMACOLOGICAL ACTION MODE OF ACTION: May be bacteriostatic or bactericidal in action depending on drug concentration at the site of infection and the susceptibility of the infecting organism. Appears to inhibit peptide synthesis in susceptible organisms. Active only against organisms of the genus Mycobacterium, such as M. tuberculosis, M. bovis, M. kansasii, and some strains of M. avium and M. intracellulare. Resistant strains of initially susceptible M. tuberculosis develop rapidly if ethionamide is used alone in the treatment of clinical tuberculosis. There is no evidence of cross resistance between ethionamide and other antituberculosis agents used in the US. Approximately 80% of an oral dose of ethionamide is rapidly absorbed from the gastrointestinal tract. Following a single 1-g oral dose in adults, peak plasma concentrations of ethionamide averaging 20 ug/ml are attained within 3 hours. The drug is widely distributed into body tissues and fluids; concentrations in plasma and various organs are approximately equal. Ethionamide is 10% bound to plasma proteins. The drug readily crosses the placenta. The plasma half-life of ethionamide is approximately 3 hours. It is extensively metabolized to active and inactive metabolites, probably in the liver. The major active metabolite is the sulfoxide, which may be converted back to ethionamide in vivo. Within 24 hours, 1-5% of an oral dose of ethionamide is excreted in urine as active drugs and metabolites; the remainder is excreted in urine as inactive metabolites. The gastrointestinal disturbances are the most frequent adverse reactions of ethionamide; they appear to be dose related and may be minimized by decreasing dosage or changing the time of drug administration. [AHFS Drug Information 1997; p 422-3; Drug Evaluations Annual 1995; p 1282-84] DISEASES STUDIED/TREATED Used as a second-line agent against tuberculosis in the HIV-infected person. It should be given only with other effective antituberculosis drugs. [Protocol ID: ACTG 238 ; Drug Evaluations Annual 1995; p 1282-4] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 1485] OTHER MAJOR USES Tuberculosis; leprosy. [PDR 1997; p 2919; AHFS Drug Information 1995; p 388-89] ADVERSE EFFECTS Adverse effects include the following, gastrointestinal effects: nausea, vomiting, abdominal pain, diarrhea, excessive salivation, metallic taste, anorexia, and weight loss; nervous system and special senses effects: mental depression, restlessness, drowsiness, dizziness, headache, postural hypotension, asthenia (occasionally), and peripheral neuritis, paresthesia, seizures, tremors, a pellagra-like syndrome, hallucinations, diplopia, optic neuritis, blurred vision, olfactory disturbances (rarely); hepatic effects: transient increase in serum bilirubin, AST (SGOT), and ALT (SPGT) concentrations, and hepatitis. Other rare adverse effects include hypersensitivity reactions including rash, stomatitis, photosensitivity, thrombocytopenia, and purpura; goiter (with or without hypothyroidism), hypoglycemia, gynecomastia, impotence, menorrhagia, joint pain, acute rheumatic symptoms, and acne. [AHFS Drug Information 1997; p 422-3] CONTRAINDICATIONS Contraindicated in patients who develop severe hypersensitivity reactions and severe hepatic damage. [PDR 1997; p 2919] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic, isonicotinic acid-derivative antituberculosis agent. [AHFS Drug Information 1997; p 422] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H10-N2-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 166.25 [USPD 1998; p. 288] CHEMICAL/PHYSICAL DATA Elemental Comp: C57.80%, H6.06%, N16.85%, S19.29% [Merck Index 1996; p. 638] CHEMICAL/PHYSICAL DATA Solubility: Very sparingly soluble in water and ether. Sparingly soluble in methanol, ethanol, propylene glycol. Soluble in hot acetone, dichlorethane. Freely soluble in pyridine. [Merck Index 1996; p 638] CHEMICAL/PHYSICAL DATA Stability: Stable at ordinary temperatures and humidities. [PDR 1997; p 2919] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Ethionamide is a yellow, crystalline, nonhygroscopic compound with a faint-to-moderate sulfide odor. [PDR 1997; p 2919] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg tablets. [PDR 1997; p 2919] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2919] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store in well-closed containers at a temperature less than 40 C, preferably between 15-30 C. [PDR 1997; p 2919; AHFS Drug Information 1997; p 422] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 REFERENCES MED/97048231. Humma LM. Prevention and treatment of drug-resistant tuberculosis. Am J Health Syst Pharm, 1996 Oct 1, 53;19:2291-8; quiz 2335-6. ICA11/96924695. Phadtare JM, Saple DG, Banka RB. Multiple drug resistant tuberculosis and mycobacteriosis in HIV infection. Int Conf AIDS.1996 Jul 7-12; 11(2):304 (abstract no. Th.B.4306). ICA11/96922556. Valencia ME, Moreno V, Soriano V, Laguana F, Ortega A, March J, Cobo G, Lahoz J. Hepatic and/or splenic abscesses formation in patients with tuberculosis (TB) and AIDS. Int Conf AIDS. 1996 Jul 7-12;11(1):326 (abstract no. Tu.B.2354). ICA11/96921374. Mellado MJ, M-Fontelos P, Cilleruelo MJ, Garcia M, Barreiro G, P-Jurado ML, Ortega A, Villota J. Nosocomial outbreak of multidrug resistant tuberculosis in HIV-infected children. Int Conf AIDS. 1996 Jul 7-12;11 (1):108 (abstract no. Mo.B.1310. MED/95349686. Stone MM, Vannier AM, Storch SK, Peterson C, Nitta AT, Zhang Y. Brief report: meningitis due to iatrogenic BCG infection in two immunocompromised children. N Eng J Med 1995 Aug 31;333(9):561-3. MED/94328758. Heym B, Honore N, Truffot-Pernot C, Banerjee A, Schurra C, Jacobs WR Jr, van Embden JD, Grosset JH, Cole ST. Implications of multidrug resistance for the future of short-course chemotherapy of tuberculosis: a molecular study [see comments]. Lancet. 1994 Jul 30;344(8918):293-8. MED/95063425. Heifets LB. Antimycobacterial drugs. Semin Respir Infect. 1994 Jun;9(2):84-103. MED/94112548. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR Jr. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis [see comments]. Science 1994 Jan 14;263(5144):227-30. ICA9/93335937. Rose DN, Weltman A. Antibiotic sensitivity pattern of Mycobacterium tuberculosis in a population with high prevalence of AIDS and antibiotic resistance; implications for choosing therapeutic regimens. Int Conf AIDS. 1993 Jun 6-11;9(1):52 (abstract no. WS-B09-5). ENTRY MONTH 199402 LAST REVISION DATE 20000801 151 UNIQUE IDENTIFIER DRG-0195 NAME OF SUBSTANCE Cycloserine [USPD 1998; p. 203] REGISTRY NUMBER 68-41-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3-Isoxazolidinone, 4-amino-, (R)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Seromycin [USP DI 2000; p. 1163] PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits cell-wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in Mycobacterium tuberculosis. After oral administration, cycloserine is readily absorbed from the gastrointestinal tract, with peak blood levels occurring in 4 to 8 hours. Blood levels of 25 to 30 mg/ml can generally be maintained with the usual dosage of 250 mg twice a day, although the relationship of plasma levels to dosage is not always consistent. Concentrations in the cerebrospinal fluid, pleural fluid, fetal blood, and mother's milk approach those found in the serum. Detectable amounts are found in ascitic fluid, bile, sputum, amniotic fluid, and lung and lymph tissues. Approximately 65% of a single dose of cycloserine can be recovered in the urine within 72 hours after oral administration. The remaining 35% is apparently metabolized to unknown substances. The maximum excretion rate occurs 2 to 6 hours after administration, with 50% of the drug eliminated in 12 hours. [PDR 1997; p 975-6] DISEASES STUDIED/TREATED Used in the treatment of active pulmonary and extrapulmonary tuberculosis (including renal disease). When the causative organisms are susceptible to the drug and when treatment with primary medications (streptomycin, isoniazid, rifampin and ethambutol) has proved inadequate. Should be administered with other effective chemotherapy and not as the sole therapeutic agent. [PDR 1997; p 976] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 1161] OTHER MAJOR USES Pulmonary and extrapulmonary tuberculosis, and acute urinary tract infections. [PDR 1997; p 976] SUBSTANCE INTERACTIONS Concurrent administration of ethionamide has been reported to potentiate neurotoxic side effects. Alcohol and cycloserine are incompatible. Concurrent administration of isoniazid may result in increased incidence of CNS effects such as dizziness or drowsiness. [PDR 1997; p 976] ADVERSE EFFECTS Most adverse effects occuring during seromycin therapy involve the nervous system. Adverse effects include convulsions, drowsiness and somnolence, headache, tremor, dysarthria, vertigo, confusion and disorientation with loss of memory, psychoses (possibly with suicidal tendencies), character changes, hyperirritability, aggression, paresis, hyperreflexia, paresthesia, seizures, coma, allergy, skin rash, and sudden development of congestive heart failure (in patients receiving 1 to 1.5 grams). [PDR 1997; p 976] CONTRAINDICATIONS Contraindicated in patients with seizure disorders, depression, severe anxiety or psychosis, renal insufficiency, excessive use of alcohol, and hypersensitivity. [PDR 1997; p 976] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A broad-spectrum antibiotic that is produced by a strain of Streptomyces orchidaceus and has also been synthesized. [PDR 1997; p 975] CHEMICAL/PHYSICAL DATA Molecular Formula: C3-H6-N2-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 102.09 [USPD 1998; p. 203] CHEMICAL/PHYSICAL DATA Elemental Comp: C35.29%, H5.92%, N27.44%, O31.34% [Merck Index 1996; p. 464] CHEMICAL/PHYSICAL DATA Solubility: Cycloserine is soluble in water and alkaline solutions. [PDR 1997; p 975] CHEMICAL/PHYSICAL DATA Stability: Forms salts with acids and bases. Neutral or acid solutions are unstable. Aqueous solution buffered to pH 10 with sodium carbonate can be stored without loss of potency for one week at refrigerator temperatures. [Merck Index 1996; p 464] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white powder. [PDR 1997; p 975] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg capsules. [AHFS Drug Information 1997; p 420] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 976] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature, 15 to 30 C. [PDR 1997; p 976] MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 REFERENCES ICA11/96924695. Phadtare JM, Saple DG, Banka RB. Multiple drug resistant tuberculosis and mycobacteriosis in HIV infection. Int Conf AIDS. 1996 Jul 7-12;11(2):304 (abstract no. Th.B.4306). MED/96183051. Tamma SL, Sundaram SK, Lev M, Coico RK. Inhibition of sphingolipid synthesis down-modulates CD4 expression by peripheral blood T lymphocytes and T lymphoma cells. Biochem Biophys Res Commun. 1996 Mar 27;220(3):916-21. MED/96147313. Mizrachi Y, Lev M, Harish Z, Sundaram SK, Rubinstein A. L-cycloserine, an inhibitor of sphingolipid biosynthesis inhibits HIV-1 cytopathic effects, replication, and infectivity. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Feb 1;11(2):137-41. MED/94248078. Katz MH. Effect of HIV treatment on cognition, behavior, and emotion. Psychiatr Clin North Am. 1994 Mar;17(1):227-30. MED/95063425. Heifets LB. Antimycobacterial drugs. Semin Respir Infect. 1994 Jun;9(2):84-103. MED/93331234. Rastogi N, David HL. Mode of action of antituberculous drugs and mechanisms of drug resistance in Mycobacterium tuberculosis. Res Microbiol. 1993 Feb;144(2):133-43. MED/94048413. Peloquin CA. Pharmacology of the antimycobacterial drugs. Med Clin North Am. 1993 Nov;77(6):1253-62. MED/87053027. Rodriguez JL, Barrio JL, Pitchenik AE. Pulmonary nocardiosis in the acquired immunodeficiency syndrome. Diagnosis with bronchoalveolar lavage and treatment with non-sulphur containing drugs. Chest. 1986 Dec;90(6):912-4. ENTRY MONTH 199402 LAST REVISION DATE 20001107 152 UNIQUE IDENTIFIER DRG-0194 NAME OF SUBSTANCE Glutamic acid hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 138-15-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME L-glutamic acid, hydrochloride [CHEMLINE ] PROTOCOL ID NUMBERS Complete NIAID ACTG 183 PHARMACOLOGICAL ACTION MODE OF ACTION: A high incidence of hypochlorhydria has been reported in AIDS patients, but the cause is uncertain. An unselected group of 43 AIDS patients, who underwent endoscopy and biopsy, were studied for hypochlorhydria. It was concluded that intragastric buffering of acid by refluxed alkaline duodenal contents may be a cause of apparent hypochlorhydria. Gastric hypochlorhydria in patients with HIV/AIDS also is associated with a significantly higher probability of systemic mycobacterium avium complex (MAC) infection, independent of CD4 count. Furthermore, the absorption of rifampin and rifabutin are impaired in an alkaline environment, potentially limiting their efficacy. [Int Conf AIDS 1996 Jul 7-12;11(1); p 137 (abstract no. PuB 7529); Int Conf AIDS 1996 Jul 7-12;11(1); p 18 (abstract no. Mo.B.118)] DISEASES STUDIED/TREATED Prevention of hypochlorhydria, in order to enhance absorption of oral ganciclovir. [Protocol ID: ACTG 183 ] CLASSIFICATION CODE Gastric acidifier [Merck Index 1996; p. 761] OTHER MAJOR USES Gastric acidifier. [Facts and Comparisons 1995; p 312] CHEMICAL/PHYSICAL DATA Molecular Formula: C5-H9-N-O4.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Elemental Comp: C40.82%, H6.17%, N9.52%, O43.50% (base) [Merck Index 1996; p. 760] SUBSTANCE DELIVERY DATA DOSAGE FORM: 340 mg capsules. [Protocol ID: ACTG 183 ; Facts and Comparisons 1995; p 312] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 183 ] MANUFACTURERS 0000002862: Major Pharmaceuticals Inc 31778 Enterprise Drive Livonia, MI 48150 Contact: Unspecified (800)642-1232 REFERENCES MED/94188289. Russell TL, Berardi RR, Barnett JL, O'Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of dipyridamole in the elderly. Pharm Res. 1994 Jan;11(1):136-43. MED/94250008. Carver PL, Berardi RR, Knapp MJ, Rider JM, Kauffman CA, Bradley SF, Atassi M. In vivo interaction of ketoconazole and sucralfate in healthy volunteers. Antimicrob Agents Chemother. 1994 Feb;38(2):326-9. ICA11/96920889. Koch J, Scott MK, Morgan D, Steuerwald M, Lor E, Cello JP. Gastric hypochlorhydria is associated with mycobacterium avium complex (MAC) infection in patients with HIV/AIDS. Int Conf AIDS. 1996 Jul 7-12;11(1):18(abstract no.Mo.B.118). ICA8/92403593. Stollman N, Rotterdam H, Kotier DP. Gastric histopathology in AIDS. Int Conf AIDS. 1992 Jul 19-24;8(3):137(abstract no. PuB 7529). MED/92174500. Knapp MJ, Berardi RR, Dressman JB, Rider JM, Carver PL. Modification of gastric pH with oral glutamic acid hydrochloride. Clin Pharm. 1991 Nov;10(11):866-9. ENTRY MONTH 199402 LAST REVISION DATE 20000801 153 UNIQUE IDENTIFIER DRG-0193 NAME OF SUBSTANCE Glycovir [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 131262-82-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 259 PHARMACOLOGICAL ACTION MODE OF ACTION: SC-49483 does not have any inherent anti-HIV activity but is converted to SC-48334 in the intestinal wall. SC-48334, an alpha glucosidase I inhibitor, when used with AZT does appear to suppress HIV-1 in vitro. A major problem with SC-48334 is diarrhea with associated weight loss, thus SC-49483 was developed to avoid this problem. The mean oral bioavailability of SC-48334 from single doses of the SC-49483 was estimated to be about 30% relative to the single oral dose of SC-48334. SC-49483 was administered orally to rats and cynomolgus monkeys for 4 weeks. At dosages which gave clinically meaningful plasma SC-48334 concentrations (8-10 mcg/ml), no diarrhea or clinically severe toxicity was observed. A 6-month clinical study of patients receiving SC-48334 plus AZT, or AZT alone showed no significant difference in mean peak increase in CD4 cells between the two treatment groups. No further development of SC-48334 is anticipated. [Protocol ID: ACTG 259 ; AmfAR Treat Dir 1995;7(4); p 56] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: ACTG 259 ] CLASSIFICATION CODE Investigational - Antiviral [Protocol ID: ACTG 259 ] ADVERSE EFFECTS Mild adverse effects noted include headache, rash, abdominal pain, diarrhea, flatulence, nausea, vomiting, temperature elevation, and dizziness. [Protocol ID: ACTG 259 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C26-H45-N-O8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 499.65 [Protocol ID: ACTG 259 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 1 g capsules. [Protocol ID: ACTG 259 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 259 ] MANUFACTURERS 0000001201: G D Searle & Co 5200 Old Orchard Road Skokie, IL 60077 Contact: Dr Richard Aspinall (708)982-8651 REFERENCES MED/96386611. Fischer PB, Karlsson GB, Butters TD, Dwek RA, Platt FM. N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with changes in antibody recognition of the V1/V2 region of gp120. J Virol. 1996 Oct;70(10):7143-52. MED/96386612. Fischer PB, Karlsson GB, Dwek RA, Platt FM. N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with impaired gp120 shedding and gp41 exposure. J Virol. 1996 Oct;70(10):7153-60. MED/97082437. Khan KN, Snook SS, Semler DE, Baron DA, Alden CL. Pathology of perbutylated-N-butyl-1-deoxynojirimycin (an alpha-glucosidase-1 inhibitor) in Sprague-Dawley rats. Toxicol Pathol. 1996 Sep-Oct;24(5):531-8. MED/96142217. Tierney M, Pottage J, Kessler H, Fischl M, Richman D, Merigan T, Powderly W, Smith S, Karim A, Sherman J, et al. The tolerability and pharmacokinetics of N-butyl-deoxynojirimycin in patients with advanced HIV disease (ACTG100). The AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases. J Acquir Immune Defic Syndr Hum Retrovirol 1995 Dec 15;10(5):549-53. MED/95363994. Fischer PB, Collin M, Karlsson GB, James W, Butters TD, Davis SJ, Gordon S, Dwek RA, Platt FM. The alpha-glucosidase inhibitor N-butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding. J Virol 1995 Sep;69(9):5791-7. MED/96118653. Kiso M, Ando K, Inagaki H, Ishida H, Hasegawa A. Synthetic and structural studies of alpha-sialyl-(2-->6) and alpha-sialyl-(2-->3) 1-deoxynojirimycin derivatives potentially useful for biomedical applications. Carbohydr Res 1995 Aug 11;272(2):159-78. MED/96021491. Cook CS, Karabatsos PJ, Schoenhard GL, Karim A. Species dependent esterase activities for hydrolysis of an anti-HIV prodrug glycovir and bioavailability of active SC-48334. Pharm Res 1995 Aug;12(8);1158-64. MED/94133083. Fischl MA, Resnick L, Coombs R, Kremer AB, Pottage JC Jr, Fass RJ, Fife KH, Powderly WG, Collier AC, Aspinall RL, et al. The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3. J Acquir Immune Defic Syndr. 1994 Feb;7(2);139-47. ICA9/93334689. Bryant M, Mueller R, Smidt M, Tiemeier D, Jacobs G, Platt F, Butters T, Karlsson N, Houseman K, Marr J. Anti-HIV properties of alpha-glucosidase inhibitor SC-48334, the active component of prodrug SC-49483. Int Conf AIDS. 1993 Jun 6-11;9(1):33 (abstract no. WS-A17-6). ENTRY MONTH 199402 LAST REVISION DATE 20000801 154 UNIQUE IDENTIFIER DRG-0192 NAME OF SUBSTANCE F105 Monoclonal Antibody (Human) [Protocol ID: ACTG 232 ] PROTOCOL ID NUMBERS Complete NIAID ACTG 232 PHARMACOLOGICAL ACTION MODE OF ACTION: F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. F105 neutralizes the IIIB, SF2 and MN strains of HIV at concentrations readily achievable in man (1.50 - 10 mcg/ml). The F105 antibody does not neutralize some strains of virus at fairly high doses in vitro assays. Nonetheless, F105 does react with GP 120 from these non-neutralized strains and also promotes cellular immunity in the form of antibody dependent cellular cytotoxicity against diverse viral strains. The F105 epitope on GP120 is a conformational epitope and overlaps significantly the CD4 binding region on GP120. Other CD4 binding site Hmab overlap with F105 and have similar neutralization profiles. F105 offers a potential alternative to RCD4-IgG as a biological treatment for HIV infection because it reacts with an immunogenic epitope on GP120 and avoids the problems related to the possible normal functions of CD4 within the immune system, and lacks the potential immunogenicity and instability of the nonbinding structures of the CD4 portion of the artificial construct. In a study investigating the disposition of the antibody in humans, F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half-life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 +/- 9.62 micrograms/ml. It was concluded that F105 can be administered as a bolus dose every 21 days. [Protocol ID: ACTG 232 ; J Clin Invest 1995 Feb;95(2); p 732-37; Clin Pharmacol Ther 1996 Jun; 59(6); p 662-7] DISEASES STUDIED/TREATED Inhibition of tumor necrosis factor production in HIV infection. [Protocol ID: ACTG 232 ] CLASSIFICATION CODE Monoclonal antibody (antiviral) [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Adverse effects include mild headache and backache. F105 was well tolerated both(100 or 500 mg/square meta) dosing levels. [AIDS Therapies 1995 Sep; p 5 (under Monoclonal Antibodies); AmfAR Treat Dir 1997;8(3); p 63] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Human monoclonal antibody, F105, is an IgG1 kappa antibody produced by a hybridoma constructed from an Epstein-Barr-virus transformant fused with a human myeloma analogue. [Protocol ID: ACTG 232 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Single use 10 ml glass vials containing 5.0 mg/ml of F105. [Protocol ID: ACTG 232 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: ACTG 232 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be stored at 2-8 C. [Protocol ID: ACTG 232 ] MANUFACTURERS 0000002682: Centocor Inc 200 Great Valley Parkway Malvern, PA 193551307 Contact: Dr Richard McCloskey (610)889-4793 REFERENCES MED/97353800. Turbica I, Simon F, Besnier JM, LeJeune B, Choutet P, Goudeau A, Barin F. Temporal development and prognostic value of antibody response to the major neutralizing epitopes of gp120 during HIV-1 infection. J Med Virol. 1997 Jul;52(3):309-15. MED/97360027. McInerney TL, McLain L, Armstrong SJ, Dimmock NJ. A human IgG1 (b12) specific for the CD4 binding site of HIV-1 neutralizes by inhibiting the virus fusion entry process, but b12 Fab neutralizes by inhibiting a postfusion event. Virology. 1997 Jul 7;233(2):313-26. MED/97018136. Chen JD, Yang Q, Yang AG, Marasco WA, Chen SY. Intra- and extracellular immunization against HIV-1 infection with lymphocytes transduced with an AAV vector expressing a human anti-gp120 antibody. Hum Gene Ther. 1996 Aug 20;7(13):1515-25. MED/96290506. Wolfe EJ, Cavacini LA, Samore MH, Posner MR, Kozial C, Spino C, Trapnell CB, Ketter N, Hammer S, Gambertoglio JG. Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1. Clin Pharmacol Ther. 1996 Jun;59(6):662-7. MED/96016013. Cavacini LA, Emes CL, Power J, Desharnais FD, Duval M, Montefiori D, Posner MR. Influence of heavy chain constant regions on antigen binding and HIV-1 neutralization by a human monoclonal antibody. J Immunol. 1995 Oct 1;155(7):3638-44. MED/95164706. Khouri YF, McIntosh K, Cavacini L, Posner M, Pagano M, Tuomala R, Marasco WA. Vertical transmission of HIV-1. Correlation with maternal viral load and plasma levels of CD4 binding site anti-gp120 antibodies. J Clin Invest. 1995 Feb;95(2):732-7. MED/95063934. Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PW, Sawyer LS, Hendry RM, Dunlop N, Nara PL, et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994 Nov 11;266(5187):1024-7. MED/94179837. Cavacini LA, Emes CL, Power J, Duval M, Posner MR. Effect of antibody valency on interaction with cell-surface expressed HIV-1 and viral neutralization. J Immunol. 1994 Mar 1;152(5):2538-45. MED/94015913. Cavacini LA, Emes CL, Power J, Underdahl J, Goldstein R, Mayer K, Posner MR. Loss of serum antibodies to a conformational epitope of HIV-1/gp120 identified by a human monoclonal antibody is associated with disease progression. J Acquir Immune Defic Syndrome. 1993 Oct;6(10):1093-102. MED/93108253. Posner MR, Cavacini LA, Emes CL, Power J, Byrn R. Neutralization of HIV-1 by F105, a human monoclonal antibody to the CD4 binding site of gp120. J Acquir Immune Defic Syndr. 1993 Jan;6(1):7-14. ENTRY MONTH 199401 LAST REVISION DATE 20000801 155 UNIQUE IDENTIFIER DRG-0191 NAME OF SUBSTANCE Anti-Rh Antibodies [Protocol ID: 93 C-155 ] PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-155 PHARMACOLOGICAL ACTION MODE OF ACTION: Patients with classic immune thrombocytopenic pupura (ITP) or HIV-related thrombocytopenia and acute or chronic disease at the time of the intial anti-D treatment were studied. The group with the best results is HIV- children, but all patient groups respond and the effect lasts more than 21 days in 50% of the responders. Duration of response is not influenced by HIV status; futhermore, HIV+ patients show no adverse effects on hemoglobin decrease or HIV disease progression. Other studies also showed that Anti-Rh(D) immunoglobulin is a safe and easily administered treatment, at low cost and slightly lower in efficacy compared with i.v.IG (intravenous immunoglobulin). [Blood 1997 Apr 15;89(8); p 2689-700; Pediatr Med Chir 1993 Jul-Aug;15(4); p 349-52] DISEASES STUDIED/TREATED HIV-associated thrombocytopenia. [Protocol ID: 93 C-155 ] CLASSIFICATION CODE Immunomodulator [Protocol ID: 93 C-155 ] ADVERSE EFFECTS Anti-D is a safe treatment providing a hemostatic platelet increase in greater than 70% of the Rh+ non-splenectomized patients. [Blood 1997 Apr 15;89(8); p 2689-700] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 93 C-155 ] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/97261972. Scaradavou A, Woo B, Woloski BM, Cunningham-Rundles S, Ettinger LJ, Aledort LM, Bussel JB. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood. 1997 Apr 15;89(8):2689-700. MED/94089497. Mascarin M, Trovo MG, Ventura A. [Anti-Rh(D): an efficacious therapeutic alternative in autoimmune hemocytopenias]. Pediatr Med Chir. 1993 Jul-Aug;15(4):349-52. ICA8/92403493. Pinier Y, Pradier C, Bernard E, Durant J, Dellamonica P. Interest of anti-D immunoglobulins (IgG) for treatment of AIDS or ARC patients with severe thrombopenia. Int Conf AIDs. 1992 Jul 19-24;8(3):121 (abstract no. PuB 7437). MED/92256204. Gringeri A, Cattaneo M, Santagostino E, Mannucci PM. Intramuscular anti-D immunoglobulins for home treatment of chronic immune thrombocytopenic purpura. Br J Haematol. 1992 Mar;80(3):337-40. MED/97406385. Smith NA, Boughton BJ. The treatment of autoimmune thrombocytopaenic purpura with anti-D immunoglobulin: similar platelet responses in homozygous and heterozygous Rh(D) positive patients. Transfus Med. 1991 Sep;1(3):183-5. ICA7/1234091. Gringeri A, Santagostino E, Cattaneo M, Simoni L, Tradati F. Anti-D immunoglobulins (IgG) for long-term treatment of patients with HIV-related or idiopathic immune thrombocytopenic purpura (ITP). Int Conf AIDS. 1991 Jun 16-21;7(1):267 (abstract no. M.B.2340). MED/91208398. Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect [see comments]. Blood. 1991 May 1;77(9):1884-93. ICA6/20052190. Santagostino E, Cattaneo M, Capitanio A, Gringeri A, Tradati F, Mannucci PM. Anti-D immunoglobulin for treatment of immune thrombocytopenic purpura (ITP): comparison between HIV-related ITP and idiopathic ITP. Int Conf AIDS. 1990 Jun 20-23;6(2):208 (abstract no. F.B.521). MED/90264050. Babu PG, Cherian T, Jairaj PK, Jayakumari H, John TJ. Lack of evidence for seroconversion to human immunodeficiency virus in recipients of anti-D immunoglobulin containing HIV antibody. Indian J Med Res. 1990 Mar;91:81-3. ENTRY MONTH 199311 LAST REVISION DATE 20000801 156 UNIQUE IDENTIFIER DRG-0190 NAME OF SUBSTANCE Paclitaxel [USPD 1998; p. 545] REGISTRY NUMBER 33069-62-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Tax-11-en-9-one, 5beta,20-epoxy-1,2alpha,4,7beta,10beta,13alph- a- hexahydroxy-, 4,10-diacetate 2-benzoate, 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Taxol [USP DI 2000; p. 2367] PROTOCOL ID NUMBERS No longer recruiting FDA 273A PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-193 PHARMACOLOGICAL ACTION MODE OF ACTION: Promotes the assembly of microtubules and inhibits the tubulin disassembly process. Following IV doses, paclitaxel plasma levels decline in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. After IV doses of 15-275 mg/m2 as 1, 6 or 24 h infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive nonrenal clearance. High drug concentrations have been reported in the bile. The efficacy of paclitaxel in treating AIDS-related Kaposi's sarcoma was evaluated in clinical trials by assessing cutaneous tumor response and by seeking evidence of clinical benefits in patients. The objective response rate was 59% in patients with prior systemic therapy. The median time to response was 8.1 weeks and the median duration of reponse was 10.4 months. Other patient benefits included instances of improved pulmonary function in patients with pulmonary involvement, improved ambulation, or resolution of ulcers. [PDR 1997; p 723-4; MeadJohnson/Bristol-Myers Squibb Package Insert Aug 1997; p 2-3] DISEASES STUDIED/TREATED FDA approved (8/5/97) for the second-line treatment of AIDS-related Kaposi's sarcoma. [MeadJohnson/Bristol-Myers Squibb Package Insert Aug 1997; p 2-3] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 2363] OTHER MAJOR USES Breast cancer and metastatic carcinoma of the ovary. [PDR 1997; p 724] SUBSTANCE INTERACTIONS Combinations involving any of the following medications or therapies may interact with this drug: blood dyscrasia-causing medications, bone marrow depressants or radiation therapy, killed virus vaccines, live virus vaccines. When paclitaxel was given as sequential infusion with cisplatin, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence. In the absence of formal clinical studies, caution should be used when giving paclitaxel concomitantly with substrates or inhibitors of the cytochrome P 450 isoenzymes CYP2C8 and CYP3A4 (all involved in the metabolism of paclitaxel). [USP DI 1997; p 2233-4] ADVERSE EFFECTS Adverse effects include neutropenia, peripheral neuropathy, mucositis, alopecia, N/V, diarrhea, cardiotoxicity, and hypotension. The adverse events profile of paclitaxel in patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma was generally similar to that seen in patients with solid tumors. In this immunosuppressed patient population, a lower-dose intensity of paclitaxel and supportive therapy including hematopoietic growth factors are recommended. Patients with AIDS-related Kaposi's sarcoma may have more severe hematologic toxicities than patients with solid tumors. [MeadJohnson/Bristol-Myers Squibb Package Insert Aug 1997; p 3] CONTRAINDICATIONS Contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel. Should not be used in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of <1000 cell/cubic mm. Patients with a history of severe hypersensitivity reaction to products containing Cremophor (polyoxyethylated castor oil) should not be treated with paclitaxel. [PDR 1997; p 724; MeadJohnson/Bristol-Myers Squibb Package Insert Aug 1997] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A natural or semisynthetic diterpene extracted from the bark of the Western (Pacific) yew (Taxus brevifolia) or from needles and twigs of a more prevalant yew (Taxus baccata). [AHFS Drug Information 1997; p 841] CHEMICAL/PHYSICAL DATA Molecular Formula: C47-H51-N-O14 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 853.93 [USPD 1998; p. 545] CHEMICAL/PHYSICAL DATA Melting Point: 213-216 C [Merck Index 1996; p. 1200] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.11%, H6.02%, N1.64%, O26.23% [Merck Index 1996; p. 1200] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Clear colorless to slightly yellow viscous solution or a white to off-white crystalline powder. [PDR 1997; p 723] SUBSTANCE DELIVERY DATA DOSAGE FORM: Single dose vials, 30 mg/5 mL, 100 mg/16.7 mL. [PDR 1997; p 727] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [PDR 1997; p 726-7] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-25 C (36-77 F) and protect from light. [PDR 1997; p 727] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES ICDB/97636617. Hausner P, Otterson G, McElroy K, Curt GA. Performance status in clinical oncology: different import in protocol and non-protocol settings (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol;15:A1617 1996. ICDB/97635859. Mega A, Akhtar MS, Safran H, Rich J, Sikov W, Flanigan T. Low dose weekly paclitaxel for HIV associated Kaposi's sarcoma (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol;15:A859 1996. ICDB/97635854. Gill PS, Tulpule A, Reynolds T, Hadjenberg J, Mocharnuk R, Espina BM, Bresnahan J, Cabriales S, Ilaw M, Shea K, et al. Paclitaxel (Taxol) in the treatment of relapsed or refractory advanced AIDS-related Kaposi's sarcoma (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol;15:A854 1996. ICDB/97636258. Younes A, Romaguera J, Sarris A, North L, Preti A, Hagemeister F, McLaughlin P, Rodriguez MA, Cabanillas F. Phase II trial of infusional taxol and high dose cytoxan with granulocyte colony stimulating factor (filgrastim) for the treatment of relapsed/refractory intermediate grade non-Hodgkin's lymphoma (NHL) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol;15:A1258 1996. MED/96140305. Sarris AH, Younes A, McLaughlin P, Moore D, Hagemeister F, Swan F, Rodriguez MA, Romaguera J, North L, Mansfield P, Callendar D, Mesina O, Cabanillas F. Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1996 Jan;14(1):233-9. MED/96228966. Arbuck SG. Paclitaxel: current developmental approaches of the National Cancer Institute. Semin Oncol. 1995 Dec;22(6 Suppl 15):55-63. MED/96050094. Sweet MJ, Hume DA. RAW264 macrophages stably transfected with an HIV-1 LTR reporter gene provide a sensitive bioassay for analysis of signalling pathways in macrophages stimulated with lipopolysaccharide, TNF-alpha or taxol. J Inflamm. 1995;45(2):126-35. MED/95326733. Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH, Humphrey RW, Feigal E, Steinberg SM, Broder S, et al. Treatment of HIV-associated Kaposi's sarcoma with paclitaxel. Lancet. 1995 Jul 1;346(8966):26-8. AIDS/95920166. Saville MW, Lietzau J, Pluda JM, Wilson W, Bailey J, Cohen R, Feigal F, Feuerstein I, Humphrey R, Broder S, et al. Use of paclitaxel (Taxol(TM)) as therapy for HIV-associated Kaposi's sarcoma (KS). Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:79. ICDB/96615860. Saville MW, Lietzau J, Pluda M, Wilson W, Bailey J, Cohen R, Feigal E, Humphrey R, Broder S, Yarchoan R. Phase II study of paclitaxel (Taxol) for the treatment of HIV-associated Kaposi's sarcoma (KS) (Meeting abstract). Blood;84(10,Suppl 1):248a 1994. ENTRY MONTH 199310 LAST REVISION DATE 20001106 157 UNIQUE IDENTIFIER DRG-0189 NAME OF SUBSTANCE Tumor Necrosis Factor soluble receptor-immunoadhesin complex [Protocol ID: 93-I-206 ] PROTOCOL ID NUMBERS Complete NIAID ACTG 928 PROTOCOL ID NUMBERS No longer recruiting CC 93 I-206 PHARMACOLOGICAL ACTION MODE OF ACTION: Tumor necrosis factor-alpha (TNF-alpha) is a naturally occuring cytokine with many functions in the human immune system. TNF-alpha levels are elevated in HIV+ people, and TNF-alpha may play a role in the pathogenesis of HIV disease. TNF-alpha may also be implicated in the wasting syndrome associated with HIV disease. In vitro, TNFR:Fc (a TNF-alpha blocking agent) has been shown to inhibit TNF-alpha induced expression of HIV-1 and limit the activation of the HIV-long terminal repeat transcription in chronically infected human cell lines. TNFR:Fc bind to TNF-alpha and TNF-gamma, whereas anti-TNF antibodies bind largely to TNF-alpha. A dose ranging safety study in which TNFR:Fc was administered subcutaneously twice weekly for 8 weeks to HIV+ subjects with CD4 count <200 cells/cubic mm showed that while the doses were well tolerated, no improvement occurred in immunologic or virologic parameters. [AmfAR Treat Dir 1997;8(3); p 58] DISEASES STUDIED/TREATED Inhibition of tumor necrosis factor production in HIV infection. [AmfAR Treat Dir 1995;7(4); p 60] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Adverse effects include skin rash and chest tightness (single IV dose). [AmfAR Treat Dir 1997;8(3); p 58] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A TNF blocking agent. [Protocol ID: 93-I-206 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: TNFR:Fc is a recombinantly produced dimer composed of two molecules of the tumor necrosis factor (TNF) receptor linked by the Fc portion of immunoglobulin. [AmfAR Treat Dir 1997;8(3); p 58] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. [Protocol ID: 93-I-206 ] MANUFACTURERS 0000003153: Natl Inst of Allergy & Infect Dis / Cln Ctr 9000 Rockville Pike / RM 11C304 Bethesda, MD 20892 Contact: Unspecified (800)411-1222 REFERENCES MED/97296311. Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, Probert L, Kollias G, McDevitt HO. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med. 1997 May 5;185(9):1573-84. MED/97107749. Lynch DH, Campbell KA, Miller RE, Badley AD, Paya CV. FasL/Fas and TNF/TNFR interactions in the regulation of immune responses and disease. Behring Inst Mitt. 1996 Oct;(7):175-84. MED/97180787. Kreuzer KA, Rockstroh JK, Jelkmann W, Theisen A, Spengler U, Sauerbruch T. Inadequate erythropoietin response to anaemia in HIV patients: relationship to serum levels of tumor necrosis factor-alpha, interleukin-6 and their soluble receptors. Br J Haematol. 1997 Feb;96(2):235-9. MED/97085691. Rizzardi GP, Barcellini W, Tambussi G, Lillo F, Malnati M, Perrin L, Lazzarin A. Plasma levels of soluble CD30, tumor necrosis factor (TNF)-alpha and TNF receptors during primary HIV-1 infection: correlation with HIV-1 RNA and the clinical outcome. AIDS. 1996 Nov;10(13):F45-50. MED/96198880. Granowitz EV, Saget BM, Angel JB, Wang MZ, Wang A, Dinarello CA, Skolnik PR. Soluble tumor necrosis factor receptors inhibit phorbol myristate acetate and cytokine-induced HIV-1 expression in chronically infected U1 cells. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Apr 15;11(5):430-7. MED/95181808. Agostini C, Zambello R, Trentin L, Cerutti A, Enthammer C, Facco M, Milani A, Sancetta R, Garbisa S, Semenzato G. Expression on TNF receptors by T cells and membrane TNF-alpha by alveolar macrophages suggests a role for TNF-alpha in the regulation of the local immune responses in the lung of HIV-1-infected patients. J Immunol. 1995 Mar 15;154(6):2928-38. MED/95209276. Wilt SG, Milward E, Zhou JM, Nagasato K, Patton H, Rusten R, Griffin DE, O'Connor M, Dubois-Dalcq M. In vitro evidence for a dual role of tumor necrosis factor-alpha in human immunodeficiency virus type 1 encephalopathy [see comments]. Ann Neurol. 1995 Mar;37(3):381-94. MED/95318750. Puccioni-Sohler M, Rieckmann P, Kitze B, Lange P, Albrecht M, Felgenhauer K. A soluble form of tumour necrosis factor receptor in cerebrospinal fluid and serum of HTLV-1-associated myelopathy and other neurological diseases. J Neurol. 1995 Mar;242(4):239-42. MED/94340806. Zangerle R, Fuchs D, Sarcletti M, Gallati H, Reibnegger G, Wachter H, Dierich MP, Most J. Increased concentrations of soluble tumor necrosis factor receptor 75 but not of soluble intercellular adhesion molecule-1 are associated with the decline of CD4+ lymphocytes in HIV infection. Clin Immunol Immunopathol. 1994 Sep;72(3):328-34. MED/93211956. Howard OM, Clouse KA, Smith C, Goodwin RG, Farrar WL. Soluble tumor necrosis factor receptor: inhibition of human immunodeficiency virus activation. Proc Natl Acad Sci USA. 1993 Mar 15;90(6):2335-9. ENTRY MONTH 199309 LAST REVISION DATE 20000801 158 UNIQUE IDENTIFIER DRG-0188 NAME OF SUBSTANCE Paromomycin sulfate [USPD 1998; p. 551] REGISTRY NUMBER 1263-89-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME D-Streptamine, O-2-amino-2-deoxy-alpha-D-glucopyranosyl-(1->- 4)-O-(O-2,6-diamino-2,6 -dideoxy-beta-L-idopyranosyl-(1->3)-beta-D-ri- bofuranosyl-(1->5))-2-d eoxy-, sulfate (salt) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Humatin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 192 PROTOCOL ID NUMBERS Recruiting NIAID DAIDS R001 PHARMACOLOGICAL ACTION MODE OF ACTION: Under aerobic conditions, the aminoglycosides are bactericidal, but their exact mechanism of action is unknown. These antibiotics must be actively transported across the cytoplasmic membrane into susceptible bacteria; two sequential energy-dependent phases, called EDP-1 and EDP-II and characterized by slow and very rapid rates of uptake, respectively, have been observed. Based on studies done primarily of streptomycin, the bacterial ribosome is considered to be the principal target of the aminoglycosides. It is still not known why the aminoglycosides are bactericidal, while other antibiotics that impair protein synthesis are usually only bacteriostatic. Bacterial cell death does not appear to correlate with the production of faulty proteins due to misreading of the genetic code. The lethal effect of the aminoglycosides may result from their high affinity for the 30S subunit that leads to essentially irreversible binding, but other mechanisms may be involved. Paromomycin is active against many gram-negative bacilli, principally members of the Enterobacteriaceae (e.g., Escherichia coli). Pseudomonas aeruginosa are resistant, however. Many strains of Staphylococcus aureus are susceptible, but most other gram-positive bacteria are resistant. Paromomycin is a luminal amebicide. Entamoeba histolytica, the causative organism of amebiasis, Dentamoeba fragilis, and various tapeworms, including Taenia saginata, T. solium, Diphyllobothrium latum, Dipylidium caninum, and Hymenolepis nana, are susceptible to paromomycin. Paromomycin is poorly absorbed in the gastrointestinal tract, and most of a single dose is eliminated in the feces. Nevertheless, to avoid excessive absorption, the drug should be used with caution in patients with renal failure, intestinal inflammation, or ulcerations. [Drug Evaluations Annual 1992; p 1383-86, 1405-6, 1606; AHFS Drug Information 1997; p 42-3] DISEASES STUDIED/TREATED Currently being investigated for treatment of cryptosporidiosis. [AmfAR Treat Dir 1997;8(3); p 76; Protocol ID: ACTG 192 ] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 3288] OTHER MAJOR USES Intestinal amebiasis- acute and chronic; management of hepatic coma- as adjunctive therapy; cestodiasis (tapeworm infections). [AHFS Drug Information 1997; p 43] SUBSTANCE INTERACTIONS Penicillins (antipseudomonal penicillins), ethacrynic acid, furosemide, bumentanide, skeletal muscle relaxants, methoxyflurane, amphotericin B, vancomycin, cisplatin, cyclosporine, intravenous indomethacin, cephalothin, and dimenhydrinate all have reported interactions with the aminoglycosides. [Drug Evaluations Annual 1992; p 1393-4] ADVERSE EFFECTS May cause nausea, abdominal cramps, and diarrhea, particularly when doses exceed 3 g daily. Overgrowth of non-susceptible organisms and a malabsorption syndrome may occur after prolonged administration. Possibility of nephrotoxicity in patients with ulcerative lesions. [Drug Evaluations Annual 1992; p 1405-6; AHFS Drug Information 1997; p 43] CONTRAINDICATIONS Contraindicated in patients with a history of previous hypersensitivity to the drug. Also contraindicated in those with intestinal obstruction or ulcerative lesions. [AHFS Drug Information 1997; p 43; Drug Evaluations Annual 1992; p 1405-6, 1606] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An aminoglycoside antibiotic derived from Streptomyces rimosus and structurally related to neomycin, streptomycin and kanamycin. [AHFS Drug Information 1997; p 42] CHEMICAL/PHYSICAL DATA Molecular Formula: C23-H45-N5-O14.x-H2-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 615.64 (base) [USPD 1998; p. 551] CHEMICAL/PHYSICAL DATA Elemental Comp: C44.87%, H7.37%, N11.38%, O36.38% (base) [Merck Index 1996; p. 1209] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, moderately soluble in methanol, sparingly soluble in abs ethanol. [Merck Index 1996; p 1210] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Amorphous white powder. [Merck Index 1996; p 1210] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules 250 mg. [AHFS Drug Information 1997; p 44] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AHFS Drug Information 1997; p 44] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store in tightly closed containers at 15-30 C. [AHFS Drug Information 1997; p 44] MANUFACTURERS 0000004009: Parke-Davis Pharmaceutical Research 2800 Plymouth Rd Ann Arbor, MI 48105 Contact: Dr J Tyler Martin (313)997-3556 MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)223-0432 REFERENCES MED/97416465. Clark RA, Bessinger R. Re: Cryptosporidiosis among patients infected with human immunodeficiency virus: factors related to symptomatic infection and survival [letter]. Am J Epidemiol. 1997 Aug 15;146(4):358-9. MED/97250598. Ventura G, Cauda R, Larocca LM, Riccioni ME, Tumbarello M, Lucia MB. Gastric cryptosporidiosis complicating HIV infection: case report and review of the literature. Eur J Gastroenterol Hepatol. 1997 Mar;9(3):307-10. MED/97215047. Blanshard C, Shanson DC, Gazzard BG. Pilot studies of azithromycin, letrazuril and paromomycin in the treatment of cyptosporidiosis. Int J STD AIDS. 1997 Feb;8(2):124-9. AIDS/97926685. Hewitt RG, Yiannoutsos CT, Carey J, Geiseler PJ, Soave R, Rosenberg R, Vazquez GJ, Wheat J, Fass RJ, Higgs ES, et al. A double-blind, placebo-controlled trial of paromomycin (par) for the treatment of cryptosporidiosis (cs) in patients with advanced HIV disease and CD4 counts under 150 (ACTG 192). 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:65 (abstract no. 4). MED/96202857. Flanigan TP, Ramratnam B, Graeber C, Hellinger J, Smith D, Wheeler D, Hawley P, Heath-Chiozzi M, Ward DJ, Brummitt C, Turner J. Prospective trial of paromomycin for cryptosporidiosis in AIDS. Am J Med. 1996 Mar;100(3):370-2. MED/96263610. Caramello P, Mazzucco G, Romeo M, Ullio A, DeRosa G, Lucchini A, Forno B, Brancale T, Macor A, Preziosi C, et al. Clinical and microscopical features of small-intestinal microsporidiosis in patients with AIDS. Infection. 1995 Nov-Dec;23(6):362-8. MED/95226747. Tan WW, Chapnick EK, Abter EI, Haddad S, Zimbalist EH, Lutwick LI. Paromomycin-associated pancreatitis in HIV-related cryptosporidiosis. Ann Pharmacother. 1995 Jan;29(1):22-4. MED/95126196. Mohri H, Fujita H, Asakura Y, Katoh K, Okamoto R, Tanabe J, Harano H, Noguchi T, Inayama Y, Amano T, et al. Case report: inhalation therapy of paromomycin is effective for respiratory infection and hypoxia by cryptosporidium with AIDS. Am J Med Sci. 1995 Jan;309(1):60-2. MED/95052871. Scaglia M, Atzori C, Marchetti G, Orso M, Maserati R, Orani A, Novati S, Olliaro P. Effectiveness of aminosidine (paromomycin) sulfate in chronic Cryptosporidium diarrhea in AIDS patients: an open, uncontrolled, prospective clinical trial. J Infect Dis. 1994 Nov;170(5):1349-50. ENTRY MONTH 199309 LAST REVISION DATE 20001107 159 UNIQUE IDENTIFIER DRG-0187 NAME OF SUBSTANCE Thymic Humoral Factor [Facts and Comparisons 1995; p 814] PROTOCOL ID NUMBERS No longer recruiting FDA 136A PHARMACOLOGICAL ACTION MODE OF ACTION: THF is reported to increase the number of T-lymphocytes and augment cell-mediated immunity. A clinical trial to evaluate efficacy and safety of a combined zidovudine/THF therapy in HIV+ subjects was conducted in 13 patients. Twenty-six patients were included as controls receiving only zidovudine. No significant difference was observed between the two groups as far as surrogate markets of HIV disease progression are concerned, but patients receiving zidovudine and THF showed a lower number of opportunistic complications. Only one patient in this group progressed to manifest AIDS while 9 of 18 controls presented disease progression. Survival time was increased in the case group. The exact immunological effect of thymus hormones in HIV infection has still to be elucidated, but a possible therapeutic role of these agents is foreseeable. However, analysis (1995) of another, multicenter study comparing THF (i.m.) and AZT (oral) in HIV+ asymptotic subjects, demonstrated no significant differences between the two groups in terms of CD4+ count increases and viral RNA decreases. Future development of THF has been discontinued in the US. [Int Conf AIDS 1993 Jun 6-11;9(1); 246 (abstract no. PO-A28-0671); AmfAR Treat Dir 1997;8(3); p 65] DISEASES STUDIED/TREATED Enhancement of immune response in HIV infection. [AmfAR Treat Dir 1995;7(4); p 59] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Mild fatigue and reduced mental acuity have been reported. [AmfAR Treat Dir 1997;8(3); p 65] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: THF is a natural peptide hormone isolated from calf thymus. THF-gamma 2 is a member of the general class of thymus-derived compounds and is a synthetic octapeptide. This octapeptide has demonstrated both in vitro and in vivo immunomodulatory properties. [AmfAR Treat Dir 1993;6(4); p 55] SUBSTANCE DELIVERY DATA DOSAGE FORM: 500 ng and 40 micrograms. [Protocol ID: 136A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [AmfAR Treat Dir 1997;8(3); p 65] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 REFERENCES MED/97191590. Maggiolo F, Taras A, Pravettoni MG, Leone M, Ingrosso A, Suter F. Zidovudine and thymus humoral factor gamma-2 in the treatment of HIV infection: preliminary clinical experience. Infection. 1997 Jan-Feb;25(1):35-8. AIDS/95920738. Maggiolo F, Taras A, Pravettoni MG, Caprioli S, Marchetti G, Suter F. AZT and THF combined therapy in HIV positive patients. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:57. ICA9/93334147. Clayette P, Chassard D, Marce D, Toutain B, Thebault JJ, Lebeaut A, Dormont D. THF-gamma 2 phase I study in healthy volunteers. Int Conf AIDS. 1993 Jun 6-11;9(1):246 (abstract no. PO-A28-0671). MED/94134981. Calenda V, Silvy F, Chermann JC. Effects of thymus humoral factor gamma-2 (THF gamma 2) on lymphohaematopoietic progenitor cells: an in vitro study. Res Immunol. 1993 Jul-Sep;144(6-7):395-406. ICA8/92401177. Kouttab N, Accetta G, Calabresi P, Skowron G. Phase I trial of intramuscular (IM) thymic humoral factor (THF) in combination with zidovudine (ZDV) in HIV infected individuals. Int Conf AIDS. 1992 Jul 19-24;8(2):B161 (abstract no. PoB 3447). MED/90318423. Trainin N. Prospects of AIDS therapy by thymic humoral factor, a thymic hormone. Nat Immun Cell Growth Regul. 1990;9(3):155-9. Luzi G, Pesce AM, De Luca S, Carlesimo M, Aiuti F. Viral Infections and Thymic Hormones: A New Therapeutic Approach. Serono Symp Publ Raven Press. 1989;59:291-302. MED/87221086. Handzel ZT, Berner Y, Segal O, Burstein Y, Buchner V, Pecht M, Levin S, Burstein R, Milchan R, Bentwich Z, et al. Immunoreconstitution of T-cell impairments in asymptomatic male homosexuals by thymic humoral factor (THF). Int J Immunopharmacol. 1987;9(2):165-73. ENTRY MONTH 199309 LAST REVISION DATE 20000801 160 UNIQUE IDENTIFIER DRG-0186 NAME OF SUBSTANCE Anti-TNF Monoclonal Antibody (Chimeric) [Protocol ID: 93 I-182 ] PROTOCOL ID NUMBERS No longer recruiting CC 93 I-182 PROTOCOL ID NUMBERS No longer recruiting CC 95 I-0133 PHARMACOLOGICAL ACTION MODE OF ACTION: Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to stimulate human immunodeficiency virus type 1 (HIV-1) replication, has been implicated in the pathogenesis of HIV-1 infection. Inhibition of TNF-alpha by a chimeric humanized monoclonal antibody, cA2, was investigated. A murine-human chimeric monoclonal antibody was constructed by cloning the heavy and light chain variable region genomic domains of A2 and joining them to the respective heavy and light chain genomic domains of human gamma1 constant regions. The resulting mouse-human chimeric IgG monoclonal antibody, designated cA2, was expressed from a stably transfected SP2/0 murine hybridoma cell line. Incorporating human constant region structure into the chimeric construct might also be expected to improve allogenic antibody effector function and increase serum circulating half-life in human subjects. To date, experience with cA2 has been gained in two phase I/II studies. In a phase I/II trial in healthy human volunteers, 9 volunteers received cA2 alone in ascending doses of 0.1, 1, 5 or 10 milligrams per kilogram bodyweight. cA2 was well tolerated by all volunteers. Tumor necrosis factor-alpha (TNF-alpha) is a monocyte-derived cytokine shown to be important in killing both tumor cells and target cells infected with certain viruses. Sustained blood levels of TNF have been found in studies of patients with sepsis and TNF levels above 540 pg/ml have been associated with a fatal outcome. Elevated serum TNF levels increase with the advancing stage of infection. TNF-alpha has also been demonstrated to enhance HIV replication in chronically infected T lymphocytic and promonocytic cell lines when administered alone. A recent study has shown that treatment of primary blood monocyte-derived macrophages with recombinant TNF-alpha enhanced HIV replication fivefold or more above control. Thus TNF-alpha appears to be one of multiple inflammatory cytokines that may serve to upregulate HIV expression and thereby accelerate clinical progression of HIV disease. TNF-alpha also functions biologically in the control of nutritional homeostasis and indeed derives its other name, cachetin, from the dysregulation that may be associated with excessive levels or activity of this cytokine. The desire to block the actions of TNF-alpha in producing enhanced HIV expression and cachexia thus serves as an important rationale for the development and clinical testing of an anti-TNF antibody. [Protocol ID: 93 I-182 ; J Infect Dis 1996 Jul;174(1); p 63-8] DISEASES STUDIED/TREATED Inhibition of tumor necrosis factor production in HIV infection. [Protocol ID: 93 I-182 ] CLASSIFICATION CODE Immunomodulator [Protocol ID: 93 I-182 ] SUBSTANCE INTERACTIONS Infusions of Interleukin-2 (IL-2) produce increases in CD4 counts in a majority of HIV-1 infected patients with baseline CD4 greater than 200. In pilot studies, dose-limiting constitutional symptoms and transient increases in viral load paralleled increases in serum levels of TNF-alpha. A study was done to determine in TNF inhibition during IL-2 treatment would reduce IL-2 associated adverse events and ablate viral activation. Patients with CD4=200-500 were randomized to receive IL-2 alone, IL-2 plus cA2, or IL-2 plus thalidomide. At the doses studied, IL-2 administered with cA2 or thalidomide was safe. Further evaluation at higher doses of cA2 on TNF blockade will be necessary to assess the contribution of TNF to IL-2 treatment toxicity. [PDR 1997; p 71] ADVERSE EFFECTS Chimeric A2 has been well tolerated in phase I/II clinical trials. [Protocol ID: 93 I-182 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Chimeric A2 (cA2) is an anti-TNF (tumor necrosis factor) mouse-human monoclonal antibody. [Protocol ID: 93 I-182 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 10 mg/kg in 150 ml of saline from original glass vial containing 300 mg of cA2 in a buffer solution (pH 7.2). [Protocol ID: 93 I-182 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [Protocol ID: 93 I-182 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The vials must be stored refrigerated at 2 to 8 C. [Protocol ID: 93 I-182 ] MANUFACTURERS 0000002682: Centocor Inc 200 Great Valley Parkway Malvern, PA 193551307 Contact: Dr Richard McCloskey (610)889-4793 REFERENCES AIDS/97926254. Walker RE, Hahn B, Kelly GG, Miller K, Piscitelli S, Figg WD, Davey RT, Falloon J, Kovacs JA, Polis MA, et al. Effects of TNF-alpha antagonists thalidomide and monoclonal anti-TNF antibody (cA2) on reducing IL-2 associated toxicities: a randomized, controlled trial. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:71 (abstract no.36). MED/96261994. Walker RE, Spooner KM, Kelly G, McCloskey RV, Woody JN, Falloon J, Baseler M, Piscitelli SC, Davey RT Jr, Polis MA, Kovacs JA, Masur H, Lane HC. Inhibition of immunoreactive tumor necrosis factor-alpha by a chimeric antibody in patients infected with human immunodeficiency virus type 1. J Infect Dis. 1996 Jul;174(1):63-8. MED/96070209. Maini RN, Elliott MJ, Brennan FM, Williams RO, Chu CQ, Paleolog E, Charles PJ, Taylor PC, Feldman M. Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease. Immunol Rev 1995 Apr;144:195-223. MED/95386252. Elliott MJ, Feldmann M, Maini RN. TNF alpha blockade in rheumatoid arthritis: rationale, clinical outcomes and mechanisms of action. Int J Immunopharmacol 1995 Feb;17(2):141-5. AIDS/95920744. Walker RE, Kelly GG, Kilgariff CE, Woody JN, Falloon J, Polis MA, Davey RT, Kovacs JA, Masur H, Lane HC. A pilot study of the safety and antiviral activity of a chimeric anti-TNF antibody in HIV infected patients. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:58. ICA6/30031790. Vyakarnam A, Matear P, Meager A, Shultz T, Loveday C, Beverley P. Inhibition of HIV-1 replication in CD4+ T cell subsets with anti-TNF neutralizing antibodies. Int Conf AIDS. 1990 Jun 20-23;6(3):161 (abstract no. S.A.317). ENTRY MONTH 199308 LAST REVISION DATE 20000801 161 UNIQUE IDENTIFIER DRG-0185 NAME OF SUBSTANCE Doxorubicin hydrochloride (liposomal) [USPD 1998; p. 256] SYNONYMS Doxil [USP DI 2000; p. 1364] PROTOCOL ID NUMBERS Complete NIAID ACTG 286 PROTOCOL ID NUMBERS No longer recruiting FDA 134A PROTOCOL ID NUMBERS No longer recruiting FDA 134B PROTOCOL ID NUMBERS No longer recruiting FDA 134C PROTOCOL ID NUMBERS No longer recruiting FDA 134D PROTOCOL ID NUMBERS Recruiting CC 01 C-0067 PHARMACOLOGICAL ACTION MODE OF ACTION: Doxorubicin hydrochloride, the active ingredient of this formulation, is thought to bind DNA and inhibit nucleic acid synthesis. There is rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis and induction of mutagenesis and chromosomal aberrations. Encapsulation in long-circulating liposomes (i.e., phospholipid bilayers formulated with surface-bound methoxypolyethylene glycol) increases blood circulation time. These liposomes have a half-life of ca. 55 hours in humans; they are stable in blood, and direct measurement shows that at least 90% of the drug remains encapsulated during circulation. Because of their small size the liposome particles may be able to penetrate the altered and often compromised vasculature of tumors. Encapsulation of doxorubicin hydrochloride alters the pharmacokinetics of the drug with resultant decreased distribution into peripheral compartments, increased distribution into Kaposi's sarcoma (KS) lesions, and decreased plasma clearance. Following IV infusion over 15 minutes of a 40-mg/square meter dose of the liposomal injection in adults with KS, peak plasma concentration averaged 20.1 microgram/ml. Plasma clearance was slow with a mean clearance value of 0.041 L/h/square meter at a dose of 20 mg/square meter. Liposomal doxorubicin may cause regression of KS via 2 different mechanisms: (1) by highly specific inhibition of KS spindle cell proliferation and (2) by induction of monocyte chemoattractant protein-1 expression in KS spindle cells, which may result in increased recruitment of phagocytic cells into the lesions. [PDR 1997; p 2613-4; AHFS Drug Information 1997; p 739; Res Virol 1994 May-Aug;145(3-4); p 261-69] DISEASES STUDIED/TREATED Treatment of AIDS related Kaposi's sarcoma. FDA approved 11/17/95 for the treatment of Kaposi's sarcoma in AIDS patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy. [PDR 1997; p 2614; FDA Bulletin ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1360] SUBSTANCE INTERACTIONS Although the AIDS patient with KS population using this drug is on various antiviral medications, drug-drug interactions of this drug and the antiviral drugs have not been evaluated. However, drugs known to interact with nonencapsulated doxorubicin hydrochloride should be considered also to interact with the encapsulated formulation. [PDR 1997; p 2614] ADVERSE EFFECTS Side effects can include stomatitis, hair loss, nausea, and hematological toxicity. One case of fatal hepatic failure in a patient with a history of symptom free hepatitis B was attributed to liposomal doxorubicin. Special attention must be given to possible cardiac toxicity, an effect exhibited by doxorubicin hydrochloride. The principle dose-limiting toxicity of the encapsulated drug in AIDS patients with KS has been myelosuppression. [AmfAR Treat Dir 1997;8(3); p 78; PDR 1997; p 2614-5; AHFS Drug Information 1997; p 741] CONTRAINDICATIONS Contraindicated in patients who have a history of hypersensitivity to conventional formulations of doxorubicin hydrochloride. [PDR 1997; p 2614] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An intravenous formulation of doxorubicin that has been encapsulated in liposomes. [PDR 1997; p 2613] CHEMICAL/PHYSICAL DATA Molecular Formula: C27-H29-N-O11.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 579.99 [USPD 1998; p. 256] CHEMICAL/PHYSICAL DATA Melting Point: 204-205 C [Merck Index 1996; p. 582] CHEMICAL/PHYSICAL DATA Elemental Comp: C59.67%, H5.38%, N2.58%, O32.38% (base) [Merck Index 1996; p. 581] SUBSTANCE DELIVERY DATA DOSAGE FORM: Doxorubicin hydrochloride liposome injection (Doxil) is supplied as a sterile, translucent, red liposomal dispersion in 10 mL glass, single use vials. Each vial contains 20 mg doxorubicin hyrochloride at a concentration of 2 mg/ml. [PDR 1997; p 2616] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion of a dose of 20mg/square meter over 30 minutes. [PDR 1997; p 2616] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refrigerate at 2-8 C (35.6 - 46.6 F). Avoid freezing. [PDR 1997; p 2616] MANUFACTURERS 0000005209: ALZA Corporation 1900 Charleston Road / PO Box 7210 Mountain View, CA 940397210 Contact: Unspecified (800)227-9953 MANUFACTURERS 0000005209: ALZA Corporation 1900 Charleston Road / PO Box 7210 Mountain View, CA 940397210 REFERENCES MED/97238119. Amantea MA, Forrest A, Northfelt DW, Mamelok R. Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma. Clin Pharmacol Ther. 1997 Mar;61(3):301-11. MED/97228822. Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi's sarcoma. Drugs. 1997 Mar; ;53(3):520-38. MED/97178757. Northfelt DW, Dezube BJ, Thommes JA, Levine R, Von Roenn JH, Dosik GM, Rios A, Krown SE, DuMond C, Mamelok RD. Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy. J Clin Oncol. 1997 Feb;15(2):653-9. AIDS/97926746. Northfelt D, Stewart S. DOXIL (pegylated liposomal doxorubicin) as first-line therapy of AIDS-related Kaposi's sarcoma (KS): integrated efficacy and safety results from two comparative trials. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:200 (abstract no.736). AIDS/97926623. Medve M, Manegold C, Hussinger D, Jablonowski H. Long term experience with liposomal doxorubicin as treatment for AIDS-related Kaposi's sarcoma. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:194 (abstract no.704). ASHM8/97153607. Newell M, Milliken S, Chipman M, Cebon J, Lewis C, Goldstein D, Cooper DA. DOX-SL (stealth liposomal doxorubicin HCL) maintenance therapy after response in AIDS-related Kaposi's sarcoma. Annu Conf Australas Soc HIV Med. 1996 Nov 14-17;8:48 (abstract no.27). ICA11/97926902. Stewart S, Jablonowski H, Goebel FD, L'Age M, Spittle M, Luthy R. Randomized comparative trial of DOXIL vs. Bleomycin and Vincristine in the treatment of AIDS-Related KS. Int Conf AIDS. 1996 Jul 7-12;11 (Program Supplement):27 (abstract no.LB.B.6026). MED/96200418. Goebel FD, Goldstein D, Goos M, Jablonowski H, Stewart JS. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. The International SL-DOX Study Group. Br J Cancer. 1996 Apr;73(8):989-94. MED/96265821. Porche DJ, Liposomal doxorubicin (Doxil). J Assoc Nurses AIDS Care. 1996 Mar-Apr;7(2):55-9. MED/97086350. Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma. J Clin Pharmacol. 1996 Jan;36(1):55-63. ENTRY MONTH 199307 LAST REVISION DATE 20000801 162 UNIQUE IDENTIFIER DRG-0184 NAME OF SUBSTANCE Thalidomide [USPD 1998; p. 723] REGISTRY NUMBER 50-35-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1H-Isoindole-1,3(2H)-dione, 2-(2,6-dioxo-3-piperidinyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Thalomid [USP DI 2000; p. 2945] PROTOCOL ID NUMBERS Complete NIAID ACTG 251 PROTOCOL ID NUMBERS No longer recruiting FDA 133A PROTOCOL ID NUMBERS No longer recruiting FDA 230A PROTOCOL ID NUMBERS No longer recruiting FDA 230B PROTOCOL ID NUMBERS No longer recruiting FDA 262A PROTOCOL ID NUMBERS No longer recruiting FDA 279A PROTOCOL ID NUMBERS No longer recruiting CC 95 I-0133 PROTOCOL ID NUMBERS No longer recruiting CC 96 D-0095 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 267 PROTOCOL ID NUMBERS Recruiting CC 96 C-0004 PHARMACOLOGICAL ACTION MODE OF ACTION: Thalidomide probably has a direct effect on the immune system since it has no antibacterial activity yet seems to be effective against some bacterial infections. The immunomodulatory effect of thalidomide is currently unknown. The possibility that the administration of this compound will accelerate the deterioration of the immunologic status of HIV patients cannot be excluded. It has been shown in vitro that thalidomide suppresses HIV and Toxic Necrosis FactOR (TNF)-alpha expression in stimulated, chronically infected promonocytic U1 cells and in PMBC (Peripheral Blood Mononuclear Cells) isolated from HIV+ patients. Effective concentrations of thalidomide range from 5-50 microgram/mL depending on the HIV-1 inducer used. The anti-TNF activity of thalidomide is also being studied as a treatment for AIDS-related wasting syndrome. [Drug Saf 1992 Mar-Apr;7(2); p 116-34; AmfAR Treat Dir 1997;8(3); p 57] DISEASES STUDIED/TREATED Currently being studied for possible treatment of mycobacterium infection and wasting syndrome in HIV infection. Successful results have been reported in treatment of various ulcerations including recurrent aphthous stomatitis (RAS). [DICP 1990 Nov; Vol 24 No 11; p 1054-6; Protocol ID: 133A, Protocol ID: 230A ; AIDS Therapies 1995 Sep] CLASSIFICATION CODE Anti-inflammatory [USP DI 2000; p. 2941] CLASSIFICATION CODE Immunomodulator [USP DI 2000; p. 2941] OTHER MAJOR USES Previously used drug that was withdrawn from market because of association with fetal abnormalities. Orphan drug indication for treatment of graft vs. host disease and transplant rejection. Thalidomide is the treatment of choice for type 2 leprosy reactions and is available only for this investigational use in the U.S. [Facts and Comparisons 1995; p 768g; Drug Saf 1992 Mar-Apr;7(2); p 116-34; USP DI 1997; p 3125-6] ADVERSE EFFECTS Thalidomide can induce severe congenital abnormalities in developing fetuses. The most common side effects are sedation and constipation; it can also induce peripheral neurotoxicity. [AmfAR Treat Dir 1997;8(3); p 57, 7; Drug Saf 1992 Mar-Apr;7(2); p 116-34; Arch Dermatol 1990;126; p 923-27] CONTRAINDICATIONS Except under unusual circumstances, thalidomide is contraindicated in women of child bearing age who might conceive during therapy. Should not be used in patients with pre-existing HIV related peripheral polyneuropathy, polyradiculopathy, or encephalopathy. [Drug Saf 1992 Mar-Apr;7(2); p 116-34] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H10-N2-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 258.23 [USPD 1998; p. 723] CHEMICAL/PHYSICAL DATA Melting Point: 269-271 C [Merck Index 1996; p. 1580] CHEMICAL/PHYSICAL DATA Elemental Comp: C60.47%, H3.90%, N10.85%, O24.78% [Merck Index 1996; p. 1580] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in water, methanol, ethanol, acetone, ethyl acetate, butyl acetate, glacial acetic acid. Very soluble in dioxane, DMF, and pyridine. Practically insoluble in ether, chloroform, and benzene. [Merck Index 1996; p 1580] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1995;7(4); p 57] MANUFACTURERS 0000002894: Andrulis Pharmaceuticals Corp PO Box 2135 Bethesda, MD 20817 Contact: Anna Marinaccio (908)271-4109 MANUFACTURERS 0000003060: Celgene Corp 7 Powder Horn Dr Warren, NJ 07059 Contact: Dr Peter Andrulis (301)419-2400 MANUFACTURERS 0000003060: Celgene Corp 7 Powder Horn Dr Warren, NJ 07059 Contact: Steve Thomas (908)805-3914 REFERENCES MED/97314548. Stirling D, Sherman M, Strauss S. Thalidomide. A surprising recovery. J Am Pharm Assoc (Wash). 1997 May-Jun;NS37(3):306-13. MED/97338527. Haslett P, Tramontana J, Burroughs M, Hempstead M, Kaplan G. Adverse reactions to thalidomide in patients infected with human immunodeficiency virus. Clin Infect Dis. 1997 Jun;24(6):1223-7. MED/97322018. Sharpstone D, Rowbottom A, Francis N, Tovey G, Ellis D, Barrett M, Gazzard B. Thalidomide: a novel therapy for microsporidiosis. Gastroenterolgy. 1997 Jun;112(6):1823-9. MED/97282675. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, Fox L, Chernoff M, Wu AW, MacPhail LA, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997 May 22;336(21):1487-93. MED/97276239. Shannon EJ, Sandoval F, Krahenbuhl JL. Hydrolysis of thalidomide abrogates its ability to enhance mononuclear cell synthesis of IL-2 as well as its ability to suppress the synthesis of TNF-alpha. Immunopharmacology. 1997 Apr;36(1):9-15. MED/97225056. Alexander LN, Wilcox CM. A prospective trial of thalidomide for the treatment of HIV-associated idiopathic esophageal ulcers. AIDS Res Hum Retroviruses. 1997 Mar 1;13(4):301-4. AIDS/97926735. Quinones F, Sierra-Madero J, Calva-Mercado JJ, Ruiz-Palacios GM. Thalidomide in patients with HIV infection and chronic diarrhea: double blind placebo controlled clinical trial. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:190 (abstract no. 682). AIDS/97926254. Walker RE, Hahn B, Kelly GG, Miller K, Piscitelli S, Figg WD, Davey RT, Falloon J, Kovacs JA, Polis MA, et al. Effects of TNF-alpha antagonists thalidomide and monoclonal anti-TNF antibody (cA2) on reducing IL-2-associated toxicities: a randomized, controlled trial. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:71 (abstract no. 36). MED/97133672. Bellomo A, Schorr-Lesnick B. Thalidomide treatment for idiopathic esophageal ulcers in patients with HIV. Gastrointest Endosc. 1996 Dec;44(6):729-31. AIDS/97229451. Thalidomide effective in treating AIDS-related mouth ulcers [news]. AIDS Patients Care STDS. 1996 Feb;10(1):51. ENTRY MONTH 199307 LAST REVISION DATE 20001106 163 UNIQUE IDENTIFIER DRG-0183 NAME OF SUBSTANCE Trimetrexate glucuronate [USPD 1998; p. 760] REGISTRY NUMBER 82952-64-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4-Quinazolinediamine, 5-methyl-6-(((3,4,5-trimethoxyphenyl)amino)me- thyl)-, mono-D-glucuronate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Neutrexin [USP DI 2000; p. 3065] PROTOCOL ID NUMBERS Complete CC 88 CC-85 PROTOCOL ID NUMBERS Complete NIAID ACTG 018 PROTOCOL ID NUMBERS Complete NIAID ACTG 029 PROTOCOL ID NUMBERS Complete NIAID ACTG 031 PROTOCOL ID NUMBERS Complete NIAID ACTG 039 PROTOCOL ID NUMBERS Complete NIAID NS 401 PROTOCOL ID NUMBERS No longer recruiting FDA 132A PROTOCOL ID NUMBERS No longer recruiting FDA 132B PROTOCOL ID NUMBERS No longer recruiting FDA 132C PROTOCOL ID NUMBERS No longer recruiting FDA 132D PROTOCOL ID NUMBERS No longer recruiting FDA 224A PROTOCOL ID NUMBERS No longer recruiting NIAID TX 301 PROTOCOL ID NUMBERS Terminated NIAID ACTG 030 PHARMACOLOGICAL ACTION MODE OF ACTION: Trimetrexate is a potent inhibitor of dihydrofolate reductase. It is more lipophilic than methotrexate and this is assumed to account for its better penetration into P. carinii. In vitro studies have shown that leucovorin provides a source of reduced folates necessary for normal cellular synthetic processes. Because the Pneumocystis carinii organism lacks the reduced folate carrier-mediated transport system, leucovorin is prevented from entering the organism. Therefore, at concentrations achieved with therapeutic doses of trimetrexate plus leucovorin, the selective transport of trimetrexate, but not leucovorin, into the P. carinii organism allows the concurrent administration of leucovorin to protect normal host cells from the cytotoxicity of trimetrexate without hindering the antifolate's inhibition of P. carinii. The drug can produce considerable myelosuppression due to its antifolate action; however, administration with leucovorin allows differential rescue of host tissues without reversal of the anti-protozoal effect. Trimetrexate has a mean oral bioavailability of 44% (range, 19% to 67%); therefore, it is administered intravenously. The drug is extensively protein bound (95%). Unlike methotrexate, which is excreted mainly unchanged in the urine, trimetrexate is extensively metabolized by the liver. At least two metabolites are active and two are conjugated with glucuronic acid. The hepatic degradation may account for the low and variable oral absorption. The terminal elimination half-life is 15-20 hours. [Drug Evaluations Annual 1992; p 1612-3; Facts and Comparisons 1995; p 411m-411r; PDR 1997; p 2761-2] DISEASES STUDIED/TREATED For use with concurrent leucovorin administration as an alternative therapy for the treatment of moderate to severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including those with AIDS, who are intolerant of, or are refractory to, trimethoprim/sulfamethoxazole (TMP-SMX), or for whom TMP-SMX is contraindicated. [PDR 1997; p 2762] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3062] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 3062] SUBSTANCE INTERACTIONS Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that may be coadministered with trimetrexate in AIDS patients for other indications, that might elicit this activity include: erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. Cimetidine may cause significant reduction in trimetrexate metabolism, and acetaminophen may alter the relative concentration of trimetrexate metabolites. [PDR 1997; p 2763] ADVERSE EFFECTS Must be used with concurrent leucovorin to avoid potentially serious or life-threatening complications including bone-marrow suppression, oral or gastrointestinal mucosal ulceration, and renal and hepatic dysfunction. Leucovorin therapy must be extended 72 hours past the last dose of trimetrexate glucuronate. Fluctuating leukopenia and thrombocytopenia and transient increases in serum concentrations of aspartate and alanine aminotransferases are observed commonly. No infections have resulted from the leukopenia. Leukopenia and thrombocytopenia respond promptly to lowering the dose by 50%. Initial three- to five-fold increases in serum concentrations of aminotransferases gradually are reversed when therapy is continued. Mucositis (stomatitis), anemia, and skin rashes occur occasionally; diarrhea, arthraglia, fever, bleeding, anorexia, nausea, and vomiting are reported even less frequently. [Drug Evaluations Annual 1992; p 1612-3; PDR 1997; p 2762] CONTRAINDICATIONS Contraindicated in patients sensitive to trimetrexate, leucovorin, or methotrexate. [PDR 1997; p 2762] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A 2,4-diaminoquinazoline, non-classical to late antagonist. [PDR 1997; p 2761] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H23-N5-O3.C6-H10-O7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 563.57 [USPD 1998; p. 760] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.77%, H6.28%, N18.96%, O12.99% (base) [Merck Index 1996; p. 1656] CHEMICAL/PHYSICAL DATA Solubility: Solubility in water: greater than 50 mg/ml [PDR 1997; p 2761] CHEMICAL/PHYSICAL DATA Stability: Precipitates if reconstituted with solutions containing chloride ions or leucovorin. [PDR 1995; p 2519] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Trimetrexate glucuronate for injection is a pale greenish-yellow powder or cake. [PDR 1997; p 2761] SUBSTANCE DELIVERY DATA DOSAGE FORM: Supplied as a sterile lyophilized powder in 5 ml, single dose vials. Each 5 ml bottle contains trimetrexate glucuronate equivalent to 25 mg of trimetrexate. [PDR 1997; p 2764] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60-90 minutes. Leucovorin must be administered daily during treatment with NeuTrexin and for 72 hours past the last dose. [PDR 1997; p 2763-4] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Reconstituted solutions are stable for 24 h at room temperature or under refrigeration. [PDR 1997; p 2764] MANUFACTURERS 0000002643: United States Bioscience Inc 100 Front St / One Tower Bridge West Conshohocken, PA 19428 Contact: Dr Michael Kurman (610)832-4510 MANUFACTURERS 0000002643: United States Bioscience Inc 100 Front St / One Tower Bridge West Conshohocken, PA 19428 Contact: Medical Affairs (800)832-4900 REFERENCES MED/97339118. Deresinski SC. Treatment of Pneumocystis carinii pneumonia in adults with AIDS. Semin Respir Infect. 1997 Jun;12(2):79-97. AIDS/97229478. Blanchet KD. Current management pratices in the treatment of Pneumocystis carinii pneumonia (PCP). AIDS Patient Care STDS. 1996 Apr;10(2):116-21. AIDS/97229561. Harris PJ. Trimetrexate glucuronate associated with anti-Kaposi sarcoma effect. AIDS Patient Care STDS. 1996 Oct;10(5):280-1. MED/96342537. Nusbaum NJ, Abraham T. AZT modulation of trimetrexate myelotoxicity: evidence from an HL60 model. Res Commun Mol Pathol Pharmacol. 1995 Dec;90(3):403-12. MED/96185167. Korraa H, Saadeh C. Options in the management of pneumonia caused by Pneumocystis carinii in patients with acquired immune deficiency syndrome and intolerance to trimethoprim/sulfamethoxazole. South Med J. 1996 Mar;89(3):272-7. MED/96008522. Drugs for AIDS and associated infections. Med Lett Drugs Ther. 1995 Oct 13;37(959):87-94. MED/95387369. Chan JH, Hong JS, Kuyper LF, Baccanari DP, Joyner SS, Tansik RL, Boytos CM, Rudolph SK. Selective inhibitors of Candida albicans dihydrofolate reductase: activity and selectivity of 5-(arylthio)-2,4-diaminoquinazolines. J Med Chem. 1995 Sep 1;38(18):3608-16. AHA/95393336. Wooten JM, Chase K, O'Connor MC, Henry RB. Dosing guidelines for foscarnet and trimetrexate. Formulary. 1995 Jun;30(6):349-52. 1994 Jul;170(1):165-72. MED/95309143. Fulton B, Wagstaff AJ, McTavish D. Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia. Drugs. 1995 Apr;49(4):563-76. ENTRY MONTH 199307 LAST REVISION DATE 20001106 164 UNIQUE IDENTIFIER DRG-0182 NAME OF SUBSTANCE Lobradimil [USPD 2000 p. 417] REGISTRY NUMBER 159768-75-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME L-Prolinamide, L-arginyl-L-prolyl-trans-4-hydroxy-L-prolyl-3- -(2-thienyl)-L-alanylgl ycyl-L-seryl-N-(2-((4-((aminoiminomethyl)amin- o)-1-carboxybutyl)amino )-1-((4-methoxyphenyl)methyl)ethyl)-, (S-(R*,R*))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 131A PHARMACOLOGICAL ACTION MODE OF ACTION: RMP-7 is believed to cause increased cerebrovascular permeability (i.e., increases permeability across blood-brain barrier) by the activation of B2 receptors on the vascular endothelium. The dose of ganciclovir used to treat cytomegalovirus (CMV) retinitis is restricted by its systemic toxicity and the hydrophilicity which limits its distribution across blood-ocular barriers. The effect of the bradykinin agonist, RMP-7, which increases the permeability of the anatomically similar blood-brain and blood tumor barriers, on the distribution of ganciclovir to various eye compartments in the guinea-pig was studied. RMP-7 significantly increased the delivery of ganciclovir to the lens and retina, indicating the potential therapeutic benefit. A placebo-controlled dose-ranging study of the effect of RMP-7 on retinal permeability is underway in volunteers and patients with AIDS with or without CMV retinitis. [J Pharmacol Exp Ther 1994 Oct;271(1); p 229-37; AmfAR Treat Dir 1997;8(3); p 77; Natl Conf Hum Retrv Rela Inf (2nd) 1995; p 106] DISEASES STUDIED/TREATED Under investigation in combination with amphotericin B in patients with cryptococcal meningitis. [AmfAR Treat Dir 1997;8(3); p 77] CLASSIFICATION CODE Adjuvant [USPD 2000 p. 417] ADVERSE EFFECTS In clinical trials, RMP-7 has been well tolerated by patients with AIDS or glioma. [Natl Conf Hum Retrv Rela Inf (2nd) 1995; p 106] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A bradykinin analog with the amino acid sequence: Arg-Pro-Hyp-Gly-Thi-Ser-Pro-Tyr (Me)-psi(CH2NH)-Arg. [Protocol ID: 131A ] CHEMICAL/PHYSICAL DATA Molecular Formula: C49-H75-N15-O12-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 1098.30 daltons [USPD 2000 p. 417] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous injection. [AmfAR Treat Dir 1993;6(4); p 150] MANUFACTURERS 0000002642: Alkermes Inc 64 Sidney Street Cambridge, MA 02139 Contact: Judy Lawler (617)494-0171 REFERENCES AIDS/95920310. Elliot PJ, Mackic JB, Graney WF, Zlokovic BV. Intravenous RMP-7 elevates ocular ganciclovir levels. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:106. MED/95303800. Straub JA, Akiyama A, Parmar P, Musso GF. Chemical pathways of degradation of the bradykinin analog, RMP-7. Pharm Res 1995 Feb; 12(2):305-8. MED/95175472. Straub JA, Akiyama A, Parmar P. In vitro plasma metabolism of RMP-7. Pharm Res 1994 Nov;11(11):1673-6. MED/95039694. Straub JA, Akiyama A, Parmar P, Musso GF. Limited enzymatic digestion for the determination of the quantities of minor diastereomeric impurities in preparation of RMP-7, a peptide containing a reduced peptide bond. J Chromatogr A. 1994 Sep 9;679(1):85-91. ENTRY MONTH 199307 LAST REVISION DATE 20001106 165 UNIQUE IDENTIFIER DRG-0181 NAME OF SUBSTANCE ALVAC-RG Rabies Glycoprotein (vCP65) [Protocol ID: AVEG 012A ] PROTOCOL ID NUMBERS Complete NIAID AVEG 012A PROTOCOL ID NUMBERS Complete NIAID AVEG 022 PROTOCOL ID NUMBERS Complete NIAID AVEG 022A PROTOCOL ID NUMBERS Complete NIAID AVEG 026 PROTOCOL ID NUMBERS Complete NIAID AVEG 029 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 027 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 032 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 034 PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 007 DISEASES STUDIED/TREATED The ALVAC vCP65 rabies glycoprotein vaccine offers an opportunity to compare the safety and immunogenicity of recombinant canarypox expressing HIV gene products with the recombinant canarypox expressing the rabies glycoprotein in humans. ALVAC-RG (vCP65) also acts as an appropriate control for immunologic trials of the various ALVAC vaccines. [Protocol ID: AVEG 012A ] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 012A ] ADVERSE EFFECTS ALVAC-RG (vCP65) is demonstrated to be safe and immunogenic when administered to human volunteers. The vaccine is well tolerated and the most common side effect reported is mild transient pain at the site of injection. [Protocol ID: AVEG 012A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ALVAC-RG (vCP65) is a recombinant canarypox virus bearing the rabies virus glycoprotein G gene under transcriptional control of the vaccinia virus H6 promoter. ALVAC-RG (vCP65) is cultivated in specific pathogen-free chick embryo fibroblasts. The recombinant virus is suspended in serum- and antibiotic-free culture medium to which a virus stabilizer is added. The solution is then lyophilized. [Protocol ID: AVEG 012A ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: The lyophilized product is a homogeneous powder that is cream in color. The reconstituted product is a clear liquid. [Protocol ID: AVEG 012A ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The vaccine is supplied as single-dose vials of sterile, lyophilized product containing approximately 10(5.5) TCID50 of ALVAC vCP65. Sterile water for injection that is adjusted to a pH of 5.0 to 7.0 is supplied as the diluent. [Protocol ID: AVEG 012A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The contents of the vial are reconstituted with 1 ml of the supplied diluent. The vial should be refrigerated at 2-8 C (35-46 F) until just prior to injection. When ready for administration, the mixture should be swirled gently for 10 seconds. The 1 ml dose should be withdrawn from the vial and administered intramuscularly. [Protocol ID: AVEG 034 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powder should be stored at 2-8 C (35-46 F). The reconstituted vaccine should be stored at 2-8 C (35-46 F) and used within two hours after reconstitution. Freezing of both forms should be avoided. [Protocol ID: AVEG 034 ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 REFERENCES MED/99090756. Belshe RB, Gorse GJ, Mulligan MJ, Evans TG, Keefer MC, Excler JL, Duliege AM, Tartaglia J, Cox WI, McNamara J, Hwang KL, Bradney A, Montefiori D, Weinhold KJ. Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine Evaluation Group. AIDS. 1998 Dec 24;12(18):2407-15. MED/98253840. Clements-Mann ML, Weinhold K, Matthews TJ, Graham BS, Gorse GJ, Keefer MC, McElrath MJ, Hsieh RH, Mestecky J, Zolla-Pazner S, Mascola J, Schwartz D, Siliciano R, Corey L, Wright PF, Belshe R, Dolin R, Jackson S, Xu S, Fast P, Walker MC, Stablein D, Excler JL, Tartaglia J, Paoletti E, et al. Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group. J Infect Dis. 1998 May;177(5):1230-46. MED/97030197. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11349-53. Review. MED/96329208. Fries LF, Tartaglia J, Taylor J, Kauffman EK, Meignier B, Paoletti E, Plotkin S. Human safety and immunogenicity of a canarypox-rabies glycoprotein recombinant vaccine: an alternative poxvirus vector system. Vaccine 1996 Apr;14(5):428-34. MED/96065461. Taylor J, Meignier B, Tartaglia J, Languet B, VanderHoeven J, Franchini G, Trimarchi C, Paoletti E. Biological and immunogenic properties of a canarypox-rabies recombinant, ALVAC-RG (vCP65) in non-avian species. Vaccine 1995 Apr;13(6):539-49. MED/95341166. Perkus ME, Tartaglia J, Paoletti E. Poxvirus-based vaccine candidates for cancer, AIDS, and other infectious diseases. J Leukoc Biol. 1995 Jul;58(1):1-13. MED/95317468. Plotkin SA, Cadoz M, Meignier B, Meric C, Leroy O, Excler JL, Tartaglia J, Paoletti E, Gonczol E, Chappuis G. The safety and use of canarypox vectored vaccines. Dev Biol Stand. 1995;84:165-70. MED/92292760. Cadoz M, Strady A, Meignier B, Taylor J, Tartaglia J, Paoletti E, Plotkin S. Immunization with canarypox virus expressing rabies glycoprotein [see comments]. Lancet. 1992;339:1429-1432. ENTRY MONTH 199306 LAST REVISION DATE 20001107 166 UNIQUE IDENTIFIER DRG-0180 NAME OF SUBSTANCE ALVAC-HIV gp160MN (vCP125) [Protocol ID: AVEG 012A ] PROTOCOL ID NUMBERS Complete NIAID AVEG 012A PHARMACOLOGICAL ACTION ALVAC vaccines are recombinant live vector vaccines that are utilized primarily to induce cellular immune responses, but they also can elicit humoral responses. In addition, when ALVAC is used as a primary immunization, the antibody response can be augmented substantially by subsequent boost with recombinant subunit protein vaccines. The ALVAC line of vaccines is based on the canarypox vector. Canarypox is a member of the pox virus family, of which vaccinia (cowpox) is also a member. The canarypox virus, which originates in birds, is considered safer than vaccinia because it does not reproduce in humans. Another advantage of the canarypox virus is its ability to transport large amounts of foreign genes. Various HIV genes have been inserted into this vector. The genes originate from the clade B virus, which is the predominant subtype of HIV-1 found in the US and Europe. After administration of ALVAC vCP125 and penetration into a mammalian cell, the virion loses its coating and the recombinant gene is expressed. Neutralizing antibodies are sometimes elicited, but these antibodies appear to be effective against only the laboratory strain from which the gp160 is derived. Antibody levels are short-lived. Cytotoxic T lymphocyte response also can occur, with some levels detectable up to two years postimmunization. When ALVAC vCP125 is used as a boost to stimulate the immunological memory created by a previous vaccination with the same vaccine, no effect is observed. However, booster with another vaccine (gp120) does improve the response to ALVAC vCP125. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.; Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.; Protocol ID: ACTG 326 ] DISEASES STUDIED/TREATED ALVAC vaccines are investigated as preventative vaccines for HIV infection. [Aventis Pasteur. Research to find an AIDS vaccine. Available at: http://www.aventispasteur.com/us/media/kit_ai- ds.html. Accessed August 7, 2000.] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 012A ] ADVERSE EFFECTS The canarypox virus does not replicate in the human host; therefore, recombinants are unlikely to cause disease in recipients or be transmitted to unvaccinated contacts. Adverse reactions reported after ALVAC vaccine administration are similar to those observed in healthy adults who have received marketed vaccines. Local and systemic side effects are mild to moderate and usually resolve within 72 hours after immunization. Local effects include transient pain, tenderness, redness, and swelling at the site of injection. Less common systemic effects include headache, malaise, fever, dizziness, and nausea. No severe adverse reactions have been reported. [Protocol ID: AVEG 202 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ALVAC vCP125 is a recombinant canarypox vaccine that expresses the glycoprotein (gp) 160 envelope protein of the MN HIV strain. ALVAC vCP125 is cultivated in specific pathogen-free chick embryo fibroblasts. The recombinant virus is suspended in a serum- and antibiotic-free culture medium to which a virus stabilizer is added. The solution is then lyophilized. [Protocol ID: AVEG 012A ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: The lyophilized product is a white to cream homogeneous powder. The reconstituted product is a pale rose to pink liquid that is slightly opalescent. [Protocol ID: AVEG 012A ] SUBSTANCE DELIVERY DATA DOSAGE FORM: The vaccine is supplied as single-dose vials of sterile lyophilized product containing either 10(6) or 10(7) of tissue culture 50% infective doses (TCID50) of ALVAC vCP125. Sterile water for injection that is adjusted to a pH of 5.0 to 7.0 is supplied as the diluent. [Protocol ID: AVEG 012A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: The contents of the vial are reconstituted with 1 ml of the supplied diluent. The 1 ml dose is withdrawn from the vial and administered intramuscularly with a 22-gauge, 1.5-inch needle into the deltoid muscle. [Protocol ID: AVEG 012A ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powder should be refrigerated (3-5 C). Once reconstituted, the vaccine should be refrigerated and used within two hours. Freezing of both forms should be avoided. [Protocol ID: AVEG 012A ] MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 REFERENCES Larsson M, Engelmayer J, Lee M, Cox W, Steinman R, Bhardwaj N. Dendritic cells infected with recombinant canarypox virus induce potent anti-HIV cytolytic and helper T cell responses from chronically infected individuals. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 830). Ignatius R, Lewis M, Cox WI, Frankel S, Mascola J, Villamide L, Mehlhop E, Steinman RM, Pope M. In vivo T cell priming in rhesus macaques by reinjected immature and mature dendritic cells bearing soluble or recombinant viral vector-encoded antigens. Conf Retroviruses Opportunistic Infect. 2000 Jan 30-Feb 2;7th: (abstract no. 434). AIDS/20710224. Evans TG; Keefer MC; Belshe RB; Schwartz D; Graham BS; Corey L; Mulligan MJ; Stablein D. Rates and determinants of positive HIV screening test results in uninfected participants in phase I/II trials of candidate HIV-1 vaccines. Natl HIV Prev Conf. 1999 Aug 29-Sep 1; (abstract no. 293). MED/98253840. Clements-Mann ML, Weinhold K, Matthews TJ, Graham BS, Gorse GJ, Keefer MC, McElrath MJ, Hsieh RH, Mestecky J, Zolla-Pazner S, Mascola J, Schwartz D, Siliciano R, Corey L, Wright PF, Belshe R, Dolin R, Jackson S, Xu S, Fast P, Walker MC, Stablein D, Excler JL, Tartaglia J, Paoletti E, et al. Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group. J Infect Dis. 1998 May;177(5):1230-46. MED/97188479. Ferrari G, Humphrey W, McElrath MJ, Excler JL, Duliege AM, Clements ML, Corey LC, Bolognesi DP, Weinhold KJ. Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1396-401. AIDS/97926165. Evans TG, Keefer MC, Wolff M, Weinhold K, Excler JL, Duliege AM, McNamara J, McElrath JM, Graham BJ, Clements ML, et al. Immunization of HIV-1 non-infected volunteers with a canarypox recombinant containing HIV-1 env, gag, pol, and nef genes (vCP 300) given simultaneously or followed by recombinant HIV-1 SF2 gp120. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:204 (abstract no. 754). MED/97030197. Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11349-53. Review. MED/97000067. Fleury B, Janvier G, Pialoux G, Buseyne F, Robertson MN, Tartaglia J, Paoletti E, Kieny MP, Excler JL, Riviere Y. Memory cytotoxic T lymphocyte responses in human immunodeficiency virus type 1 (HIV-1)-negative volunteers immunized with a recombinant canarypox expressing gp 160 of HIV-1 and boosted with a recombinant gp160. J Infect Dis. 1996 Oct;174(4):734-8. ICA11/96920847. Clements ML, Weinhold K, Siliciano R, Schwartz D, Matthews T, Graham B, Keefer M, McElrath J, Gorse G, Hsieh R, et al. HIV immunity induced by canarypox (ALVAC)-MN gp160, -SF2 rgp120 or both. Int Conf AIDS. 1996 Jul 7-12;11(1):10 (abstract no. Mo.A.281). MED/95341166. Perkus ME, Tartaglia J, Paoletti E. Poxvirus-based vaccine candidates for cancer, AIDS, and other infectious diseases. J Leukoc Biol. 1995 Jul;58(1):1-13. Review. MED/95317468. Plotkin SA, Cadoz M, Meignier B, Meric C, Leroy O, Excler JL, Tartaglia J, Paoletti E, Gonczol E, Chappuis G. The safety and use of canarypox vectored vaccines. Dev Biol Stand. 1995;84:165-70. MED/95306141. Pialoux G, Excler JL, Riviere Y, Gonzalez-Canali G, Feuillie V, Coulaud P, Gluckman JC, Matthews TJ, Meignier B, Kieny MP, et al. A prime-boost approach to HIV preventive vaccine using a recombinant canarypox virus expressing glycoprotein 160 (MN) followed by a recombinant glycoprotein 160 (MN/LAI). The AGIS Group, and l'Agence Nationale de Recherche sur le SIDA [published erratum appears in AIDS Res Hum Retroviruses 1995 Jul:11(7):875]. AIDS Res Hum Retroviruses. 1995 Mar;11(3):373-81. MED/95287062. Egan MA, Pavlat WA, Tartaglia J, Paoletti E, Weinhold KJ, Clements ML, Siliciano RF. Induction of human immunodeficiency virus type 1 (HIV-1)-specific cytolytic T lymphocyte responses in seronegative adults by a nonreplicating, host-range-restricted canarypox vector (ALVAC) carrying the HIV-1MN env gene. J Infect Dis. 1995 Jun;171(6):1623-7. ENTRY MONTH 199306 LAST REVISION DATE 20001107 167 UNIQUE IDENTIFIER DRG-0179 NAME OF SUBSTANCE Netivudine [USPD 1998; p. 505] REGISTRY NUMBER 84558-93-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4(1H,3H)-Pyrimidinedione, 1-beta-D-arabinofuranosyl-5-(1-propynyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 130A PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro activity against varicella zoster virus (VZV). Data from pharmacokinetic studies in HIV negative volunteers suggest that potential therapeutic concentrations can be achieved with once daily dosing; elimination is mostly renal. Bioavailability and disposition of 882C87, an anti-varicella zoster virus (VZV) agent, have been investigated in healthy young and elderly volunteers. The mean bioavailability of a 200 mg tablet was 21.1% in the young and 24.6% in the elderly, which is sufficient to achieve plasma concentrations well above the IC50 for anti-VZV activity. Plasma concentrations of 882C87 after 50 mg i.v. were higher in the elderly than in the young, associated with a significantly longer half-life and decreased renal and total clearance. After i.v. administration, the main route of elimination of 882C87 was renal with 81.6% recovered unchanged in urine in the young and 71.2% in the elderly. The pyrimidine base, 5-propynyluracil (5-PU) was unquantifiable in plasma and only present in trace amounts in urine. Experimental data suggest that 5-PU is formed from unabsorbed 882C87 in the gut lumen and then absorbed and excreted in urine. [AmfAR Treat Dir 1993;6(4); p 58; AmfAR Treat Dir 1995;7(4); p 62; Br J Clin Pharmacol 1995 Feb;39(2); p 143-9] DISEASES STUDIED/TREATED Treatment of localized herpes zoster. [Protocol ID: 130A ; AmfAR Treat Dir 1995;7(4); p 62] CLASSIFICATION CODE Investigational - Antiviral [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] OTHER MAJOR USES 882C87 is a potential once daily treatment for shingles. [Br J Clin Pharmacol 1995 Feb;39(2); p 143-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A nucleoside analog. [AmfAR Treat Dir 1993;6(3); p 46] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H14-N2-O6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 282.25 [USPD 1998; p. 505] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200 mg tablets. [Protocol ID: 130A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1995;7(4); p 62] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 REFERENCES MED/97012635. Peck RW, Crome P, Wood MJ, McKendrick MW, Bannister B, Mandal BK, Crooks RJ. Multiple dose netivudine, a potent anti-varicella zoster virus agent, in healthy elderly volunteers and patients with shingles. J Antimicrob Chemother. 1996 Mar;37(3):583-97. MED/97120396. Le Roy F, Godin M, Legallicler B, Fillastre JP, Bidault R, Posner J, Peck RW. Pharmacokinetics of netivudine in haemodialysis patients [letter]. J Antimicrob Chemother. 1996 Nov;38(5):913-5. MED/96346908. Fillastre JP, Godin M, Legallicier B, Chretien P, Bidault R, Gillotin C, Wooton R, Posner J, Peck RW. Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment. J Antimicrob Chemother. 1996 May;37(5):965-74. MED/96152187. Peck R, Wiggs R, Callaghan J, Wooton R, Crome P, Fraser I, Frick L, Posner J. Inhibition of dihydropyrimidine dehydrogenase by 5-propynyluracil, a metabolite of the anti-varicella zoster virus agent netivudine. Clin Pharmacol Ther. 1996 Jan;59(1):22-31. MED/95377331. Andrei G, Snoeck R, Reymen D, Liesnard C, Goubau P, Desmyter J, De Clercq E. Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. Eur J Clin Microbiol Infect Dis 1995 Apr;14(4):318-29. MED/95260647. Peck RW, Wootton R, Lee DR, Jackson SH, Posner J. The bioavailability and disposition of 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)ura- cil (882C87), a potent, new anti-varicella zoster virus agent. Br J Clin Pharmacol 1995 Feb;39(2):143-9. MED/95209347. Peck RW, Weatherley BC, Wootton R, Crome P, Posner J, et al. Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers. Antimicrob. Agents Chemother.; VOL 39 ISS Jan 1995, P20-27, (REF 9). MED/94341482. Darby G. Acyclovir--and beyond. J Int Med Res. 1994;22 Suppl 1:33A-42A. MED/94065699. Wood MR, McKendrick MW, Bannister B, Mandal BK, Peck RW, Crooks RJ. Preliminary pharmacokinetics and safety of 882C87 in patients with herpes zoster. J Med Virol. 1993;Suppl 1:154-7. ENTRY MONTH 199306 LAST REVISION DATE 20001106 168 UNIQUE IDENTIFIER DRG-0178 NAME OF SUBSTANCE QS-21 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID AVEG 016 PROTOCOL ID NUMBERS Complete NIAID AVEG 016A PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 036 PROTOCOL ID NUMBERS Terminated NIAID ACTG 279 PHARMACOLOGICAL ACTION MODE OF ACTION: The potential and desired effects of this adjuvant may include the following: an increase in antibody responses directed to neutralizing epitopes, a reduction in the time interval needed to achieve high neutralizing antibody titers, an increase in the duration of the immune responses, the induction of CD8+ MHC-restricted CTL, and a decrease in the amount of immunogen needed in the vaccine preparation. The saponin adjuvant, QS-21, has been extensively tested in experimental vaccine formulations in animals and in one human trial, and results to date indicate that this adjuvant may offer several of the above desired effects in combination with a subunit HIV-1 envelope vaccine. [Protocol ID: AVEG 016 ; AIDS Res Hum Retroviruses 1995 Feb;11(2); p 203-09; J Immunol 1992 Mar 1;158(4); p 1519-25] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. [Protocol ID: AVEG 016 ; AIDS Res Hum Retroviruses 1995 Feb;11(2); p 203-9] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 016 ] ADVERSE EFFECTS Adverse effects include tenderness at site of intramuscular injection and mild flu-like symptoms. [Protocol ID: AVEG 016 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A nontoxic saponin derived from the soapbark tree Quillaja saponaria. The molecule contains 8 monosaccharides, 2 fatty acids, and a triterpene aldehyde (< 10 EU/mg), at C4. [Protocol ID: AVEG 016 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C92-H148-O46 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 1990 [Compendium of Vaccine Adjuvants and Excipients (2nd Edition) (CVAE) Available at: http://www.niaid.nih.gov/aidsvaccine/pdf/comp- endium.pdf. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: 3 ml vial containing 0.5 mg/ml QS-21, 20 mM succinate pH 5.5, and 120 mM NaCl. [Protocol ID: AVEG 016 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: AVEG 016 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refrigerate at 2-8 C. [Protocol ID: AVEG 016 ] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 REFERENCES MED/21127281. Evans TG, McElrath MJ, Matthews T, Montefiori D, Weinhold K, Wolff M, Keefer MC, Kallas EG, Corey L, Gorse GJ, Belshe R, Graham BS, Spearman PW, Schwartz D, Mulligan MJ, Goepfert P, Fast P, Berman P, Powell M, Francis D; NIAID AIDS Vaccine Evaluation Group. QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immunization in humans. Vaccine 2001 Feb 28;19(15-16):2080-91. MED/21103255. Boyaka PN, Marinaro M, Jackson RJ, van Ginkel FW, Cormet-Boyaka E, Kirk KL, Kensil CR, McGhee JR. Oral QS-21 requires early IL-4 help for induction of mucosal and systemic immunity. J Immunol 2001 Feb 15;166(4):2283-90. MED/98241732. Sasaki S, Sumino K, Hamajima K, Fukushima J, Ishii N, Kawamoto S, Mohri H, Kensil CR, Okuda K. Induction of systemic and mucosal immune responses to human immunodeficiency virus type 1 by a DNA vaccine formulated with QS-21 saponin adjuvant via intramuscular and intranasal routes. MED/98214877. Kensil CR, Wu JY, Anderson CA, Wheeler DA, Amsden J. QS-21 and QS-7: purified saponin adjuvants. Dev Biol Stand 1998;92:41-7. MED/97405277. Newman MJ, Wu JY, Gardner BH, Anderson CA, Kensil CR, Recchia J, Coughlin RT, Powell MF. Induction of cross-reactive cytotoxic T-lymphocyte responses specific for HIV-1 gp120 using saponin adjuvant (QS-21) supplemented subunit vaccine formulations. Vaccine 1997 Jun;15(9):1001-7. MED/97120481. Cleland JL, Barron L, Daugherty A, Eastman D, Kensil C, Lim A, Weissburg RP, Wrin T, Vennari J, Powell MF. Development of a single-shot subunit vaccine for HIV-1. 3. Effect of adjuvant and immunization schedule on the duration of the humoral immune response to recombinant MN gp120. J Pharm Sci 1996 Dec;85(12):1350-7. MED/97116205. Kensil CR, Soltysik S, Wheeler DA, Wu JY. Structure/function studies on QS-21, a unique immunological adjuvant from Quillaja saponaria. Adv Exp Med Biol 1996;404:165-72. MED/96402439. Cleland JL, Kensil CR, Lim A, Jacobsen NE, Basa L, Spellman M, Wheeler DA, Wu JY, Powell MF. Isomerization and formulation stability of the vaccine adjuvant QS-21. J Pharm Sci. 1996 Jan;85(1):22-8. MED/96146013. Jacobsen NE, Fairbrother WJ, Kensil CR, Lim A, Wheeler DA, Powell MF. Structure of the saponin adjuvant QS-21 and its base-catalyzed isomerization product by 1H and natural abundance 13C NMR spectroscopy. Carbohydr Res 1996 Jan 4;280(1):1-14. MED/96145955. Soltysik S, Wu JY, Recchia J, Wheeler DA, Newman MJ, Coughlin RT, Kensil CR. Structure/function studies of QS-21 adjuvant: assessment of triterpene aldehyde and glucuronic acid roles in adjuvant function. Vaccine 1995;13(15):1403-10. MED/96057700. Kensil CR, Wu JY, Soltysik S. Structural and immunological characterization of the vaccine adjuvant QS-21. Pharm Biotechnol 1995;6:525-41. MED/95260529. Powell MF, Eastman DJ, Lim A, Lucas C, Peterson M, Vennari J, Weissburg RP, Wrin T, Kensil CR, Newman MJ, et al. Effect of adjuvants on immunogenicity of MN recombinant glycoprotein 120 in guinea pigs. AIDS Res Hum Retroviruses. 1995 Feb;11(2):203-9. MED/95169484. Cleland JL, Powell MF, Lim A, Barron L, Berman PW, Eastman DJ, Nunberg JH, Wrin T, Vennari JC. Development of a single-shot subunit vaccine for HIV-1. AIDS Res Hum Retroviruses 1994;10 Suppl 2:S21-6. MED/95159643. Livingston PO, Adluri S, Helling F, Yao TJ, Kensil CR, Newman MJ, Marciani D. Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 1994 Nov;12(14):1275-80. MED/95078004. Newman MJ, Munroe KJ, Anderson CA, Murphy CI, Panicali DL, Seals JR, Wu JY, Wyand MS, Kensil CR. Induction of antigen-specific killer T lymphocyte responses using subunit SIVmac251 gag and env vaccines containing QS-21 saponin adjuvant. AIDS Res Hum Retroviruses. 1994 Jul;10(7):853-61. ENTRY MONTH 199306 LAST REVISION DATE 20000801 169 UNIQUE IDENTIFIER DRG-0177 NAME OF SUBSTANCE Threonyl Muramyl Dipeptide [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 66112-59-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME D-alpha-Glutamine, N(sup 2)-(N-(N-acetylmuramoyl)-L-threonyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PHARMACOLOGICAL ACTION MODE OF ACTION: The mechanisms in which adjuvants augment vaccine immunogenicity may include 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen-presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell help for B cell and CTL response, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, the adjuvant may induce a more favorable antibody response with high titers, which appear earlier in the course of immunization and persist over time, as well as increase memory responses and CD8+ MHC Class I-restricted CTL. Among 130 analogs of muramyl dipeptides tested on animals, threonyl muramyl dipeptide showed the greatest separation of potency as an adjuvant from potency in the production of side-effects. [Protocol ID: AVEG 015 ; Mol Immunol 1991 Mar;28(3); p 279-84; Ann N Y Acad Sci 1995 May 31;754; p 153-60] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. [Protocol ID: AVEG 015 ] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 015 ] ADVERSE EFFECTS This formulation does not produce tissue damage or elicit an inflammatory reaction at injection sites, and no systemic reaction is demonstrable (in monkeys). [Modern Approaches to New Vaccines p 56-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic muramyl dipeptide analog. [Semin Immunol 1990 Sep;2(5); p 369-74] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H34-N4-O12 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 522.51 [USPD 1998; p. 716] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial containing 0.5 ml. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Vials should be stored at 5 C. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000001094: BIOCINE Co 4560 Horton St Emeryville, CA 946082916 Contact: Dr David Chernoff (510)601-2775 REFERENCES MED/97304250. Hjorth RN, Bonde GM, Piner ED, Goldberg KM, Levner MH. The effect of Syntex adjuvant formulation (SAF-m) on humoral immunity to the influenza virus in the mouse. Vaccine 1997 Apr;15(5):541-6. MED/96342144. Gupta RK, Griffin P Jr, Chang AC, Rivera R, Anderson R, Rost B, Cecchini D, Nicholson M, Siber GR. The role of adjuvants and delivery systems in modulation of immune response to vaccines. Adv Exp Med Biol 1996;397:105-13. MED/96155133. Gupta RK, Siber GR. Adjuvants for human vaccines--current status, problems and future prospects. Vaccine 1995 Oct;13(14):1263-76. MED/94378704. Hjorth RN, Bonde GM, Piner ED, Goldberg KM, Levner MH, Hung PP. Relevance of the guinea-pig necrotic inflammation footpad reaction to safety concerns with MDP-based adjuvants. Vaccine. 1994 Jun;12(8):687-90. MED/93190590. Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK. Adjuvants-- a balance between toxicity and adjuvanticity. Vaccine. 1993;11(3):293-306. MED/91203949. Allison AC, Byars NE. Immunological adjuvants: desirable properties and side-effects. Mol Immunol. 1991 Mar;28(3):279-84. MED/92182252. Allison AC, Byars NE. Adjuvant formulations and their mode of action. Semin Immunol. 1990 Sep;2(5):369-74. MED/90069604. Murphey-Corb M, Martin LN, Davison-Fairburn B, Montelaro RC, Miller M, West M, Ohkawa S, Baskin GB, Zhang JY, Putney SD, et al. A formalin-inactivated whole SIV vaccine confers protection in macaques. Science. 1989 Dec 8;246(4935):1293-7. ICDB/88647963. Allison AC, Byars NE. Development of an adjuvant formulation that can elicit protective immunity against retroviruses. Vaccines 87. Modern Approaches to New Vaccines: Prevention of AIDS and Other Viral, Bacterial, and Parasitic Diseases. Chanock RM et al, eds. New York, Cold Spring Harbor Laboratory, p. 56-9, 1987. ENTRY MONTH 199306 LAST REVISION DATE 20001106 170 UNIQUE IDENTIFIER DRG-0176 NAME OF SUBSTANCE MF59 [Int Conf AIDS 1993 Jun 6-11;9(1); 70 (abstract no. WS-B27-2)] PROTOCOL ID NUMBERS Complete NIAID ACTG 214 PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PROTOCOL ID NUMBERS Complete NIAID AVEG 024 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 028 PROTOCOL ID NUMBERS Terminated NIAID ACTG 233 PHARMACOLOGICAL ACTION MODE OF ACTION: The mechanisms in which adjuvants augment vaccine immunogenicity may include 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen-presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell help for B cell and CTL response, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, the adjuvant may induce a more favorable antibody response with high titers, which appear earlier in the course of immunization and persist over time, as well as increase memory responses and CD8+ MHC Class I-restricted CTL. [Protocol ID: AVEG 015 ; J Infect Dis 1994 Nov;170(5); p 1288-91; Ann N Y Acad Sci 1995 May 31;754] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. Used as an emulsifier system in conjunction with other adjuvants such as MTP-PE. [Protocol ID: AVEG 015 ; J Infect Dis 1994 Nov;170(5); J Infect Dis 1994 Nov;170(5)] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: MF59 is a safe, practical, and potent adjuvant for use with human vaccines. The formulation is easily manufactured, may be sterilized by filtration, and is both compatible and efficacious with all antigens tested to date. MF59 has been shown to be a potent stimulator of cellular and humoral responses to subunit antigens in both animal models and clinical studies. Toxicology studies in animal models and Phase I-III studies in humans have demonstrated the safety of MF59 with HSV, HIV, and influenza vaccines. This emulsion consists of 0.5% polysorbate 80 and 0.5% sorbitan trioleate. Squalene (5.0%), a metabolizable lipid, constitutes the oil phase. [Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Emulsion. [Int Conf AIDS 1996 Jul 7-12;11(1); Abstract no. MoB 0025; Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial with a fill volume of 0.65 ml and a withdrawable volume of 0.50 ml. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Int Conf AIDS 1993 Jun 6-11;9(1); 70 (abstract no. WS-B27-2)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store refrigerated at 2-8 C. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 MANUFACTURERS 0000001094: BIOCINE Co 4560 Horton St Emeryville, CA 946082916 Contact: Dr David Chernoff (510)601-2775 REFERENCES AIDS/97926054. Barnett SW, Duliege AM, Sinangil F, Walker CM, Hansen L, Boggio K, Steimer KS. HIV vaccine efforts at Chiron: polynucleotide, protein subunit, and prime/boost approaches. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:219 (abstract no.S30). AIDS/97926200. Schooley RT, Spino C, Chiu S, DeGruttola V, Kuritzkes DR. Poor immunogenicity of HIV-1 envelope vaccines with alum or MF59 adjuvant in HIV-infected individuals: results of two randomized trials. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:204 (abstract no.756). MED/96301139. Graham BS, Keefer MC, McElrath MJ, Gorse GJ, Schwartz DH, Weinhold K, Matthews TJ, Esterlitz JR, Sinangil F, Fast PE. Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. Ann Intern Med. 1996 Aug 15;125(14):270-9. ICA11/96923724. Duliege AM, Sinangil F, Walker C, Dekker C, Boggio K, Clements ML, McElrath J, Kahn J, Graham B, Excler JL, et al. Recombinant HIV subunit vaccines development: a collaborative effort. Int Conf AIDS. 1996 Jul 7-12;11(2):122 (abstract no.We.B.3376). ICA11/96920850. McElrath MJ, Montefiori D, Wolff M, Clements M, Gorse G, Keefer M, Graham B, Duliege AM, Francis D, Matthews T, et. al. Safety, immunity, and risk behavior in HIV-1-uninfected volunteers representing diverse risk populations following recombinant envelope vaccinations: a three-year followup. Int Conf AIDS, 1996 Jul 7-12;11(1):10 (absract no. Mo.A.284). MED/96303587. Keefer MC, Graham BS, McElrath MJ, Matthews TJ, Stablein DM, Corey L, Wright PF, Lawrence D, Fast PE, Weinhold K, et al. Safety and immunogenicity of Env 2-3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP-PE/MF59. NIAID AIDS Vaccine Evaluation Group. AIDS Res Hum Retroviruses. 1996 May 20;12(8):683-93. AIDS/97920758. Nitayaphan S, Khamboonruang C, Chiu J, Morgan P, Suriyanon V, Sirisophana N, Duleige A-M, Boggio K, McNeil J, Michael R. Post-immunization reactogenicity and toxicity of Biocine(R) HIV SF2 gp120/MF59 vaccine in seronegative Thai volunteers. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:186 [Poster 66]. AIDS/97920787. McElrath MJ, Montefiori DM, Clements ML, Belshe RB, Dolin R, Graham BS, Duliege A-M, Francis D, Bolognesi DP, Matthews TJ, et al. Longitudinal vaccine-induced immunity and risk behavior of study participants of AVEG phase II protocol 201. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:216 [Poster 96]. AIDS/97920686. Clements ML, Weinhold K, Schwartz D, Siliciano R, Matthews T, Graham B, Keefer M, McElrath J, Gorse G, Hsieh R, et al. HIV immunity induced by canarypox (ALVAC)-(MN)gp160, (SF2)gp120 or both. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:91. AIDS/95920551. Lambert JS, McNamara J, Katz S, Livingston R, Fenton T, Geheb H, Duliege AM, Francis D, Volvowitz F, Hawkins E, et al. Safety and immunogenicity of recombinant envelope HIV vaccines in asymptomatic HIV infected children. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:151. ENTRY MONTH 199306 LAST REVISION DATE 20000801 171 UNIQUE IDENTIFIER DRG-0175 NAME OF SUBSTANCE Syntex adjuvant formulation [Vaccine 1993 11(3); p 1-5] PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PHARMACOLOGICAL ACTION MODE OF ACTION: The mechanisms in which adjuvants augment vaccine immunogenicity may include 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen-presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell help for B cell and CTL response, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, the adjuvant may induce a more favorable antibody response with high titers, which appear earlier in the course of immunization and persist over time, as well as increase memory responses and CD8+ MHC Class I-restricted CTL. Vaccines using SAF have protected guinea pigs against genital herpes simplex virus infections and subhuman primates against Epstein-Barr virus and simian immunodeficiency virus infections. [Protocol ID: AVEG 015 ; Semin Immunol 1990 Sep;2(5); p 369-74] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. [Protocol ID: AVEG 015 ] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 015 ] ADVERSE EFFECTS Adverse effects include discomfort at the site of injection; mild acute elevations in white blood count, CPK and sedimentation rate have been observed. [Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An emulsion consisting of squalene, Pluronic L121 block polymer and Tween 80 in phosphate-buffered saline. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.6 ml vial. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store refrigerated at 2-8 C. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000001094: BIOCINE Co 4560 Horton St Emeryville, CA 946082916 Contact: Dr David Chernoff (510)601-2775 REFERENCES MED/97304250. Hjorth RN, Bonde GM, Piner ED, Goldberg KM, Levner MH. The effect of Syntex adjuvant formulation (SAF-m) on humoral immunity to the influenza virus in the mouse. Vaccine. 1997 Apr;15(5):541-6. ICA11/96920819. Buge SL, Lubeck M, Kalyan N, Cheng S, Richardson E, Markham P, Miller C, Udem S, Robert-Guroff M. Adenovirus host range mutant-SIV recombinant vaccine trial in rhesus macaques. Int Cont AIDS. 1996 Jul 7-12;11(1):4 (abstract no.Mo.A.102). MED/94209040. Allison AC. Adjuvants and immune enhancement. Int J Technol Assess Health Care. 1994 Winter;10(1):107-20. MED/93190590. Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK. Adjuvants--a balance between toxicity and adjuvanticity. Vaccine. 1993;11(3):293-306. MED/93067447. Allison AC, Byars NE. Syntex adjuvant formulation. Res Immunol. 1992 Jun;143(5):519-25. MED/96043088. Robuccio JA, Griffith JW, Chroscinski EA, Cross PJ, Light TE, Lang CM. Comparison of the effects of five adjuvants on the antibody response to influenza virus antigen in guinea pigs. Lab Anim Sci 1995 Aug;45(4);420-6. MED/95272066. Houston L, Moncla BJ, Page R, Engel D. Response of guinea pigs to a vaccine containing a new adjuvant (SAF) and gram-negative bacteria. Lab Anim Sci 1995 Feb;45(1):59-66. ENTRY MONTH 199306 LAST REVISION DATE 20000801 172 UNIQUE IDENTIFIER DRG-0174 NAME OF SUBSTANCE Lipid A, Liposome-encapsulated monophosphoryl [Protocol ID: AVEG 015 p 1-5] PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PHARMACOLOGICAL ACTION MODE OF ACTION: The mechanisms in which adjuvants augment vaccine immunogenicity may include 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell help for B cell and CTL response, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, the adjuvant may induce a more favorable antibody response with high titers, which appear earlier in the course of immunization and persist over time, as well as increase memory responses and CD8+ MHC Class I-restricted CTL. Encapsulation of poorly immunogenic circumsporozoite protein repeat peptides in monophosphoryl lipid A containing liposomes is a successful adjuvant strategy in humans for inducing high levels of specific antibody production. The mechanism of the adjuvant action of liposomal lipid A is partly due to increased antigen presentation by macrophages and partly due to the recruitment of an increased number of macrophages serving as antigen-presenting cells. [Protocol ID: AVEG 015 ; Proc Natl Acad Sci USA 1992 Jan 1;89(1); p 358-62; Infect Immun 1992 Jun;60(6); p 2438-44] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. [Protocol ID: AVEG 015 ] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 015 ] ADVERSE EFFECTS Moderate but acceptable transient local reactogenicity was noted at high doses of the vaccine formulation, but little or no systemic toxicity was seen despite doses up to 2200 mcg. [Proc Natl Acad Sci USA 1992 Jan 1;89(1); p 358-62] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Liposomes made of phospholipids and cholesterol that contain monophosphoryl lipid A. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial with 8.8 mg MPL per ml. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 4 C. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000004645: Walter Reed Army Institute of Research (WRAIR) Vaccine Clinical Research Center Rockville, MD 20850 Contact: Catherine Chaddic (301)251-8351 REFERENCES ICA11/96923146. VanCott TC, Kaminski R, Lewis M, Mascola J, Wassef N, Alving C, Ulrich T, Richardson C, Lowell G, Burnett P, et al. Mucosal and systemic immune responses to parenteral and intranasal administration of an oligomeric HIV-1 gp160 vaccine. Int Conf AIDS. 996 Jul 7-12;11(2):13 (abstract no.We.A.391). MED/95351596. Alving CR. Liposomal vaccines: clinical status and immunological presentation for humoral and cellular immunity. Ann N Y Acad Sci. 1995 May 31;754:143-52. MED/95120365. Wassef NM, Alving CR, Richards RL. Liposomes as carriers for vaccines. Immunomethods. 1994 Jun;4(3):217-22. MED/94226318. Hui GS. Liposomes, muramyl dipeptide derivatives, and nontoxic lipid A derivatives as adjuvants for human malaria vaccines. Am J Trop Med Hyg. 1994;50(4 Suppl):41-51. MED/93322093. Alving CR. Lipopolysaccharide, lipid A, and liposomes containing lipid A as immunologic adjuvants. Immunobiology. 1993 Apr;187(3-5):430-46. ENTRY MONTH 199306 LAST REVISION DATE 20000801 173 UNIQUE IDENTIFIER DRG-0173 NAME OF SUBSTANCE Lipid A, Monophosphoryl [Compendium of Vaccine Adjuvants and Excipients (2nd Edition) (CVAE) Available at: http://www.niaid.nih.gov/aidsvaccine/pdf/comp- endium.pdf. Accessed: June 30, 2000.] PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PHARMACOLOGICAL ACTION MODE OF ACTION: Monophosphoryl lipid A has been shown to be a potent immunologic adjuvant. The mechanism in which adjuvants augment vaccine immunogenicity may include 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell help for B cell and CTL response, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, the adjuvant may induce a more favorable antibody response with high titers, which appear earlier in the course of immunization and persist over time, as well as increase memory responses and CD8+ MHC Class I-restricted CTL. Animal studies suggest monophosphoryl lipid A increases antibody formation by inducing the helper T cell population to secrete interferon gamma. The latter activates the macrophage to secrete increased levels of interleukin 1, thereby resulting in increased responsiveness throughout the ensuing sequence of cellular and molecular events leading to antibody synthesis. [Adv Exp Med Biol 1990; No 256; p 567-79; Protocol ID: AVEG 015 ] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. [Protocol ID: AVEG 015 ] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 015 ] OTHER MAJOR USES An immunological adjuvant. Induction of endotoxin tolerance with monophosphoryl lipid A improves survival from peritonitis. [Protocol ID: AVEG 015 ; J Lab Clin Med 1994 Jan;123(1); p 89-93] ADVERSE EFFECTS Mild to moderate symptoms include headache, chills, myalgia, and pain at the site of injection. [Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A monophosphorylated lipid; a non-toxic derivative of lipid A. [Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA Molecular Weight: 1540-1670 (average) [Compendium of Vaccine Adjuvants and Excipients (2nd Edition) (CVAE) Available at: http://www.niaid.nih.gov/aidsvaccine/pdf/comp- endium.pdf. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 100 mcg per ml. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Vials should be stored at 2-6 C. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000002608: RIBI ImmunoChem Research Inc 553 Old Corvallis Road Hamilton, MT 59840 Contact: Dr David Rechtman (406)363-6214 REFERENCES MED/97296236. VanCott TC, Mascola JR, Kaminski RW, Kalyanaraman V, Hallberg PL, Burnett PR, Ulrich JT, Rechtman DJ, Birx DL. Antibodies with specificity to native gp120 and neutralization activity against primary human immunodeficiency virus type 1 isolates elicited by immunization with oligomeric gp160. J Virol. 1997 Jun 71(6):4319-30. AIDS/97926186. VanCott TC, Lewis M, Kaminski R, Mascola J, Kalyanaraman V, Veit SD, Lu Y, Jenkins S, Richardson C, Ulrich T, Birx DL. Protection of rhesus macaques from SHIV challenge using oligomeric gp160 formulated in MPL or polyphoshazene adjuvants. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:204 (abstract no.755). ICA11/96923146. VanCott TC, Kaminski R, Lewis M, Mascola J, Wassef N, Alving C, Ulrich T, Richardson C, Lowell G, Burnett P, et al. Mucosal and systemic immune responses to parenteral and intransal administration of an oligomeric HIV-1 gp160 vaccine. Int Conf AIDS. 1996 Jul 7-12;11(2):13 (abstract no.We.A.391). MED/95366230. Schultz N, Oratz R, Chen D, Zeleniuch-Jacquotte A, Abeles G, Bystryn JC. Effect of DETOX as an adjuvant for melanoma vaccine. Vaccine 1995 Apr;13(5):503-8. MED/95094547. Astiz ME, Rackow EC, Still JG, Howell ST, Cato A, Von Eschen KB, Ulrich JT, Rudbach JA, McMahon G, Vargas R, et al. Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double-blind, randomized, controlled trial. Crit Care Med 1995 Jan;23(1):9-17. MED/95077062. Hoffman SL, Edelman R, Bryan JP, Schneider I, Davis J, Sedegah M, Gordon D, Church P, Gross M, Silverman C, et al. Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant. Am J Trop Med Hyg 1994 Nov;51(5):603-12. MED/95007435. Johnson AG. Molecular adjuvants and immunomodulators: new approaches to immunization. Clin Microbiol Rev 1994 Jul:7(3):277-89. ENTRY MONTH 199306 LAST REVISION DATE 20000801 174 UNIQUE IDENTIFIER DRG-0172 NAME OF SUBSTANCE Aluminum hydroxide [USPD 1998; p. 40] REGISTRY NUMBER 21645-51-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME aluminum hydrate [Merck Index 1996; p 61] PROTOCOL ID NUMBERS Complete NIAID ACTG 214 PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PROTOCOL ID NUMBERS Complete NIAID AVEG 016 PROTOCOL ID NUMBERS Complete NIAID AVEG 016A PROTOCOL ID NUMBERS Complete NIAID AVEG 019 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 028 PROTOCOL ID NUMBERS No longer recruiting FDA VAX 002 PROTOCOL ID NUMBERS Terminated NIAID ACTG 279 PHARMACOLOGICAL ACTION MODE OF ACTION: The mechanisms in which adjuvants augment vaccine immunogenicity may include 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen-presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell help for B cell and CTL response, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, the adjuvant may induce a more favorable antibody response with high titers, which appear earlier in the course of immunization and persist over time, as well as increase memory responses and CD8+ MHC Class I-restricted CTL. [Protocol ID: AVEG 015 ] DISEASES STUDIED/TREATED Primary HIV infection: as a vaccine adjuvant for the enhancement of the immune response. [Protocol ID: AVEG 015 ] CLASSIFICATION CODE Immunologic adjuvant [Merck Index 1996; p. 61] OTHER MAJOR USES Alum has been used as an adjuvant since the 1920's and is the only adjuvant approved by the FDA for use in human vaccines; aluminum hydroxide is an antacid and a antihyperphosphatemic. [USAN 1997; p 39; Merck Index 1996; p 61; Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Aluminum salt (alum). [Protocol ID: AVEG 015 ] CHEMICAL/PHYSICAL DATA Molecular Formula: Al-H3-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 78.00 [USPD 1998; p. 40] CHEMICAL/PHYSICAL DATA Elemental Comp: Al34.59%, H3.88%, O61.53% [Merck Index 1996; p. 61] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water; soluble in alkaline aqueous solution, HCl, H2SO4, and other strong acids in the presence of some water. [Merck Index 1996; p 61] CHEMICAL/PHYSICAL DATA Stability: Forms gels on prolonged contact with water. Absorbs acids and CO2. [Merck Index 1996; p 61] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, bulky, amorphous powder. [Merck Index 1996; p 61] SUBSTANCE DELIVERY DATA DOSAGE FORM: Aluminum hydroxide (2mg) in water (q.s. to 1 ml). [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 4 C. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/96057687. Hem SL, White JL. Structure and properties of aluminum-containing adjuvants. Pharm Biotechnol. 1995;6:249-76. MED/96155148. Aggerbeck H, Fenger C, Heron I. Booster vaccination against diphtheria and tetanus in man. Comparison of calcium phosphate and aluminium hydroxide as adjuvants--II. Vaccine. 1995 Oct;13(14):1366-74. MED/96155133. Gupta RK, Siber GR. Adjuvants for human vaccines--current status, problems and future prospects. Vaccine. 1995 Oct;13(14):1263-76. MED/95386258. Vogel FR. The role of adjuvants in retroviral vaccines. Int J Immunopharmacol; VOL 17, ISS 2, 1995, P85-90 (REF: 43). MED/95351597. Vogel FR. Immunologic adjuvants for modern vaccine formulations. Ann N Y Acad Sci 1995 May 31;754:153-60. MED/95397586. Men Y, Thomasin C, Merkle HP, Gander B, Corradin G. A single administration of tetanus toxoid in biodegradable microspheres elicits T cell and antibody responses similar or superior to those obtained with aluminum hydroxide. Vaccine 1995 May;13(7):683-9. MED/95066310. Ma J, Bulger PA, Davis DR, Perilli-Palmer B, Bedore DA, Kensil CR, Young EM, Hung CH, Seals JR, Pavia CS, et al. Impact of the saponin adjuvant QS-21 and aluminium hydroxide on the immunogenicity of recombinant OspA and OspB of Borrelia burgdorferi. Vaccine 1994 Aug;12(10):925-32. MED/94025902. Goto N, Kato H, Maeyama J, Eto K, Yoshihara S. Studies on the toxicities of aluminium hydroxide and calcium phosphate as immunological adjuvants for vaccines[see comments]. Vaccine; VOL 11, ISS 9, 1993, P914-8. MED/93067443. Nicklas W. Aluminum salts. Res Immunol. 1992 Jun;143(5):489-94. MED/93090458. Bomford R, Stapleton M, Winsor S, McKnight A, Andronova T. The control of the antibody isotype response to recombinant human immunodeficiency virus gp120 antigen by adjuvants. AIDS Res Hum Retroviruses. 1992 Oct;8(1):1765-71. ENTRY MONTH 199306 LAST REVISION DATE 20000801 175 UNIQUE IDENTIFIER DRG-0171 NAME OF SUBSTANCE Lentinan [USPD 1998; p. 413] REGISTRY NUMBER 37339-90-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 126A PROTOCOL ID NUMBERS No longer recruiting FDA 126B PHARMACOLOGICAL ACTION MODE OF ACTION: Demonstrates immune potentiating activity by stimulating the T-cell mediated cytotoxic immune response and also effecting nonspecific macrophage mediated responses. Analysis of the cellular antimetastatic activity of combinations of lentinan and interleukin-2 revealed the involvement of a tumor associated antigen-specific delayed type hypersensitivity response. It is suggested that the life prolonging effect of the combination is mediated by antigen-specific T cells. Lentinan appears to represent Host Defense Potentiators (HDPs), which can restore or augment the ability of responsiveness of the host to lympho-cytokines or other intrinsic bioactive factors through maturation, differentiation or proliferation of the important cells for host defense mechanisms. HDPs such as lentinan are the most appropriate drugs to prevent cancer occurrence or the manifestations of AIDS symptoms in HIV carriers. [Int Conf AIDS 1990 Jun 20-23;6(3); abstract no SB487; Jpn J Cancer Res 1994 Dec;85(12); p 1288-97; Dev Biol Stand 1992;77; p 191-97] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection. [Protocol ID: 126A ] CLASSIFICATION CODE Antineoplastic [Merck Index 1996; p. 927] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Treatment of cancer. [Dev Biol Stand 1992;77; p 191-97] ADVERSE EFFECTS Adverse effects include acute lumbar pain, anaphylaxis, rigors, vasovagal response, and exacerbation of granulocytopenia. Elevated liver function tests, rash and mild chest pains occur in some cancer patients receiving lentinan. [Int Conf AIDS 1990 Jun 20-23;6(3); abstract no SB487; AmfAR Treat Dir 1995;7(4); p 33] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Neutral polysaccharide isolated from the edible mushroom, lentinus edodes. Primary structure is a beta-1,3-D-glucan having 2 beta-1,6-glucopyranoside branchings for every 5 beta-1,3- linear linkages. [Merck Index 1996; p 927] CHEMICAL/PHYSICAL DATA Molecular Formula: (C6-H10-O5)n [Merck Index 1996; p. 927] CHEMICAL/PHYSICAL DATA Molecular Weight: 400,000 - 800,000 [Merck Index 1996; p. 927] CHEMICAL/PHYSICAL DATA Solubility: Soluble in aqueous alkali, formic acid; slightly soluble in hot water and DMSO; insoluble in cold water, alcohol, ether, chloroform, pyridine, and hexamethylphosphoramide. [Merck Index 1996; p 927] CHEMICAL/PHYSICAL DATA Stability: Stable against sulfuric and hydrochloric acids. [Merck Index 1996; p 927] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White powder. [Merck Index 1996; p 927] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 126A ] MANUFACTURERS 0000001159: AJI-Pharma USA Inc 500 Frank Burr Blvd Teaneck, NJ 07666 Contact: Dr Maxwell Gordon (201)836-1196 REFERENCES ICA11/96920916. Chang RY, Kong XB. Meta-survey of plant and herb material as a treatment for HIV. Int Conf AIDS. 1996 Jul 7-12;11(1):22 (abstract no.Mo.B.303). MED/96056222. Moriyama A, Murata I, Kuroda T, Yoshikawa I, Tabaru A, Ogami Y, Otsuki M. Pericardiac metastasis from advanced gastric cancer. J Gastroenterol 1995 Aug;30(4):512-6. MED/95155164. Hamuro J, Takatsuki F, Suga T, Kikuchi T, Suzuki M. Synergistic antimetastatic effects of lentinan and interleukin 2 with pre- and post-operative treatments. Jpn J Cancer Res. 1994 Dec;85(12):1288-97. MED/94185237. Suto T, Fukuda S, Moriya N, Watanabe Y, Sasaki D, Yoshida Y, Sakata Y. Clinical study of biological response modifiers as maintenance therapy for hepatocellular carcinoma. Cancer Chemother Pharmacol 1994;33 Suppl:S145-8. ICA10/94369733. Kaneko Y, Mimura T, Guralnik M, Baker M, Goodgame J, DeMarzo C, Pierce D, Lang W, Gordon M. Phase II study of combination of lentinan with ddI in HIV-positive patients. Int Conf AIDS. 1994 Aug 7-12;10(1):212 (abstract no. PBO276). ICA10/94372558. Masihi KN, Chihara G, Kaneko Y. Inhibition of TNF production by lentinan and curdlan sulfate. Int Conf AIDS. 1994 Aug 7-12;10(2):95 (abstract no. PAO261). MED/92394698. Arinaga S, Karimine N, Takamuku K, Nanbara S, Inoue H, Nagamatsu M, Ueo H, Akiyoshi T. Enhanced induction of lymphokine-activated killer activity after lentinan administration in patients with gastric carcinoma. Int J Immunopharmacol. 1992 May;14(4):535-9. MED/93050820. Chihara G. Recent progress in immunopharmacology and therapeutic effects of polysaccharides. Dev Biol Stand. 1992;77:191-7. ICA6/30048790. Abrams D, Greco M, Wong R, Goosby E, Gorter R, Gordon M, Guralnik M, Kaneko Y. Results of a phase I/II placebo-controlled dose finding pilot study of lentinan in patients with HIV infection. Int Conf AIDS. 1990 Jun 20-23;6(3):207 (abstract no. S.B.487). ENTRY MONTH 199305 LAST REVISION DATE 20000801 176 UNIQUE IDENTIFIER DRG-0170 NAME OF SUBSTANCE Curdlan sulfate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 115743-28-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Curdlan, hydrogen sulfate [CHEMLINE ] PROTOCOL ID NUMBERS Complete FDA 127A PHARMACOLOGICAL ACTION MODE OF ACTION: The activity of curdlan sulfate is comparable to other sulfated polysaccharides with anti-HIV activity in vitro (e.g. dextran sulfate). These compounds are thought to inhibit HIV by blocking virion adsorption to target cell surfaces. [AmfAR Treat Dir 1993;6(4); p 25; AIDS Res Hum Retroviruses 1991 Apr;7(4); p 409-15] DISEASES STUDIED/TREATED Tested for the treatment of Cytomegalovirus retinitis. [AmfAR Treat Dir 1995;7(4); p 173] CLASSIFICATION CODE Investigational - Virion receptor binding antagonist [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Sulfated polysaccharide compound with 1-6-beta-D-glucan as a main chain. [AmfAR Treat Dir 1993;6(4); p 25] CHEMICAL/PHYSICAL DATA Molecular Weight: 79,000 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile aqueous solution. [Protocol ID: 127A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [AmfAR Treat Dir 1995;7(4); p 173] MANUFACTURERS 0000001159: AJI-Pharma USA Inc 500 Frank Burr Blvd Teaneck, NJ 07666 Contact: Dr Maxwell Gordon (201)836-1196 REFERENCES ICA11/96924573. Sekigawa I, Takeda N, Neoh LP, Ogasawara H, Kaneko H, Yamaguchi K, Hishikawa T, Hashimoto H, Hirose S, Mimura T, et al. The role of curdlan sulfate on the binding of HIV-1 gp120 to CD4 molecules. Int Conf AIDS. 1996 Jul 7-12;11(2):281 (abstract no.Th.B.4179). MED/96098544. Gordon M, Guralnik M, Kaneko Y, Mimura T, Goodgame J, Lang W. Further clinical studies of curdlan sulfate (CRDS)--an anti-HIV agent. J Med. 1995;26(3-4):97-131. MED/96073117. Yoshida T, Yasuda Y, Mimura T, Kaneko Y, Nakashima H, Yamamoto N, Uryu T. Synthesis of curdlan sulfates having inhibitory effects in vitro against AIDS viruses HIV-1 and HIV-2. Carbohydr Res. 1995 Oct 23;276(2):425-36. MED/95088509. Gordon M, Guralnik M, Kaneko Y, Mimura T, Baker M, Lang W. A phase I study of curdlan sulfate--an HIV inhibitor. Tolerance, pharmacokinetics and effects on coagulation and on CD4 lymphocytes. J Med. 1994;25(3-4):163-80. MED/94303188. Jagodzinski PP, Wiaderkiewicz R, Kurzawski G, Kloczewiak M, Nakashima H, Hyjek E, Yamamoto N, Uryu T, Kaneko Y, Posner MR, et al. Mechanism of the inhibitory effects of curdlan sulfate on HIV-1 infection in vitro. Virology. 1994 Aug 1;202(2):735-45. ICA10/94369696. Gordon M, Guralnik M, Lang W, Baker M, Goodgame J, DeMarzo C, Mimura T, Kaneko Y. Phase I/II study of curdlan sulfate--an HIV inhibitor. Int Conf AIDS. 1994 Aug 7-12;10(1):204 (abstract no. PBO244). ICA10/94372558. Masihi KN, Chihara G, Kaneko Y. Inhibition of TNF production by lentinan and curdlan sulfate. Int Conf AIDS. 1994 Aug 7-12;10(2):95 (abstract no. PAO261). MED/92304364. Uryu T, Ikushima N, Katsuraya K, Shoji T, Takahashi N, Yoshida T, Kanno K, Murakami T, Nakashima H, Yamamoto N. Sulfated alkyl oligosaccharides with potent inhibitory effects on human immunodeficiency virus infection. Biochem Pharmacol. 1992 Jun 9;43(11): 2385-92. MED/92385163. Aoki T, Kaneko Y, Nguyen T, Stefanski MS, Ting RC, Manak MM. Curdlan sulfate and HIV-1: II. In vitro long-term treatment of HIV-1 infection with curdlan sulfate. AIDS Res Hum Retroviruses. 1992 May;8(5):605-12. ENTRY MONTH 199305 LAST REVISION DATE 20000801 177 UNIQUE IDENTIFIER DRG-0169 NAME OF SUBSTANCE Amitriptyline hydrochloride [USPD 1998; p. 49] REGISTRY NUMBER 549-18-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Propanamine, 3-(10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5- -ylidene)-N,N-dimethyl- , hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS (component of) Etrafon [USPD 1998; p. 2439] SYNONYMS Elavil [USP DI 2000; p. 294] SYNONYMS Endep [USP DI 2000; p. 294] PROTOCOL ID NUMBERS Complete NIAID ACTG 242 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 022 PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically, this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. Since norepinephrine and serotonin can carry pain messages to the brain from other parts of the body, reducing the reabsorption of these substances can potentially decrease the pain felt by a person. Amitriptyline is rapidly absorbed from the GI tract and from parenteral sites. Peak plasma concentrations occur within 2-12 h after oral or IM therapy. The plasma half-life ranges from 10-50 h. About 25-50% of a dose is excreted as inactive metabolites within 24 h. [PDR 1997; p 2945; Protocol ID: CPCRA 022 ; AHFS Drug Information 1997; p 1680] DISEASES STUDIED/TREATED Relief or reduction of pain caused by HIV-associated peripheral neuropathy. [Protocol ID: CPCRA 022 ] CLASSIFICATION CODE Antidepressant [USP DI 2000; p. 288] CLASSIFICATION CODE Antineuralgic [USP DI 2000; p. 288] OTHER MAJOR USES Relief of symptoms of depression; relief of neuropathic pain in various peripheral neuropathies. [Protocol ID: CPCRA 022 ; PDR 1997; p 2945] SUBSTANCE INTERACTIONS Interacts with monoamine oxidase inhibitors, cimetidine, drugs metabolized by cytochrom p450 2D6, selective serotonin reuptake inhibitors, ethchlorvynol, sympathomimetic and anticholinergic agents. May block the antihypertensive action of guanethidine or similarly acting compounds. May potentiate the effects of alcohol, barbiturates, and other CNS depressants. [PDR 1997; p 2946] ADVERSE EFFECTS Adverse reaction in order of decreasing severity are listed in the following, cardiovasuclar: myocardial infarction, stroke, nonspecific ECG changes and changes in AV conduction, heart block, arrhythmias, hypotension (particularly orthostatic hypotension), syncope, hypertension, tachycardia, palpitation; CNS and neuromuscular: coma, seizures, hallucinations, delusions, confusional states, disorientation, incoordination, ataxia, tremors, peripheral neuropathy, numbness, tingling, and paresthesias of the extremities, extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria, disturbed concentration, excitement, anxiety, insomnia, restlessness, nightmares, drowsiness, dizziness, weakness, fatigue, headache, syndrome of inappropriate antidiuretic hormone secretion, tinnitus, alteration in EEG patterns; anticholinergic: paralytic ileus, hyperpyrexia, urinary retension, dilatation of the urinary tract, constipation, blurred vision, disturbance of accommodation, increased ocular pressure, mydriasis, dry mouth; allergic: skin rash, urticaria, photosensitization, edema of face and tongue; hematologic: bone marrow depression including agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia; gastrointestinal: rarely hepatitis (including altered liver function and jaundice), nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, parotid swelling, black tongue; endocrine: testicular swelling and gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, impotence, elevation and lowering of blood sugar levels. Other adverse effects include alopecia, edema, weight gain or loss, urinary frequency and increased perspiration. After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise. Gradual dosage reduction has been reported, within two weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring withing 2-7 days following cessation of chronic therapy with tricyclic antidepressants. [PDR 1997; p 2946] CONTRAINDICATIONS Contraindicated in patients with prior hypersensitivity to the drug and those in the acute recovery phase following myocardial infarction. Amitriptyline hydrochloride should not be given concomitantly with monoamine oxidase inhibitors. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and monoamine oxidase inhibiting drugs simultaneously. When it is desired to replace a monoamine oxidase inhibitor with amitriptyline hydrochloride, a minimum of 14 days should be allowed to elapse after the former is discontinued. The drug should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. [PDR 1997; p 2945-6] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Dibenzocycloheptadiene-derivative tricyclic antidepressant. [AHFS Drug Information 1997; p 1679] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H23-N.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 313.87 [USPD 1998; p. 49] CHEMICAL/PHYSICAL DATA Melting Point: 196-197 C [Merck Index 1996; p. 86] CHEMICAL/PHYSICAL DATA Elemental Comp: C86.59%, H8.36%, N5.05% (base) [Merck Index 1996; p. 85] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water, chloroform, and alcohol. [Merck Index 1996; p 86] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White or pratically white, odorless or pratically odorless, crystalline powder or small crystals with a bitter, burning taste. [PDR 1997; p 2945; AHFS Drug Information 1997; p 1679] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (10, 25, 50, 75, 100, and 150 mg); solution (10 mg/ml, 10 ml per vial). [PDR 1997; p 2947] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intramuscular injection. [PDR 1997; p 2945] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store tablets and solution at or below 30 C (86 F). Protect 10 mg tablets from light. Store tablets in well-closed containers. Protect 10 mg solution from freezing. [PDR 1997; p 2947] MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Dr Janice Albrecht (908)298-7985 MANUFACTURERS 0000005385: Intervention provided by participating unit , Contact: Unspecified (800)526-4099 MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Cheryl Karol (508)366-1100 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Unspecified (800)236-9933 REFERENCES AIDS/96701690. McGuire S. Fun in the sun? Posit Aware. 1996 Jul/Aug;7(4):10-1. AIDS/95700461. Lein B. Potential therapy for painful neuropathy. PI Perspect. 1995 May;:no 16(11). AIDS/95700101. Chavez C, Prickly business. The finer points of acupuncture. Posit Aware. 1995 Jan/Feb;:14-5. MED/95126437. Holsboer F, Grasser A, Friess E, Wiedemann K. Steroid effects on central neurons and implications for psychiatric and neurological disorders. Ann NY Acad Sci. 1994 Nov 30;746:345-59; discussion 359-61. MED/95054645. Benoliel R, Eliav E, Elishoov H, Sharav Y. Diagnosis and treatment of persistent pain after trauma to the head and neck. J Oral Maxillofac Surg. 1994 Nov;52(11):1138-47; discussion 1147-8. MED/93263324. McQuay HJ, Carroll D, Glynn CJ. Dose-response for analgesic effect of amitriptyline in chronic pain. Anaesthesia. 1993 Apr;48(4):281-5. MED/93211712. Kerrick JM, Fine PG, Lipman AG, Love G. Low-dose amitriptyline as an adjunct to opioids for postoperative orthopedic pain: a placebo-controlled trial. Pain. 1993 Mar;52(3):325-30. MED/92220132. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy [see comments]. N Engl J Med. 1992 May 7;326(19):1250-6. MED/92150091. Watson CP, Chipman M, Reed K, Evans RJ, Birkett N. Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain. 1992 Jan;48(1):29-36. MED/93040556. Bowsher D. Acute herpes zoster and postherpetic neuralgia: effects of acyclovir and outcome of treatment with amitriptyline [see comments]. Br J Gen Pract. 1992 Jun;42(359):244-6. ENTRY MONTH 199304 LAST REVISION DATE 20001107 178 UNIQUE IDENTIFIER DRG-0168 NAME OF SUBSTANCE Interleukin-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 224 PHARMACOLOGICAL ACTION MODE OF ACTION: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. IL-4 can suppress the generation of TNF and IL-6, a mitogen for AIDS-related Kaposi's sarcoma cells, which may result in suppression of Kaposi's sarcoma lesions. [AmfAR Treat Dir 1997;8(3); p 72; MeSH ; Protocol ID: ACTG 224 ] DISEASES STUDIED/TREATED AIDS-related Kaposi's sarcoma. [AmfAR Treat Dir 1997;8(3); p 72] CLASSIFICATION CODE Immunomodulator [AmfAR Treat Dir 1997;8(3); p 72] ADVERSE EFFECTS Adverse effects include headache, fever, nausea, vomiting, poor appetite, rigors, fatigue, myalgias, pain, edema, rhinitis/nasal symptoms, sinusitis, hypersensitivity reactions, cardiac injury, arrhythmias, confusion, altered consciousness, nervous system problems, weight loss, bone pain, liver problems, low blood pressure, and blood clots. [AmfAR Treat Dir 1995;7(4); p 66; Protocol ID: ACTG 224 ] CONTRAINDICATIONS Contraindicated in pregnant women. [Protocol ID: ACTG 224 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A naturally occurring cytokine. [AmfAR Treat Dir 1997;8(3); p 72] CHEMICAL/PHYSICAL DATA Solubility: Soluble in sterile water for injection. [Protocol ID: ACTG 224 ] CHEMICAL/PHYSICAL DATA Stability: Lyophilized powder stable for 24 months. Reconstituted solution stable for 24 hours. [Protocol ID: ACTG 224 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Lyophilized powder. [Protocol ID: ACTG 224 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. [AmfAR Treat Dir 1997;8(3); p 72; Protocol ID: ACTG 224 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (36-46 F). [Protocol ID: ACTG 224 ] MANUFACTURERS 0000001199: Schering - Plough Research 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Professional Information (800)526-4099 REFERENCES AIDS/97926808. Lemaitre F, Giangrande I, Michelet C, Dejour R, Cornillet B, Cartier F, Genetet B, Genetet N. No evidence for a shift from a TH1 to a TH2-type response in HIV infection: analysis of IL-2,IL-4 and IFN-g production at cellular level in peripheral blood lymphocytes. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:85 (abstract no. 113). MED/96314094. Tascini C, Baldelli F, Monari C, Retini C, Pietrella D, Francisci D, Bistoni F, Vecchiarelli A. Inhibition of fungicidal activity of polymorphonuclear leukocytes form HIV-infected patients by interleukin (IL)-4 and IL-10. AIDS. 1996 May;10(5):477-83. MED/95395370. Capsoni F, Minonzio F, Ongari AM, Carbonelli V, Galli A, Zanussi C. IL-10 up-regulates human monocyte phagocytosis in the presence of IL-4 and IFN-gamma. J Leukoc Biol 1995 Sep;58(3):351-8. ICA10/94370788. Miles SA, Mitsuyasu R, LaFleur F, Ryback M, Kasden P, Suckow C, Groopman J, Scadden D. Phase I/II trial of interleukin-4 in KS (ACTG 224). Int Conf AIDS. 1994 Aug 7-12;10(1):46 (abstract no. 159B). MED/94355266. Sosman JA, Fisher SG, Kefer C, Fisher RI, Ellis TM. A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients. Ann Oncol 1994 May;5(5):447-52. MED/93314717. Dugas B, Renauld JC, Pene J, Bonnefoy JY, Peti-Frere C, Braquet P, Bousquet J, Van Snick J, Mencia-Huerta JM. Interleukin-9 potentiates the interleukin-4-induced immunoglobulin (IgG, IgM and IgE) production by normal human B lymphocytes. Eur J Immunol 1993 Jul;23(7):1687-92. MED/93309160. Czuczman MS, Class K, Scheinberg DA. Interleukin-4 priming enhances a target for human complement-mediated cytotoxicity of CLL. Leukemia 1993 Jul;7(7):1020-5. MED/94033156. Ghosh AK, Smith NK, Prendiville J, Thatcher N, Crowther D, Stern PL. A phase I study of recombinant human interleukin-4 administered by the intravenous and subcutaneous route in patients with advanced cancer: immunological studies. Eur Cytokine Netw 1993 May-Jun;4(3):205-11. ICDB/93692092. Gill P, Puri PK. Interleukin-4 receptor (IL-4R) expression on AIDS-related Kaposi's sarcoma (AIDS-KS) cells and inhibition of tumor cell growth and cytokine production by IL-4 (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res. 1993;34:A1121. ENTRY MONTH 199304 LAST REVISION DATE 20000801 179 UNIQUE IDENTIFIER DRG-0167 NAME OF SUBSTANCE rgp120/HIV-1MN Monovalent Octameric V3 Peptide Vaccine [Protocol ID: AVEG 011 ] PROTOCOL ID NUMBERS Complete NIAID AVEG 011 PROTOCOL ID NUMBERS No longer recruiting FDA 091 PHARMACOLOGICAL ACTION MODE OF ACTION: The V3 peptides are the immunogenic portion of the multiple antigen peptide, and the lysine core matrix is not immunogenic. Immunogenicity studies with the octameric IIIB V3 peptide formulated in alum adjuvant have been carried out in a variety of species including mice, rabbits and rhesus macaques. Pre-clinical studies using guinea pigs demonstrated that HIV-1 IIIB V3 octameric peptide induced high titer anti-IIIB neutralizing antibody with crossreactivity against RF and MN strains. A 300 microgram dose of MN V3 octameric peptide formulated with alum given at 0, 4, and 8 weeks to African Green Monkeys induced ELISA reciprocal antibody titers ranging as high as 10--5 and reciprocal virus neutralizing antibody titers as high as 256. Pigtail macaques after four doses of the same candidate vaccine demonstrated reciprocal neutralizing antibody titers as high as 1,000 and ELISA reciprocal antibody titers as high as 10,000. Two of two pigtail macaques given a multivalent V3 octameric peptide containing 20 micrograms of MN V3 octameric peptide developed neutralizing antibodies. [Protocol ID: AVEG 011 ] DISEASES STUDIED/TREATED Prophylaxis against HIV infection. [Protocol ID: AVEG 011 ] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 011 ] ADVERSE EFFECTS Adverse effects may include those associated with intramuscular injection of any polypeptide, such as pain, redness, and swelling at the injection site, as well as possible fever, chills, aches, pains, and fatigue. [Protocol ID: AVEG 011 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Monovalent (MN strain) synthetic vaccine based on eight V3-derived peptides attached to a heptalysyl core to form radial-octamers. The heptalysyl core bearing eight reactive NH2-termini serves as a carrier onto which eight V3 peptides are attached by solid-phase synthesis. The antigenic principal neutralizing determinant matrix, with an 8-fold molar excess of peptide over the core, forms greater than 95% of the mass of the octamer. [Protocol ID: AVEG 011 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 500 mcg vials. [Protocol ID: AVEG 011 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular. [Protocol ID: AVEG 011 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 2 and 8 C (35.6-46.4 F). [Protocol ID: AVEG 011 ] MANUFACTURERS 0000002563: United Biomedical Inc 25 Davids Drive Happauge, NY 11788 Contact: Dr Bruce Forrest (516)273-2828 REFERENCES MED/97143413. Kelleher AD, Emery S, Cunningham P, Duncombe C, Carr A, Golding H, Forde S, Hudson J, Roggensack M, Forrest BD, et al. Safety and immunogenicity of UBI HIV-1MN octameric V3 peptide vaccine administered by subcutaneous injection. AIDS Res Hum Retroviruses. 1997 Jan 1;13(1):29-32. AIDS/97920741. Kahn J, Murcar N, Elbeik T, Staprans S, Hanson C, Mayer Y, Doyle R, Gonzalez L, Koff W. UBI HIV-1MN octameric V3 pepitde vaccine in HIV-1 negative humans. Conf Adv AIDS Vaccine Dev; 1996 Feb 11-15;:167 [Poster 47]. ASHM7/96343538. Emery S, Kelleher T, Duncombe C, Cunningham P, Hudson J, Golding H, Forde S. A phase I/II study of a candidate, prophylactic HIV-vaccine in HIV-seronegative volunteers at high-risk for infection. The Australian HIV-Vaccine Collaborative Group. Annu Conf Australas Soc HIV Med. 1995 Nov 16-19;7:89 (abstract no. 108). MED/95052714. Fraisier C, Ebersold A, Blomberg J, Desgranges C. Primary in vitro immunization with multimeric synthetic peptides of HIV-1 envelope glycoproteins: generation of neutralizing human monoclonal antibodies. J Immunol Methods 1994 Nov 10;176(1):9-22. ICA10/9437110. Gorse GJ, Keefer M, Weinhold K, Matthews T, Stablein D, Potts B, Forrest B. Phase I study of HIV-1 MN V3 octameric peptide vaccine. Int Conf AIDS. 1994 Aug 7-12;10(2):123 (abstract no. PAO375). ICA10/94370975. Kahn J, Richardson J, Murcar N, Koff W, Forrest B. Phase 1 study of HIV-1 MN octameric V3 peptide vaccine in HIV-1 negative adults. Int Conf AIDS. 1994 Aug 7-12;10(1):91 (abstract no. 318A). MED/95000929. Morgado MG, Sabino EC, Shpaer EG, Bongertz V, Brigido L, Guimaraes MD, Castilho EA, Galvao-Castro B, Mullins JI, Hendry RM, et al. V3 region polymorphisms in HIV-1 from Brazil: prevalance of subtype B strains divergent from North American/European prototype and detection of subtype F. AIDS Res Hum Retroviruses 1994 May;10(5):569-76. ENTRY MONTH 199303 LAST REVISION DATE 20000801 180 UNIQUE IDENTIFIER DRG-0166 NAME OF SUBSTANCE Delavirdine mesylate [USPD 1998; p. 214] REGISTRY NUMBER 147221-93-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-[3-(Isopropylamino)-2-pyridyl]-4-[(5-methan- esulfon- amidoindol-2-yl)carbonyl]piperazine monomethanesulfonate [USPD 1998; p 214] SYNONYMS Rescriptor [USP DI 2000; p. 1213] PROTOCOL ID NUMBERS Complete NIAID ACTG 260 PROTOCOL ID NUMBERS Complete NIAID ACTG 261 PROTOCOL ID NUMBERS Complete NIAID ACTG 359 PROTOCOL ID NUMBERS No longer recruiting FDA 125A PROTOCOL ID NUMBERS No longer recruiting FDA 228A PROTOCOL ID NUMBERS No longer recruiting FDA 228B PROTOCOL ID NUMBERS No longer recruiting FDA 228C PROTOCOL ID NUMBERS No longer recruiting FDA 228D PROTOCOL ID NUMBERS No longer recruiting FDA 228E PROTOCOL ID NUMBERS No longer recruiting FDA 228F PROTOCOL ID NUMBERS No longer recruiting FDA 228G PROTOCOL ID NUMBERS No longer recruiting FDA 229H PROTOCOL ID NUMBERS No longer recruiting FDA 229J PROTOCOL ID NUMBERS No longer recruiting CC 93 I-109 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 370 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS Recruiting FDA 228H PROTOCOL ID NUMBERS Terminated FDA 292E PROTOCOL ID NUMBERS Terminated NIAID ACTG 374 PHARMACOLOGICAL ACTION Delavirdine binds directly to HIV-1 reverse transcriptase and blocks RNA-dependent and DNA-dependent DNA polymerase activities. HIV-1 group 0, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine. Human DNA polymerase activities are not affected. Delavirdine used alone or with other antiretroviral agents may confer cross-resistance to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, the potential of cross-resistance between delavirdine and nucleoside analogue reverse transcriptase inhibitors is low because of different sites of binding on the viral enzyme and distinct mechanisms of action. The potential of cross-resistance between delavirdine and protease inhibitors is also low because of the different enzyme targets involved. Delavirdine is distributed primarily into blood plasma. In the body, delavirdine is converted to several inactive antimetabolites, primarily through the enzyme cytochrome P450 3A (CYP3A). The metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. The mean elimination time from plasma is 5.8 hours. Elimination is 44% through the feces, and 51% through the urine. Less than 5% of the dose is recovered unchanged from the urine. Resistance to delavirdine emerges rapidly in vitro and when used as a monotherapy. Resistance is commonly associated with mutations in the reverse transcriptase enzyme at position 103, which causes cross-resistance with other NNRTIs. [USP DI 1999; p 1184; AmfAR Treat Dir 1998;9(2); 1998;9(2); p 35] DISEASES STUDIED/TREATED The FDA approved delavirdine 4/4/97 for use in combination with appropriate antiretrovirals for the treatment of HIV infection. Delavirdine should always be administered with at least one other antiretroviral agent. In clinical studies it has been used in combination with zidovudine/lamivudine or didanosine, for initial management. Clinical trial ACTG 359 showed that adding delavirdine to dual protease inhibitor salvage therapy decreases viral load in about 30 to 40% of patients. [AHFS Drug Information 1998; p 531; Pharmacia. Available at: http://www.pnu.com. Accessed: May 15, 2000.] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1211] CLASSIFICATION CODE Nonnucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 597] SUBSTANCE INTERACTIONS Delavirdine is metabolized by and inhibits the 3A isoenzyme of the cytochrome P450 system. Since this system is the pathway for the metabolism of many common drugs, delavirdine is likely to have interactions with such drugs. Coadministration with alprazolam, midazolam, or triazolam should be avoided. Plasma levels are reduced through coadministration with carbamazepine, phenobarbital, or phenytoin. Interactions with delavirdine must be expected with cimetidine, famotidine, nizatidine, or ranitidine. Coadministration with ddI lowers the plasma levels of both drugs. Coadministration with indinavir increases indinavir plasma levels; reduced levels of that drug should be taken. Coadministration of rifabutin should be avoided because substantial elevation of the rifabutin plasma levels occurs. Coadministration of saquinavir causes a fivefold increase in saquinavir plasma levels. Terfenadine and astemizole are also expected to interact with delavirdine. Coadministration of rifampin causes a substantial decrease in delavirdine plasma levels. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 36] ADVERSE EFFECTS As with other NNRTIs, the most significant side effect of delavirdine is a rash which occurs in about 18% of the patients. Other side effects reported for delavirdine are blisters, conjunctivitis, fever, joint aches, muscle aches, oral lesions, and swelling. Alanine aminotransferase and aspartate aminotransferase levels may be increased, while neutrophil counts may be decreased. [USP DI 1999; p 1184; AmfAR Treat Dir 1998;9(2); 1998;9(2); p 36] CONTRAINDICATIONS Therapy with delavirdine is contraindicated in patients receiving rifampin and rifabutin. Because delavirdine is metabolized primarily by the liver, risk-benefits should be considered when giving the drug to patients with impaired hepatic functions. [AmfAR Treat Dir 1997;8(3); p 31; USP DI 1999; p 1184] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Delavirdine is a BHAP (bis[heteroaryl]piperazine) compound with in vitro activity comparable to other non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). However, all of these compounds are unique. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 35] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H28-N6-O3-S.C-H4-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 552.68 [USPD 1998; p. 214] SUBSTANCE DELIVERY DATA DOSAGE FORM: Usual dosage for HIV infection is 400 mg three times a day. [USP DI 1999; p 1186] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [USP DI 1999; p 1184] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 20 - 25 C (68-77 F) in a tight container. Protect from high humidity. [USP DI 1999; p 1187] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 REFERENCES MED/99355060. Friedland GH, Pollard R, Griffith B, Hughes M, Morse G, Bassett R, Freimuth W, Demeter L, Connick E, Nevin T, Hirsch M, Fischl M. Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team. J Acquir Immune Defic Syndr 1999 Aug 1;21(4):281-92. MED/99277996. Para MF, Meehan P, Holden-Wiltse J, Fischl M, Morse G, Shafer R, Demeter LM, Wood K, Nevin T, Virani-Ketter N, Freimuth WW. ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team. Antimicrob Agents Chemother 1999 Jun;43(6):1373-8. MED/99254254. Barry M, Mulcahy F, Merry C, Gibbons S, Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999 Apr;36(4):289-304. Review. MED/99173595. Been-Tiktak AM, Boucher CA, Brun-Vezinet F, Joly V, Mulder JW, Jost J, Cooper DA, Moroni M, Gatell JM, Staszewski S, Colebunders R, Stewart GJ, Hawkins DA, Johnson MA, Parkin JM, Kennedy DH, Hoy JF, Borleffs JC. Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial. Int J Antimicrob Agents 1999 Jan;11(1):13-21. MED/98433394. Adams WJ, Aristoff PA, Jensen RK, Morozowich W, Romero DL, Schinzer WC, Tarpley WG, Thomas RC. Discovery and development of the BHAP nonnucleoside reverse transcriptase inhibitor delavirdine mesylate. Pharm Biotechnol 1998;11:285-312. Review. MED/99054853. Miller V, de Bethune MP, Kober A, Sturmer M, Hertogs K, Pauwels R, Stoffels P, Staszewski S. Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride. Antimicrob Agents Chemother 1998 Dec;42(12):3123-9. MED/99069417. Pelemans H, Esnouf RM, Jonckheere H, De Clercq E, Balzarini J. Mutational analysis of Tyr-318 within the non-nucleoside reverse transcriptase inhibitor binding pocket of human immunodeficiency virus type I reverse transcriptase. J Biol Chem 1998 Dec 18;273(51):34234-9. MED/98328440. Ferry JJ, Herman BD, Carel BJ, Carlson GF, Batts DH. Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1;18(3):252-9. MED/97205218. Demeter LM, Meehan PM, Morse G, Gerondelis P, Dexter A, Berrios L, Cox S, Freimuth W, Reichman RC. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. J Acquir Immune Defic Syndr Hum Retrovirol 1997 Feb 1;14(2):136-44. MED/96261387. Freimuth WW. Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor. Adv Exp Med Biol 1996;394:279-89. Review. ENTRY MONTH 199303 LAST REVISION DATE 20000801 181 UNIQUE IDENTIFIER DRG-0165 NAME OF SUBSTANCE Thymalfasin [USPD 1998; p. 729] REGISTRY NUMBER 62304-98-7 [USPD 1998] STANDARD CHEMICAL NAME Thymosin alpha1 [CHEMLINE ] PROTOCOL ID NUMBERS Complete NIAID ACTG 236 PHARMACOLOGICAL ACTION MODE OF ACTION: Appears to both increase IL-2 receptors on lymphocytes in vitro and enhance lymphocyte maturation in vivo. In one study, thymosin alpha 1 enhanced CD4 lymphocyte levels if given with low doses of alpha interferon and AZT. In another study, thymosin alpha 1 pretreatment significantly restored the boosting capacity of two cytokines, IL-2 and IFN, although combined administration of thymosin alpha 1 with IL-2 or IFN did not substantially modify the depressed natural killer cell response. Ten HIV-positive patients treated with 600 mcg/day thymosin alpha 1 showed no immunological or clinical improvements at that dosage. A partial homology exists between thymosin alpha 1 and the HIV gag gene protein p17/18. In prior research, an antiserum prepared against thymosin alpha 1 effectively neutralized the AIDS-associated virus and blocked its replication in H9 cells. The antiviral activity of the antiserum was found to be due to the region of homology between thymosin alpha 1 and p17. Comparison of the primary sequences of thymosin alpha 1 and the gag protein revealed a 44-50% homology in an 18-amino acid region, between positions 11 and 28 on thymosin alpha 1 and positions 92 and 109 on the gag protein. Normal thymosin alpha 1 levels have been shown to be 670 +/- 163 pg/ml for males and 652 +/- 162 pg/ml for females. [Protocol ID: ACTG 236 ; Bull N Y Acad Med 1989 Jan;65(1); p 111-9; Science 1986 May 30;232(4754); p 1135-7] DISEASES STUDIED/TREATED Enhancement of CD4 lymphocyte levels in patients being treated for primary HIV infection. [Protocol ID: ACTG 236 ] CLASSIFICATION CODE Immunomodulator [Current AIDS Therapies 1991] OTHER MAJOR USES Treatment of hepatitis B. [PR Newswire 1993 Jan 7] ADVERSE EFFECTS Appeared nontoxic in humans in several chronic administration studies. [Int J Clin Lab Res 1994;24(1); p 23-8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: 28-amino acid peptide that can be manufactured synthetically. A lymphokine isolated from a mixture of about 30 low-molecular weight thymic peptides called thymosin fraction 5. [Current AIDS Therapies 1991] CHEMICAL/PHYSICAL DATA Molecular Formula: C129-H215-N33-O55 [USPD 1998; p. 729] CHEMICAL/PHYSICAL DATA Molecular Weight: 3108.33 [USPD 1998; p. 729] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous. [Protocol ID: ACTG 236 ] MANUFACTURERS 0000002541: Alpha I Biomedicals / Viral Technologies Inc 6707 Democracy Boulevard Suite 111 Bethesda, MD 20817 Contact: Dr Vincent Simmon (301)564-4400 REFERENCES MED/97292861. Baumann CA, Badamchian M, Goldstein AL. Thymosin alpha 1 antagonizes dexamethasone and CD3-induced apoptosis of CD4+ CD8+ thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways. Mech Ageing Dev. 1997 Mar;94(1-3):85-101. MED/96061931. Kubota S, Adachi Y, Copeland TD, Oroszlan S. Binding of human prothymosin alpha to the leucine-motif/activation domains of HTLV-I Rex and HIV-1 Rev. Eur J Biochem. 1995 Oct 1;233(1):48-54. MED/95354186. Baxevanis CN, Gritzapis AD, Spanakos G, Tsitsilonis OE, Papamichail M. Induction of tumor-specific T lymphocyte responses in vivo by prothymosin alpha. Cancer Immunol Immunother. 1995 Jun;40(6):410-8. MED/96183643. Ramachandran R, Katzenstein DA, Winters MA, Kundu SK, Merigan TC. Polyethylene glycol-modified interleukin-2 and thymosin alpha 1 in human immunodeficiency virus type 1 infection. J Infect Dis. 1996 Apr;173(4):1005-8. MED/95232136. Dusheiko GM. Treatment and prevention of chronic viral hepatitis. Pharmacol Ther. 1995 Jan;65(1):47-73. MED/95127515. Lopez M, Carpano S, Cavaliere R, Di Lauro L, Ameglio F, Vitelli G, Frasca AM, Vici P, Pignatti F, Rosselli M, et al. Biochemotherapy with thymosin alpha 1, interleukin-2 and dacarbazine in patients with metastatic melanoma: clinical and immunological effects. Ann Oncol 1994 Oct;5(8):741-6. MED/95105072. Hadden JW. T-cell adjuvants. Int J Immunopharmacol. 1994 Sep;16(9):703-10. MED/94235899. Garaci E, Rocchi G, Perroni L, D'Agostini C, Soscia F, Grelli S, Mastino A, Favalli C. Combination treatment with zidovudine, thymosin alpha 1 and interferon-alpha in human immunodeficiency virus infection. Int J Clin Lab Res. 1994;24(1):23-8. ICA7/3214891. Garaci E, Andreoni M, Mastino A, Antonucci G, Soscia F, Sarmati L, Perroni L, Giannini V, Pavalli C, Rocchi G. Effect of thymosin alpha-1 and interferon alpha associated with zidovudine in HIV-seropositive patients. Int Conf AIDS. 1991 Jun 16-21;7(2):219 (abstract no. W.B.2148). MED/95007065. Goldstein AL. Clinical application of thymosin alpha-1 [editorial; comment]. Cancer Invest. 1994;12(5):545-7. ENTRY MONTH 199303 LAST REVISION DATE 20000801 182 UNIQUE IDENTIFIER DRG-0164 NAME OF SUBSTANCE Saquinavir [USPD 1998; p. 655] REGISTRY NUMBER 149845-06-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Butanediamide, N(1)-[3-[3-[[(1,1-dimethylethyl)amino]carbony- l]octahydro-2(1H)-isoqu inolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2- -[(2-quinolinylcarbonyl )amino]-, [3S-[2[1R*(R*),2S*],3alpha,4abeta,8abeta]]-, monomethanesulfonate [USPD 1998; p 655] SYNONYMS Fortovase [USP DI 2000; p. 2753] SYNONYMS Invirase [USP DI 2000; p. 2753] PROTOCOL ID NUMBERS Complete NIAID ACTG 229 PROTOCOL ID NUMBERS Complete NIAID ACTG 333 PROTOCOL ID NUMBERS Complete NIAID ACTG 359 PROTOCOL ID NUMBERS Complete NIAID ACTG 378 PROTOCOL ID NUMBERS Complete NIAID ACTG 401 PROTOCOL ID NUMBERS Complete NIAID ACTG A5047 PROTOCOL ID NUMBERS No longer recruiting FDA 212A PROTOCOL ID NUMBERS No longer recruiting FDA 229A PROTOCOL ID NUMBERS No longer recruiting FDA 229B PROTOCOL ID NUMBERS No longer recruiting FDA 229C PROTOCOL ID NUMBERS No longer recruiting FDA 229D PROTOCOL ID NUMBERS No longer recruiting FDA 229E PROTOCOL ID NUMBERS No longer recruiting FDA 229F PROTOCOL ID NUMBERS No longer recruiting FDA 229G PROTOCOL ID NUMBERS No longer recruiting FDA 229H PROTOCOL ID NUMBERS No longer recruiting FDA 229J PROTOCOL ID NUMBERS No longer recruiting FDA 229K PROTOCOL ID NUMBERS No longer recruiting FDA 229L PROTOCOL ID NUMBERS No longer recruiting FDA 229M PROTOCOL ID NUMBERS No longer recruiting FDA 229N PROTOCOL ID NUMBERS No longer recruiting FDA 229P PROTOCOL ID NUMBERS No longer recruiting FDA 229Q PROTOCOL ID NUMBERS No longer recruiting FDA 229R PROTOCOL ID NUMBERS No longer recruiting FDA 229S PROTOCOL ID NUMBERS No longer recruiting FDA 232E PROTOCOL ID NUMBERS No longer recruiting FDA 238J PROTOCOL ID NUMBERS No longer recruiting FDA 264A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 397 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 398 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS Recruiting FDA 302B PROTOCOL ID NUMBERS Recruiting NIAID ACTG 386 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5043 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Terminated NIAID ACTG 374 PHARMACOLOGICAL ACTION MODE OF ACTION: Saquinavir is a selective, competitive, reversible inhibitor of HIV protease, which plays an essential role in the replication cycle of HIV and the formation of infectious virus. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes. Because saquinavir is a structural analogue of the HIV phenylalanine-proline protease cleavage site, the drug inhibits the function of the enzyme and thus blocks maturation of the virus. Saquinavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly. Thus, the drug is active in a subset of chronically infected cells that generally are not affected by dideoxynucleoside reverse transcriptase inhibitors. Saquinavir does not affect early stages of the HIV replication cycle; however, the drug interferes with the production of infectious HIV and limits further infectious spread of the virus. Studies indicate that saquinavir exerts cytotoxic properties at concentrations at least 1000 times greater than those required for antiretroviral activity. The relative bioavailability of saquinavir mesylate in soft gelatin capsules is three times that of the drug in hard capsules. Peak plasma concentrations of the drug (in soft gelatin capsules) are about 2 times higher in HIV-infected patients than in healthy volunteers. Distribution of the drug into body tissues and fluids (such as the central nervous system) has not been fully characterized. Saquinavir is about 97% bound to plasma proteins in concentrations up to 30 microg/ml. The drug is metabolized in the liver to several monohydroxylated and dihydroxylated inactive metabolites. Metabolism is mediated by cytochrome P450; the isoenzyme CYP3A4 is involved in more than 90% of this metabolism. Systemic clearance is rapid. Saquinavir is excreted primarily in the feces, both as unabsorbed drug and as metabolites. [AHFS Drug Information 1999; p 614-7] DISEASES STUDIED/TREATED The FDA has approved saquinavir (Fortovase [soft-gel capsule] and Invirase [hard-gel capsule]) for use in combination with other antiretroviral agents for the treatment of HIV infection. Studies have shown a reduction in AIDS-defining illness or death for patients who received Invirase plus zalcitabine, compared to zalcitabine or Invirase alone. Further, studies have shown increased saquinavir concentrations and improved antiviral activity for Fortovase compared to Invirase. [Fortovase Homepage. Available at: http://www.fortovase.com. Accessed: May 15, 2000.] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 2751] CLASSIFICATION CODE Protease inhibitor [AHFS Drug Information 2000; p. 649] SUBSTANCE INTERACTIONS Metabolism by saquinavir is mediated by the P450 isoenzyme CYP3A/4. Drugs that induce this isoenzyme (e.g., rifampin, rifabutin, phenobarbital, phenytoin, dexamethasone, or carbamazepine) may reduce saquinavir plasma concentration. Conversely, drugs that inhibit this isoenzyme may increase plasma concentration of saquinavir. Also, saquinavir may alter the pharmacokinetics of other drugs that are metabolized by this enzyme system; that may create the possibility of serious adverse effects. Patients on saquinavir should not receive astemizole, cisapride, or terfenadine. They should be closely monitored if they are also being given clindamycin, calcium channel blockers, dapsone, quinidine, or triazolam (all drugs metabolized by the P450 isoenzyme CYP3A/4). Concomitant administration of saquinavir and the antifungal ketoconazole may increase concentration of saquinavir. Results from studies evaluating the use of a 3-drug regimen of saquinavir, zidovudine, and zalcitabine indicate no alteration in the pharmacokinetic parameters of any of the drugs. Based on studies by the manufacturer (DuPont Merck) of efavirenz, physicians should not prescribe efavirenz in combination therapies that use saquinavir (Fortovase) as the only protease inhibitor, unless it is the only possible alternative. The study shows that Fortovase plasma concentrations decrease by 60%, and efavirenz plasma concentrations decrease by 10%, when used in standard doses. DuPont Merck also advises against the use of any other saquinavir-containing double protease-inhibitor therapies, with the possible exception of ritonavir/saquinavir. Data is not available on the potential drug interactions when combining efavirenz, ritonavir, and saquinavir. [BETA 1998 Jul; 1998 Jul; p 9] ADVERSE EFFECTS Saquinavir appears to be well tolerated. The most frequently reported adverse events among patients receiving saquinavir were diarrhea, abdominal discomfort, and nausea. Other reactions reported in trials of saquinavir, alone and with zidovudine and zalcitabine, include the following: dyspepsia, mucosa damage, headache, paresthesia, extremity numbness, dizziness, peripheral neuropathy, musculoskeletal pain, myalgia, asthenia, appetite disturbances, rash, and pruritus. [Protocol ID: ACTG 333 ; PDR 1999; p 2687-8; AHFS Drug Information 1999; p 618-20] CONTRAINDICATIONS Saquinavir is contraindicated in patients hypersensitive to the drug or any ingredient in the formulation. The risk of spontaneous bleeding may be increased in patients with hemophilia receiving saquinavir. The drug should be used with caution in patients with impaired liver functions, or with diabetes. [AHFS Drug Information 1999; p 619-20] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Peptide-based protease inhibitor. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 29-31] CHEMICAL/PHYSICAL DATA Molecular Formula: C38-H50-N6-O5.C-H4-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 766.96 [USPD 1998; p. 655] CHEMICAL/PHYSICAL DATA Elemental Comp: C68.04%, H7.51%, N12.53%, O11.92% (base) [Merck Index 1996; p. 1438] CHEMICAL/PHYSICAL DATA Solubility: Aqueous solubility of 2.22 mg/ml at 25 C. Saquinavir itself is insoluble in water. [AHFS Drug Information 1999; p 614] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white, very fine powder. [PDR 1999; p 2685] SUBSTANCE DELIVERY DATA DOSAGE FORM: 200-mg capsules. Soft gel capsules (Fortovase), hard gel capsules (Invirase). [AHFS Drug Information 1999; p 622] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 2688] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Hard capsules: store at 15-30 C (59-86 F). Soft capsules: store in tight container at lower than 25 C. [PDR 1999; p 2688; AHFS Drug Information 1999; p 614] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Unspecified (800)526-6367 REFERENCES MED/99385799. Kravick S, Gallicano K, Roth V, Cassol S, Hawley-Foss N, Badley A, Cameron DW. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr 1999 Aug 15;21(5):371-5. MED/99284278. Revicki DA, Moyle G, Stellbrink HJ, Barker C. Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group. AIDS 1999 May 7;13(7):851-8. MED/99284263. Cohen Stuart JW, Schuurman R, Burger DM, Koopmans PP, Sprenger HG, Juttmann JR, Richter C, Meenhorst PL, Hoetelmans RM, Kroon FP, Bravenboer B, Hamaan D, Boucher CA, Borleffs JC. Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study). AIDS 1999 May 7;13(7):F53-58. MED/98195465. Vella S, Floridia M. Saquinavir. Clinical pharmacology and efficacy. Clin Pharmacokinet 1998 Mar;34(3):189-201. MED/98191627. Perry CM, Noble S. Saquinavir soft-gel capsule formulation. A review of its use in patients with HIV infection. Drugs 1998 Mar;55(3):461-86. Review. MED/99217477. Cameron DW, Japour AJ, Xu Y, Hsu A, Mellors J, Farthing C, Cohen C, Poretz D, Markowitz M, Follansbee S, Angel JB, McMahon D, Ho D, Devanarayan V, Rode R, Salgo M, Kempf DJ, Granneman R, Leonard JM, Sun E. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1999 Feb 4;13(2):213-24. MED/99217470. Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K. Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999 Feb 4;13(2):F23-28. MED/99059878. Schapiro JM, Lawrence J, Speck R, Winters MA, Efron B, Coombs RW, Collier AC, Merigan TC. Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS clinical trials group 229. J Infect Dis 1999 Jan;179(1):249-53. MED/99045103. Andreoni M, Sarmati L, Nicastri E, Ventura L, Ercoli L, Parisi SG, Giannini G, Galluzzo C, Vella S. Saquinavir delays the emergence of zidovudine resistance in HIV-1 seropositive patients treated with combination therapy. J Med Virol 1998 Dec;56(4):332-6. AIDS/99703962. Baker R. Efavirenz and Fortovase. BETA 1998 Jul:9. ENTRY MONTH 199303 LAST REVISION DATE 20000922 183 UNIQUE IDENTIFIER DRG-0163 NAME OF SUBSTANCE Wobenzym [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 72506-65-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Wobenzym [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting FDA 122A PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro treatment of human PBMNC with proteolytic enzymes (bromelain, papain) and amylase leads to production of large amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1 beta) and interleukin-6 (IL-6) in a time and dose dependent manner. A commercial mixture of these enzymes (Wobenzym) showed similar effects. Intact bromelain, papain or amylase, which are components of Wobenzym, induce cytokine production in peripheral blood mononuclear cells (PBMNC) in vitro. IFN-alpha (interferon alpha) and IFN-gamma, which had no effect alone, synergistically increased TNF (tumor necrosis factor) production when applied together with the enzymes. After ingestion of milligram doses of the polyenzyme preparation, PBMNC of healthy volunteers acquire the ability to produce TNF-alpha, IL (interleukin)-1 beta and IL-6. This may explain the antitumor effects of such enzymes. The polyenzyme preparation also may have strong immunomodulary effects in combination with IFN-gamma. In another study, WOBENZYM appeared to stabilize CD4 count and HIV-RNA level in subjects with CD4 counts 200 to 500 over 42 weeks. The presence of acid-labile alpha interferon permitted selection of non responders to WOBENZYM therapy and hence served as a surrogate marker that may indicate the need to initiate anti-retroviral therapy. Careful attention to surrogate markers in HIV subjects with CD4 counts 200-500 may permit individualization of therapy and stabilization of disease with WOBENZYM in a subgroup. The use of WOBENZYM alone and in combination with anti-retrovirals in selected groups of HIV seropositive individuals with CD4 counts 200 to 500 should be further investigated. [Cancer Biother 1994 Fall;9(3); p 253-63; Oncology 1993;50(6); p 403-7; Int Conf AIDS 1996 Jul 7-12;11(2); p 91 (abstract no. We.B.3198)] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection. [Protocol ID: 122A ] CLASSIFICATION CODE Immunomodulator [Oncology 1993;50(6); p 403-7] OTHER MAJOR USES Nutritional supplement given with phytotherapy for cancer; treatment of rheumatoid arthritis; adjuvant treatment for postoperative pain. [Schweiz Rundsch Med Prax 1990 May 29;79(22); p 706-8; Rheumatology 1985 Mar-Apr;44(2); p 51-6; Anaesthetist 1993;42(12); p 856-61] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An oral pharmaceutical preparation of 7 enzymes, (trypsin, chymotrypsin, papain, bromelain, pancreatin, lipase, amylase), and the flavinoid rutin with known immunomodulating and anti-inflammatory properties. [Int Conf AIDS 1996 Jul 7-12;11(2); p 91 (abstract no. We.B.3198)] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets. [Protocol ID: 122A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 122A ] MANUFACTURERS 0000002504: Mucos Pharma GmbH and Co Alpenstrasse 29 Geretsried 1, Contact: Unspecified REFERENCES MED/97341027. Mudrak J, Bobak L, Sebova I. Adjuvant therapy with hydrolytic enzymes in recurrent laryngeal papillomatosis. Acta Otolaryngol Suppl (Stockh) 1997;527:128-30. ICA11/96923551. Lange M, Maitra U, Inada Y, Stauder G, Klein EB. Effects of enzyme therapy on HIV-RNA and CD4 counts in HIV seropositive subjects with CD4 count 200 to 500. Int Conf AIDS. 1996 Jul 7-12;11(2):91 (abstract no. We.B.3198). MED/95392632. Zavadova E, Desser L, Mohr T. Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation. Cancer Biother 1995 Summer;10(2):147-52. MED/94051003. Desser L, Rehberger A, Kokron E, Paukovits W. Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of polyenzyme preparations. Oncology 1993 Nov-Dec;50(6):403-7. MED/95120056. Desser L, Rehberger A, Paukovits W. Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro. Cancer Biother. 1994 Fall;9(3):253-63. ENTRY MONTH 199302 LAST REVISION DATE 20000801 184 UNIQUE IDENTIFIER DRG-0162 NAME OF SUBSTANCE gp160 Vaccine (Immuno-AG) [Protocol ID: ACTG 205 ] PROTOCOL ID NUMBERS Complete NIAID ACTG 205 PROTOCOL ID NUMBERS Complete NIAID ACTG 221 PROTOCOL ID NUMBERS Complete NIAID ACTG 246/946 PROTOCOL ID NUMBERS Complete NIAID AVEG 004 PROTOCOL ID NUMBERS Complete NIAID AVEG 004A PROTOCOL ID NUMBERS Complete NIAID AVEG 004B PROTOCOL ID NUMBERS Complete NIAID AVEG 010 PROTOCOL ID NUMBERS Complete NIAID AVEG 013A PROTOCOL ID NUMBERS Complete NIAID AVEG 013B PHARMACOLOGICAL ACTION MODE OF ACTION: It has been theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cellular immune responses. However, recent data from non-HIV infected people who received experimental vaccines indicated that antibodies induced by recombinant subunit vaccines are not effective in neutralizing primary (clinical) isolates of HIV. It is not clear what the implications of data are for therapeutic vaccine trials. The conformational similarity of rgp160 to the native gp160 may have positive implications for its ability to block primary infection of diverse HIV strains. An ongoing trial with MN rg160 showed that upon administration of the third and fourth doses, vaccine-induced envelope-specific T-cell memory and HIV-1 MN neutralizing antibodies were reported in the majority of patients treated. In another recent trial in 609 HIV+ patients with >400 CD4 cells/cubic mm, the primary endpoints were disease progression and /or a 50% decline in mean CD4+ count over baseline. The study showed that there were no differences between placebo and treatment groups for either the primary endpoints or endpoints which assessed immunologic or virologic responses. [AmfAR Treat Dir 1997;8(3); p 60-1] DISEASES STUDIED/TREATED HIV infection. [AmfAR Treat Dir 1997;8(3); p 60-1] CLASSIFICATION CODE Vaccine [Protocol ID: ACTG 205 ] ADVERSE EFFECTS VaxSyn (recombinant gp160) has been well tolerated when given IM. Local reactions are common including tenderness and induration at the injection site. Mild fever, myalgia or fatigue may accompany local reactions. Interdermal administration results in subcutaneous nodule formation, prolonged skin discoloration, occasional purulent drainage and local pruritis. Other side effects include headaches and nausea. [AmfAR Treat Dir 1997;8(3); p 60-1] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: rgp 160 is a recombinant form of purified envelope glycoprotein gp160 derived from either the IIIB or MN strain of HIV-1. It is fully glycosylated, with a 3-dimensional shape approximately identical to gp160. [AmfAR Treat Dir 1997;8(3); p 60-1] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Formulated powder. [Protocol ID: ACTG 205 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Liquid. [Protocol ID: ACTG 205 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular. [AmfAR Treat Dir 1997;8(3); p 60-1] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (35-46 F). [Protocol ID: ACTG 205 ] MANUFACTURERS 0000005211: Baxter Healthcare Corporation Hyland Immuno Division / 550 North Brand Blvd Glendale, CA 91203 Contact: Unspecified (800)423-2090 REFERENCES AIDS/97288124. Lambert JS, McNamara J, Katz S, Livingston R, Moye J. Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children. Pediatric AIDS Clinical Trials Group Study ACTG 218. American Pediatric Association and Society for Pediatric Research annual meeting; 1996 May 6-10; Washington D.C. Pediatr AIDS HIV Infect. 1996 Aug;7(4):279 (unnumbered abstract). MED/97296236. VanCott TC, Mascola JR, Kaminski RW, Kalyanaraman V, Hallberg PL, Burnett PR, Ulrich JT, Rechtman DJ, Birx DL. Antibodies with specificity to native gp120 and neutralization activity against primary human immunodeficiency virus type 1 isolates elicited by immunization with oligomeric gp160. J Virol. 1997 Jun;71(6):4319-30. MED/97289463. Lambert JS, Viscidi R, Walker MC, Clayman B, Winget M, Wolff M, Schwartz DH. Antibody to human immunodeficiency virus type 1 (HIV-1) gp160 in mucosal specimens of asymptomatic HIV-1-infected volunteers parenterally immunized with an experimental recombinant HIV-1 IIIB gp160 vaccine. The National Institute of Allergy and Infectious Disease-sponsored AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1997 May 4(3):302-8. MED/97301714. Kim JH, Loveland JE, Sitz KV, Ratto Kim S, Mclinden RJ, Tencer K, Davis K, Burke DS, Boswell RN, Redfield RR, et al. Expansion of restricted cellular immune reponses to HIV-1 envelope by vaccination: IL-7 and IL-12 differentially augment cellular proliferative responses to HIV-1. Clin Exp Immunol. 1997 May;108(2):243-50. MED/97304241. Veljkovic V, Johnson E, Metlas R. Molecular basis of the inefficacy and possible harmful effects of AIDS vaccine candidates based on HIV-1 envelope glycoprotein gp120. Vaccine. 1997 Apr;15(5):473-4. MED/97240800. Pincus SH, Messer KG, Cole R, Ireland R, VanCott TC, Pinter A, Schwartz DH, Graham BS, Gorse GJ. Vaccine-specific antibody responses induced by HIV-1 envelope subunit vaccines. J Immunol. 1997 Apr 1;158(7):3511-20. MED/97236827. Ruff AL, Guarnieri FG, Staveley-O'Carroll K, Siliciano RF, August JT. The enhanced immune response to the HIV gp160/LAMP chimeric gene product targeted to the lysosome membrane protein trafficking pathway. J Biol Chem. 1997 Mar 28;272(13):8671-8. MED/97347307. Artenstein AW, VanCott TC, Sitz KV, Robb ML, Wagner KF, Veit SC, Rogers AF, Garner RP, Byron JW, Burnett PR, et al. Mucosal immune responses in four distinct compartments of women infected with human immunodeficiency virus type 1: a comparison by site and correlation with clinical information. J Infect Dis. 1997 Feb;172(2):265-71. MED/97226783. Moukrim Z, Cho YY, Mbika JP, Achour A. Lymphoproliferative response to synthetic V3 loop P18 peptide and HIV-1 envelope glycoprotein among individuals immunized with gp160 candidate vaccines. Biomed Pharmacother. 1996;59(10):494-9. ENTRY MONTH 199302 LAST REVISION DATE 20000801 185 UNIQUE IDENTIFIER DRG-0161 NAME OF SUBSTANCE Fluorouracil [USPD 1998; p. 319] REGISTRY NUMBER 51-21-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4(1H,3H)-Pyrimidinedione, 5-fluoro- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Adrucil [USP DI 2000; p. 1574] SYNONYMS Efudex [USP DI 2000; p. 1576] SYNONYMS Fluoroplex [USP DI 2000; p. 1576] PROTOCOL ID NUMBERS Complete NIAID ACTG 200 PHARMACOLOGICAL ACTION MODE OF ACTION: Fluorouracil acts as an antimetabolite interfering with DNA synthesis by inhibiting thymidylate synthetase activity. This enzyme catalyzes the methylation of deoxyuridylic acid to thymidylic acid, a DNA precursor. TOPICAL APPLICATION: Since topically applied fluorouracil shows specificity for keratoses, it has been suggested that absorption of the drug into cells is selectively greater in diseased skin than in normal skin. Studies with radiolabeled drug indicate that following topical applications, negligible amounts of the drug are absorbed systemically as determined by the radioactivity measured in plasma, urine and expired CO2. To date there is no published information regarding the metabolic fate of topically applied fluorouracil. [AHFS Drug Information 1997; p 2786-7] DISEASES STUDIED/TREATED Vaginal application of cream to prevent recurrence of cervical/vaginal dysplasia. [Protocol ID: ACTG 200 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1574] OTHER MAJOR USES Topical treatment of multiple actinic or solar keratoses; topical treatment of superficial basal cell carcinomas, only if conventional methods are impractical; topical treatment of intraepithelial neoplasia of skin and vagina. [PDR 1995; p 2033; Protocol ID: ACTG 200 ] ADVERSE EFFECTS Topical application: Adverse effects include localized pain, pruritis, hyperpigmentation, burning, allergic contact dermatitis, scarring, soreness, tenderness, suppuration, scaling, and swelling. Other adverse effects include alopecia, insomnia, stomatitis, irritability, medicinal taste, photosensitivity, lacrimation, telangiectasia, and urticaria. Laboratory abnormalities include leukocytosis, thrombocytopenia, toxic granulation, and eosinophilia. [PDR 1997; p 2281] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to any components of the product and in pregnant women. Patients receiving fluorouracil topical therapy should avoid exposure to sunlight or other ultraviolet rays. Topical fluorouracil should not be applied on the eyelids or directly into the eyes, nose or mouth because irritation may occur. [PDR 1997; p 2281; Protocol ID: ACTG 200 ; AHFS Drug Information 1995; p 2477] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fluorinated pyrimidine, antagonist. [AHFS Drug Information 1997; p 2768] CHEMICAL/PHYSICAL DATA Molecular Formula: C4-H3-F-N2-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 130.08 [USPD 1998; p. 319] CHEMICAL/PHYSICAL DATA Elemental Comp: C36.93%, H2.32%, F14.61%, N21.54%, O24.60% [Merck Index 1996; p. 708] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in water; slightly soluble in alcohol. [AHFS Drug Information 1997; p 2768] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to practically white crystalline powder. [PDR 1997; p 2280] SUBSTANCE DELIVERY DATA DOSAGE FORM: Cream 1% or 5%, solution 1%, 2%, or 5%. [AHFS Drug Information 1997; p 2769] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical (cream or solution). [PDR 1997; p 2281] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15-30 C (59-86 F). Protect from freezing. Store in tight container. [AHFS Drug Information 1997; p 2768] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Professional Services (800)526-6367 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000005205: Allergan Inc PO Box 19534 / 2525 Dupont Drive Irvine, CA 926239534 Contact: Unspecified (800)526-6367 REFERENCES MED/97313215. Peddada AV, Smith DE, Rao AR, Frost DB, Kagan AR. Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 1997 Mar 15;37(5):1101-5. MED/97088114. Bottomley DM, Aqel N, Selvaratnam G, Phillips RH. Epidermoid anal cancer in HIV infected patients. Clin Oncol (R Coll Radiol). 1996;8(5):319-22. MED/97039259. Findenig G, Mader RM, Fritzer-Szekeres M, Steger GG, Jaeger W, Szekeres T. Modulation of 5-fluorouracil resistance in human colon tumor cell lines by azidothymidine. Oncol Res. 1996;8(5):189-96. MED/96300570. Gong YF, Bechtold CM, Robinson BS, Lin PF. Potentiation of the stavudine anti-human immunodeficiency virus activity by 5-fluorouracil [letter]. Antimicrob Agent Chemother. 1996 May;40(5):1329. MED/96152477. De Brabander M, Vandebroek J, Wassenaar H, De Cree J, Baisier A, Demoen B, De Ridder R, Jagers E, Roels V, Vogels O, et al. Immunological alterations induced by adjuvant treatment of postoperative colon carcinoma Duke's B or C with levamisole in combination with 5-FU. Anticancer Res. 1995 Sep-Oct;15(5B):2271-7. ICDB/95613710. Clark JW, Beitz J, Cummings F, Sikov W, Browne M, Akerley W, Wanebo H, Weitberg AB, Kennedy T, Bigley J, Darnowski JD. Phase II study of 5-fluorouracil (5-FU), leucovorin (LV) and azidodeoxythymidine (AZT) in patients with metastatic colorectal cancer (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol;14:A557 1995. MED/96090564. Marchbanks K, Dudley MN, Posner MR, Darnowski J. Pharmacokinetics and pharmacodynamics of high-dose zidovudine administered as a continuous infusion in patients with cancer. Pharmacotherapy. 1995 Jul-Aug;15(4):451-7. MED/95220719. Miyazaki K, Mizutani H, Katabuchi H, Fukuma K, Fujisaki S, Okamura H. Activated (HLA-DR+) T-lymphocyte subsets in cervical carcinoma and effects of radiotherapy and immunotherapy with sizofiran on cell-mediated immunity and survival. Gynecol Oncol. 1995 Mar;56(3):412-20. MED/94357034. Chadha M, Rosenblatt EA, Malamud S, Pisch J, Berson A. Squamous-cell carcinoma of the anus in HIV-positive patients. Dis Colon Rectum. 1994 Sep;37(9):861-5. MED/94204241. Smith DE, Shah KH, Rao AR, Frost DB, Latino F, Anderson PJ, Peddada AV, Kagan AR. Cancer of the anal canal: treatment with chemotherapy and low-dose radiation therapy. Radiology. 1994 May;191(2):569-72. ENTRY MONTH 199301 LAST REVISION DATE 20001107 186 UNIQUE IDENTIFIER DRG-0160 NAME OF SUBSTANCE Guaifenesin [USPD 1998; p. 348] REGISTRY NUMBER 93-14-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,2-Propanediol, 3-(2-methoxyphenoxy)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS (component of) Deconsal II [PDR 2000; p. 1705] SYNONYMS Robitussin [Facts and Comparisons p. 712] PROTOCOL ID NUMBERS Terminated NIAID ACTG 186 PHARMACOLOGICAL ACTION MODE OF ACTION: Increases sputum and bronchial secretions by reducing adhesiveness and surface tension. By reducing the viscosity of secretions, guaifenesin increases the efficiency of the cough reflex and ciliary action in removing accumulated secretions from the trachea and bronchi. The drug is readily absorbed from the gastrointestinal tract and readily metabolized and excreted in the urine. It has a plasma half-life of 1 hour. The major urinary metabolite is beta-(2-methoxyphenoxy) lactic acid. In study that assessed changes in nasal symptoms among 23 HIV-infected patients receiving either 3 weeks of guaifenesin (2400 mg daily) or placebo, the guaifenesin group reported less nasal congestion and thinner postnasal drainage. Guaifenesin appears to be effective in managing HIV-infected patients with symptomatic rhinosinusitis. [PDR 1997; p 1605; Laryngoscope 1992 Nov;102(11); p 1225-8] DISEASES STUDIED/TREATED Prevention of recurrent HIV-associated sinusitis. [Protocol ID: ACTG 186 ] CLASSIFICATION CODE Expectorant [USP DI 2000; p. 1659] OTHER MAJOR USES Used as expectorant in pharyngitis, bronchitis, and asthma. [PDR 1997; p 1605] SUBSTANCE INTERACTIONS May interfere with laboratory test for diagnosis of carcinoid syndrome; may falsely elevate the VMA test for catechols. [PDR 1997; p 1605] ADVERSE EFFECTS No serious adverse effects have been reported with the use of guaifenesin. Doses of guaifenesin larger than those required for expectorant action may produce emesis, but GI upset at ordinary dosage levels is rare. [PDR 1995; p 461; AHFS Drug Information 1997; p 2092] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to guaifenesin. [PDR 1997; p 1605] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H14-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 198.22 [USPD 1998; p. 348] CHEMICAL/PHYSICAL DATA Melting Point: 78.5-79 C [Merck Index 1996; p. 777] CHEMICAL/PHYSICAL DATA Elemental Comp: C60.59%, H7.12%, O32.29% [Merck Index 1996; p. 777] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, ethanol, chloroform, glycerol, propylene glycol, DMF; moderately soluble in benzene; practically insoluble in petroleum ether. [Merck Index 1996; p 777] CHEMICAL/PHYSICAL DATA Stability: Powder tends to become lumpy on storage. [AHFS Drug Information 1997; p 2092] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to slightly gray, crystalline powder, having a bitter taste; may have a slight characteristic odor [AHFS Drug Information 1997; p 2091] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, solution. [AHFS Drug Information 1997; p 2092] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AHFS Drug Information 1997; p 2092] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at temperatures no greater than 30 C (86 F). Protect from freezing. [Protocol ID: ACTG 186 ] MANUFACTURERS 0000002480: Adams Laboratories Inc 14801 Sovereign Rd Fort Worth, TX 761552645 Contact: Andrew Morgan (817)545-7791 MANUFACTURERS 0000002480: Adams Laboratories Inc 14801 Sovereign Rd Fort Worth, TX 761552645 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 REFERENCES MED/97217517. Marks SC, Kissner DG. Management of sinusitis in adult cystic fibrosis. Am J Rhinol. 1997 Jan-Feb;11(1):11-4. MED/95140436. Friedman WH, Katsantonis GP, Bumpous JM. Staging of chronic hyperplastic rhinosinusitis: treatment strategies. Otolaryngol Head Neck Surg. 1995 Feb;112(2):210-4. MED/95180023. Sisson JH, Yonkers AJ, Waldman RH. Effects of guaifenesin on nasal mucociliary clearance and ciliary beat frequency in healthy volunteers. Chest 1995 Mar;107(3):747-51. IPA/95. /1081197. Wagner DL, Patel VS. Steady-state human pharmacokinetics and bioavailability of guaifenesin and pseudoephedrine in a sustained-release tablet relative to immediate-release liquids. Int J Pharm; VOL 114 ISS Feb 14 1995, P171-176, (REF 6). MED/95023331. Brock MH, Dansereau RJ, Patel VS. Use of in vitro and in vivo data in the design, development, and quality control of sustained-release decongestant dosage forms. Pharmacotherapy 1994 Jul-Aug;14(4):430-7. MED/93198678. Croughan-Minihane MS, Petitti DB, Rodnick JE, Eliaser G. Clinical trial examining effectiveness of three cough syrups [see comments]. J Am Board Fam Pract 1993 Mar-Apr;6(2):109-15. MED/93023477. Wawrose SF, Tami TA, Amoils CP. The role of guaifenesin in the treatment of sinonasal disease in patients infected with the human immunodeficiency virus (HIV). Laryngoscope. 1992 Nov;102(11):1225-8. ENTRY MONTH 199212 LAST REVISION DATE 20001107 187 UNIQUE IDENTIFIER DRG-0159 NAME OF SUBSTANCE Pseudoephedrine hydrochloride [USPD 1998; p. 614] REGISTRY NUMBER 345-78-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzenemethanol, alpha-(1-(methylamino)ethyl)-, (S-(R*,R*))-, hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS component of Deconsal II [USP DI 2000; p. 1088] SYNONYMS Sudafed [Facts and Comparisons p. 687] PROTOCOL ID NUMBERS Complete FDA 243A PROTOCOL ID NUMBERS Terminated NIAID ACTG 186 PHARMACOLOGICAL ACTION MODE OF ACTION: Acts directly on alpha-adrenergic receptors in the mucosa of the respiratory tract producing vasoconstriction which results in shrinkage of swollen nasal mucous membranes, reduction of edema and nasal congestion, and increase in nasal airway patency. May relax bronchial smooth muscle by stimulation of beta-adrenergic receptors. After oral administration of 60 mg of pseudoephedrine hydrochloride, nasal decongestion occurs within 30 minutes and persists for 4-6 hours. Pseudoephedrine may cross the placenta and may enter CSF. The drug may be distributed into milk. Pseudoephedrine is incompletely metabolized to an inactive metabolite in the liver by N-demethylation. The drug and its metabolite are excreted into the urine; 50-75% of the dose is excreted unchanged. [AHFS Drug Information 1997; p 986-7] DISEASES STUDIED/TREATED Prevention of recurrent HIV-associated sinusitis. [Protocol ID: ACTG 186 ] CLASSIFICATION CODE Decongestant [USP DI 2000; p. 1207] OTHER MAJOR USES Relief of nasal congestion in pharyngitis, bronchitis, and asthma. [PDR 1997; p 1605] SUBSTANCE INTERACTIONS May interact with beta-adrenergic blockers and monoamine oxidase (MAO) inhibitors; digitalis glycosides; guanethidine, mecamylamine, methyldopa, reserpine, and veratrum alkaloids; and tricyclic antidepressants. [PDR 1997; p 1605] ADVERSE EFFECTS Adverse effects include tachycardia, palpitations, headache, dizziness, nausea, anxiety, nervousness, restlessness, tremor, weakness, pallor, respiratory difficulty, burning on urination, insomnia, hallucinations, convulsions, depression, abnormal heart rhythms, and low blood pressure. [PDR 1997; p 1606; Protocol ID: ACTG 186 ] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity or idiosyncrasy to sympathomimetic amines, severe hypertension, or severe coronary artery disease, and in those on monoamine oxidase (MAO) inhibitor therapy. [PDR 1997; p 1605] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Sympathomimetic amine; adrenergic (vasoconstrictor). [AHFS Drug Information 1997; p 986-7] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H15-N-O.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 201.70 [USPD 1998; p. 614] CHEMICAL/PHYSICAL DATA Melting Point: 181-182 C [Merck Index 1996; p. 611] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, alcohol, and chloroform. [Merck Index 1996; p 611] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Fine, white to off-white crystals or powder having a faint, characteristic odor. [AHFS Drug Information 1997; p 986] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, capsules (extended release), solution. [AHFS Drug Information 1997; p 988] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AHFS Drug Information 1997; p 987] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at temperatures no greater than 30 C (86 F). Protect from freezing and light. [Protocol ID: ACTG 186 ; AHFS Drug Information 1997; p 986] MANUFACTURERS 0000002480: Adams Laboratories Inc 14801 Sovereign Rd Fort Worth, TX 761552645 Contact: Andrew Morgan (817)545-7791 MANUFACTURERS 0000002480: Adams Laboratories Inc 14801 Sovereign Rd Fort Worth, TX 761552645 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97259411. Garcia Ortiz JC, Terron M, Bellido J. Nonpigmenting fixed exanthema from ephedrine and pseudoephedrine. Allergy. 1997 Feb;52(2):229-30. MED/97171284. Gillies H, Derman WE, Noakes TD, Smith P, Evans A, Gabriels G. Pseudoephedrine is without ergogenic effects during prolonged exercise. J Appl Physiol. 1996 Dec;81(6):2611-7. MED/97084436. Nomeir AA, Mojaverian P, Kosoglou T, Affrime MB, Nezamis J, Rodwanski E, Lin CC, Cayen MN. Influence of food on the oral bioavailability of loratadine and pseudoephedrine from extended-release tablets in healthy volunteers. J Clin Pharmacol. 1996 Oct;36(10):923-30. MED/97168298. Lyon CC, Turney JH. Pseudoephedrine toxicity in renal failure. Br J Clin Pract. 1996 Oct-Nov;50(7):396-7. MED/95362927. Bronsky E, Boggs P, Findlay S, Gawchik S, Georgitis J, Mansmann H, Sholler L, Wolfe J, Meltzer E, Morris R, et al. Comparative efficacy and safety of a once-daily loratadine-pseudoephedrine combination versus its components alone and placebo in the management of seasonal allergic rhinitis. J Allergy Clin Immunol 1995 Aug;96(2):139-47. IPA/95. /1081197. Wagner DL, Patel VS. Steady-state human pharmcokinetics and bioavailability of guaifenesin and pseudoephedrine in a sustained-release tablet relative to immediate-release liquids. Int J Pharm; VOL 114 ISS Feb 14 1995, P171-176, (REF 6). MED/96134446. Pade V, Aluri J, Manning L, Stavchansky S. Bioavailability of pseudoephedrine from controlled release formulations in the presence of guaifenesin in human volunteers. Biopharm Drug Dispos 1995 Jul;16(5):381-91. MED/94315089. Krivda SJ, Benson PM. Nonpigmenting fixed drug eruption. J Am Acad Dermatol 1994 Aug;31 (2 pt 1):291-2. MED/95075901. Martinez Gallardo F, Lopez Fiesco A, Zamora G. Symptomatic treatment of common cold in children with a new combination of naproxen sodium plus pseudoephedrine hydrochloride: a comparative trial against pseudoephedrine syrup. Proc West Pharmacol Soc 1994;37:157-8. MED/94028386. Pratter MR, Bartter T, Akers S, DuBois J. An algorithmic approach to chronic cough. Ann Intern Med 1993 Nov 15;119(10):977-83. ENTRY MONTH 199212 LAST REVISION DATE 20001107 188 UNIQUE IDENTIFIER DRG-0158 NAME OF SUBSTANCE Beclomethasone dipropionate [USPD 1998; p. 82] REGISTRY NUMBER 5534-09-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Pregna-1,4-diene-3,20-dione, 9-chloro-11-hydroxy-16-methyl-17,21-bis(1-oxo- propoxy)-, (11beta,16beta)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Beclovent [USP DI 2000; p. 994] SYNONYMS Beconase [USP DI 2000; p. 1001] SYNONYMS Vancenase [USP DI 2000; p. 1001] SYNONYMS Vanceril [USP DI 2000; p. 994] PROTOCOL ID NUMBERS Terminated NIAID ACTG 186 PHARMACOLOGICAL ACTION MODE OF ACTION: Mechanism of anti-inflammatory action is unknown. The precise mechanism of the aerosolized drug's action in the nose is also unknown. The effects of beclomethasone dipropionate on hypothalamic-pituitary adrenal (HPA) function have been evaluated in adult volunteers by other routes of administration. There was no suppression of early morning plasma cortisol concentrations when beclomethasone was administered in a dose of 1000 mcg/day for a month as an oral aerosol or for 3 days by intramuscular injection. However, partial suppression of plasma cortisol concentration was observed when beclomethasone dipropionate was administered in doses of 2000 mcg per day either by aerosol or intramuscularly. Immediate suppression of plasma cortisol concentrations was observed after single doses of 4000 mcg of the drug. Suppression of HPA function has been reported in adult patients who received 1600 mcg daily doses. Absorption of the drug occurs rapidly from all respiratory and gastrointestinal tissues. The principal route of excretion of the drug and its metabolites is the feces; 12 - 15% is excreted in the urine. Studies have shown that the degree of binding to plasma proteins is 87%. [PDR 1997; p 1065-6] DISEASES STUDIED/TREATED Prevention of recurrent HIV-associated sinusitis. [Protocol ID: ACTG 186 ] CLASSIFICATION CODE Anti-inflammatory [USP DI 2000; p. 990] CLASSIFICATION CODE Corticosteroid [USP DI 2000; p. 996] OTHER MAJOR USES Indicated for the relief of the symptoms of seasonal or perennial rhinitis in those cases poorly responsive to conventional treatment. [PDR 1997; p 1066] ADVERSE EFFECTS Adverse effects include hypersensitivity, mild nasopharyngeal irritation, sneezing, headache, nausea, lightheadedness, nasal stuffiness, nosebleeds, rhinorrhea, or tearing eyes. Localized infections of the nose and pharynx with Candida albicans have occurred rarely. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol to beclomethasone dipropionate. [PDR 1997; p 1064; Protocol ID: ACTG 186 ] CONTRAINDICATIONS Contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required, or if there is hypersensitivity to any ingredients of the preparation. [PDR 1997; p 1064] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Anti-inflammatory corticosteroid; diester of beclomethasone. [AHFS Drug Information 1997; p 2134] CHEMICAL/PHYSICAL DATA Molecular Formula: C28-H37-Cl-O7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 521.05 [USPD 1998; p. 82] CHEMICAL/PHYSICAL DATA Melting Point: 117-120 C [Merck Index 1996; p. 170] CHEMICAL/PHYSICAL DATA Elemental Comp: C64.62%, H7.15%, Cl8.67%, O19.56% (base) [Merck Index 1996; p. 170] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to creamy-white, odorless powder. [PDR 1997; p 1065] SUBSTANCE DELIVERY DATA DOSAGE FORM: 6.7 g cannisters, 16.8 g cannisters. [PDR 1997; p 1067] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Inhalation of nasal spray. [PDR 1997; p 1067] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). [PDR 1997; p 1068] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Medical & Consumer Relations (919)483-9959 MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Medical and Consumer Relations (800)437-0992 REFERENCES ICA10/94369606. Lopez J, Rosello X, Jane E. Stomatitis aphthous in patients HIV+, treatment. Int Conf AIDS. 1994 Aug 7-12;10(1):183 (abstract no. PBO159). MED/94188673. Davies RJ, Lund VJ, Harten-Ash VJ. The effect of intranasal azelastine and beclomethasone on the symptoms and signs of nasal allergy in patients with perennial allergic rhinitis. Rhinology 1993 Dec;31(4):159-64. MED/93314270. Woodman K, Bremner P, Burgess C, Crane J, Pearce N, Beasley R. A comparative study of the efficacy of beclomethasone dipropionate delivered from a breath activated and conventional metered dose inhaler in asthmatic patients. Curr Med Res Opin 1993;13(2):61-9. MED/93326504. Davies B. A comparison of beclomethasone dipropionate and budesonide in the treatment of asthma [see comments]. Br J Clin Pract 1993 Mar-Apr;47(2):87-93. MED/94015690. Abzug MJ, Cotton MF. Severe chickenpox after intranasal use of corticosteroids [see comments]. J Pediatr 1993 Oct;123(4):577-9. MED/92310754. Chapnick EK, Gradon JD, Lutwick LI. Treatment of human immunodeficiency virus associated with oral aphthous ulcers with inhaled steroids [letter]. N Y State J Med. 1992 May;92(5):221. MED/89048746. Le Gros V, Stern M. [Obstructive bronchial aspergillosis of favorable course under corticoids in a HIV seropositive patient (letter)]. Ann Med Interne (Paris). 1988;139(4):285-6. ENTRY MONTH 199212 LAST REVISION DATE 20001107 189 UNIQUE IDENTIFIER DRG-0157 NAME OF SUBSTANCE Cefuroxime axetil [USPD 1998; p. 147] REGISTRY NUMBER 64544-07-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxy- lic acid, 3-(((aminocarbonyl)oxy)methyl)-7-((2-furanyl(- methoxyimino)acetyl)ami no)-8-oxo-, 1-(acetyloxy)ethyl ester, (6R-(6alpha,7beta(Z)))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Ceftin [USP DI 2000; p. 844] PROTOCOL ID NUMBERS Terminated NIAID ACTG 186 PHARMACOLOGICAL ACTION MODE OF ACTION: The bactericidal action of cefuroxime results from inhibition of cell wall synthesis by binding to essential target proteins. Cefuroxime axetil is absorbed from the gastrointestinal tract and hydrolyzed within the intestinal mucosa and blood to release cefuroxime. Cefuroxime is distributed in the extracellular fluid compartment. The axetil moiety is metabolized to acetaldehyde and acetic acid. The drug is excreted unchanged in the urine. It is approximately 50% protein bound; the half-life is 1.2 hours. Absorption is greater when taken after food. The drug has broad spectrum antibacterial activity and is highly stable to bacterial beta-lactamases, especially those found in the Enterobacteriaceae. It is active against gram positive and gram negative cocci, gram negative bacilli, and anaerobes. [PDR 1997; p 1067; Protocol ID: ACTG 186 ] DISEASES STUDIED/TREATED Prevention of recurrent HIV-associated sinusitis. [Protocol ID: ACTG 186 ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 820] OTHER MAJOR USES Treatment of pharyngitis and tonsillitis, otitis media, lower respiratory tract infections, urinary tract and gonorrhea infections, and skin infections. [PDR 1997; p 1068] SUBSTANCE INTERACTIONS Probenecid increases cefuroxime blood levels; drugs lowering gastric acidity may decrease cefuroxime bioavailability. [PDR 1997; p 1069] ADVERSE EFFECTS Adverse effects include anaphylaxis, nausea, vomiting, diarrhea, loose stools, rash, pruritus, urticaria, headaches, dizziness, vaginitis, transient elevations of transaminases and LDH, eosinophilia, positive Coomb's test, and seizures. [PDR 1997; p 1069; Protocol ID: ACTG 186 ] CONTRAINDICATIONS Contraindicated in patients with known allergy to the cephalosporin group of antibiotics. [PDR 1997; p 1068] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semi-synthetic, broad spectrum cephalosporin antibiotic; acetoxyethylester of cefuroxime; beta lactam class antibiotic. [PDR 1997; p 1067] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H22-N4-O10-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 510.48 [USPD 1998; p. 147] CHEMICAL/PHYSICAL DATA Stability: Reconstituted oral suspension is stable for 10 days. [PDR 1997; p 1070] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to cream colored amorphous powder. [AHFS Drug Information 1997; p 173] SUBSTANCE DELIVERY DATA DOSAGE FORM: 125, 250, and 500 mg tablets, oral suspension 125 mg/5 ml. [PDR 1997; p 1070] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1070] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15-30 C (59-86 F). Protect from excessive moisture. Store reconstituted suspension between 2-25 C. [PDR 1997; p 1070] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97126739. Brenner SA, Morgan J, Rickert PD, Rimland D. Cladophialophora bantiana isolated from an AIDS patient with pulmonary infiltrates. J Med Vet Mycol. 1996 Nov-Dec;34(6):427-9. MED/95070643. Burack JH, Hahn JA, Saint-Maurice D, Jacobson MA. Microbiology of community-acquired bacterial pneumonia in persons with and at risk for human immunodeficiency virus type 1 infection. Implications for rational empiric antibiotic therapy. Arch Intern Med. 1994 Nov 28;154(22):2589-96. MED/95023339. Goddard JK, Janning SW, Gass JS, Wilson RF. Cefuroxime-induced acute renal failure. Pharmacotherapy 1994;14(4):488-91. ICA10/94369606. Lopez J, Rosello X, Jane E. Stomatitis aphthous in patients HIV+, treatment. Int Conf AIDS. 1994 Aug 7-12;10(1):183 (abstract no. PBO159). MED/93372451. Mevorach D, Lossos IS, Oren R. Cefuroxime-induced fever. Ann Pharmacother 1993;27(7-8):881-2. MED/93152634. Bygdeman SM, Ruden AK, Jonsson A, Lidbrink P, Olofsson MB, Backman M, Gastrin B, Kallings I, Ramberg M, Rylander M, et al. Antibiotic susceptibility, serovars and auxotypes of gonococcal isolates in Stockholm. Relation to geographical origin of the infection. Int J STD AIDS. 1993 Jan-Feb;4(1):33-40. MED/92397909. Camacho AE, Cobo R, Otte J, Spector SL, Lerner CJ, Garrison NA, Miniti A, Mydlow PK, Giguere GC, Collins JJ. Clinical comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of patients with acute bacterial maxillary sinusitis. Am J Med. 1992 Sep;93(3):271-6. MED/92208399. Idemyor V, Cherubin CE. Pleurocerebral Nocardia in a patient with human immunodeficiency virus. Ann Pharmacother. 1992 Feb;26(2):188-9. MED/90168274. Telzak EE, Hii J, Polsky B, Kiehn TE, Armstrong D. Nocardia infection in the acquired immunodeficiency syndrome. Diagn Microbiol Infect Dis. 1989 Nov-Dec;12(6):517-9. ENTRY MONTH 199212 LAST REVISION DATE 20001107 190 UNIQUE IDENTIFIER DRG-0156 NAME OF SUBSTANCE Adefovir [USPD 1998; p. 24] REGISTRY NUMBER 106941-25-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Phosphonic acid, ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 217A PROTOCOL ID NUMBERS No longer recruiting FDA 217B PROTOCOL ID NUMBERS No longer recruiting CC 93 I-29 PHARMACOLOGICAL ACTION MODE OF ACTION: PMEA, like the other nucleoside analogues, inhibits HIV replication by inducing premature viral DNA chain termination through inhibition of the viral enzyme reverse transcriptase. PMEA is converted to the mono- and diphosphorylated metabolites (PMEAp and PMEApp). Being an alternative substrate to dATP, PMEApp acts as a potent DNA chain terminator, and this may explain its anti-retrovirus activity. It is active in vitro against many human and animal viruses, including HIV-1 and HIV-2, as well as human herpes viruses. PMEA inhibits HIV induced cytopathogenicity in MT-4 cells and HIV expression in H9 cells at a concentration of 1.6-2 microM. PMEA has been shown to be effective in delaying or preventing the development of retrovirus-induced diseases in mice, cats, and monkeys. Some in vitro results suggest that PMEA may be more effective at inhibiting HIV replication when administered on an intermittent schedule. In vivo PMEA was more effective at preventing Moloney murine sarcoma virus (MSV)-induced tumors in mice when given as a single dose at the time of viral inoculation rather than divided over several administrations. In phase I/II studies of intravenous PMEA in patients, the mean terminal half-life was 1.6 hours. Approximately 90 percent of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98 percent was recovered by 24 h postdosing. Overall mean total serum clearance of the drug was essentially the same as the renal clearance. Since PMEA is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60 percent of clearance. Oral bioavailability of PMEA at a 3.0 mg/kg dose was < 12 percent when based on serum concentration and was 16.4 percent when based on urinary recovery. Subcutaneous bioavailability of PMEA at a 3.0 mg/kg dose was 102 percent when based on serum concentration and was 84.8 percent when based on urinary recovery. [AmfAR Treat Dir 1995;7(4); p 53; Proc Natl Acad Sci USA 1991 Feb 15;88(4); p 1499-503; Int J Cancer 1995 Mar;61(1); p 130-37] DISEASES STUDIED/TREATED HIV infection. [AmfAR Treat Dir 1997;8(3); p 24; Int J Cancer 1995 Mar;61(1); p 130-37] CLASSIFICATION CODE Investigational - Acyclic nucleoside phosphonate analog [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Adverse effects include reversible elevated liver enzymes and neutropenia following IV PMEA. [AmfAR Treat Dir 1997;8(3); p 24] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An adenine nucleoside analogue. [AmfAR Treat Dir 1997;8(3); p 24] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H12-N5-O4-P [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 273.19 [USPD 1998; p. 24] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous, subcutaneous. [AmfAR Treat Dir 1995;7(4); p 54] MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: James Rooney (415)572-6597 REFERENCES AIDS/97702375. James JS. GS 840 (adefovir dipivoxil): broad-spectrum antiviral trial, CD4 count under 100. AIDS Treat News. 1997 Feb 7;(No 264):4-5. AIDS/97926548. Cherrington JM, Fuller MF, Lalezari JP, Miner R, Chen MS, Drew WL. In vitro antiviral susceptibilities of isolates from CMV retinitis patients receiving first or second line cidofovir therapy: relationship to clinical outcome. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:120 (abstract no. 304). MED/96322477. Freeman S, Gardiner JM. Acyclic nucleosides as antiviral compounds. Mol Biotechnol. 1996 Apr;5(2):125-37. MED/97014996. Arends S, van Halteren E, Kamp W, Schokker J. Safety of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in patients with human immunodeficiency virus infection: a pilot study. Pharm World Sci. 1996 Jan;18(1):30-4. MED/96183929. Pauwels R, De Clercq E. Development of vaginal microbicides for the prevention of heterosexual transmission of HIV. J Acquir Immunne Defic Syndr Hum Retrovirol. 1996 Mar 1;11(3):211-21. MED/96139529. Cundy KC, Barditch-Crovo P, Walker RE, Collier AC, Ebeling D, Toole J, Jaffe HS. Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother. 1995 Nov;39(11):2401-5. MED/96012180. Cundy KC, Petty BG, Flaherty J, Fisher PE, Polis MA, Wachsman M, Lietman PS, Lalezari JP, Hitchcock MJ, Jaffe HS. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1995 Jun;39(6):1247-52. MED/95221021. Balzarini J, Verstuyf A, Hatse S, Goebels J, Sobis H, Vandeputte M, De Clercq E. The human immunodeficiency virus (HIV) inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a strong inducer of differentiation of several tumor cell lines. Int J Cancer. 1995 Mar 29;61(1):130-7. MED/95174749. Robbins BL, Connelly MC, Marshall DR, Srinivas RV, Fridland A. A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent. Mol Pharmacol. 1995 Feb;47(2):391-7. MED/95070043. Gong YF, Marshall DR, Srinivas RV, Fridland A. Susceptibilities of zidovudine-resistant variants of human immunodeficiency virus type 1 to inhibition by acyclic nucleoside phosphonates. Antimicrob Agents Chemother. 1994 Jul;38(7):1683-7. ENTRY MONTH 199212 LAST REVISION DATE 20001107 191 UNIQUE IDENTIFIER DRG-0155 NAME OF SUBSTANCE Daunorubicin (liposomal) [USPD 1998; p. 210] REGISTRY NUMBER 20830-81-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Free base daunorubicin: (8S-cis)-8-Acetyl-10-[(3-amino-2,3,6-trideoxy- -alpha- L-lyxo-hexopyranosyl)oxyl-7,8,9,10-tetrahydro- -6,8,11 -trihydroxy-1-methoxy-5,12-naphthacenedione [Merck Index 1996; p 479] SYNONYMS DaunoXome (citrate salt) [USP DI 2000; p. 1206] PROTOCOL ID NUMBERS No longer recruiting FDA 121A PHARMACOLOGICAL ACTION MODE OF ACTION: The liposomal preparation of daunorubicin is formulated to maximize the selectivity of daunorubicin for solid tumors in situ. While in circulation, the formulation helps to protect the entrapped drug from chemical and enzymatic degradation, minimizes protein binding and generally decreases uptake by normal tissues. The mechanism of uptake of the drug by the tumor is believed to be due to increased permeability of the tumor neovasculature to some particles in the size range of liposomal daunorubicin. Following i.v. injection, plasma clearance of daunorubicin shows monoexponential decline. Plasma pharmacokinetics of liposome daunorubicin differ substantially from those reported for daunorubicin hydrochloride. Plasma clearance for the liposome daunorubicin is 17.3 mL/min (+/-6.1); distribution half-life is 4.41 hrs (+/-2.33). Low levels of daunorubicinol, the major active metabolite of the drug, were detected in the plasma after i.v. administration of the liposome. [PDR 1997; p 1842-3] DISEASES STUDIED/TREATED FDA approved 4/8/96 as first-line therapy for advanced HIV-associated Kaposi's sarcoma. [NeXstar Pharmaceuticals Press Release 4/30/96] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1203] OTHER MAJOR USES Chemotherapy drug (daunorubicin hydrochloride). [PDR 1997; p 635] ADVERSE EFFECTS Myelosuppression is the most commonly experienced adverse effect. Vomiting, stomatitis, and alopecia were rare and mild. In AIDS patients with advanced Kaposi's sarcoma severe neutropenia occurred in 2%, while the most common nonhematological toxicities were mild to moderate fatigue, low grade fever and diarrhea. Toxicity was most often related to dosages of 50-60 mg/m2. [Lancet 1993 May 15;341(8855); 1242-3; J Clin Oncol 1995 Apr;13(4); p 996-1003; PDR 1997; p 1843] CONTRAINDICATIONS Therapy with liposome daunorubicin is contraindicated in patients with less than advanced HIV-associated Kaposi's sarcoma, or in patients who have experienced serious hypersensitivity reactions to previous doses of the drug or any of its constituents. [PDR 1997; p 1842-3] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An intravenous formulation of daunorubicin that has been encapsulated in targeted liposomes. Daunorubicin is a cytotoxic anthracycline aminoglycoside antibiotic isolated from Streptomyces coeruleorubidus. [AmfAR Treat Dir 1997;8(3); p 70] CHEMICAL/PHYSICAL DATA Molecular Formula: C27-H29-N-O10 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 527.53 [Merck Index 1996; p. 479] CHEMICAL/PHYSICAL DATA Melting Point: 208-209 C [Merck Index 1996; p. 479] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.47%, H5.54%, N2.66%, O30.33% [Merck Index 1996; p. 479] CHEMICAL/PHYSICAL DATA Solubility: Daunorubicin hydrochloride is soluble in water, methanol, and aqueous alcohols. [Merck Index 1989; p 445] CHEMICAL/PHYSICAL DATA Stability: Daunorubicin hydrochloride powder for injection sould be started at 15-25 C. Re constituted solutions are stable for 24 hours at room temperatures. [AHFS Drug Information 1997; p 731-2] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Daunorubicin hydrochloride is in the form of thin red needle shaped crystals. [Merck Index 1996; p 479] SUBSTANCE DELIVERY DATA DOSAGE FORM: Administered intravenously over 60 minutes at a dose of 40 mg/m2. [PDR 1997; p 1844] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [PDR 1997; p 1844; J Clin Oncol 1995 Apr;13(4); p 996-1003] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refrigerated at 2-8 C (36-46 F). Do not freeze. Protect from light. [PDR 1997; p 1844] MANUFACTURERS 0000002463: NeXstar Pharmaceuticals Inc 650 Cliffside Dr San Dimas, CA 91773 Contact: Jeanni Brenning (909)394-4110 MANUFACTURERS 0000002463: NeXstar Pharmaceuticals Inc 650 Cliffside Dr San Dimas, CA 91773 Contact: Unspecified (800)403-3945 REFERENCES ICDB/97626167. Uthayakumar S, Money-Kyrle J, Muyshondt C, Hannon F, Philip R, Gazzard B, Boag FC. DaunoXome (liposomal daunorubicin) in early Kaposi's sarcoma, a cross-over trial versus observation (Meeting abstract). Anti-Cancer Treatment, Sixth International Congress, p. 100. Paris, France, February 6-9, 1996. AIDS/97220426. Wernz JC. Liposomal drug targeting in the treatment of Kaposi's sarcoma. AIDS Patient Care STDS. 1996 Dec;10(6):362-7. MED/96399355. Girard PM, Bouchaud O, Goetschel A, Mukwaya G, Eestermans G, Ross M, Rozenbaum W, Saimot AG. Phase II study of liposomal encapsulated daunorubicin in the treatment of AIDS-associated mucocutaneous Kaposi's sarcoma. AIDS. 1996 Jun; 10(7):753-7. MED/96314099. Uthayakumar S, Bower M, Money-Kyrle J, Muyshondt c, Youle M, Hannon F, Philips R, Gazzard BG, Boag F. Randomized cross-over comparison of liposomal daunorubicin versus observation for early Kaposi's sarcoma. AIDS. 1996 May;10(5):515-9. MED/96326437. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. ICDB/96617992. Bresnahan J, Scadden D, Grynkiewicz P. DaunoXome: a novel approach to the treatment of HIV-associated Kaposi's sarcoma (Meeting abstract). Oncol Nurs Forum; 22(2):364 1995. ICDB/95613982. Gill PS, Wernz J, Scadden DT, Cohen P, vonRoenn J, Chew T, Kempin S, Silverberg I, Gonzales G, Rarick MU, et al. A randomized trial of liposomal daunorubicin (DX) vu Adriamycin, bleomycin and vincristine (ABV) in 232 patients with advanced AIDS-related Kaposi's sarcoma (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res; 14:A830 1995. MED/95222331. Gill PS, Espina BM, Muggia F, Cabriales S, Tulpule A, Esplin JA, Liebman HA, Forssen E, Ross ME, Levine AM. Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin. J Clin Oncol. 1995 Apr;13(4):996-1003. MED/94273846. Schurmann D, Dormann A, Grunewald T, Ruf B. Successful treatment of AIDS-related pulmonary Kaposi's sarcoma with liposomal daunorubicin. Eur Respir J. 1994 Apr;7(4):824-5. ICA9/93336230. Chew T, Jacobs M, Huckabee M, Ross M. A phase II clinical trial of DaunoXome (VS103, liposomal daunorubicin) in Kaposi's sarcoma of AIDS patients. Int Conf AIDS. 1993 Jun 6-11;9(1):58 (abstract no. WS-B15-3). ENTRY MONTH 199212 LAST REVISION DATE 20000801 192 UNIQUE IDENTIFIER DRG-0154 NAME OF SUBSTANCE Ro 24-7429 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 139339-45-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 7-Chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1, 4-benzodiazepin-2-amine [MeSH ] PROTOCOL ID NUMBERS Complete NIAID ACTG 213 PROTOCOL ID NUMBERS No longer recruiting FDA 128A PHARMACOLOGICAL ACTION MODE OF ACTION: Ro 24-7429 inhibits HIV-1 through direct binding with the HIV-1 tat protein. Tat is a viral protein which upregulates viral gene expression and replication through interaction with the TAR sequence of the HIV-1 long terminal repeat (LTR). It is not clear if tat is essential for HIV replication. Ro 24-7429 exhibits broad activity in vitro against a wide variety of viral isolates in both acutely and chronically infected cells. The compound is extensively bound to plasma proteins; binding in human serum is estimated to be 98.7%. In a study of Kaposi's sarcoma patients 13 out of 23 discontinued treatment due to side effects. Ro 24-7429 dosed at 75, 150, or 300 mg/day, was compared with nucleoside analogues (zidovudine or didanosine) for 12 weeks in 96 human HIV-infected patients to assess safety and activity. Nucleoside-treated patients had a mean 0.66 log10 reduction in infectious peripheral blood mononuclear cells, while Ro 24-7429 recipients had a mean 0.02 log10 reduction (P = .02). No dose-response relationships were observed in the Ro 24-7429 groups. In this study, Ro 24-7429 treatment showed no evidence of antiviral activity. Due to these results the manufacturer has discontinued development of Ro 24-7429. [AmfAR Treat Dir 1993;6(4); p 53-4; Protocol ID: ACTG 213 ; J Infect Dis 1995 Nov;172(5); p 1246-52] DISEASES STUDIED/TREATED HIV infection. [AmfAR Treat Dir 1993;6(4); p 53-4] CLASSIFICATION CODE Investigational - Tat inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Rash, headache, and discolored urine were the most frequently reported side effects of Ro 24-7429. Other adverse effects include headaches, gastrointestinal problems, abnormal EKG, mild neurologic changes, and possible elevation in serum creatinine. [AmfAR Treat Dir 1993;6(4); p 53-4; Protocol ID: ACTG 213 ] CONTRAINDICATIONS Contraindicated in persons with hypersensitivity to benzodiazepines. [Protocol ID: ACTG 213 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A benzodiazepine derivative; structural analog of Ro 5-3335. [AmfAR Treat Dir 1993;6(4); p 53-4] CHEMICAL/PHYSICAL DATA Molecular Formula: C14-H13-Cl-N4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets. [Protocol ID: ACTG 213 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1993;6(4); p 137] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 REFERENCES MED/96185991. Patki AH, Lederman MM. HIV-1 Tat protein and its inhibitor Ro 24-7429 inhibit lymphocyte proliferation and induce apoptosis in peripheral blood mononuclear cells from healthy donors. Cell Immunol. 1996 Apr 10;169(1):40-6. MED/96036380. Haubrich RH, Flexner C, Lederman MM, Hirsch M, Pettinelli CP, Ginsberg R, Lietman P, Hamzeh FM, Spector SA, Richman DD. A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team. J Infect Dis 1995 Nov;172(5):1246-52. AIDS/95920511. Georges DL, Hsu MC, Connell E, Tam S, Lederman MM. The HIV-1 Tat antagonist Ro 24-7429 is highly protein bound and relatively inactive at physiologic serum concentrations. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:144. AIDS/95920464. Patki AH, Lederman MM. HIV-1 Tat and its inhibitor Ro 24-7429 induce apoptosis and inhibit lymphocyte proliferation in peripheral blood mononuclear cells of HIV-1 seronegative subjects. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2:;135. AIDS/95920368. Haubrich RH, Flexner C, Lederman M, Hirsch M, Herman S, Studlack M, Wang J, Dreyer K, Richman DD. Quantitative HIV RNA measured by reverse transcription PCR (RT PCR) as a marker of activity of antiviral therapy. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:117. MED/95114129. Luznik L, Kraus G, Guatelli J, Richman D, Wong-Staal F. Tat-independent replication of human immunodeficiency viruses. J Clin Invest. 1995 Jan;95(1):328-32. MED/94365505. Dunne AL, Siregar H, Mills J, Crowe SM. HIV replication in chronically infected macrophages is not inhibited by the Tat inhibitors Ro-5-3335 and Ro-24-7429. J Leukoc Biol. 1994 Sep;56(3):369-73. MED/94250013. Connell EV, Hsu MC, Richman DD. Combinative interactions of a human immunodeficiency virus (HIV) Tat antagonist with HIV reverse transcriptase inhibitors and an HIV protease inhibitor. Antimicrob Agents Chemother. 1994 Feb;38(2):348-52. ICA9/93335654. Petty B, Ginsberg R, Noe D, Barditch-Crovo P, Flexner C, Lietman P. Ro 24-7429 (TAT antagonist) safety, tolerance, and pharmacokinetics in HIV-infected subjects. Int Conf AIDS. 1993 Jun 6-11;9(1):476 (abstract no. PO-B26-2045). MED/93341998. Hsu MC, Dhingra U, Earley JV, Holly M, Keith D, Nalin CM, Richou AR, Schutt AD, Tam SY, Potash MJ, et al. Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro. Proc Natl Acad Sci USA. 1993 Jul 15;90(14):6395-9. ENTRY MONTH 199212 LAST REVISION DATE 20000801 193 UNIQUE IDENTIFIER DRG-0153 NAME OF SUBSTANCE rgp120/HIV-1MN [AmfAR Treat Dir 1997;8(3); p 58] PROTOCOL ID NUMBERS Complete NIAID ACTG 209 PROTOCOL ID NUMBERS Complete NIAID ACTG 214 PROTOCOL ID NUMBERS Complete NIAID ACTG 218 PROTOCOL ID NUMBERS Complete NIAID ACTG 235 PROTOCOL ID NUMBERS Complete NIAID AVEG 006X PROTOCOL ID NUMBERS Complete NIAID AVEG 009 PROTOCOL ID NUMBERS Complete NIAID AVEG 010 PROTOCOL ID NUMBERS Complete NIAID AVEG 016 PROTOCOL ID NUMBERS Complete NIAID AVEG 016A PROTOCOL ID NUMBERS Complete NIAID AVEG 016B PROTOCOL ID NUMBERS Complete NIAID AVEG 201 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 230 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 028 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 036 PHARMACOLOGICAL ACTION MODE OF ACTION: It has been theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cell immune responses. MN rgp 120/HIV-1 was compared in preclinical studies with IIIB rgp120/HIV-1 to assess differences in fusion inhibition of rgp120 to recombinant CD4, reactivity with the principal neutralizing determinant (PND) of gp120 and ability to neutralize various clinical isolates of HIV-1. The two products stimulated roughly approximate levels of antibodies to gp120. According to the manufacturer, the vaccine based in MN was capable of reacting with the PND of five diverse isolates while the IIIB vaccine only reacted with the PND of the IIIB strain of HIV-1. Single doses of MN rgp120/HIV-1 up to 300 micrograms have been administered safely to animals. In one study MN rgp120 was evaluated in 57 HIV-negative persons. The vaccine was safe and immunogenic. Three injections induced antibodies that neutralized MN rpg120 (46/48), SF-2 (45/48) or IIIB (30/48) strains of HIV. The manufacturer (Genentech) has halted the development of gp120 as a potential treatment for HIV+ individuals because no clinical benefits could be shown in a phase II trial with 573 asymptomatic HIV+ individuals. [AmfAR Treat Dir 1997;8(3); p 59] DISEASES STUDIED/TREATED HIV infection. [AmfAR Treat Dir 1997;8(3); p 58-9] CLASSIFICATION CODE Vaccine [Protocol ID: ACTG 230 ] SUBSTANCE INTERACTIONS Interacts with corticosteroids or other known immunosuppressive drugs, any experimental agents, and antituberculous medications. [Protocol ID: AVEG 009 ] ADVERSE EFFECTS No clinically significant adverse events have been attributed to the vaccine. [Int Conf AIDS 1993 Jun 6-11;9(1); 491 (abstract no. PO-B27-2137)] CONTRAINDICATIONS Contraindicated in the presence of prior history of clinically significant cardiac, pulmonary, hepatic, renal or autoimmune disease (other than HIV infection); pregnancy; and breastfeeding. [AmfAR Treat Dir 1991 April; p 19] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: MN rgp120/HIV-1 is a genetically engineered form of envelope glycoprotein gp120 derived from HIV-1 strain MN. The HIV-1 strain MN is highly representative of strains commonly found in North America; the principal neutralizing determinant (PND) of the MN strain is found in approximately 60% of isolates in the United States whereas the PND of strain IIIB is found in only 5% of isolates in the U.S. MN rgp120/HIV-1 is propagated in a mammalian cell line. [AmfAR Treat Dir 1993;6(4); p 37-38] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular (IM) injection. [AmfAR Treat Dir 1991 April; p 19] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 REFERENCES MED/97213946. Binley JM, Klasse PJ, Cao Y, Jones I, Markowitz M, Ho DD, Moore JP. Differential regulation of the antibody responses to Gag and Env proteins of human immunodeficiency virus type 1. J Virol. 1997 Apr;71(4):2799-809. MED/97120481. Cleland JL, Barron L, Daugherty A, Eastman JD, Kensil C, Lim A, Weissburg RP, Wrin T, Vennari J, Powell MF. Development of a single-shot subunit vaccine for HIV-1. 3. Effet of adjuvant and immunization schedule on the duration of the humoral immune response to recombinant MN gp120. J Pharm Sci. 1996 Dec;85(12):1350-7. MED/97126117. Parren PW, Fisicaro P, Labrijn AF, Binley JM, Yang WP, Ditzel HJ, Barbas CF 3rd, Burton DR. In vitro antigen challenge of human antibody libraries for vaccine evaluation: the human immunodeficiency virus type 1 envelope. J Virol. 1996 Dec;70(12):9046-50. MED/97120475. Shiver JW, Davies ME, Perry HC, Freed DC, Liu MA. Humoral and cellular immunities elicited by HIV-1 vaccination. J Pharm Sci. 1996 Dec;85(12):1317-24. MED/97071928. Gorse GJ, Yang EY, Belshe RB, Berman PW. Salivary binding antibodies induced by human immunodeficiency virus type 1 recombinant gp120 vaccine. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Nov;3(6):769-73. MED/96400824. Gorse GJ, Patel GB, Newman FK, Belshe RB, Berman PW, Gregory TJ, Matthews TJ. Antibody to native human immunodeficiency virus type 1 envelope glycoproteins induced by IIIB and MN recombinant gp120 vaccines. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Jul;3(4):378-86. AIDS/97920693. Belshe RB, Bolognesi D, Clements ML, Corey L, Fast P, Graham B, Keefer M, Mestecky J, Mulligan M. Candidate HIV-1 vaccines: what is available for expanded clincial trials? Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:107. AIDS/97920667. Zolla-Pazner S, Berman P, Xu S, Gregory T. Detection of primary isolate-neutralizing antibodies in the sera of humans immunized with a rgp120MN vaccine. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:36. MED/96135351. Warner JF, Jolly D, Mento S, Galpin J, Haubrich R, Merritt J. Retroviral vectors for HIV immunotherapy. Ann N Y Acad Sci 1995 Nov 27;772:105-16. MED/96057683. Fast PE, Sawyer LA, Wescott SL. Clinical considerations in vaccine trials with special reference to candidate HIV vaccines. Pharm Biotechnol 1995;6:97-134. ENTRY MONTH 199212 LAST REVISION DATE 20000801 194 UNIQUE IDENTIFIER DRG-0152 NAME OF SUBSTANCE rgp120/HIV-1IIIB [AmfAR Treat Dir 1995;7(4); p 38] PROTOCOL ID NUMBERS Complete NIAID ACTG 214 PROTOCOL ID NUMBERS Complete NIAID AVEG 006X PROTOCOL ID NUMBERS Complete NIAID AVEG 009 PROTOCOL ID NUMBERS Complete NIAID AVEG 010 PROTOCOL ID NUMBERS No longer recruiting FDA 075A PHARMACOLOGICAL ACTION MODE OF ACTION: It has been theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cell immune responses. One animal study showed IIIB rgp120/HIV-1 protected two chimpanzees from infection with a homologous strain of cell-free HIV after three inoculations with 300 micrograms of vaccine. However, a similar study performed with another recombinantly produced vaccine based on gp120 from HIV strain IIIB showed the vaccine did not protect chimpanzees from infections with a homologous strain of HIV. In human studies IIIB rgp120/HIV produced significant increases in proliferative responses to the gp120 antigens. In persons seronegative for HIV, the vaccine was safe and immunogenic. Three injections of the vaccine induced antibodies that neutralized IIIB strains of HIV-1. However, the manufacturer has halted the development of this vaccine because their gp120 model, designed to slow the development of AIDS-related symptoms, has shown no clinical benefits. (Phase II trial with 573 asymptomatic HIV+ individuals). [AmfAR Treat Dir 1997;8(3); p 59] DISEASES STUDIED/TREATED HIV infection. [AmfAR Treat Dir 1997;8(3); p 58] CLASSIFICATION CODE Vaccine [Protocol ID: 075A ] SUBSTANCE INTERACTIONS Interacts with corticosteroids or other known immunosuppressive drugs, any experimental agents, and antituberculous medications. [Protocol ID: 075A ] ADVERSE EFFECTS No clinically significant adverse events have been attributed to the vaccine. [Int Conf AIDS 1993 Jun 6-11;9(1); 491 (abstract no. PO-B27-2137)] CONTRAINDICATIONS Contraindicated in the presence of prior history of clinically significant cardiac, pulmonary, hepatic, renal or autoimmune disease (other than HIV infection); pregnancy; and breastfeeding. [AmfAR Treat Dir 1991 April; p 19] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Vaccine preparation IIIB rgp120/HIV is a genetically engineered form of envelope glycoprotein gp120 derived from HIV-1 strain IIIB. It is propagated in mammalian cells. [AmfAR Treat Dir 1997;8(3); p 58] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection (IM). [AmfAR Treat Dir 1991 April; p 19] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 REFERENCES MED/97071928. Gorse GJ, Yang EY, Belshe RB, Berman PW. Salivary binding antibodies induced by human immunodeficiency virus type 1 recombinant gp120 vaccine. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Nov;3(6):769-73. MED/96400824. Gorse GJ, Patel GB, Newman FK, Belshe RB, Berman PW, Gregory TJ, Matthews TJ. Antibody to native human immunodefiency virus type 1 envelope glycoprotiens induced by IIIB and MN recombinant gp120 vaccines. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Jul;3(4):378-86. AIDS/97920693. Belshe RB, Bolognesi D, Clements ML, Corey L, Fast P, Graham B, Keefer M, Mestecky J, Mulligan M. Candidate HIV-1 vaccines: what is available for expanded clinical trials? Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:107. AIDS/95920553. Yang E, Gorse G, Belshe R, Berman P. Salivary antibody response to HIV-1 recombinant gp120 (rgp 120) vaccine. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:151. MED/96135351. Warner JF, Jolly D, Mento S, Galpin J, Haubrich R, Merritt J. Retroviral vectors for HIV immunotherapy. Ann N Y Acad Sci 1995 Nov 27;772:105-16. MED/96057683. Fast PE, Sawyer LA, Wescott SL. Clinical considerations in vaccine trials with special reference to candidate HIV vaccines. Pharm Biotechnol 1995;6:97-134. MED/93316697. Schwartz DH, Gorse G, Clements ML, Belshe R, Izu A, Duliege AM, Berman P, Twaddell T, Stablein D, Sposto R, et al. Induction of HIV-1-neutralising and syncytium-inhibiting antibodies in uninfected recipients of HIV-1IIIB rgp120 subunit vaccine. Lancet 1993 Jul 10;342(8863):69-73. ICA9/93335754. Allan JD, Conant M, Lavelle J, Mitsuyasu R, Twaddell T, Kahn J. Safety and immunogenicity of MN and IIB rgp 120/HIV-1 vaccines in HIV-1 infected subjects with CD4 counts > 500 cells/mm3. Int Conf AIDS. 1993 Jun 6-11;9(1):491 (abstract no. PO-B27-2137). ICA9/93336306. Belshe R, Keefer M, Graham B, Matthews T, Twaddell T, Fast P. Safety and immunogenicity of HIV-1 (MN or combination MN/IIIB) rgp120 vaccines in low risk volunteers. The NIAID AIDS Vaccine Evaluation Network. Int Conf AIDS. 1993 Jun 6-11;9(1):70 (abstract no. WS-27-1). ICA9/93335755. Hamilton BL, Byrn RA, Giorgi J, Izu AE. T cell proliferation as a measure of the immunogenicity of HIV/gp120 vaccines in seropositive subjects. Int Conf AIDS. 1993 Jun 6-11;9(1):491 (abstract no. PO-B27-2136). ENTRY MONTH 199212 LAST REVISION DATE 20000801 195 UNIQUE IDENTIFIER DRG-0151 NAME OF SUBSTANCE Crofelemer [USPD 2000 p. 191] PROTOCOL ID NUMBERS No longer recruiting FDA 120A PROTOCOL ID NUMBERS No longer recruiting FDA 270A PROTOCOL ID NUMBERS No longer recruiting FDA 293A PHARMACOLOGICAL ACTION MODE OF ACTION: SP-303 was found to have antiviral activity against two strains of type 1 herpes-type simplex virus, including a thymidine-kinase-deficient strain, and a strain of 2 herpes simplex virus. The 50% effective concentration (EC50s) were 1-2 microM. Acyclovir, which was run in parallel, had values of 4-28 microM. Surprisingly, the compound was inactive against human cytomegalovirus. SP-303 was also virucidal at 50 microM. Interferon was not induced. The mode of antiviral action of this biopolymer was through inhibition of virus penetration into cells (EC50 = 2.1 +/- 0.2 microM). SP-303 also significantly reduced lesion formation in a mouse vaginal model when applied topically at 5-10%. Nine AIDS patients with acyclovir-unresponsive mucocutaneous herpes simplex virus infection were treated with topical SP-303T ointment. Although a transient decrease in lesion size was observed in 4 patients, and 3 patients sustained a quantitative decrease in virus burden, neither complete healing nor cessation ointment effected no significant improvement in the clinical course of 9 AIDS patients with acyclovir-unresponsive HSV infection. [Chemotherapy 1993 May-Jun;39(3); p 203-11; Antiviral Res 1994 Dec;25(3-4); p 185-92] DISEASES STUDIED/TREATED Treatment of herpes simplex virus lesions. [Protocol ID: 120A ; AmfAR Treat Dir 1997;8(3); p 77] CLASSIFICATION CODE Antidiarrheal [USPD 2000 p. 191] CLASSIFICATION CODE Antiviral [USPD 2000 p. 191] OTHER MAJOR USES Under investigation in animal studies for effect on influenza A virus. Topical therapy for herpes simplex virus infection. [Antiviral Res 1993 May;21(1); p 37-48; Antiviral Res 1994 Dec;25(3-4); p 185-92; Chemotherapy 1994 Jan-Feb;40(1); p 42-50] ADVERSE EFFECTS Patients complained of pain or burning upon applicaton of the SP-303T ointment. [Antiviral Res 1994 Dec;25(3-4); p 185-92] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A natural plant flavonoid polymer. [Chemotherapy 1993 May-Jun;39(3); p 203-11] CHEMICAL/PHYSICAL DATA Molecular Weight: avg. 2300 daltons [USPD 2000 p. 191] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical. [Protocol ID: 120A ] MANUFACTURERS 0000003957: Shaman Pharmaceuticals Inc 213 East Grand Ave South San Francisco, CA 94080 Contact: Unspecified (415)873-8367 REFERENCES MED/95225642. Safrin S, McKinley G, McKeough M, Robinson D, Spruance SL. Treatment of acyclovir-unresponsive cutaneous herpes simplex virus infection with topically applied SP-303. Antiviral Res 1994 Dec;25(3-4):185-92. MED/94139476. Sidwell RW, Huffman JH, Moscon BJ, Warren RP. Influenza virus-inhibitory effects of intraperitoneally and aerosol-administered SP-303, a plant flavonoid. Chemotherapy 1994 Jan-Feb;40(1):42-50. MED/93284919. Barnard DL, Huffman JH, Meyerson LR, Sidwell RW. Mode of inhibition of respiratory syncytial virus by a plant flavonoid, SP-303. Chemotherapy 1993 May-Jun;39(3):212-7. MED/93284918. Barnard DL, Smee DF, Huffman JH, Meyerson LR, Sidwell RW. Antiherpesvirus activity and mode of action of SP-303, a novel plant flavonoid. Chemotherapy 1993 May-Jun;39(3):203-11. MED/93230616. Tao P. [The inhibitory effects of catechin derivatives on the activities of human immunodeficiency virus reverse transcriptase and DNA polymerases]. Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao. 1992 Oct; 14(5)334-8. ENTRY MONTH 199212 LAST REVISION DATE 20000801 196 UNIQUE IDENTIFIER DRG-0150 NAME OF SUBSTANCE Cimetidine [USPD 1998; p. 166] REGISTRY NUMBER 51481-61-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N-Cyano-N'-methyl-N''-(2-(((5-methyl-1H-imida- zol-4-yl) methyl)thio)ethyl)guanidine [Merck Index 1996; p 383] SYNONYMS Tagamet [USP DI 2000; p. 1709] PROTOCOL ID NUMBERS No longer recruiting FDA 119A PHARMACOLOGICAL ACTION MODE OF ACTION: Competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells and thus is a histamine H2-receptor antagonist. Cimetidine inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine, and insulin. Cimetidine may have an immunomodulatory effect by virtue of its interaction with H2 receptors on cells in the immune system. In clinical studies of the drug significant increases in immunoglobulins, B-lymphocytes, complement C4, and CD4 counts have been reported. Cimetidine is rapidly absorbed after oral administration and peak levels occur in 45-90 minutes. Half-life is approximately 2 hours. Principally excreted in the urine. [PDR 1997; p 2694-5; AmfAR Treat Dir 1995;7(4); p 23] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection. [AmfAR Treat Dir 1995;7(4); p 23] CLASSIFICATION CODE Antiulcer agent [USP DI 2000; p. 1704] CLASSIFICATION CODE Gastric acid secretion inhibitor [USP DI 2000; p. 1704] CLASSIFICATION CODE Histamine (H2) receptor antagonist [USP DI 2000; p. 1704] OTHER MAJOR USES Treatment of active duodenal ulcer, active benign gastric ulcer, erosive gastroesophageal reflux disease, and pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome), and prevention of upper gastrointestinal bleeding in critically-ill patients. [PDR 1997; p 2695-6] SUBSTANCE INTERACTIONS Interacts with warfarin-like anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline, and metronidazole. [PDR 1997; p 2696] ADVERSE EFFECTS Adverse effects may include diarrhea, dizziness and somnolence (usually mild), headache, reversible confusion states, gynecomastia, reversible impotence, decreased white blood cell counts, increases in serum transaminase, fever and allergic reactions, small increases in plasma creatinine, bradycardia, tachycardia, A-V heart block, reversible arthralgia and myalgia, and various skin reactions. [PDR 1997; p 2696] CONTRAINDICATIONS Cardiac arrhythmias and hypotension may result from rapid IV injection of cimetidine. In immunocomprosided patients, decreased gastric acidity, including that produced by cimetidine, may increase the possibility of hyperinfection caused by Stongyloides stercoralis. Cimetidine is contraindicated in patients with known hypersensitivity to the drug. [AHFS Drug Information 1997; p 2267] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Histamine H2-receptor antagonist. Chemically related to histamine. Contains an imidazole ring. [PDR 1997; p 2694] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H16-N6-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 252.35 [USPD 1998; p. 166] CHEMICAL/PHYSICAL DATA Melting Point: 141-143 C [Merck Index 1996; p. 383] CHEMICAL/PHYSICAL DATA Elemental Comp: C47.60%, H6.39%, N33.30%, S12.71%. [Merck Index 1996; p. 383] CHEMICAL/PHYSICAL DATA Solubility: Soluble in alcohol; slightly soluble in water; very slightly soluble in chloroform; insoluble in ether. [PDR 1995; p 2401] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystals; has a bitter taste and characteristic odor. [PDR 1997; p 2694; Merck Index 1996; p 383] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, flavored liquid, or vials for injection. [PDR 1997; p 2697] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, IV, and IM. [PDR 1997; p 2697] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature (15-30 C; 59-86 F). [PDR 1997; p 2697] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 REFERENCES MED/97081558. Cohen CJ, Hellinger JA, Day J, Salitsky N, Shevitz A, Zackin R, DeGruttola V. Lack of effect of cimetidine on lymphocyte subsets in patients infected with human immunodeficiency virus type 1. Clin Infect Dis. 1996 Nov;23(5):1049-54. MED/96367756. Wargon O. Cimetidine for mucosal warts in an HIV positive adult. Australas J Dermatol. 1996 Aug;37(3):149-50. MED/96178932. Polizzi B, Origgi L, Zuccaro G, Matti P, Scorza R. Case report: successful treatment with cimetidine and zinc sulphate in chronic mucocutaneous candidiasis. Am J Med Sci. 1996 Apr;311(4):189-90. MED/96162732. Fletcher CV, Henry WK, Noormohamed SE, Rhame FS, Balfour HH Jr. The effect of cimetidine and ranitidine administration with zidovudine. Pharmacotherapy. 1995 Nov-Dec;15(6):701-8. MED/95326733. Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH, Humphrey RW, Feigal E, Steinberg SM, Broder S, et al. Treatment of HIV-associated Kaposi's sarcoma with paclitaxel. Lancet. 1995 Jul 1;346(8966):26-8. MED/96172399. Urrea AA, Velez GM, Nogues AE, Carmarasa JG. Psoriasis in an HIV-positive patient treated with cemetidine [letter]. Dermatology. 1995;191(1):77. MED/93312029. Stashower ME, Yeager JK, Smith KJ, Skelton HG, Wagner KF. Cimetidine as therapy for treatment-resistant psoriasis in a patient with acquired immunodeficiency syndrome. Arch Dermatol 1993 Jul;129(7):848-50. MED/93051675. Colin-Jones DG, Langman MJ, Lawson DH, Logan RF, Paterson KR, Vessey MP. Postmarketing surveillance of the safety of cimetidine: 10 year mortality report. Gut 1992 Sep;33(9):1280-4. MED/93070256. Munnings HA. Cimetidine. Potential for its use in HIV disease [letter]. West Indian Med J. 1992 Sep;41(3):95. ENTRY MONTH 199212 LAST REVISION DATE 20000801 197 UNIQUE IDENTIFIER DRG-0149 NAME OF SUBSTANCE Saccharomyces boulardii [AmfAR Treat Dir 1997;8(3); p 77] PROTOCOL ID NUMBERS No longer recruiting FDA 083A PHARMACOLOGICAL ACTION MODE OF ACTION: Mechanism of action is unclear. In the prevention and treatment of Clostridium difficile-associated diarrhea and colitis S. boulardii may reduce some of the enterotoxic effects of toxin A by inhibiting toxin A-receptor binding. This effect appears to be manifested by a secreted product of the yeast, possibly a protease. The product is not systematically absorbed. [AmfAR Treat Dir 1995;7(4); p 70; Gastroenterology 1993 Apr;104(4); p 1108-15; AmfAR Treat Dir 1997;8(3); p 77] DISEASES STUDIED/TREATED Under investigation for the treatment of chronic diarrhea in HIV-infected people. [AmfAR Treat Dir 1997;8(3); p 77] CLASSIFICATION CODE Antidiarrheal [AmfAR Treat Dir 1997;8(3); p 77] OTHER MAJOR USES Antibiotic-associated diarrhea; pseudomembranous colitis. [Gastroenterology 1989;96(4); p 981-8; Pharm Res 1991 Jun; p 796-800] ADVERSE EFFECTS No toxicfies have been observed to date. [AmfAR Treat Dir 1997;8(3); p 77] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Nonpathogenic yeast. [AmfAR Treat Dir 1997;8(3); p 77] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules. [Gastroenterology 1989;96(4); p 981-8] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1997;8(3); p 77] MANUFACTURERS 0000002376: Biocodex Inc 1910 Fairview Ave East / Suite 208 Seattle, WA 981023699 Contact: Kris Moyer (206)322-5602 REFERENCES AIDS/96700555. James JS. Diarrhea, and the experimental treatment Saccharomyces boulardii. AIDS Treat News. 1995 Jun 2;(no 224):1-4. MED/96023548. Hassett J, Meyers S, McFarland L, Mulligan ME. Recurrent Clostridium difficile infection in a patient with selective IgG1 deficiency treated with intravenous immune globulin and Saccharomyces boulardii. Clin Infect Dis 1995 Jun;20 Suppl 2:S266-8. MED/95177126. McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL. Prevention beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol 1995 Mar;90(3):439-48. MED/95104725. Arnheim K. [Intestine-associated immune system stimulation. Saccharomyces boulardii-mechanism of action]. Fortschr Med. 1994 Oct 30;112(30):52-3. MED/93272686. Born P, Lersch C, Zimmerhackl B, Classen M. [The Saccharomyces boulardii therapy of HIV-associated diarrhea (letter)]. Dtsch Med Wochenschr. 1993 May 21;118(20):765. MED/93220318. Plein K, Hotz J. Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable phase of Crohn's disease with special respect to chronic diarrhea--a pilot study. Z Gastroenterol 1993 Feb;31(2):129-34. MED/94119825. Klein SM, Elmer GW, McFarland LV, Surawicz CM, Levy RH. Recovery and elimination of the biotherapeutic agent, Saccharomyces boulardii, in healthy human volunteers. Pharm Res 1993 Nov;10(11):1615-9. MED/93301802. Buts JP, Corthier G, Delmee M. Saccharomyces boulardii for Clostridium difficile-associated enteropathies in infants. J Pediatr Gastroenterol Nutr 1993 May;16(4):419-25. ICA6/10036390. Saint-Marc T, Sellem C, Rosello L, Touraine JL. Treatment of chronic diarrhea with Saccharomyces boulardii. Int Conf AIDS. 1990 Jun 10-23;6(1):212 (abstract no. Th.B.363). ENTRY MONTH 199210 LAST REVISION DATE 20000801 198 UNIQUE IDENTIFIER DRG-0148 NAME OF SUBSTANCE TNP-470 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 129298-91-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME (3R,4S,5S,6R)-5-methoxy-4- [(2R,3R)-2-methyl-3-(3-methyl-2-butenyl) -oxiranyl]-1-oxaspiro [2,5] oct-6-yl(chloroacetyl) carbamate [J Pharmacol Exp Ther 1993 Jan;264(1); 469-74] PROTOCOL ID NUMBERS Complete NIAID ACTG 215 PROTOCOL ID NUMBERS No longer recruiting NCI 92 C-228 PHARMACOLOGICAL ACTION MODE OF ACTION: Little is know about TNP-470's molecular mode of antiangiogenesis action. However, fumagillin (structurally related to TNP-470), covalently binds to and inhibits a specific protein - methionine aminopeptidase-2. This enzyme is involved in the proliferation of the cells that line blood vessels. Another study showed that TNP-470 also binds to and inhibits this enzyme. In preclinical studies in mice and rats, TNP-470 has shown significant antitumor activity against 55 types of human and animals tumors at a dose which is not toxic. This is among the broadest spectrum of efficacy of any anticancer drug. Pharmacokinetics from one clinical study suggests that TNP-470 has a rapid clearance (max 1164 +/- 718 L/hr) and an extremely short plasma half life (range 5.5-10 min). There have been no effects on CD4 cells or HIV p24 antigen. TNP-470 is currently being evaluated in Phase II clinical studies against a range of solid tumors, including Kaposi's sarcoma. [Proc Annu Meet Am Soc Clin Oncol 1994;13; p 13:A8; Chem Eng News 1997 June 16; p 39] DISEASES STUDIED/TREATED Under investigation for treatment of Kaposi's sarcoma. [AmfAR Treat Dir 1997;8(3); p 78] CLASSIFICATION CODE Antineoplastic [AmfAR Treat Dir 1995;7(4); p 71] OTHER MAJOR USES Solid tumors. [AmfAR Treat Dir 1997;8(3); p 78] SUBSTANCE INTERACTIONS Possible interaction with steroids, NSAIDS, anticoagulants, or any other agent that may exacerbate bleeding. [Protocol ID: 92 C-228 ] ADVERSE EFFECTS Adverse effects include anorexia; anemia; thrombocytopenia; neutropenia; seizures; ataxia; small focal hemorrhage in lung, retina, and brain (at very high doses); abnormal liver function tests; increased CPK; minimally increased APTT; rash to penicillin; confusion; atrial fibrillation; and anaphylaxis. [Protocol ID: 92 C-228 ; Protocol ID: ACTG 215 ] CONTRAINDICATIONS Contraindicated in persons with hypersensitivity to TNP-470, fumagillin, cyclodextrin, or other related compounds. [Protocol ID: 92 C-228 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Analogue of fumagillin (a naturally secreted antibiotic of Aspergillus fumigatus fresenius). [AmfAR Treat Dir 1997;8(3); p 78] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H28-Cl-N-O6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 401.89 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Protocol ID: 92 C-228 ] MANUFACTURERS 0000002606: TAKEDA America Inc 101 Carnegie Center / Suite 207 Princeton, NJ 08540 Contact: Dr Mikihiko Obayashi (609)452-1113 MANUFACTURERS 0000001028: Natl Cancer Institute / Adult Intramural Studies 9000 Rockville Pike / Clinical Ctr Bethesda, MD 20892 Contact: Dr Wayne Saville (301)402-3630 REFERENCES MED/97307228. Harris AL. Antiangiogenesis for cancer therapy. Lancet. 1997 May;349 Suppl 2:SIII3-5. MED/96076278. Volm MD, von Roenn JH. Treatment strategies for epidemic Kaposi's sarcoma. Curr Opin Oncol. 1995 Sep;7(5):429-36. MED/95042404. Scott PA, Harris Al. Current approaches to targeting cancer using antiangiogenesis therapies. Cancer Treat Rev. 1994 Oct;20(4):393-412. ICDB/95611689. Pluda JM. Inhibitors of angiogenesis and metastasis: preclinical and early clinical studies (Meeting abstract). Ann Oncol; 5(Suppl 5):A014 1994. ICDB/95606242. Krown SE. AIDS-related Kaposi's sarcoma: clinical aspects (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res; 35:659-60 1994. ICDB/94600005. Pluda JM, Wyvill K, Figg WD, Whitcup SM, Lietzau J, Saville MW, Cohen R, Feigal E, Parks D, Foli A, et al. A Phase I study of an angiogenesis inhibitor, TNP-470 (AGM-1470), administered to patients (pts) with HIV-associated Kaposi's sarcoma (KS) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol; 13:A8 1994. AIDS/95921068. Pluda JM, Wyvill K, Lietzau J, Figg D, Saville MW, Nguyen BY, Foli A, Bailey J, Cooper M. A phase I trial of TNP-470 (AGM-1470) administered to patients with HIV-associated kaposi's sarcoma (KS). Natl Conf Retroviruses Relat Infect (1st). 1993 Dec 12-16;:61. MED/93163898. Takamiya Y, Friedlander RM, Brem H, Malick A, Martuza RL. Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470. J Neurosurg 1993 Mar;78(3):470-6. MED/94011518. Schoof DD, Obando JA, Cusack JC Jr, Goedegebuure PS, Brem H, Eberlein TJ. The influence of angiogenesis inhibitor AGM-1470 on immune system status and tumor growth in vitro. Int J Cancer 1993 Oct 21;55(4):630-5. MED/91144577. Kusaka M, Sudo K, Fujita T, Marui S, et al. Potent anti-angiogenic action of AGM-1470: comparison to the fumagillin parent. Biochem Biophys Res Commun 1991 Feb 14; 174(3):1070-6. ENTRY MONTH 199210 LAST REVISION DATE 20000801 199 UNIQUE IDENTIFIER DRG-0147 NAME OF SUBSTANCE Tretinoin [USPD 1998; p. 753] REGISTRY NUMBER 302-79-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Retinoic acid, all-trans- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Retin-A [USP DI 2000; p. 3050] SYNONYMS Vesanoid [USP DI 2000; p. 3046] PROTOCOL ID NUMBERS No longer recruiting NCI 92 C-146 PROTOCOL ID NUMBERS Terminated CC 95 C-144 PHARMACOLOGICAL ACTION MODE OF ACTION: Tretinoin is a major endogenous metabolite of vitamin A which induces differentiation and/or growth inhibition in many tumorogenic cell lines, including KS cells in culture. Tretinoin has been shown to decrease HIV replication in chronically infected macrophages, monocytic and T cell lines and conversely to promote HIV replication in macrophages and monocytic cell lines recently infected. Possibly decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Tretinoin activity is due primarily to the parent drug. Orally administered it is well absorbed into systemic circulation. Approximately two thirds of the administered drug can be recovered from urine. Terminal elimination half-life is 0.5 - 2 hours (in patients with acute promyelocytic leukemia). There is evidence that tretinoin induces its own metabolism. [Int Conf AIDS 1993 Jun 6-11;9(1); 238 (abstract no. PO-A25-0621); Int Conf AIDS 1993 Jun 6-11;9(1); 397 (abstract no. PO-B12-1571); PDR 1997; p 2327-8] DISEASES STUDIED/TREATED Under investigation for the oral treatment of Kaposi's sarcoma. [AmfAR Treat Dir 1997;8(3); p 67; J Clin Oncol 1995 May;13(5); p 1238-41] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3044] CLASSIFICATION CODE Keratolytic [USP DI 2000; p. 3046] OTHER MAJOR USES Acne vulgaris (topically). Acute promyelcoytic leukemia (orally). [PDR 1997; p 2327, 1945-7] SUBSTANCE INTERACTIONS Caution should be exercised with concomitant use of topical medication; medicated or abrasive soaps and cleansers; soaps and cosmetics that have a strong drying effect; products with high concentrations of alcohol, astringents, spices, or lime; and particularly preparations containing sulfur, resorcinol, or salicylic acid. Topical preparation should not be administered if patient is also taking drugs know to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothizines, sulfonamides, because of possible augmented phototoxicity. [PDR 1997; p 1945-6] ADVERSE EFFECTS Adverse effects with topical administration include swelling or cracking of lips; headaches; dryness of skin, mouth or eyes; fatigue; loss of appetite; nausea or vomiting; visual problems; nasal congestion or nose bleeds; skin rashes; itching; aching discomfort of bones or joints; increased blood triglyceride levels; and increased pressure in the brain. Adverse effects reported with oral administration include severe nausea and vomiting, headaches, rash, generalized malaise, hypercalcemia, pancreatitis, dryness of the skin, myalgia, and increases in liver enzyme activity and triglycerides were noticed. [Int Conf AIDS 1993 Jun 6-11;9(1); 397 (abstract no. PO-B12-1571); Int Conf AIDS 1993 Jun 6-11;9(1); 395 (abstract no. PO-B12-1562); PDR 1997; p 2328-9] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to any of the product ingredients. Oral tretinoin has been shown to be teratogenic in rodents and subhuman primates. There is a high risk that severely deformed infants will result if the drug is given during pregnancy. [PDR 1997; p 1945-7; 2327] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An experimental derivative of vitamin A, it is a potent regulator of epithelial differentiation within many neoplastic cell systems. [AmfAR Treat Dir 1997;8(3); p 67] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H28-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 300.44 [USPD 1998; p. 753] CHEMICAL/PHYSICAL DATA Elemental Comp: C79.96%, H9.39%, O10.65% [Merck Index 1996; p. 1404] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water, slightly soluble in alcohol. [AHFS Drug Information 1997; p 2750] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow to light orange, crystalline powder. [AHFS Drug Information 1997; p 2750] SUBSTANCE DELIVERY DATA DOSAGE FORM: 0.025% and 0.01% gel; 0.025%, 0.05%, and 0.1% cream; 0.05% liquid; 10 mg capsules. [PDR 1997; p 2329] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical; Oral. [Int Conf AIDS 1993 Jun 6-11;9(1); 397 (abstract no. PO-B12-1571); PDR 1997; p 1945-7; 2327-9] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Liquid and gel: store below 86 F. Cream: store below 80 F. Protect from light. [PDR 1997; p 1946; 2329] MANUFACTURERS 0000001008: Ortho Pharmaceutical Corp Route 202 / PO Box 300 Raritan, NJ 088690602 Contact: Dr H C Stevenson (301)496-8798 MANUFACTURERS 0000002565: Natl Cancer Institute 9000 Rockville Pike / Clinical Ctr Bethesda, MD 20892 Contact: Mrs Dorothy Thompson (908)704-5150 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Unspecified - Biotech (800)325-7504 REFERENCES MED/97006452. Toma S, Iacona I, Palumbo R, Moresco L, Raffo P, Regazzi MB. Modulation of all-trans-retinoic acid administered on intermittent schedule by alpha-interferon 2a in a patient with AIDS-related Kaposi's sarcoma [letter]. AIDS. 1996 Aug;10(9):1049-50. MED/97034540. Lee FC, Mitsyasu RT. Chemotherapy of AIDS--related Kaposi's sarcoma. Hematol Oncol Clin North Am. 1996 Oct;10(5):1051-68. MED/95363479. Bailey J, Pluda JM, Foli A, Saville MW, Bauza S, Adamson PC, Murphy RF, Cohen RB, Broder S, Yarchoan R. Phase I/II study of intermittent all-trans-retinoic acid, alone and in combination with interferon alfa-2a, in patients with epidemic Kaposi's sarcoma. J Clin Oncol. 1995 Aug;13(8):1966-74. MED/95256948. Adamson PC, Bailey J, Pluda J, Poplack DG, Bauza S, Murphy RF, Yarchoan R, Balis FM. Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule. J Clin Oncol. 1995 May;13(5):1238-41. MED/95150064. Bonhomme L, Fredj G, Ecstein E, Maurisson G, Farabos C, Misset JL, Jasmin C. Treatment of AIDS-associated Kaposi's sarcoma with oral tretinoin. Am J Hosp Pharm. 1994 Oct 1;51(19):2417-9. MED/95106828. Gill PS, Espina BM, Moudgil T, Kidane S, Esplin JA, Tulpule A, Levine AM. All-trans retinoic acid for the treatment of AIDS-related Kaposi's sarcoma: results of a pilot phase II study. Leukemia. 1994;8 Suppl 3:S26-32. ICA9/93335133. Von Roenn J, von Gunten C, Mullane M, French S, Blough R, Benson AB 3d. All-transretinoic acid (TRA) in the treatment of AIDS-related Kaposi's sarcoma. Int Conf AIDS 1993 Jun 6-11;9(1):397 (abstract no. PO-B12-1571) ICA9/93334092. Dubreuil-Lemaire ML, Bourgault I, Levy Y, Venet A, Deforges L, Sobel A. In vivo effects of retinoic acid on HIV replication in CD4(+) fresh cells from HIV infected patients. Int Conf AIDS 1993 Jun 6-11;9(1):238 (abstract no. PO-A25-0621). MED/92385172. Fauci AS. Pharmacologic regulation of HIV expression. AIDS Res Hum Retroviruses. 1992 May;8(5):707-10. ICA6/40209090. Bonhomme L, Fredj G, Averous S, Szekely AM, Meyer P, Ecstein E, Lang JM, Trumbic B, Misset JL, Jasmin C. Topically applied All Trans-Retinoic acid for the treatment of Kaposi's sarcoma (Ks). Int Conf AIDS. 1990 Jun 20-23;6(2):376 (abstract no. 2090). ENTRY MONTH 199210 LAST REVISION DATE 20001106 200 UNIQUE IDENTIFIER DRG-0146 NAME OF SUBSTANCE Lymphocytes, Activated [Protocol ID: 92 I-248 ] PROTOCOL ID NUMBERS No longer recruiting CC 92 I-248 PROTOCOL ID NUMBERS No longer recruiting CC 93 I-110 PROTOCOL ID NUMBERS No longer recruiting CC 94 I-206 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 006 PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PROTOCOL ID NUMBERS Recruiting CC 96 HG-51 PROTOCOL ID NUMBERS Terminated NIAID SPIRAT 2 PHARMACOLOGICAL ACTION MODE OF ACTION: Type of adoptive immunotherapy. Peripheral blood lymphocytes are obtained from a donor by leukapheresis. T lymphocytes are then induced to polyclonal proliferation with anti-CD3 and rIL-2 stimulation. After expansion in culture, the activated lymphocytes are infused into an HIV seropositive recipient. Pharmacokinetic data has been collected on subjects who were infused with 0.8 x 10--9 to 10 x 10--9 cells including less than or equal to 10--9 cells labelled with 111 indium. In three subjects the infusion was repeated and IL-2, 10--6 units/day for 5 days, was given by continuous infusion. In the vascular compartment, the initial (distribution) t1/2 was approximately 10 minutes but after 60-90 minutes, clearance remained stable and slow for up to 120 hours. The t1/2 (elimination) was 16.5 hours (mean,N-3) when IL-2 was given and 32.6 hours without IL-2 (N=4). The label appeared rapidly in the lungs, reaching a maximum of 67% (N=4) of the body burden in four hours. Significant amounts (7-14%) were also seen in the liver, spleen, and bone marrow at this time. Over the next 60-72 hours, the label shifted from the lungs to the other organs stabilizing at about 72 hours with 46.3%, 23.3%, 20% and 27.5% in the bone marrow, liver, spleen and lungs, respectively. The distribution was not significantly affected by IL-2 infusion. Over 96 hours, about 10% of the label appeared in the urine. The lifespan of these cells remains unclear, but maximally 90% remain intact for 5 days. [Blood 1993 Apr 15;81(8); p 2093-101; Int Conf AIDS 1992 Jul 19-24;8(2); B162 (abstract no. PoB 3452)] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection. [Blood 1993 Apr 15;81(8); p 2093-101] CLASSIFICATION CODE Immunomodulator [Blood 1993 Apr 15;81(8); p 2093] ADVERSE EFFECTS Adverse effects may include chills, fever, tachycardia, nausea, vomiting, shortness of breath, muscle aches, joint aches, local pain and redness at site of infusion, skin rash, and severe allergic reaction. [Protocol ID: 92 I-248 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: CD8+ T lymphocytes. [Blood 1993 Apr 15;81(8); p 2093-101] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [Blood 1993 Apr 15;81(8); p 2093-101] MANUFACTURERS 0000002448: New England Med Ctr / Tufts Univ 750 Washington St / PO Box 245 Boston, MA 02111 Contact: Dr Judy Lieberman (617)956-6520 MANUFACTURERS 0000003153: Natl Inst of Allergy & Infect Dis / Cln Ctr 9000 Rockville Pike / RM 11C304 Bethesda, MD 20892 Contact: Unspecified (800)411-1222 REFERENCES MED/95354184. de Gast GC, Haagen IA, Van Houten AA, Klein SC, Duits AJ, de Weger RA, Vroom TM, Clark MR, Phillips J, van Dijk AJ, et al. CD8 T cell activation after intravenous administration of CD3 x CD19 bispecfic antibody in patients with non-Hodgkin lymphoma. Cancer Immunol Immunother. 1995 Jun;40(6):390-6. MED/95077735. Klimas N, Patarca R, Walling J, Garcia R, Mayer V, Moody D, Okarma T, Fletcher MA. Clinical and immunological changes in AIDS patients following adoptive therapy with activated autologous CD8 T cells and interleukin-2 infusion. AIDS. 1994 Aug;8(8):1073-81. ICA10/94369770. Lieberman J, Fabry JA, Skolnik PR, Parkerson GR, Fong DM, Kagan J, Standiford H, Lee E, Landry B. Immunotherapy with autologous HIV-specific CTL. Int Conf AIDS. 1994 Aug 7-12;10(1):220 (abstract no. PBO311). MED/95275723. Ruta SM, Alexandrescu R, Antipa C, Tirdei G, Popescu A, Cernescu C. Considerations about the prophylactic role of T cell vaccination in HIV infection. Rev Roum Virol. 1994 Jan-Jun;45(1-2):47-54. MED/94107964. Walker R, Blaese RM, Carter CS, Chang L, Klein H, Lane HC, Leitman SF, Mullen CA, Larson M. A study of the safety and survival of the adoptive transfer of genetically marked syngeneic lymphocytes in HIV-infected identical twins. Hum Gene Ther. 1993 Oct;4(5):659-80. MED/93229748. Whiteside TL, Elder EM, Moody D, Armstrong J, Ho M, Rinaldo C, Huang X, Torpey D, Gupta P, McMahon D, et al. Generation and characterization of ex vivo propagated autologous CD8+ cells used for adoptive immunotherapy of patients infected with human immunodeficiency virus. Blood 1993 Apr 15;81(8):2085-92. MED/93229749. Ho M, Armstrong J, McMahon D, Pazin G, Huang XL, Rinaldo C, Whiteside T, Tripoli C, Levine G, Moody D, et al. A phase I study of adoptive transfer of autologous CD8+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS. Blood 1993 Apr 15;81(8):2093-101. ICA9/93335779. Moody DJ, Kremer AB, Kahn J, Okarma TB. Impact of CD8+ cellular therapy with concomitant IL-2 administration on the peripheral blood lymphocyte composition in AIDS patients with Kaposi's sarcoma. Int Conf AIDS. 1993 Jun 6-11;9(1):495 (abstract no. PO-B28-2162). MED/93380194. Torpey D 3d, Huang XL, Armstrong J, Ho M, Whiteside T, McMahon D, Pazin G, Heberman R, Gupta P, Tripoli C, et al. Effects of adoptive immunotherapy with autologous CD8+ T lymphocytes on immunologic parameters: lymphocyte subsets and cytotoxic activity. Clin Immunol Immunopathol. 1993 Sep;68(3):263-72. ICA8/92401183. Tauxe N, Ho M, Levine J, McMahon D, Elder E, Whiteside T, Moody D, Okarma T, Armstrong J, Herberman R. Distribution and trafficking of autologous, expanded CD8+ cells infused in subjects with AIDS or ARC. Int Conf AIDS 1992 Jul 19-24;8(2):B162 (abstract no. PoB 3452). ENTRY MONTH 199209 LAST REVISION DATE 20000801 201 UNIQUE IDENTIFIER DRG-0145 NAME OF SUBSTANCE Cidofovir [USPD 1998; p. 164] REGISTRY NUMBER 149394-66-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Phosphonic acid, [[2-(4-amino-2-oxo-l(2H)-pyrimidinyl)-l-(hydr- oxymethyl)ethoxy]methyl ]-, dihydrate, (S)- [USPD 1998; p 164] SYNONYMS Vistide [USP DI 2000; p. 897] PROTOCOL ID NUMBERS Complete NIAID ACTG 281 PROTOCOL ID NUMBERS Complete NIAID ACTG 350 PROTOCOL ID NUMBERS No longer recruiting FDA 216A PROTOCOL ID NUMBERS No longer recruiting FDA 216B PROTOCOL ID NUMBERS No longer recruiting FDA 218A PROTOCOL ID NUMBERS No longer recruiting FDA 218B PROTOCOL ID NUMBERS No longer recruiting FDA 219A PROTOCOL ID NUMBERS No longer recruiting FDA 276A PROTOCOL ID NUMBERS No longer recruiting CC 92 I-251 PROTOCOL ID NUMBERS No longer recruiting NCI 97 C-27 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 363 PROTOCOL ID NUMBERS Recruiting CC 97 C-0024 PROTOCOL ID NUMBERS Terminated NIAID ACTG 352 PHARMACOLOGICAL ACTION MODE OF ACTION: Cidofovir is converted by via cellular enzymes to the pharmacologically active diphosphate metabolite which has inhibitory activity against a broad specturm of herpes viruses including herpes simplex types 1 and 2, varicella zoster, cytomegalovirus (CMV), and Epstein-Barr virus. Cidofovir diphosphate exerts its antiviral effect by interfering with DNA synthesis and inhibiting viral replication. Its inhibitory activity is highly selective because it has greater affinity for viral DNA polymerases than for human DNA polymerases. Clinical trials showed no evidence of cidofovir accumulation after 4 weeks of repeated administration (by IV infusion) of 3 mg/kg/week to HIV+ patients with or without asymptomatic CMV infection. In patients with normal renal functions, approximately 80-100% of the cidofovir dose was recovered in the urine in 24 hours. Renal clearance of cidofovir was greater than creatinine clearance, indicating that renal tubular secretion contributed to the elimination of cidofovir. When the drug was given with oral probenecid (as required by the manufacturer) approximately 70-85% of the administered dose was excreted as unchanged drug, and the clearance of cidofovir was reduced to a level consistent with creatinine clearance. In vitro, cidofovir was less than 6% bound to plasma or serum protein. CSF concentration of cidofovir (following IV infusion of Vistide 5mg/kg) was undetectable at 15 minutes after end of 1 hr infusion (one patient). In trials with patients having previously untreated CMV retinitis or disease that relapsed after treatment with other antivirals, with immediate or delayed (until disease progression) cidofovir treatment, median time to relapse was 120 or 22 days for the immediate or delayed groups respectively. In another trial with cidofovir in patients with relapsing CMV retinitis, the median time for CMV retinitis progression was 115 or 49 days (depending on dosage and schedule). CMV isolates with reduced susceptibility to cidofovir have been found. Cidofovir-resistant isolates were cross resistant to ganciclovir, but remained resistant to foscarnet. To date, all clinical isolates with a high level of resistance to ganciclovir have been shown to be cross resistant to cidofovir. [AHFS Drug Information 1999; p 518; PDR 1999; p 1079] DISEASES STUDIED/TREATED Treatment of herpes simplex virus and cytomegalovirus (CMV) retinitis in patients with AIDS. FDA approved 6/27/96 for CMV retinitis. [USP DI 1999; p 865; Gilead Sciences Package Insert July 1996; AHFS Drug Information 1999; p 518] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 895] SUBSTANCE INTERACTIONS In one trial with 10 patients receiving zidovudine and cidofovir, there was no evidence of cidofovir having an effect on the pharmacokinetics of zidovudine. [PDR 1999; p 1079] ADVERSE EFFECTS Nephrotoxicity: Renal toxicity, as manifested by a greater than 1+ proteinuria, serum creatinine elevations of 0.4 mg/dl or more, or decreased creatinine clearance of 55ml/min or less, occurred in 47 of 89 patients receiving cidofovir at a maintenance dose of 5 mg/kg every other week. Prior foscarnet use was associated with increased risk of nephrotoxicity. Neutropenia: In clinical trials, at the 5 mg/kg maintenance dose, neutropenia to 500 cells/mm3 or less occurred in 20% of patients. Granulocyte colony stimulating factor was used in 34% of patients. Ocular hypertony: ocular hypotony (50% or more change from baseline) has also been reported. Metabolic acidosis: a diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal tubule function, was reported in 2% of patients. Decrease in serum bicarbonate of 16 meq/l or less associated with evidence of renal tubular damage occurred in about 9% of patients. In clinical trials therapy was withdrawn due to adverse events in about 25% of patients treated with 5 mg/kg every other week as maintenance therapy. Serious clinical adverse events occurring in more than 5% of patients included the following: fever, infection, dyspnea, pneumonia, nausea with vomiting, asthenia, and diarrhea. [Gilead Sciences Package Insert June 1996; p 4; PDR 1999; p 1081] CONTRAINDICATIONS Cidofovir is contraindicated in patients with a serum creatinine greater than 1.5mg/dL, a calculated creatinine clearance of less than and equal to 55mL/min, or a urine protein greater than and equal to 100mg/dL. With patients receiving drugs having nephrotoxic potential, these drugs must be discontinued at least 7 days before start of cidofovir therapy. Cidofovir therapy is contraindicated in patients with a history of severe hypersensitivity to cidofovir, probenecid or other sulfur-containing medications. [PDR 1999; p 1080] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic acyclic purine nucleotide analog of cytosine. [AHFS Drug Information 1999; p 518] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H14-N3-O6-P.2H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 315.22 [USPD 1998; p. 164] CHEMICAL/PHYSICAL DATA Elemental Comp: C34.42%, H5.05%, N15.05%, O34.38%, P11.09% (base) [Merck Index 1996; p. 381] CHEMICAL/PHYSICAL DATA Stability: Administer within 24h after preparation. [Gilead Sciences Package Insert June 1996; p 5] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [PDR 1999; p 1079] SUBSTANCE DELIVERY DATA DOSAGE FORM: Cidofovir (Vistide), 75mg/mL for intravenous injection, is supplied as non-preserved solution in single-use, clear glass vials. [PDR 1999; p 1082] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: For the treatment of CMV retinitis, cidofovir (Vistide) is administered systemically by intravenous infusion. It should not be used for intravitreal injection since this route has been associated with [AHFS Drug Information 1999; p 518] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 20-25 C (68-77 F). [PDR 1999; p 1082] MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: James Rooney (415)572-6597 MANUFACTURERS 0000002300: Gilead Sciences Inc 333 Lakeside Dr Foster City, CA 94404 Contact: Medical Information (650)574-3000 REFERENCES MED/99208415. Jacobson MA,Wilson S, Stanley H, Holtzer C, Cherrington J, Safrin S. Phase I study of combination therapy with intravenous cidofovir and oral ganciclovir for cytomegalovirus retinitis in patients with AIDS. Clin Infect Dis 1999 Mar;28(3):528-33. MED/99212049. Erice A. Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev. 1999 Apr;12(2):286-97. MED/99156123. Lin AP, Holland GN, Engstrom RE. Vitrectomy and silicone oil tamponade for cidofovir-associated hypotony with ciliary body detachment. Retina. 1999;19(1):75-6. MED/99137809. Karavellas MP, Plummer DJ, Macdonald JC, Torriani FJ, Shufelt CL, Azen SP, Freeman WR. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis. 1999 Mar;179(3):697-700. MED/99085589. Simonart T, Noel JC, De Clereq E, Snoeck R. Abatement of cutaneous Kaposi's sarcoma associated with cidofovir treatment [letter] Clin Infect Dis. 1998 Dec;27(6):1562. MED/99136578. Brody SR, Humphreys MH, Gambertoglio JG, Schoenfeld P, Cundy KC, Aweeka FT. Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high-flux hemodialysis. Clin Pharmacol Ther. 1999 Jan;65(1):21-8. AIDS/99703972. Bowers M. Cidofovir. BETA. 1998 Jul;41-2. MED/99034675. Taoufik Y, Gasnault J, Karaterki A, Pierre Ferey M, Marchadier E, Goujard C, Lannuzel A, Delfraissy JF, Dussaix E. Prognostic value of JC virus load in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Infect Dis. 1998 Dec;178(6):1816-20. MED/99075349. Jabs DA, Bolton SG, Dunn JP, Palestine AG, Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol. 1998 Dec;126(6):817-22. AIDS/98929435. Pavia AT, Meadows KP, Tyring SK, Rallis TM. Treatment of recalcitrant molluscum contagiosum with cidofovir 5th Conf Retrovir Oppor Infect. 1998 Feb 1-5;:174 (abstract no. 504). ENTRY MONTH 199209 LAST REVISION DATE 20000801 202 UNIQUE IDENTIFIER DRG-0144 NAME OF SUBSTANCE Atevirdine mesylate [USPD 1998; p. 67] REGISTRY NUMBER 138540-32-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Piperazine, 1-(3-(ethylamino)-2-pyridinyl)-4-((5-methoxy-- 1H-indol-2-yl)carbonyl) -, monomethanesulfonate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 187 PROTOCOL ID NUMBERS Complete NIAID ACTG 199 PROTOCOL ID NUMBERS No longer recruiting FDA 117A PROTOCOL ID NUMBERS No longer recruiting FDA 210A PHARMACOLOGICAL ACTION MODE OF ACTION: BHAP (bis(heteroaryl)piperagine) compounds are non-nucleoside chemicals with anti-HIV activity. BHAP compounds have in vitro activities comparable to other non-nucleoside reverse transcriptase inhibitors (nevirapine). However, all these compounds have unique structures. Atevirdine is a non-nucleoside reverse transcriptase inhibitor with demonstrated in vitro antiretroviral activity against HIV-1. Resistance to BHAP compounds develops rapidly in vitro. BHAP-resistant virus results from a single amino acid substitution at codon 236. The development of this resistance has been reported to sensitize HIV-1 reverse transcriptase to inhibition by other non-nucleoside reverse transcriptase inhibitors. Atevirdine is active against clinical HIV-1 isolates. In a clinical trial of Atevirdine and AZT in 20 patients with CD4 counts <500/cubic mm, 5/9 patients treated for >16 weeks had HIV-1 isolates sensitive to Atevirdine, while 4/9 developed resistance to the drug between weeks 6 and 24. In a study to investigate the effect of atevirdine in asymptomatic antiretroviral naive HIV-infected patients with CD4+ cell counts of between 200 and 750 cells per mm3, there was no statistically significant effect of atevirdine on viral loads (HIV p24 antigen and HIV-1 RNA levels by PCR) or CD4+ cell counts. The data does not support the use of atevirdine as a monotherapy in the treatment of HIV-infected patients. [Antimicrob Agents Chemother 1996 Nov;40(11); p 2664-8; AmfAR Treat Dir 1995;7(4); p 21; Protocol ID: ACTG 187 ] DISEASES STUDIED/TREATED Primary HIV infection. [AmfAR Treat Dir 1995;7(4); p 21-2] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE INTERACTIONS BHAP (bis(heteroaryl)piperazine) compounds are mutually competitive with nevirapine. [AmfAR Treat Dir 1993;6(4); p 22-3] ADVERSE EFFECTS Two subjects receiving Atevirdine and AZT developed grade III fevers, one subject developed a rash and four subjects developed palpitations. [AmfAR Treat Dir 1995;7(4); p 22] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A bis(heteroaryl)piperazine (BHAP) compound. [AmfAR Treat Dir 1995;7(4); p 21-2] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H25-N5-O2.C-H4-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 475.57 [USPD 1998; p. 67] SUBSTANCE DELIVERY DATA DOSAGE FORM: 50 and 200 mg tablets. [Protocol ID: ACTG 187 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 187 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15 and 30 C (59 and 87 F). [Protocol ID: ACTG 187 ] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 REFERENCES MED/97070561. Been-Tiktat AM, Williams I, Vrehen HM, Richens J, Aldam D, van Loon AM, Loveday C, Boucher CA, Ward P, Weller IV, Borleffs JC. Safety, tolerance, and efficacy of atevirdine in asymptomatic human immunodeficiency virus-infected individuals. Antimicrob Agents Chemother. 1996 Nov;40(11):2664-8. MED/97057725. Brew BJ, Dunbar N, Druett JA, Freund J, Ward P. Pilot study of the efficacy of atevirdine in the treatment of AIDS dementia complex. AIDS. 1996 Oct;10(12):1357-60. MED/97004297. Morse GD, Fischl MA, Shelton MJ, Borin MT, Driver MR, DeRemer M, Lee K, Wajszczuk CP. Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections. Antimicrob Agents Chemother. 1996 Mar;40(3):767-71. MED/95314189. Been-Tiktak AM, Vrehen HM, Schneider MM, van der Feltz M, Branger T, Ward P, Cox SR, Harry JD, Borleffs JC. Safety, tolerance, and pharmacokinetics of atevirdine mesylate (U-87201E) in asymptomatic human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1995 Mar;39(3):602-7. MED/95146774. Reichman RC, Morse GD, Demeter LM, Resnick L, Bassiakos Y, Fischl M, Para M, Powderly W, Leedom J, Greisberger C, et al. Phase I study of atevirdine, a non nucleoside reverse transcriptase inhibitor, in combination with zidovudine for human immunodeficiency virus type 1 infection. ACTG 199 Study Team. J Infect Dis. 1995 Feb;171(2):297-304. MED/95150224. Roberts S, Bawdon R, Sobhi S, Dax J, Gilstrap L 3rd, Wimberly D. The maternal-fetal transfer of bisheteroarylypiperazine (U-87201-E) in the ex vivo human placenta. Am J Obstet Gynecol. 1995 Jan;172(1 Pt 1):88-91. AIDS/95920767. Shelton MJ, Morse GD, Borin MT, Driver MR, Wajszczuk CP, DeRemer MF, Lee K, Fischl MA. Didanosine (ddI) reduces atevirdine (ATV) absorption. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:82. ICA10/94371473. Wagner KF, Mayers DL, Cox SR, Batts DH. A pilot phase I study of oral monotherapy with U-87201E (atevirdine, ATV) in late stage HIV disease. Int Conf AIDS. 1994 Aug 7-12;10(2):209 (abstract no. PB0848). ICA10/94370882. Brew BJ, Dunbar N, Druett J. Pilot study of the efficacy of atevirdine in AIDS dementia complex (ADC). Int Conf AIDS. 1994 Aug 7-12;10(1):70 (abstract no. 232B). AIDS/95921590. Reichman R, Demeter L, Fischl M, Para M, Powderly W, Leedom J, Resnick L, Morse G, Timpone J, Batts D, et al. Phase I study of atevirdine (ATV), a non-nucleoside reverse transcriptase inhibitor (NNRTI). Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:159. ENTRY MONTH 199206 LAST REVISION DATE 20001107 203 UNIQUE IDENTIFIER DRG-0143 NAME OF SUBSTANCE Sparfloxacin [USPD 1998; p. 680] REGISTRY NUMBER 110871-86-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 111542-93-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3-Quinolinecarboxylic acid, 1,4-dihydro-5-amino-1-cyclopropyl-6,8-difluor- o-7-(3,5-dimethyl-1-pip erazinyl)-4-oxo-, cis- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Zagam [USP DI 2000; p. 1569] PROTOCOL ID NUMBERS No longer recruiting CC 92 I-165 PHARMACOLOGICAL ACTION MODE OF ACTION: Potent inhibitor of bacterial DNA gyrase, an enzyme that regulates the supercoiling, uncoiling, and spatial geometry of bacterial DNA. Sparfloxacin has enhanced bactericidal activity against gram-positive organisms. Since Mycobacterium avium complex (MAC) can bind to and invade intestinal mucosal cells, this study examined whether subinhibitory concentrations of antibiotics which have anti-MAC activity in vitro affect the interaction between MAC and HT-29 intestinal mucosal cells. MAC exposed to sparfloxacin at 1 and 7 mcg/ml inhibited binding by 77-93%. Such binding inhibition may be one underlying mechanism for the prophylactic effects of rifabutin and quinolones (e.g., sparfloxacin). In human monocyte-derived macrophages infected with Mycobacterium avium complex, sparfloxacin exhibited better efficacy than rifapentine, azithromycin or temafloxacin. [Antimicrob Agents Chemother 1994 May;38(5); p 1200-2; Antimicrob Agents Chemother 1991 Jul;35(7); p 1356-9; Protocol ID: 92 I-165 ] DISEASES STUDIED/TREATED Being investigated for treatment of tuberculosis. Treatment of MAI (Mycobacterium avium-intracellulare) bacteremia in HIV-infected individuals. [Tuber Lung Dis 1992 Dec;73(6); p 378-83; Protocol ID: 92 I-165 ; AmfAR Treat Dir 1993;6(3); p 154] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 1556] OTHER MAJOR USES Sparfloxacin is expected to be useful for treatment of Chlamydia trachomatis infection in humans. [Int Conf AIDS 1994 Aug 7-12;10(2); p 270] SUBSTANCE INTERACTIONS In vitro synergism studies showed that sparfloxacin plus ethambutol plus rifamycin were synergistic against 10 strains of Mycobacterium avium complex. [Antimicrob Agents Chemother 1990 Feb; p 2442-4] ADVERSE EFFECTS Adverse effects include hypersensitivity to sunlight and gastrointestinal distress. [Protocol ID: 92 I-165 ] CONTRAINDICATIONS Contraindicated in individuals with prolonged QT intervals on EKG. [Protocol ID: 92 I-165 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic, broad spectrum, fluoroquinolone antibacterial agent. [Protocol ID: 92 I-165 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H22-F2-N4-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 392.41 [USPD 1998; p. 680] CHEMICAL/PHYSICAL DATA Melting Point: 266-269 C [Merck Index 1996; p. 1493] CHEMICAL/PHYSICAL DATA Elemental Comp: C58.16%, H5.65%, F9.68%, N14.28%, O12.23% [Merck Index 1996; p. 1492] SUBSTANCE DELIVERY DATA DOSAGE FORM: 100 mg tablets. [Protocol ID: 92 I-165 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 92 I-165 ] MANUFACTURERS 0000001190: Rhone - Poulenc Rorer 500 Arcola Road Collegeville, PA 19426 Contact: David Lester (610)454-5399 MANUFACTURERS 0000004009: Parke-Davis Pharmaceutical Research 2800 Plymouth Rd Ann Arbor, MI 48105 Contact: Dr J Tyler Martin (313)997-3556 REFERENCES MED/95108409. Dautzenberg B. Clinical trials in Mycobacterium avium therapy: lessons to take home. Res Microbiol. 1994 Mar-Apr;145(3):197-206. MED/93372464. Peloquin CA. Controversies in the management of Mycobacterium avium complex infection in AIDS patients. Ann Pharmacother. 1993 Jul-Aug;27(7-8):928-37. MED/93184292. Grosset JH. Treatment of tuberculosis in HIV infection [see comments]. Tuber Lung Dis. 1992 Dec;73(6):378-83. ICA8/32401247. Barlow D, Dimian C, Band B, Phillips I. Chlamydia and Ureaplasma--genital symptoms. Int Conf AIDS. 1992 Jul 19-24;8(2):B173 (abstract no. PoB 3519). ICA7/3217691. Pialoux G, Dupont B, Chamaret S, Lecoeur H, Levy C, Montagnier L. Pilot study of sparfloxacine + antiretroviral drug in systemic mycoplasma infection in AIDS patients. Int Conf AIDS. 1991 Jun 16-21;7(2):226 (abstract no. W.B.2176). ICA7/3105191. Perronne C, Gikas A, Truffot C, Grosset J, Vilde JL, Pocidalo JJ. Sparfloxacin activity against mycobacterium avium complex (MAC) multiplication within human macrophages. Int Conf AIDS. 1991 Jun 16-21;7(2):104 (abstract no. W.A.1051). MED/92027610. Perronne C, Gikas A, Truffot-Pernot C, Grosset J, Vilde JL, Pocidalo JJ. Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobacterium avium complex within human macrophages. Antimicrob Agents Chemother. 1991 Jul;35(7):1356-9. MED/91207046. Yajko DM, Sanders CA, Nassos PS, Hadley WK. In vitro susceptibility of Mycobacterium avium complex to the new fluoroquinolone sparfloxacin (CI-978; AT-4140) and comparison with ciprofloxacin. Antimicrob Agents Chemother. 1990 Dec;34(12):2442-4. ENTRY MONTH 199205 LAST REVISION DATE 20001107 204 UNIQUE IDENTIFIER DRG-0142 NAME OF SUBSTANCE Hepatitis B Vaccine (Recombinant) [USP DI 2000; p. 1703] SYNONYMS Engerix-B [USP DI 2000; p. 1703] SYNONYMS Recombivax HB [USP DI 2000; p. 1703] PROTOCOL ID NUMBERS Complete NIAID ACTG 205 PROTOCOL ID NUMBERS Complete NIAID AVEG 003 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5046s PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1024 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PHARMACOLOGICAL ACTION MODE OF ACTION: Heptitis B surface antigen, which is present in hepatits B virus vaccine (recombinant), promotes the productions of antibody to hepatitis B surface antigen (anti-HBs); anti-HBs neutralize the hepatitis B virus so that its infectivity or pathogenic properties are inhibited. Protection against hepatitis B is virtually complete in individuals who develop adequate antibody levels after vaccination. [AHFS Drug Information 1997; p 2589] DISEASES STUDIED/TREATED Used as non-HIV viral vaccine control. [Protocol ID: ACTG 205 ] CLASSIFICATION CODE Immunizing agent, active [USP DI 2000; p. 1698] OTHER MAJOR USES Immunization against infection caused by all known subtypes of hepatitis B virus. [PDR 1997; p 2657] ADVERSE EFFECTS Generally well tolerated. No serious adverse reactions attributable to the vaccine have been reported during the course of clinical trials. Injection site reactions (including erythema and swelling) and systemic complaints were reported in one trial following 8% and 17% of the injections respectively. [PDR 1997; p 1789] CONTRAINDICATIONS Hypersensitivity to yeast or any other component of the vaccine is a contraindication. Should be administered with caution to individuals with thrombocytopenia, or a bleeding disorder, or with severely compromised cardiopulmonary status, or to individuals in whom a febrile or adverse systemic reaction could pose a substantial risk. [PDR 1997; p 2657; AHFS Drug Information 1997; p 2595-6] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Noninfectious recombinant DNA hepatitis B vaccine. A recombinantly produced hepatitis B surface antigen obtained from genetically engineered Saccharomyces cerevisiae (yeast) cells and adsorbed on aluminum hydroxide. [PDR 1997; p 2656] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Slightly opaque, white sterile suspension. [PDR 1997; p 2656] SUBSTANCE DELIVERY DATA DOSAGE FORM: 20 mcg/ml single-dose vials. [PDR 1997; p 2658] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular. [PDR 1997; p 2656] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 2 and 8 C. Do not freeze. [PDR 1997; p 2658] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 REFERENCES MED/96183604. Beyrer C, Celentano DD, Linpisarn S, Natpratan C, Feng W, Eiumtrakul S, Khamboonruang C, Nelson KE. Hepatitis B immunization: a potential incentive to HIV vaccine trial participation in Thailand? J Acquir Imunne Defic Syndr Hum Retrovirol. 1996 Apr 1;11(4):396-400. MED/95294564. Arrazola MP, de Juanes JR, Ramos JT, Aragon AJ, Garcia de Codes A. Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus. J Med Virol. 1995 Mar;45(3):339-41. MED/95147123. Maris JM, Butler RB, Cohen AR. Loss of detectable antibody to hepatitis B surface antigen in immunized patients with hemophilia but without human immunodeficiency virus infection. J Pediatr. 1995 Feb;126(2):269-71. MED/95231938. Choudhury SA, Peters VB. Responses to hepatitis B vaccine boosters in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1995 Jan;14(1):65-7. MED/95101164. Rutstein RM, Rudy B, Codispoti C, Watson B. Response to hepatitis B immunization by infants exposed to HIV. AIDS. 1994 Sep;8(9):128-4. MED/94111894. Diamant EP, Schechter C, Hodes DS, Peters VB. Immunogenicity of hepatitis B vaccine in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1993 Oct;12(10):877-8. MED/94293131. Zuccotti GV, Riva E, Flumine P, Locatelli V, Fiocchi A, Tordato G, Giovannini M. Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus. J Pediatr. 1994 Jul; 125(1):70-2. MED/94249668. Hessol NA, Koblin BA, van Griensven GJ, Bacchetti P, Liu JY, Stevens CE, Coutinho RA, Buchbinder SP, Katz MH. Progression of human immunodeficiency virus type 1 (HIV-1) infection among homosexual men in hepatitis B vaccine trial cohorts in Amsterdam, New York City, and San Francisco, 1978-1991. Am J Epidemiol. 1994 Jun 1;139(11):1077-87. MED/94280734. Tayal SC, Sankar KN. Impaired response to recombinant hepatitis B vaccine in asymptomatic HIV-infected individuals [letter]. AIDS. 1994 Apr;8(4):558-9. MED/94063888. Huengsberg MI, Radcliffe KW, Boxall EH. Hepatitis B infection post Engerix B vaccination [letter]. Genitourin Med. 1993 Oct;69(5):406-7. ENTRY MONTH 199205 LAST REVISION DATE 20000801 205 UNIQUE IDENTIFIER DRG-0141 NAME OF SUBSTANCE Cytomegalovirus Immune Globulin (Human) [Medimmune. Available at: http://www.medimmune.com/medimmune/products/c- ytopi1.htm. Accessed September 27, 2000.] SYNONYMS CytoGam [Medimmune. Available at: http://www.medimmune.com/medimmune/products/c- ytopi1.htm. Accessed September 27, 2000.] PROTOCOL ID NUMBERS No longer recruiting CC 92 I-124 PHARMACOLOGICAL ACTION MODE OF ACTION: Cytomegalovirus Immune Globulin (Human) contains IgG antibodies representative of the large number of normal persons who contributed to the plasma pools from which the product was derived. The globulin contains a relatively high concentration of antibodies directed against Cytomegalovirus (CMV). In the case of persons who may be exposed to CMV, this drug can raise the relevant antibodies to levels sufficient to attenuate or reduce the incidence of serious CMV disease. [PDR 1997; p 1630] DISEASES STUDIED/TREATED Treatment of HIV-infected patients with CMV viruria. [Protocol ID: 92 I-124 ] CLASSIFICATION CODE Immunomodulator [Protocol ID: 92 I-124 ] OTHER MAJOR USES Attenuation of primary CMV disease associated with kidney transplantation. [PDR 1997; p 1630] SUBSTANCE INTERACTIONS Antibodies present in immune globulin preparations may interfere with the immune response to live virus vaccines, such as measles, mumps and rubella. Vaccination should be deferred until approximately three months after administration of the drug. [PDR 1997; p 1630-1] ADVERSE EFFECTS May cause minor reactions such as flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, and wheezing. Other possible severe reactions include angioedema and anaphylactic shock. [PDR 1997; p 1630-1] CONTRAINDICATIONS Contraindicated in individuals with a history of severe reaction associated with the administration of this or other human immunoglobulin preparations and in individuals with selective IgA deficiency [PDR 1997; p 1630-1] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Purified immunoglobulin derived from pooled plasma selected for high titers of antibody for CMV. Pooled plasma is fractionated by ethanol precipitation of proteins according to Cohn Methods 6 and 9, modified to yield a product suitable for intravenous administration. Composed primarily of IgG with trace amounts of IgA and IgM. [PDR 1997; p 1630] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Immunoglobulin containing standardized amount of antibody to Cytomegalovirus, formulated as sterile liquid, stabilized with 5% sucrose and 1% human albumin. [PDR 1997; p 1630] SUBSTANCE DELIVERY DATA DOSAGE FORM: 2500mg (+/- 500mg) vials. 1000mg (+/- 200mg) vials. [PDR 1997; p 1631] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [PDR 1997; p 1630] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be stored between 2 and 8 C (35.6m 46.4 F) and used within 6 hours after entering vial. [PDR 1997; p 1631] MANUFACTURERS 0000001078: MedImmune Inc 35 West Watkins Mill Rd Gaithersburg, MD 20878 Contact: Unspecified (301)527-4300 MANUFACTURERS 0000001078: MedImmune Inc 35 West Watkins Mill Rd Gaithersburg, MD 20878 Contact: Bill Laps, Regulatory Affairs (570)839-6176 MANUFACTURERS 0000003865: Pasteur Merieux Connaught / Connaught Laboratories Route 611 / Box 187 / 1 Discovery Drive Swiftwater, PA 183700187 Contact: Dr John Zahradnik (570)839-4647 REFERENCES MED/97054767. Franciotta D, Zardini E, Bono G, Brustia R, Minoli L, Cosi V. Antigen-specific oligoclonal IgG in AIDS-related cytomegalovirus and toxoplasma encephalitis. Acta Neurol Scand. 1996 Sep; 94(3):215-8. MED/94160325. Stratta RJ, Taylor RJ, Bynon JS, Lowel JA, Cattral MS, Frisbie K, Miller S, Radio SJ, Brennan DC. Viral prophylaxis in combined pancreas-kidney transplant recipients. Transplantation 1994 Feb 27;57(4):506-12. MED/94009116. Gungor T, Funk M, Linde R, Kynast I, Allendorf A, Lotz C, Ehrenforth S, Hofmann D, Kornhuber B, Kreuz W. Combined therapy in human immunodeficiency virus-infected children--a 4-year experience. Eur J Pediatr. 1993 Aug;152(8):650-4. MED/92390256. Levinson ML, Jacobson PA. Treatment and prophylaxis of cytomegalovirus disease[see comments]. Pharmacotherapy. 1992;12(4):300-18. MED/92200817. ASHP therapeutic guidelines for intravenous immune globulin. ASHP Commission on Therapeutics[see comments]. Clin Pharm. 1992 Feb;11(2):117-36. MED/92036358. Platt D, Maderazo E, Chime-Udeh E. The use of intravenous immune globulin in organ transplantation. Conn Med 1991 Aug;55(8):468-70. ICA8/92400997. Traina C, Bellante E. Prevention of the cytomegalovirus infection with the early administration of anti CMV human immunoglobulins in HIV positive patients. Int Conf AIDS. 1992 Jul 19-24;8(2):B131 (abstract no. PoB 3267). MED/91263197. Kempf C, Jentsch P, Poirier B, Barre-Sinoussi F, Morgenthaler JJ, Morell A, Germann D. Virus inactivation during production of intravenous immunoglobulin. Transfusion. 1991 Jun;31(5):423-7. MED/90225723. Jacobsen MA, O'Donnell JJ, Rousell R, Dionian B, Mills J 5th. Failure of adjunctive cytomegalovirus intravenous immune globulin to improve efficacy of ganciclovir in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis a phase I study. Antimicrob Agents Chemother. 1990 Jan;34(1):176-8. MED/88213602. Nielsen SL, Sorensen I, Anderson HK. Kinetics of specfic immunoglobulins M, E, A and G in congenital, primary, and secondary cytomegalovirus infection studied by antibody-capture enzyme-linked immunosorbent assay. J Clin Microbiol. 1988 Apr;26(4):-61. MED/87105126. Flik J, Milbradt H, Wahlers T, Schafers HJ, Haverich A. Transient HIV-antibody positive tests in heart transplantation patients after repeated administration of CMV immune globulin preparation. Dtsch Med Worchenschr.1987 Jan 30;112(5):178-81. ENTRY MONTH 199205 LAST REVISION DATE 20000927 206 UNIQUE IDENTIFIER DRG-0140 NAME OF SUBSTANCE Sitamaquine [USPD 2000 p. 652] REGISTRY NUMBER 57695-04-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,6-Hexanediamine, N,N-diethyl-N'-(6-methoxy-4-methyl-8-quinolin- yl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed Nov 6, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 173 PROTOCOL ID NUMBERS Complete NIAID ACTG 314 PHARMACOLOGICAL ACTION MODE OF ACTION: WR 6026 has been proven effective against PCP in mice. Studies on dogs characterize WR 6026 as a drug of relatively high systemic clearance, large volume of distribution, relatively short half-life, and low systemic availability, probably due to presystematic elimination in the liver. In recent human trials, WR has been well tolerated in most subjects given doses from 30 mg/day to 120 mg/day. [Int Conf AIDS 1993 Jun 6-11;9(1); 498 (abstract no PO-B29-2180); AmfAR Treat Dir 1993;6(4); p 66; Eur J Drug Metab Pharmacokinet 1991; Spec No 3; Spec No 3;136-9] DISEASES STUDIED/TREATED Being investigated as prophylaxis or treatment for Pneumocystis carinii pneumonia in HIV-infected patients. [AmfAR Treat Dir 1993;6(4); p 66; Protocol ID: ACTG 173 ] CLASSIFICATION CODE Antiprotozoal [AmfAR Treat Dir 1993;6(4); p 66] OTHER MAJOR USES Leishmaniasis. [AmfAR Treat Dir 1993;6(4); p 66; Clin Infect Dis 1994 Dec;19(6); p 1034-39] ADVERSE EFFECTS Only moderate toxicities have been observed, and dose limiting toxicity has not prevented dose-escalation. Two subjects in a blinded study developed a skin rash. GI distress, headache and methemoglobinemia were reported in patients receiving .25-1.0 mg/kg/day. [Int Conf AIDS 1993 Jun 6-11;9(1); 498 (abstract no. PO-B29-2180); Clin Infect Dis 1994 Dec;19(6); p 1034-39] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: One of several 8-aminoquinolone analogues developed by the Walter-Reed Army Institute for Research. [AmfAR Treat Dir 1993;6(4); p 66] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H33-N3-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 343.51 [USPD 2000 p. 652] SUBSTANCE DELIVERY DATA DOSAGE FORM: 15 and 30 mg gelatin capsules. [Protocol ID: ACTG 173 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 173 ] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/95195065. Sherwood JA, Gachihi GS, Muigai RK, Skillman DR, Mugo M, Rashid JR, Wasunna KM, Were JB, Kasili SK, Mbugua JM, et al. Phase 2 efficacy trial of an oral 8-aminoquinoline (WR6026) for treatment of visceral leishmaniasis. Clin Infect Dis; VOL 19, ISS 6, 1994, P1034-9. ICA9/93335796. Petty B, Black J, Hendrix C, Bassiakos Y, et al. Escalating multiple-dose safety and tolerance of WR 6026 in HIV-infected subjects. Int Conf AIDS 1993 Jun 6-11;9(1):498 (abstract no. PO-B29-2180). MED/94001585. Goheen MP, Bartlett MS, Shaw MM, Queener SF, Smith JW. Effects of 8-aminoquinolines on the ultrastructural morphology of Pneumocystis carinii. Int J Exp Pathol 1993 Aug;74(4):379-87. MED/91072877. Steinhaus RK, Baskin SI, Clark JH, Kirby SD. Formation of methemoglobin and metmyoglobin using 8-aminoquinoline derivatives or sodium nitrite and subsequent reaction with cyanide. J Appl Toxicol 1990 Oct;10(5):345-51. ENTRY MONTH 199204 LAST REVISION DATE 20000801 207 UNIQUE IDENTIFIER DRG-0139 NAME OF SUBSTANCE Nimodipine [USPD 1998; p. 512] REGISTRY NUMBER 66085-59-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 2-methoxyethyl 1-methylethyl ester [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed Nov 6, 2000.] SYNONYMS Nimotop [USP DI 2000; p. 3491] PROTOCOL ID NUMBERS Complete NIAID ACTG 162 PHARMACOLOGICAL ACTION MODE OF ACTION: A calcium channel blocker with preferential cerebrovascular activity. The drug inhibits calcium ion transfer into smooth muscle cells and thus inhibits contractions of vascular smooth muscle. Nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within 1 hour. It is over 95% bound to plasma proteins. The terminal elimination half-life is 8-9 hours, but earlier elimination rates are much more rapid, equivalent to 1-2 hours. Nimodipine is eliminated almost exclusively in the form of metabolites, and less than 1% is recovered in the urine as unchanged drug. The metabolism of nimodipine is decreased in patients with impaired hepatic function. [PDR 1997; p 603; MeSH ] DISEASES STUDIED/TREATED Under investigation for the treatment of AIDS dementia complex. [AmfAR Treat Dir 1995;7(4); p 68] CLASSIFICATION CODE Calcium channel blocker [USP DI 2000; p. 736] CLASSIFICATION CODE Subarachnoid hemorrhage therapy [USP DI 2000; p. 736] OTHER MAJOR USES Indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured congenital aneurysms who are in good neurological condition post-ictus (eg, Hunt and Hess Grades I-III). [PDR 1997; p 603] SUBSTANCE INTERACTIONS Possibly enhances the cardiovascular action of other calcium channel blockers. In European trials, nimodipine occasionally intensified the effect of antihypertensive compounds taken concomitantly by patients with hypertension. [PDR 1997; p 603] ADVERSE EFFECTS The most frequently reported adverse effects include decreased blood pressure, edema, and headache. [PDR 1997; p 604] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A 1,4-dihydropyridine structurally related to nifedipine. [AHFS Drug Information 1997; p 1444] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H26-N2-O7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 418.45 [USPD 1998; p. 512] CHEMICAL/PHYSICAL DATA Melting Point: 125 C [Merck Index 1996; p. 1126] CHEMICAL/PHYSICAL DATA Elemental Comp: C60.28%, H6.26%, N6.69%, O26.76% [Merck Index 1996; p. 1126] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water, soluble in glycerin and PEG 400. [AHFS Drug Information 1997; p 1444] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow crystalline substance. [PDR 1997; p 603] SUBSTANCE DELIVERY DATA DOSAGE FORM: 30 mg capsules. [PDR 1997; p 604] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 604] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15 and 30 C (59 and 86 F). Protect from light and freezing. [PDR 1997; p 604] MANUFACTURERS 0000001074: Miles Inc Pharmaceutical Division 400 Morgan Lane West Haven, CT 06516 Contact: Dr Kenneth Kashkin (203)937-2468 MANUFACTURERS 0000005230: Bayer Corporation 400 Morgan Lane West Haven, CT 065164175 Contact: Unspecified (800)288-8371 REFERENCES ICA10/94369701. Galgani S, Narciso P, Balestra P, Pigorini F, Pau F, Sette P, Tozzi V, Alba L, Grisetti S, Visco G. Nimodipine+ZDV vs ZDV in patients with ADC. Int Conf AIDS. 1994 Aug 7-12;10(1):205 (abstract no. PBO248). MED/93210137. Stefano GB, Smith EM, Cadet P, Hughes TK Jr. HIV gp120 alteration of DAMA and IL-1 alpha induced chemotaxic responses in human and invertebrate immunocytes. J Neuroimmunol. 1993 Mar;43(1-2):177-84. MED/93140018. Gallo JM, Swagler AR, Mehta M, Qian M. Pharmacokinetic evaluation of drug interactions with anti-human immunodeficiency virus drugs. VI. Effect of the calcium channel blocker nimodipine on zidovudine kinetics in monkeys. J Pharmacol Exp Ther. 1993 Jan;264(1):315-20. MED/92273850. Gibaldi M. Drug interactions: Part I. Ann Pharmacother. 1992 May;26(5):709-13. MED/93299757. Grobe-Einsler R. Clinical aspects of nimodipine. Clin Neuropharmacol. 1993; 16 Suppl 1:S39-45. MED/92027518. Lipton SA. Calcium channel antagonists and human immunodeficiency virus coat protein-mediated neuronal injury. Ann Neurol. 1991 Jul;30(1):110-4. MED/91156903. [Drug for the control of stroke may help AIDS patients (news)]. Schweiz Rundsch Med Prax. 1990 Oct 30;79(44):1 p. following 1326. MED/90223047. Dreyer EB, Kaiser PK, Offermann JT, Lipton SA. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists [see comments]. Science. 1990 Apr 20;248(4953):364-7. MED/90223042. Gibbons A. Is AIDS dementia due to increases in calcium? [news; comment]. Science. 1990 Apr 20;248(4953):303. ENTRY MONTH 199203 LAST REVISION DATE 20001106 208 UNIQUE IDENTIFIER DRG-0138 NAME OF SUBSTANCE Dronabinol [USPD 1998; p. 258] REGISTRY NUMBER 1972-08-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 6H-Dibenzo(b,d)pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-penty- l-, (6aR-trans)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Marinol [USP DI 2000; p. 1370] PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 004 PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of action is not known. Cannabinoid receptors in neural tissue may mediate the effects of the drug. The antiemetic effects may be due to inhibition of the vomiting control mechanism in the medulla oblongata. Central sympathomimetic activity may result in tachycardia or conjunctival injection. Dose-related reversible effects on appetite, mood, cognition, memory, and perception also occur. Although the drug is 90-95% absorbed after a single oral dose, only 10-20% reaches systemic circulation due to first-pass hepatic metabolism and high lipid solubility. Distributed into breast milk, the drug is highly bound to protein. Extensive hepatic metabolism yields active and inactive metabolites. Dronabinol and its active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Psychoactive effects last 4-6 hours; appetite stimulating effects last 24 hours or longer. Elimination occurs in 4 hours (alpha phase) and 25-36 hours terminal (beta) phase and is through feces (50%) and urine (10-15%) within 72 hours. [USP DI 1997; p 1287-8] DISEASES STUDIED/TREATED FDA approved 12/23/92 for appetite stimulation and the prevention of weight loss in HIV-infected patients. [AmfAR Treat Dir 1995;7(4); p 64; USP DI 1997; p 1287] CLASSIFICATION CODE Antiemetic [USP DI 2000; p. 1368] CLASSIFICATION CODE Appetite stimulant [USP DI 2000; p. 1368] OTHER MAJOR USES Nausea and vomiting associated with cancer chemotherapy. [USP DI 1997; p 1287] SUBSTANCE INTERACTIONS May interact with barbiturates, disulfiram, theophylline, sympathomimetics and hypnotics and sedatives. May delay absorption of alcohol. [Drug Interactions Index 1992; p 527] ADVERSE EFFECTS The most frequently reported adverse reactions involved the central nervous system (CNS). In decreasing order of frequency these events were drowsiness, dizziness, muddled thinking and brief impairment of coordination, sensory and perceptual functions. About 25% of patients reported a minor CNS adverse effect during the first 2 weeks, and about 4% reported such an event each week for the next 6 weeks. [PDR 1997; p 2355] CONTRAINDICATIONS Contraindicated in pregnant and nursing women, in patients whose nausea and vomiting arise from any cause other than cancer chemotherapy, and in patients with known hypersensitivity to either dronabinol or sesame oil. Should be used with caution in patients with hypertension or heart disease; in manic, depressive, or schizophrenic patients; and in patients receiving other psychoactive drugs. [PDR 1997; p 2354-5; USP DI 1997; p 1288-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetically manufactured version of the active substance in marijuana, delta-9-tetrahydrocannabinol. [AmfAR Treat Dir 1997;8(3); p 70] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H30-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 314.47 [USPD 1998; p. 258] CHEMICAL/PHYSICAL DATA Elemental Comp: C80.21%, H9.62%, O10.18% [Merck Index 1996; p. 1573] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water, formulated in sesame oil. [PDR 1997; p 2353] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Light yellow resinous oil [PDR 1997; p 2353] SUBSTANCE DELIVERY DATA DOSAGE FORM: 2.5, 5, and 10 mg soft gelatin capsules. [PDR 1997; p 2355] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2355] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 8 and 15 C (46 and 59 F). Protect from freezing. [PDR 1997; p 2355] MANUFACTURERS 0000001072: Roxane Laboratories Inc 1809 Wilson Rd / PO Box 16532 Columbus, OH 432288601 Contact: Clinical and Medical Info (800)327-4865 MANUFACTURERS 0000001072: Roxane Laboratories Inc 1809 Wilson Rd / PO Box 16532 Columbus, OH 432288601 Contact: Information (800)520-1631 REFERENCES MED/97198330. Whitfield RM, Bechtel LM, Starich GH. The impact of ethanol and Marinol/marijuana usage on HIV+/AIDS patients undergoing azidothymidine, azidothymidine/dideoxycytidine, or dideoxyinosine therapy. Alcohol Clin Exp Res. 1997 Feb;21(1):122-7. MED/97238671. Burstein S. Marijuana as a medicine [letter]. Nature. 1997 Mar 27;386(6623):320. MED/97238771. Tashkin DP, Roth MD, Dubinett SM. Medicinal marijuana? [letter]. N Engl J Med. 1997 Apr 17;336(16):1186; discussion 1186-7. AIDS/97702169. Reiter GS. The HIV wasting syndrome. AIDS Clin Care. 1996 Nov;8(11):89-91, 93, 96. MED/95248169. Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage. 1995 Feb;10(2):89-97. AIDS/95700084. Beal J, Flynn N. AIDS-associated anorexia. J Physicians Assoc AIDS Care. 1995 Jan;2(1):19-22. MED/94348155. Cat LK, Coleman RL. Treatment for HIV wasting syndrome. Ann Pharmacother. 1994 May;28(5):595-597. MED/93372440. Struwe M, Kaempfer SH, Geiger CJ, Pavia AT, Plasse TF, Shepard KV, Ries K, Evans TG. Effect of dronabinol on nutritional status in HIV infection. Ann Pharmacother. 1993 Jul-Aug;27(7-8):827-831. ICA8/92403597. Struwe M, Kaempfer SH, Pavia AT, Geiger CJ, Shepard KV, Plasse TF, Evans T. Randomized study of dronabinol in HIV related weight loss. Int Conf AIDS. 1992 Jul 19-24;8(3):137 (abstract no. PuB 7531). ICA8/92403498. Plasse T, Conant M, Gorter R, Shepard KV. Dronabinol stimulates appetite and causes weight gain in HIV patients. Int Conf AIDS. 1992 Jul 19-24;8(3):122 (abstract no. PuB 7442). ENTRY MONTH 199203 LAST REVISION DATE 20001107 209 UNIQUE IDENTIFIER DRG-0137 NAME OF SUBSTANCE Letrazuril [USPD 1998; p. 413] REGISTRY NUMBER 103337-74-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME (+-)-(2,6-Dichloro-4-(4,5-dihydro-3,5-dioxo-a- s-triazin-2(3H)-yl)phen yl)(p-fluorophenyl)acetonitrile [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 198 PHARMACOLOGICAL ACTION MODE OF ACTION: Thirty-five AIDS patients with chronic cryptosporidiosis were treated with letrazuril at an initial oral daily dose of 50 mg. Treatment was continued for > or = 10 days and for as long as there was response. Twenty-three subjects had a clinical response within a mean of 1.7 weeks of treatment initiation. Twenty-two patients had a partial response (> 50% reduction in bowel movements per day for > or = 1 week), one patient had a complete response (two or fewer bowel movements per day). Of the responders, 15 had a clinical relapse with worsening diarrhea at an average of 1.2 months following initiation of letrazuril. The other eight had symptom control for an average of 2.9 months from initiation of treatment. Microbiologic eradication was demonstrated in 10 (40%) of 25 patients. In conclusion, severely immunocompromised AIDS patients with refractory cryptosporidiosis may show a modest, short-lived response to letrazuril. Microbiologic response is variable and relapse high. Cryptosporidium is also a well-recognized cause of AIDS-related sclerosing cholangitis. The combination of paromomycin and letrazuril should be considered in the treatment of this condition. [J Acquir Immune Defic Syndr Hum Retrovirol 1995 Sep 1;10(1); p 48-53; AIDS 1993 Nov;7(11); p 1449-51] DISEASES STUDIED/TREATED Being investigated for the treatment of cryptosporidiosis. Paromomycin and letrazuril should be considered in the treatment of AIDS-related sclerosing cholangitis. [AmfAR Treat Dir 1997;8(3); p 73; AIDS 1993 Nov;7(11); p 1449-51] CLASSIFICATION CODE Antiprotozoal [AmfAR Treat Dir 1993;6(4); p 76] ADVERSE EFFECTS Rash is a major limiting side effect of the drug. [J Acquir Immune Defic Syndr Hum Retrovirol 1995 Sep 1;10(1); p 48-53] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Experimental oral antibiotic related to diclazuril. [AmfAR Treat Dir 1997;8(3); p 73] CHEMICAL/PHYSICAL DATA Molecular Formula: C17-H9-Cl2-F-N4-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 391.19 [USPD 1998; p. 413] SUBSTANCE DELIVERY DATA DOSAGE FORM: 10, 25, and 50 mg capsules. [Protocol ID: ACTG 198 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1997;8(3); p 73; AIDS 1993 Aug;8(8); p 1109-13] MANUFACTURERS 0000001153: Janssen Research Foundation 1125 Trenton-Harbourton Rd Titusville, NJ 085600200 Contact: Professional Services (800)526-7736 REFERENCES MED/95376337. Loeb M, Walach C, Phillips J, Fong I, Salit I, Rachlis A, Walmsley S. Treatment with letrazuril of refractory cryptosporidial diarrhea complicating AIDS. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Sep 1;10(1):48-53. MED/95077740. Harris M, Deutsch G, MacLean JD, Tsoukas CM. A phase I study of letrazuril in AIDS-related cryptosporidiosis. AIDS. 1994 Aug;8(8):1109-13. MED/94107511. Hamour AA, Bonnington A, Hawthorne B, Wilkins EG. Successful treatment of AIDS-related cryptosporidial sclerosing cholangitis. AIDS. 1993 Nov;7(11):1449-51. MED/94030768. Murdoch DA, Bloss DE, Glover SC. Successful treatment of cryptosporidiosis in an AIDS patient with letrazuril [letter]. AIDS. 1993 Sep;7(9):1279-80. ICA9/93334980. Rubbert A, Schwab J, Kalden JR, Nusslein H. Myositis, fever, rash and thrombopenia after letrazuril treatment of intestinal cryptosporidiosis: a case report. Int Conf AIDS. 1993 Jun 6-11;9(1):373 (abstract no. PO-B10-1430). ICA9/93336200. Harris M, Deutsch G, MacLean JD, Tye L, Tsoukas CM. A phase I study of Letrazuril in AIDS related cryptosporidiosis. Int Conf AIDS. 1993 Jun 6-11;9(1):56 (abstract no.WS-B13-5). ICA9/93335029. Walach C, Loeb M, Phillips J, Salit I, Rachlis A, Fong I, Walmsley S. Use of letrazuril in refractory cryptosporidiosis in AIDS. Int Conf AIDS. 1993 Jun 6-11;9(1):380 (abstract no.PO-B10-1472). MED/93228900. Victor GH, Conway B, Hawley-Foss NC, Manion D, Sahai J. Letrazuril therapy for cryptosporidiosis: clinical response and pharmacokinetics [letter]. AIDS. 1993 Mar;7(3):438-40. ICA8/92404516. Hamour AA, Khoo S, Bonnington A, Barnes A, Fraser I, Bailey G, Wilkins EG, Denning DW, Dunbar EM, Mandal BK. Successful management of AIDS-related sclerosing cholangitis with paromomycin and letrazuril. Int Conf AIDS. 1992 Jul 19-24;8(3):87 (abstract no. PuB 7229). ICA8/92400987. Guillem S, Gomez M, Romeu J, Raventos A, Fernandez A, Condom MJ, Clotet B. Letrazuril for the treatment of severe cryptosporidial diarrhea in AIDS. Int Conf AIDS. 1992 Jul 19-24;8(2):B129 (abstract no. PoB 3257). ENTRY MONTH 199202 LAST REVISION DATE 20001107 210 UNIQUE IDENTIFIER DRG-0136 NAME OF SUBSTANCE Sorivudine [USPD 1998; p. 679] REGISTRY NUMBER 77181-69-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4(1H,3H)-Pyrimidinedione, 1-beta-D-arabinofuranosyl-5-(2-bromoethenyl)-- , (E)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Bravadir [USP DI 2000; p. 3327] PROTOCOL ID NUMBERS Complete NIAID ACTG 169 PROTOCOL ID NUMBERS No longer recruiting FDA 255A PROTOCOL ID NUMBERS No longer recruiting NCI 95 C-14 PHARMACOLOGICAL ACTION MODE OF ACTION: Brovavir is transported into viral-infected cells and converted to monophosphate analogues by virus-encoded thymidine kinase. Requires a virus-encoded thymidylate kinase to be converted to a diphosphate analogue. Does not appear to be incorporated into cellular DNA, but acts as an inhibitor of virus-encoded DNA polymerase. Low toxic potential for normal cells. In prior human studies, mean serum elimination half-life was 5 hours. Pre-clinical toxicity profile suggests that brovavir may be as well tolerated as acyclovir. [AmfAR Treat Dir 1993;6(4); p 58; Protocol ID: ACTG 169 ] DISEASES STUDIED/TREATED Active against HSV-1 and varicella-zoster virus (VZV). [AmfAR Treat Dir 1997;8(3); p 77] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 3327] OTHER MAJOR USES Treatment of herpes zoster in immunocompromised patients. [USP DI 1997; p 3123] ADVERSE EFFECTS In studies in Japan, no apparent side effects were noted when HIV-negative subjects were given oral doses up to 600 mg/d for 5 days. [AmfAR Treat Dir 1997;8(3); p 77] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An antiviral nucleoside analog. [AmfAR Treat Dir 1993;6(4); p 58] CHEMICAL/PHYSICAL DATA Molecular Formula: C11-H13-Br-N2-O6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 349.14 [USPD 1998; p. 679] CHEMICAL/PHYSICAL DATA Melting Point: 195-200 C [Merck Index 1996; p. 1491] CHEMICAL/PHYSICAL DATA Elemental Comp: C37.84%, H3.75%, Br22.89%, N8.02%, O27.50% [Merck Index 1996; p. 1491] CHEMICAL/PHYSICAL DATA Solubility: Soluble in ethanol. [Merck Index 1996; p 1491] SUBSTANCE DELIVERY DATA DOSAGE FORM: 40 mg capsules. [Protocol ID: ACTG 169 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1997;8(3); p 77] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/96261368. Whitley RJ. Sorivudine: a potent inhibitor of varicella zoster virus replication. Adv Exp Med Biol. 1996;394:41-4. MED/96035247. Burdge DR, Voigt R, Lindley JI, Gage L, Sacks SL. Sorivudine (BV-ara-U) for the treatment of complicated refractory varicella zoster virus infection in HIV-infected patients [letter]. AIDS. 1995 Jul;9(7):810-2. MED/95377331. Andrei G, Snoeck R, Reymen D, Liesnard C, Goubau P, Desmyter J, De Clercq E. Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. Eur J Clin Microbiol Infect Dis. 1995 Apr;14(4):318-29. MED/96136232. Whitley RJ. Sorivudine: a promising drug for the treatment of varicella-zoster virus infection. Neurology. 1995 Dec;45(12 Suppl 8):S73-5. MED/95225340. Pinnolis MK, Foxworthy D, Kemp B. Treatment of progressive outer retinal necrosis with sorivudine. Am J Ophthalmol. 1995 Apr;119(4):516-7. AIDS/95920768. Olsen SJ, Saag M, Sommadossi JP, Hedden BC, Raymond R, Stewart MB. Safety and pharmacokinetic interaction of sorivudine (BV-ara-U) and zidovudine. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:82. ASHM6/95291766. Boag F, Bodsworth NJ, Burdge D, Genereux M, Barleffs JC, Evans B, Colebunders R, Modai J, Thomas M, Marcoccia J, et al. The safety and efficacy of sorivudine (BV-ara-U) for the treatment of zoster in HIV-infected adults: results of a multinational acyclovir controlled trial. Annu Conf Australas Soc HIV Med. 1994 Nov 3-6;6:166 (unnumbered abstract). MED/93124537. Talarico CL, Phelps WC, Biron KK. Analysis of the thymidine kinase genes from acyclovir-resistant mutants of varicella-zoster virus isolated from patients with AIDS. J Virol. 1993 Feb;67(2):1024-33. MED/94012339. De Clercq E. Antivirals for the treatment of herpesvirus infections. J Antimicrob Chemother. 1993 Jul;32 Suppl A:121-32. MED/91244710. Hiraoka A, Masaoka T, Nagai K, Horiuchi A, Kanamaru A, Niimura M, Hamada T, Takahashi M. Clinical effect of BV-ara-U on varicella-zoster virus infection in immunocompromised patients with haematological malignancies. J Antimicrob Chemother 1991 Mar;27(3):361-7. ENTRY MONTH 199201 LAST REVISION DATE 20001107 211 UNIQUE IDENTIFIER DRG-0135 NAME OF SUBSTANCE Dacarbazine [USPD 1998; p. 206] REGISTRY NUMBER 4342-03-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1H-Imidazole-4-carboxamide, 5-(3,3-dimethyl-1-triazenyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS DTIC [USP DI 2000; p. 1176] SYNONYMS DTIC-Dome [USP DI 2000; p. 1176] PROTOCOL ID NUMBERS Complete NIAID ACTG 149 PHARMACOLOGICAL ACTION MODE OF ACTION: Dacarbazine is thought to be an alkylating agent, but other mechanisms of action are possible. Although the exact mechanism of action is unknown three hypotheses have been offered: (1) inhibition of DNA synthesis by acting as a purine analog; (2) action as an alkylating agent; and (3) interactions with SH groups. After intravenous administration, volume of distribution exceeds total body water content, suggesting localization in some body tissue, probably the liver. Disappearance from plasma is biphasic with initial half-life of 19 minutes and terminal half-life of 5 hours. Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations, dacarbazine is not appreciably bound to human plasma protein. The drug is extensively degraded in humans. [PDR 1997; p 593] DISEASES STUDIED/TREATED Treatment of Hodgkin's disease in HIV-infected patients. [AmfAR Treat Dir 1995;7(4); p 63; Protocol ID: ACTG 149 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1174] OTHER MAJOR USES Treatment of metastatic malignant melanoma and for Hodgkin's disease as a second-line therapy when used in combination with other effective agents. [PDR 1997; p 593] SUBSTANCE INTERACTIONS May interact with allopurinol, blood dyscrasia-causing medications, bone marrow depressants or radiation therapy, hepatic enzyme inducers, killed-virus vaccines, or live-virus vaccines. [USP DI 1995; p 1027-28] ADVERSE EFFECTS The most common adverse effect is hemopoietic depression; other reported adverse effects include hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis, and anaphylaxis. Symptoms of anorexia, nausea and vomiting are the most frequently noted of all toxic reactions (90%). Also noted, but more rare, are flu-like symptoms, myalgias, malaise, alopecia, facial flushing, facial paresthesia, erythematous and urticarial rashes, and photosensitivity. [PDR 1997; p 593] CONTRAINDICATIONS Contraindicated in patients with demonstrated hypersensitivity to dacarbazine. [PDR 1997; p 593] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The synthetic analog of the naturally occurring purine precursor 5-amino-IH-imidazole-4-carboxamide. [AHFS Drug Information 1997; p 727] CHEMICAL/PHYSICAL DATA Molecular Formula: C6-H10-N6-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 182.19 [USPD 1998; p. 206] CHEMICAL/PHYSICAL DATA Melting Point: 205 C [Merck Index 1996; p. 475] CHEMICAL/PHYSICAL DATA Elemental Comp: C39.56%, H5.53%, N46.13%, O8.78% [Merck Index 1996; p. 475] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water and in alcohol. [AHFS Drug Information 1997; p 727] CHEMICAL/PHYSICAL DATA Stability: Dacarbazine is sensitive to light and heat; elevated temperatures may cause a color change from ivory to pink which is indicative of some decomposition. Dacarbazine solutions are physically incompatible with solutions of hydrocortisone sodium succinate. [AHFS Drug Information 1997; p 728] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: A colorless to an ivory colored solid which is light sensitive. [PDR 1997; p 593] SUBSTANCE DELIVERY DATA DOSAGE FORM: 100 or 200 mg vials. [PDR 1997; p 594] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [PDR 1997; p 593] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2.8 C (36-46 F) or up to 8 hours at room temperature (under normal room light conditions). [AHFS Drug Information 1997; p 728] MANUFACTURERS 0000005230: Bayer Corporation 400 Morgan Lane West Haven, CT 065164175 Contact: Unspecified (800)288-8371 MANUFACTURERS 0000005385: Intervention provided by participating unit , Contact: Unspecified (800)288-8371 MANUFACTURERS 0000005230: Bayer Corporation 400 Morgan Lane West Haven, CT 065164175 REFERENCES MED/95325896. Tirelli U, Errante D, Dolcetti R, Gloghini A, Serraino D, Vaccher E, Franceschi S, Boiocchi M, Carobone A. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol. 1995 Jul;13(7):1758-67. MED/95307451. Levy R, Colonna P, Tourani JM, Gastaut JA, Brice P, Raphael M, Taillan B, Andrieu JM. Human immunodeficiency virus associated Hodgkin's disease: report of 45 cases from the French Registry of HIV-Associated Tumors. Leuk Lymphoma. 1995 Feb;16(5-6):451-6. MED/94153883. Muhonen T, Hahka-Kemppinen M, Pakkala S, Pyrhonen S. Decreasing CD4/CD8 ratio during prolonged four-drug chemotherapy plus interferon treatment for metastatic melanoma. J Immunother. 1994 Jan;15(1):67-73. MED/93259517. Novati S, Malfitano A, Sacchi P, Patruno SF, Tornari PM, Rondanelli EG. HIV-related Hodgkin's disease. Report of nine cases. Haematologica. 1993 Jan-Feb;78(1):34-7. ICA9/93335180. Errante D, Tirelli U, Milo D, Rizzardini G, Nasti G, Chieppa F. Chemotherapy (CT) with and without zidovudine (AZT) for Hodgkin's disease (HD) and HIV infection: a comparison in 49 patients (PTS). Int Conf AIDS 1993 Jun 6-11;9(1):404 (abstract no. PO-B13-1611). ICA9/93335187. Bouabdallah R, Quiles N, Bonnet E, Petit N, et al. Hodgkin's disease (HD) in HIV infected patients: clinical, histologic and therapeutic aspects. Int Conf AIDS 1993 Jun 6-11;9(1):405 (abstract no. PO-B13-1617). ICA8/92400016. Vaccher E, Tirelli U, Milo D, Chieppa F, Alberici F, Branz F, Ambrosini G, Giudici M, Lazzarin A, Cargnel A, et al. Hodgkin's disease and HIV infection (HD-HIV): a report of 92 patients from the GICAT (Italian Cooperative Group on AIDS and Tumors), with emphasis on prospective study with combined chemotherapy and zidovudine (AZT) in 16 patients. Int Conf AIDS. 1992 Jul 19-24;8(1):Mo16 (abstract no. MoB 0059). ICDB/92680733. Tirelli U, Errante D, Vaccher E, Spina M, Gastaldi R, Rizzardini G, Mandelli F, Milo D, Nosari AM, Rossi G, et al. Hodgkin's Disease and HIV Infection (HD-HIV): A Report of 92 Patients from the GICAT (Italian Cooperative Group on AIDS and Tumors), with Emphasis on Prospective Study with Combined Chemotherapy (CT) and Zidovudine (AZT) in 16 Patients (Meeting Abstract). Proc Annu Meet Am Soc Clin Oncol; 11:A2 1992. MED/91265397. Monfardini S, Tirelli U, Vaccher E, Foa R, Gavosto F. Hodgkin's disease in 63 intravenous drug users infected with human immunodeficiency virus. Gruppo Italiano Cooperativo AIDS & Tumori (GICAT). Ann Oncol. 1991 Feb;2 Suppl 2:201-5. ICA7/1217891. Sloand E, Kumar P, Pierce P. Treatment of pulmonary Kaposi's sarcoma (PKS) with combination chemotherapy. Int Conf AIDS. 1991 Jun 16-21;7(1):226 (abstract no. M.B.2178). ENTRY MONTH 199201 LAST REVISION DATE 20001107 212 UNIQUE IDENTIFIER DRG-0134 NAME OF SUBSTANCE Vinblastine sulfate [USPD 1998; p. 779] REGISTRY NUMBER 143-67-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Vincaleukoblastine, sulfate (1:1) (salt) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Velban [USP DI 2000; p. 3135] PROTOCOL ID NUMBERS Complete NIAID ACTG 149 PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro studies suggest an interference with metabolic pathways of amino acids leading from glutamic acid to the citric acid cycle and to urea. In vivo studies tend to confirm the in vitro results. Other studies indicate that vinblastine affects cell energy production required for mitosis and interferes with nucleic acid synthesis. In vitro, the drug arrests growing cells in metaphase. Pharmacokinetic studies in cancer patients have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle, and terminal half-lives are 3.7 minutes, 1.6 hours, and 24.8 hours, respectively. Major route of excretion may be through the biliary system; thus, toxicity may be increased in patients with hepatic excretory insufficiency. [PDR 1997; p 1538] DISEASES STUDIED/TREATED Treatment of Hodgkin's disease in HIV-infected patients; Kaposi's sarcoma. [Int Conf AIDS 1993 Jun 6-11;9(1); p 63 (abstract WS-B20-4)] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3131] OTHER MAJOR USES Treatment of generalized Hodgkin's disease; lymphocytic lymphoma; histiocytic lymphoma; mycosis fungoides; advanced carcinoma of the testis; Kaposi's sarcoma; Letterer-Siwe disease (histiocytosis X); choriocarcinoma resistant to other chemotherapeutic agents; and breast carcinoma unresponsive to appropriate endocrine surgery and hormonal therapy. [PDR 1997; p 1538] SUBSTANCE INTERACTIONS Concomitant administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome p450 isoenzymes in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of adverse reactions. Possible interaction with allopurinol, colchicine, probenecid, sulfinpyrazone, blood dyscrasia-causing medications, bone marrow depressants, radiation therapy, killed-virus vaccines, and live-virus vaccines. [PDR 1997; p 1539] ADVERSE EFFECTS Adverse effects include leukopenia, thrombocytopenia (generally in patients with bone marrow impairment by prior therapy), anemia, alopecia, constipation, anorexia, nausea, vomiting, abdominal pain, other gastrointestinal effects, hypertension, neurologic effects, acute shortness of breath, bronchospasm, malaise, bone pain, pain in tumor-containing tissue, jaw pain. [PDR 1997; p 1539] CONTRAINDICATIONS Contraindicated in patients with significant granulocytopenia (unless caused by disease being treated) or with bacterial infections. Also contraindicated in pregnant women. Toxicity of the drug is enhanced in the presence of hepatic insufficiency. [PDR 1997; p 1538] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Alkaloid extracted from Vinca rosea Linn, commonly known as periwinkle. [PDR 1997; p 1537] CHEMICAL/PHYSICAL DATA Molecular Formula: C46-H58-N4-O9.H2-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 909.07 [USPD 1998; p. 779] CHEMICAL/PHYSICAL DATA Melting Point: 284-285 C [Merck Index 1996; p. 1703] CHEMICAL/PHYSICAL DATA Elemental Comp: C68.13%, H7.21%, N6.91%, O17.76% (base) [Merck Index 1996; p. 1702] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water, soluble in methanol, slightly soluble in ethanol, insoluble in benzene, ether and naphtha. [PDR 1997; p 1537] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off white powder. [PDR 1997; p 1537] SUBSTANCE DELIVERY DATA DOSAGE FORM: 10 mg vials. [PDR 1997; p 1540] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. FATAL IF GIVEN INTRATHECALLY. Given intralesionally for oral Kaposi's sarcoma. [PDR 1997; p 1540; Int Conf AIDS 1993 Jun 6-11;9(1); p 63 (abstract no. WS-B20-4)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The vials should be stored in a refrigerator (2-8 C, or 36-46 F). Unused portions of the remaining solutions made with normal saline that do not contain preservatives should be discarded immediately. Unused preservative-containing solutions made with normal saline may be stored in a refrigerator for future use for a maximum of 28 days. [PDR 1997; p 1540] MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES ASHM8/97153742. Stubbs MA, Swaney L. The use of intralesional vinblastine in the treatment of oral Kaposi's sarcoma. Annu Conf Australas Soc HIV Med. 1996 Nov 14-17;(8):130(poster no.160). ICA11/96921347. Lesueur A, Salmon D, Blanche P, Essam E, Dupin N, Clauvel JP, Sicard D. Polyarteritis nodosa in an HIV-infected patient with Castleman's disease: potential role of KSHV and efficacy of treatment with immunoglobulin. Int Conf AIDS. 1996 Jul 7-12;11(1):103 (abstract no.Mo.B.1283). ICA11/96923590. Bertelli D, Barni C, Casari S, Paraninfo G, Cadeo GP. Adriamycin, bleomycin and vinblastine (ABV) chemotherapy in the treatment of AIDS-related Kaposi's sarcoma (KS). Int Conf AIDS. 1996 Jul 7-12;11(2):97 (abstract no.We.B.3238). MED/96209026. McCormick SU. Intralesional vinblastine injections for the treatment of oral Kaposi's sarcoma: report of 10 patients with 2-year follow up. J Oral Maxillofac Surg. 1996 May;54(5):583-7; discussion 588-9. MED/96182955. Friedman M, Venkatesan TK, Caldarelli DD. Intralesional vinblastine for treating AIDS-associated Kaposi's sarcoma of the oropharynx and larynx. Ann Otol Rhinol Laryngol. 1996 Apr;105(4):272-4. MED/95405898. Tami TA, Sharma PK. Intralesional vinblastine therapy for Kaposi's sarcoma of the epiglottis. Otolaryngol Head Neck Surg. 1995 Sep;113(3):283-5. MED/95325896. Tirelli U, Errante D, Dolcetti R, Gloghini A, Serraino D, Vaccher E, Franceschi S, Boiocchi M, Carbone A. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol. 1995 Jul;13(7):1758-67. MED/95320453. Conant MA. Management of human immunodeficiency virus-associated malignancies. Recent Results Cancer Res. 1995;139:423-32. MED/94123248. Errante D, Tirelli U, Gastaldi R, Milo D, Nosari AM, Rossi G, Fiorentini G, Carbone A, Vaccher E, Monfardini S. Combined antineoplastic and antiretroviral therapy for patients with Hodgkin's disease and human immunodeficiency virus infection. A prospective study of 17 patients. The Italian Cooperative Group on AIDS and Tumors (GICAT). Cancer. 1994 Jan 15;73(2):437-44. MED/93326502. Moyle G, Youle M, Barton S. Intralesional vinblastine in the treatment of oral Kaposi's sarcoma. Br J Clin Pract. 1993 Mar-Apr;47(2):79-80. ENTRY MONTH 199201 LAST REVISION DATE 20001107 213 UNIQUE IDENTIFIER DRG-0133 NAME OF SUBSTANCE Tuberculin Purified Protein Derivative [USPD 1998; p. 765] REGISTRY NUMBER 92129-86-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Aplisol [USP DI 2000; p. 3073] SYNONYMS Aplitest [USP DI 2000; p. 3073] SYNONYMS Tubersol [USP DI 2000; p. 3073] PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 008 PHARMACOLOGICAL ACTION MODE OF ACTION: The reaction to intracutaneously injected tuberculin is a delayed (cellular) hypersensitivity reaction. The reaction which characteristically shows a delayed course, reaching its peak more than 24 hours after administration, consists of induration due to cell infiltration and occasionally vesiculation and necrosis. Clinically, a delayed hypersensitivity reaction to tuberculin is a manifestation of previous infection with M. tuberculosis or a variety of non-tuberculosis bacteria. The sensitization following infection with mycobacteria occurs primarily in the regional lymph nodes. Small lymphocytes (T lymphocytes) proliferate in response to the antigenic stimulus to give rise to specifically sensitized lymphocytes. After several weeks, these lymphocytes enter the blood stream and circulate for long periods of time. Subsequent restimulation of these sensitized lymphocytes with the same or a similar antigen, such as the intradermal injection of tuberculin, evokes a local reaction mediated by these cells. The tuberculin reaction is characterized by the early predominance of mononuclear cells (small and medium sized lymphocytes and monocytes). Only a small proportion of these cells appear to be lymphocytes sensitized to tuberculin. Most cells are brought into the reaction through the release of biologically active substances by sensitized lymphocytes. An increase in vascular permeability leading to erythema and edema also occurs in tuberculin reactions. Characteristically, delayed hypersensitivity reactions to tuberculin begin at 5 to 6 hours, are maximal at 48 to 72 hours and subside over a period of days. In those who are elderly or those who are being tested for the first time, reactions may develop slowly and may not peak until after 72 hours. [PDR 1997; p 2988-9] DISEASES STUDIED/TREATED Diagnostic aid to detect Mycobacterium tuberculosis infections. [AHFS Drug Information 1997; p 1963-5] CLASSIFICATION CODE Diagnostic aid - Tuberculosis [USP DI 2000; p. 3073] OTHER MAJOR USES Diagnostic aid to detect Mycobacterium tuberculosis infections. [AHFS Drug Information 1997; p 1963-5] SUBSTANCE INTERACTIONS The reaction to tuberculin skin test may be suppressed if the test is given within 4-6 weeks following immunization with live or inactivated viral vaccines (e.g., influenza, measles, mumps, rubella, poliovirus, smallpox, yellow fever). The reaction to tuberculin skin test may also be suppressed in patients receiving systemic corticosteroids or aminocaproic acid therapy. Vaccination with BCG generally results in tuberculin sensitivity; however, the degree of tuberculin sensitivity is highly variable and depends on the strain of BCG used, dosage and method of administration of the vaccines, age and nutritional status of the individual at vaccination, number of years since vaccination, and factors known to affect the reaction to the tuberculin skin test. [AHFS Drug Information 1997; p 1966] ADVERSE EFFECTS In highly sensitive individuals, strongly positive reactions including vesiculation, ulceration, or necrosis may occur at the test site. Strongly positive test reactions may result in scarring at the test site. Immediate erythematous or other reactions may occur at the injection site. [PDR 1997; p 2999; AHFS Drug Information 1997; p 1965] CONTRAINDICATIONS Tubersol should not be administered to known tuberculin positive reactors because of the severity of reactions (e.g., vesiculation, ulceration or necrosis) that may occur at the test site in highly sensitive persons. [PDR 1997; p 2988] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Purified protein fraction isolated from culture filtrates of human type strains of Mycobacterium tuberculosis. [AHFS Drug Information 1997; p 1962] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Sterile aqueous solution or multiple puncture device. [AHFS Drug Information 1997; p 1962] SUBSTANCE DELIVERY DATA DOSAGE FORM: Multiple puncture device and solution. [AHFS Drug Information 1997; p 1728] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Multiple puncture devices, or intradermal injections by the Mantoux method. [AHFS Drug Information 1997; p 1966] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Solutions should be stored at 2-8 C and protected from light and should not be frozen; multiple puncture devices should be stored unrefrigerated at temperatures not exceeding 30 C. [AHFS Drug Information 1997; p 1962] MANUFACTURERS 0000004009: Parke-Davis Pharmaceutical Research 2800 Plymouth Rd Ann Arbor, MI 48105 Contact: Dr J Tyler Martin (313)997-3556 MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)223-0432 MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)223-0432 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 REFERENCES MED/97255180. Girardi E, Antonucci G, Ippolito G, Raviglione MC, Rapiti E, Di Perri G, Babudieri S. Association of tuberculosis risk with the degree of tuberculin reaction in HIV-infected patients. The Gruppo Italiano di Studio Tubercolosi e AIDS. Arch Intern Med. 1997 Apr 14;157(7):797-800. MED/97154575. Hecker MT, Johnson JL, Whalen CC, Nyole S, Mugerwa RD, Ellner JJ. Two-step tuberculin skin testing in HIV-infected persons in Uganda. Am J Respir Crit Care Med. 1997 Jan;155(1):81-6. MED/97042402. Gourevitch MN, Hartel D, Schoenbaum EE, Klein RS. Lack of association of induration size with HIV infection among drug users reacting to tuberculin. Am J Respir Crit Car Med. 1996 Oct;154(4):Pt 1, 1029-33. MED/96423799. Jones SG. Tuberculin testing in patients with human immunodeficiency virus/acquired immune deficiency syndrome. AACN Clin Issues. 1996 Aug;7(3):378-89. ICA11/96925537. Toledo A Jr, Machado LG, Carvalhais LM, Tupinambas U, Bello AP, Padua CJ, Antunes CM, Greco DB. PPD tuberculin test and skin test anergy in an HIV infection high risk population in Belo Horizonte, Brazil. Int Conf AIDS. 1996 Jul 7-12;11(2):452 (abstract no.Pub.B.1089). ICA11/96921685. Carvalho AC, Brito ZN, Oliveira OT, Soares F, Ferraz L, Cunha MP, Dall'Olio C, Fonseca A, Boechat N, Lapa e Silva JR, et. al. Tuberculin skin test conversion among close contacts of pulmonary tuberculosis patients, infected or not by HIV. Int Conf AIDS. 1996 Jul 7-12;11(1):165 (abstract no.Mo.C.1642). AIDS/96920283. Del Rio C, Rangel A, Valdes M, Uribe P. Positive PPD and correlation with CD4+ cell counts among patients with HIV infection in Mexico. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:105. MED/96341227. Saad MH, Kritski AL, Werneck-Barroso E, Cavalcante S, Ferreira MA, de Souza Fonseca L. Use of the 2,3-diacyl-trehalose and the purified protein derivative in the serodiagnosis of tuberculosis in AIDS. Mem Inst Oswaldo Cruz. 1996 Jan-Feb;91(1):97-100. MED/96203001. Janis EM, Allen DW, Glesby MJ, Carey LA, Mundy LM, Gopalan R, Chaisson RE. Tuberculin skin test reactivity, anergy, and HIV infection in hospitalized patients. Longcope Firm of the Osler Medical Housestaff. Am J Med. 1996 Feb;100(2):186-92. MED/96160384. Hoffman ND, Kelly C, Futterman D. Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort. Pediatrics. 1996 Feb;97(2):198-203. ENTRY MONTH 199201 LAST REVISION DATE 20000801 214 UNIQUE IDENTIFIER DRG-0132 NAME OF SUBSTANCE Somatrem [USPD 1998; p. 677] REGISTRY NUMBER 82030-87-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Protropin [USP DI 2000; p 1657] PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-234 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-21 PHARMACOLOGICAL ACTION MODE OF ACTION: Protropin has been shown to be therapeutically equivalent to pituitary-derived human growth hormone. Treatment of children who lack endogenous growth hormone secretion with Protropin resulted in an increase in growth rate and an increase in insulin-like growth factor-I levels similar to that seen with pituitary-derived human growth hormone. Protropin stimulates skeletal growth by increasing both the number and the size of the skeletal muscle cells, resulting in linear growth; influences the size of internal organs; increases red cell mass; stimulates protein synthesis; influences carbohydrate metabolism; induces lipid mobilization; stimulates chondroitin sulfate and collagen synthesis; stimulates urinary excretion of hydroxyproline. [PDR 1997; p 1053] DISEASES STUDIED/TREATED Studied as a treatment for HIV-related wasting and being investigated for its role in the human immune system. [AmfAR Treat Dir 1995;7(4); p 42-43, 66] CLASSIFICATION CODE Growth hormone [USP DI 2000; p. 1654] OTHER MAJOR USES Indicated for long-term treatment of children with growth failure caused by inadequate pituitary growth hormone secretion. [PDR 1997; p 1053] SUBSTANCE INTERACTIONS Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Protropin. If glucocorticoid replacement is required, the dose should be carefully adjusted. [PDR 1997; p 1053] ADVERSE EFFECTS A small percentage of patients receiving Protropin therapy may develop antibodies to Protropin; in some cases, when binding capacity exceeds 2 mg/L, growth attenuation has been observed. Injection site pain was reported infrequently in children treated with Protropin. Other adverse reactions include infrequent, mild, and transient peripheral edema; rare carpal tunnel syndrome; rare increased growth of pre-existing nevi; rare gynecomastia; and rare pancreatitis. Patients with a history of an intracranial lesion should be examined frequently for progression or recurrence of the lesion. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Progression of scoliosis can occur in children who experience rapid growth. Intracranial hypertension with papilledema, visual changes, headache, nausea and/ or vomiting has been reported in a small number of patients treated with growth hormone products. Protropin may also induce a state of insulin resistance. [PDR 1997; p 1053-4] CONTRAINDICATIONS Protropin should not be used in patients with closed epiphyses, active neoplasia, and known sensitivity to benzyl alcohol. [PDR 1997; p 1053] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The genetically engineered version of pituitary-derived human growth hormone. Contains the sequence of 191 amino acids constituting pituitary-derived human growth hormone plus one additional amino acid (methionine) at the N-terminus of the molecule. [PDR 1997; p 1053] CHEMICAL/PHYSICAL DATA Molecular Formula: C995-H1537-N263-O301-S8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 22,256.39 [USPD 1998; p. 677] CHEMICAL/PHYSICAL DATA Solubility: Water soluble. [PDR 1997; p 1053] CHEMICAL/PHYSICAL DATA Stability: Should be used within 14 days following proper reconstitution. [PDR 1997; p 1054] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White lyophilized powder. [PDR 1997; p 1053] SUBSTANCE DELIVERY DATA DOSAGE FORM: 5 or 10 mg (approximately 15 or 30 IU) in vials. [PDR 1997; p 1054] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular or subcutaneous injection. [PDR 1997; p 1054] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Protropin vials must be stored at 2-8 C(36-46 F), and freezing must be avoided. After proper reconstitution, vial contents are stable for 14 days at 2-8 C, and freezing must be avoided. [PDR 1997; p 1054] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Unspecified (800)821-8590 REFERENCES MED/97067807. Waters D, Danska J, Hardy K, Koster F, Qualls C, Nickell D, Nightingale S, Gesundheit N, Watson D, Schade D. Recombinant human growth hormone, insulin-like growth factor I, and combination therapy in AIDS-associated wasting. A randomized, double-blind, placebo-controlled trial [see comments]. Ann Intern Med. 1996 Dec 1; 125(11):865-72. MED/97067808. Schambelan M, Mulligan K, Grunfeld C, Daar ES, LaMarca A, Kotler DP, Wang J, Bozzette SA, Breitmeyer JB. Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group [see comments]. Ann Intern Med. 1996 Dec 1;125(11):873-82. MED/96320090. Lee PD, Pivarnik JM, Bukar JG, Muurahainen N, Berry PS, Skolnik PR, Nerad JL, Kudsk KA, Jackson L, Ellis KJ, et al. A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab. 1996 Aug;81(8):2968-75. ICA11/96921450. Tai VW, Mulligan K, Culp J, Schambelan M. The effects of chronic growth hormone therapy on dietary intake in patients with HIV-associated weight loss. Int Conf AIDS. 1996 Jul 7-12;11(1):122 (abstract no.Mo.B.1388). AIDS/96156177. Laurence J. Growth hormone in HIV/AIDS: current uses and future prospects. Pediatr AIDS HIV Infect. 1995 Oct;6(5):281-91. AIDS/95920649. Schambelan M, Mulligan K, Grunfeld C, Daar E, Lamarca A, Breitmeyer J. Recombinant human growth hormone (rhGH) increases lean body mass (LBM) and improves functional performance in patients with HIV-associated wasting. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:170. AIDS/95920542. Hirschfeld S, Tudor-Williams G, Stocker V, Jacobsen F, Laue L, Cutler GB, Pizzo PA. Effects of recombinant human growth hormone and recombinant insulin-like growth factor-in administration in children with human immunodeficiency virus infection and growth failure. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:149. MED/94149144. Lieberman SA, Butterfield GE, Harrison D, Hoffman AR. Anabolic effects of recombinant insulin-like growth factor-I in cachectic patients with the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1994 Feb;78(2):404-10. ICA9/93335814. Mulligan K, Hellerstein MK, Neese RA, Grunfeld C, Schambelan M. Effects of recombinant human growth hormone (rhGH) on lipid metabolism in persons with HIV-associated wasting. Int Conf AIDS. 1993 Jun 6-11;9(1):500 (abstract no. PO-B29-2188). MED/93195670. Krentz AJ, Koster FT, Crist DM, Finn K, Johnson LZ, Boyle PJ, Schade DS. Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex. J Acquir Immune Defic Syndr. 1993 Mar;6(3):245-51. ENTRY MONTH 199112 LAST REVISION DATE 20000801 215 UNIQUE IDENTIFIER DRG-0131 NAME OF SUBSTANCE Insulin-Like Growth Factor I [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 139659-92-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Insulin-like growth factor I [USP DI 1995; p 2981] SYNONYMS Myotrophin [USP DI 2000; p. 3307] PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-234 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-21 PHARMACOLOGICAL ACTION MODE OF ACTION: Insulin-like growth factor I (IGF-I) is believed to be secreted by the liver and circulating in the blood. It has growth regulating, insulin-like, and mitogenic activities. The growth factor has a major but not absolute dependence on somatotropin. It is believed to be mainly active in adults in contrast to IGF-II which is a major fetal growth factor. Cumulative nitrogen retention was positive in 10 patients receiving low dose (4 mcg/kg/h) and high dose (12 mg/kg/h) IV infusions for 10 days. [CHEMLINE ; J Clin Endocrinol Metab 1994 Feb;78(2); p 404-10] DISEASES STUDIED/TREATED Mediates effects of human growth hormone, used to treat HIV-associated wasting. [AmfAR Treat Dir 1995;7(4); p 66; J Clin Endocrinol Metab 1994 Feb;78(2); p 404-10] CLASSIFICATION CODE Immunomodulator [AmfAR Treat Dir 1995;7(4); p 66] OTHER MAJOR USES Amytrophic lateral sclerosis (ALS). [USP DI 1995; p 2981] ADVERSE EFFECTS Hypoglycemia and jaw tenderness, primarily at high doses, headache, flushing and mild pruritic macropapular eruptions have been reported. [AmfAR Treat Dir 1997;8(3); p 73; J Clin Endocrinol Metab 1994 Feb;78(2); p 404-10] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A polypeptide structurally related to insulin, identical to the endogenous protein and is considered a mediator of the effects of growth hormone. [AmfAR Treat Dir 1993;6(4); p 62] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous or subcutaneous injection. [AmfAR Treat Dir 1995;7(4); p 66; J Clin Endocrinol Metab 1994 Feb;78(2); p 404-10] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 MANUFACTURERS 0000005354: Cephalon Inc 145 Brandywine Parkway West Chester, PA 19380 Contact: Unspecified (800)821-8590 REFERENCES MED/97067807. Waters D, Danska J, Hardy K, Koster F, Qualls C, Nickell D, Nightingale S, Gesundheit N, Watson D, Schade D. Recombinant human growth hormone, insulin-like growth factor I, and combination therapy in AIDS-associated wasting. A radomized, double-blind, placebo-controlled trial [see comments]. Ann Intern Med. 1996 Dec 1;125(11):865-72. MED/96320100. Ellis KJ, Lee PD, Pivarnik JM, Bukar JG, Gesundheit N. Changes in body composition of human immunodeficiency virus-infected males receiving insulin-like growth factor I and growth hormone. J Clin Enocrinol Metab. 1996 Aug;81(8):3033-8. MED/96320090. Lee PD, Pivarnik JM, Bukar JG, Muurahainen N, Berry PS, Skolnik PR, Nerad JL, Kudsk KA, Jackson L, Ellis KJ, et al. A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab. 1996 Aug;81(8):2968-75. MED/97006156. Wolf SE, Barrow RE, Herndon DN. Growth hormone and IGF-I therapy in the hypercatabolic patient. Baillieres Clin Endocrinol Metab. 1996 Jul;10(3):447-63. AIDS/95920542. Hirschfeld S, Tudor-Williams G, Stocker V, Jacobsen F, Laue L, Cutler GB, Pizzo PA. Effects of recombinant human growth hormone and recombinant insulin-like growth factor-I administration in children with human immunodeficiency virus infection and growth failure. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb. 2;:149. MED/95401029. Hussain MA, Froesch ER. Clinical uses of insulin-like growth factor I. Adv Endocrinol Metab. 1995;6:143-65. AIDS/95920735. Sattler F, Dube M, Montgomery AB, Lopresti J, Leedom J, Nicoloff J. Phase I study of insulin like growth factor I (IGF-1) in HIV. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:57. MED/94149144. Lieberman SA, Butterfield GE, Harrison D, Hoffman AR. Anabolic effects of recombinant insulin-like growth factor I in cachetic patients with the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1994 Feb;78(2):404-10. MED/94107096. Kudsk KA, Mowatt-Larssen C, Bukar J, Fabian T, Oellerich S, Dent DL, Brown E. Effect of recombinant human insulin-like growth factor I and early total parenteral nutrition on immune depression following severe head injury. Arch Surg. 1994 Jan;129(1):66-70; discussion 70-1. ICA10/94371535. Bukar JG, Jackson L, Muro J, Jenks BH, Bakst R, Brodsky M, Gesundheit N. Effect of a combination of growth hormone (rhGH) and insulin-like growth factor I (rhIGF-I) on the appetite of HIV-1+ patients (PTS) with weight (WT) loss. Int Conf AIDS. 1994 Aug 7-12;10(2):222 (abstract no. PB0903). ENTRY MONTH 199112 LAST REVISION DATE 20000801 216 UNIQUE IDENTIFIER DRG-0130 NAME OF SUBSTANCE Valproic acid [USPD 1998; p. 773] REGISTRY NUMBER 99-66-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Pentanoic acid, 2-propyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Depakene [USP DI 2000; p. 3092] PROTOCOL ID NUMBERS Complete NIAID ACTG 191 PHARMACOLOGICAL ACTION MODE OF ACTION: Valproic acid competitively inhibits GABA transaminase and succinic aldehyde dehydrogenase, enzymes which are important for GABA catabolism, thereby increasing the brain gamma-aminobutyric acid (GABA) level. Increased GABA levels may protect the organism against seizure. The drug is rapidly absorbed after oral administration and dissociates to the valproate ion in the gastrointestinal tract. Peak plasma concentrations of valproate ion are observed 1 to 4 hours after a single oral dose of valproic acid. A slight delay in absorption may occur when the drug is taken with food, but total absorption is not affected. Valproate is primarily metabolized in the liver. The major metabolic routes are glucuronidation, mitochondrial beta oxidation, and microsomal oxidation. Metabolites are eliminated primarily in the urine. Valproate is highly bound (90%) to plasma proteins in the therapeutic range; however, protein binding is concentration-dependent and decreases at high valproate concentrations. Binding is variable among patients and may be affected by fatty acids or by highly bound drugs such as salicylate. The therapeutic range is considered to be 50-100 mcg/ml total valproate although some patients may be controlled at lower or higher plasma concentrations. The plasma half-life of valproate is generally 6-16 hours. [PDR 1997; p 416; AHFS Drug Information 1997; p 1664] DISEASES STUDIED/TREATED Possible inhibition of the metabolic inactivation of zidovudine (AZT), resulting in a longer duration of AZT effects in the body. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 100 (abstract no PuB 7307)] CLASSIFICATION CODE Anticonvulsant [USP DI 2000; p. 3086] CLASSIFICATION CODE Antimanic [USP DI 2000; p. 3086] OTHER MAJOR USES Valproic acid is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include adsence seizures. [PDR 1997; p 416] SUBSTANCE INTERACTIONS Valproate may potentiate the action of CNS depressants (ie, alcohol, benzodiazepines, etc). Concomitant administration of valproate with drugs that exhibit extensive protein binding (eg, aspirin, carbamazepine, dicumarol, and phenytoin) may result in alteration of serum drug concentrations. Valpoate can cause an increase in serum phenobarbital concentrations by impairment of nonrenal clearance, resulting in severe CNS depression. Combination of valproate and phenobarbital has also been reported to produce CNS concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Primidone is metabolized into a barbiturate and, therefore, may also be involed in a similar or identical interaction. Concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures. Caution is recommended when valproate is used with drugs affecting coagulation (eg, apirin, warfarin). [PDR 1997; p 417] ADVERSE EFFECTS The most commonly reported side effects at the initiation of therapy are nausea, vomiting and indigestion. These effects are usually transient, and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, constipation, both anorexia with some weight loss and increased appetite with weight gain have been reported. Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Other adverse effects include tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, spots before eyes, dysarthria, dizziness, incordination, coma and encephalopathy with fever; transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, Steven-Johnson syndrome; emotional upset, depression, psychosis, agression, hyperactivity and behavioral deterioration; musculoskeletal weakness; thrombocytopenia and inhibition of the secondary phase of platelet aggregation, relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, and acute intermittent prophyria; hepatotoxicity; irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, abnormal thyroid function tests; acute pancreatitis including fatalities; hyperammonemia, hyponatremia, and inappropiate ADH secretion, Fanconi's syndrome, hyperglycinemia; enuresis; reversible or irreversible hearing loss; edema of the extremities; lupus erythematosus; and fever. [PDR 1997; p 417] CONTRAINDICATIONS Contraindications include hepatic disease or significant hepatic dysfunction; known hypersensitivity to valproic acid. Possible contraindication: pregnancy (should be used in pregnant women only if absolutely essential for control of seizures). [PDR 1997; p 416] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A carboxylic acid with anticonvulsant properties. [AHFS Drug Information 1997; p 1664] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H16-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 144.21 [USPD 1998; p. 773] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.63%, H11.18%, O22.19% [Merck Index 1996; p. 1691] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water, very soluble in organic solvents. [PDR 1997; p 416] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Colorless liquid with characteristic odor. Colorless to pale yellow, slightly viscous, clear liquid with a characteristic odor. [PDR 1997; p 416; AHFS Drug Information 1997; p 1664] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (250 mg valproic acid); syrup (250 mg valproic acid per 5 ml as the sodium salt). [PDR 1997; p 418] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 417] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store capsules at 59-77 F (15-25 C); store syrup below 86 F (30 C). [PDR 1997; p 418] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/97159688. Witvrouw M, Schmit Jc, Van Remoortel B, Daelemans D, Este JA, Vandamme AM, Desmyter J, De Clercq E. Cell type-dependent effect of sodium valproate on human immunodeficiency virus type 1 replication in vitro. AIDS Res Hum Retroviruses. 1997 Jan 20;13(2):187-92. MED/95008594. Lertora JJ, Rege AB, Greenspan DL, Akula S, George WJ, Hyslop NE Jr, Agrawal KC. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 1994 Sep;56(3):272-8. MED/94251837. Simon G, Moog C, Obert G. Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus. Chem Biol Interact. 1994 Jun;91(2-3):111-21. ICA8/92403357. Lertora J, Akula S, Greenspan D, Rege A, Agrawal K, George W, Hyslop N. Valproic acid inhibits zidovudine glucuronidation in patients with HIV infection. Int Conf AIDS. 1992 Jul 19-24;8(3):100 (abstract no. PuB 7307). ICDB/92685725. Agrawal KC, DiPiazza NJ, Aggarwal SK. INHIBITION OF HUMAN HEPATIC GLUCURONOSYL TRANSFERASE (GT) ACTIVITY TO ALTER ZIDOVUDINE (AZT) METABOLISM (MEETING ABSTRACT). Proc Annu Meet Am Assoc Cancer Res. 1992;33:A2389. ENTRY MONTH 199112 LAST REVISION DATE 20001107 217 UNIQUE IDENTIFIER DRG-0129 NAME OF SUBSTANCE Levofloxacin [USPD 1998; p. 416] REGISTRY NUMBER 100986-85-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 7H-Pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxy- lic acid, 2,3-dihydro-9-fluoro-3-methyl-10-(4-methyl-1-- piperazinyl)-7-oxo-, hemihydrate, (S)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Levaquin [USP DI 2000; p. 1567] PROTOCOL ID NUMBERS Complete NIAID ACTG 222 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting FDA 105A/B PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 008 PHARMACOLOGICAL ACTION MODE OF ACTION: Exact mechanism of anti-HIV activity is unknown, but in vitro studies have shown that some fluoroquinolones (ciprofloxacin, norfloxacin, and ofloxacin) can inhibit HIV reverse transcriptase. Levofloxacin has exhibited activity against gram-positive and gram-negative bacteria, chlamydia, mycoplasma, legionella, and mycobacteria. It has a half-life of 6-7 hours, with peak concentrations reached in approximately 1.5 hours. In a series of in vitro experiments levofloxacin was about two-fold (with a range between equal and four-fold) more active than ofloxacin. [AmfAR Treat Dir 1995;7(4); p 67; Protocol ID: ACTG 222 ; Protocol ID: DATRI 008 p 7] DISEASES STUDIED/TREATED Primary HIV infection; tuberculosis. [AmfAR Treat Dir 1995;7(4); p 67; Protocol ID: DATRI 008 ; Protocol ID: ACTG 222 ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 1556] OTHER MAJOR USES Ofloxacin is used for the treatment of mild to moderate urinary tract infections; prostatitis; lower repiratory tract infections; skin and skin structure infections caused by susceptible gram-negative and -positive aerobic bacteria; acute, umcomplicated gonorrhea and nongonococcal urethritis and cervicitis caused by susceptible Chlamydia. [AHFS Drug Information 1997; p 607] ADVERSE EFFECTS Adverse effects include gastrointestinal disturbance, nausea, insomnia, and headache. [AmfAR Treat Dir 1997;8(3); p 74] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The fluoroquinolone levofloxacin (L-ofloxacin) is the antimicrobially active isomer of ofloxacin. Ofloxacin is a commercially available fluoroquinoline composed of a racemic mixture of the d- and l-enantiomers, of which the l-enantiomer is the active form. Levofloxacin is an investigational drug whose formulation consists solely of the l-enantiomer. [AmfAR Treat Dir 1997;8(3); p 74] CHEMICAL/PHYSICAL DATA Molecular Formula: C18-H20-F-N3-O4.1/2(H2-O) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 370.38 [USPD 1998; p. 416] CHEMICAL/PHYSICAL DATA Melting Point: 225-227 C [Merck Index 1996; p. 1163] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (200, 300, or 400 mg; film-coated); concentrate for IV infusion (400 mg per vial at 20 or 40 mg/ml); injection, pre-mixed (200 or 400 mg per vial at 4 mg/ml, in 5% dextrose) (Ofloxacin). [AHFS Drug Information 1997; p 615] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous (ofloxacin). [AHFS Drug Information 1997; p 614] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Ofloxacin tablets should be stored in well-closed containers at less than 30 C. Ofloxacin concentrate for injection and ofloxacin injection for IV infusion in glass bottles should be store at 15-30 C and protected from light. Ofloxacin injection for IV infusion in flexible containers should be stored at 25 C or lower, the injection should be protected from light and excess heat and should not be frozen. Diluted solutions (0.4-4 mg/ml) are stable in glass or plastic IV containers for 72 hours when stored at 24 C or lower, or for 4 days when refrigerated at 5 C. [AHFS Drug Information 1997; p 602] MANUFACTURERS 0000001008: Ortho Pharmaceutical Corp Route 202 / PO Box 300 Raritan, NJ 088690602 Contact: Mrs Dorothy Thompson (908)704-5150 MANUFACTURERS 0000001008: Ortho Pharmaceutical Corp Route 202 / PO Box 300 Raritan, NJ 088690602 Contact: Unspecified - Biotech (800)325-7504 REFERENCES ICA11/96922560. El-Sadr WM, Perlman DC, Matts JP, Nelson E, Cohn D, Telzak E, Chirgwin K, Salomon N, Olibrice M, Hafner R. Outcome of an induction regimen for the treatment of HIV-related tuberculosis (TB): evaluation of the addition of a quinolone. Int Conf AIDS. 1996 Jul 7-12;11(1):327 (abstract no.Tu.B.2358). AIDS/95921004. Onyeji CO, Nightingale CH, Tessier PR, Nicolau DP, Bow LM. Activities of clarithromycin, azithromycin and ofloxacin in combination with liposomal or unencapsulated GM-CSF against intramacrophage mycobacterium avium-M. intracellulare. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:264. ICA10/94369988. Nakata K, Matsui T, Miyazaki S, Arakawa S, Ishigami J, Kamidono S. In vitro and in vivo activities of sparfloxacin against Chlamydia trachomatis. Inf Conf AIDS. 1994 Aug 7-12;10(1):270 (abstract no. PB0509). MED/94379808. Rastogi N, Goh KS, Bryskier A. Activities of roxithromycin used alone and in combination with ethambutol, rifampin, amikacin, ofloxacin, and clofazimine against Mycobacterium avium complex. Antimicrob Agents Chemother. 1994 Jun;38(6):1433-8. MED/94304129. Goodwin SD, Gallis HA, Chow AT, Wong FA, Flor SC, Barlett JA. Pharmacokinetics and safety of levofloxacin in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1994 Apr;38(4):799-804. ASM94/94313129. Rastogi N, Labrousse V, Bryskier A. Intracellular activity of roxithromycin used alone and in association with other drugs against the Mycobacterium avium complex in human macrophages. Abstr Gen Meet Am Soc Microbiol. 1994;94:9 (abstract no. A-44). ICA9/93334778. Salomon N, Goldstein S, Perlman DC, Yancovitz SR. Utility of an ofloxacin-containing regimen in the management of hepatotoxicity in HIV-infected persons with tuberculosis. Int Conf AIDS. 1993 Jun 6-11;9(1):342 (abstract no. PO-B07-1242). MED/93163839. De Simone C, Trinchieri V, Tzantzoglou S, Famularo G, Moretti S, Delia S. AIDS patients with bacterial lower respiratory tract infections: treatment with ofloxacin versus sulbactam-ampicillin. J Chemother. 1992 Dec;4(6):376-80. ICA8/92404330. Bilaud E, Moinard D, Bourgeot V, Raffi F. Mycobacterium haemophilum (MH) cutaneous infection: a case in an AIDS patient. Int Conf AIDS. 1992 Jul 19-24;8(3):56 (abstract no. PuB 7043). MED/92314085. Nayagam AT, Smith MD, Ridgway GL, Allason-Jones E, Robinson AJ, Stock J. Comparison of ofloxacin and metronidazole for the treatment of bacterial vaginosis. Int J STD AIDS. 1992 May-Jun;3(3):204-7. ENTRY MONTH 199111 LAST REVISION DATE 20001107 218 UNIQUE IDENTIFIER DRG-0128 NAME OF SUBSTANCE Penicillin G potassium [USPD 1998; p. 556] REGISTRY NUMBER 113-98-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Monopotassium 3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-th- ia -1-azabicyclo (3.2.0) heptane-2-carboxylate [PDR 1997; p 2022] SYNONYMS Pfizerpen [USP DI 2000; p. 2405] PROTOCOL ID NUMBERS Complete NIAID ACTG 145 PHARMACOLOGICAL ACTION MODE OF ACTION: Binds to serum proteins, mainly albumin. Exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. Acts through the inhibition of biosynthesis of cell wall mucopeptide, rendering the cell wall osmotically unstable. Not active against penicillinase-producing bacteria, including many strains of staphylococci. About 15-30% of oral doses are absorbed in fasting individuals. Serum levels of 20 mcg/ml were reported following IV infusions of penicillin G potassium in subjects receiving 2 million units every 2 hours or 3 million units every 3 hours. The drug is widely distributed in the body with a volume of distribution of 0.53-0.67 L/kg in normal adults. The serum half-life is 0.4-0.9 hours in adults with normal renal function. Penicillin G and its metabolites are excreted in the urine. [PDR 1997; p 2022-3; AHFS Drug Information 1997; p 275-6] DISEASES STUDIED/TREATED Bactericidal action against penicillin G-susceptible microorganisms. [PDR 1997; p 2023] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2389] OTHER MAJOR USES Bactericidal action against penicillin G-susceptible microorganisms. [PDR 1997; p 2023] SUBSTANCE INTERACTIONS Penicillins, including natural penicillins, are physically and/or chemically incompatible with aminoglycosides. Inactivation of aminoglycosides may occur if the drugs are administered in the same syringe or IV infusion container. When concomitant therapy is indicated, penicillins and aminoglycosides should be administered seperately. Probenecid competitively inhibits renal tubular secretion of penicillins. Oral administration of probenecid shortly before or simutaneously with penicillin generally produces higher and prolonged serum concentrations of the penicillin. Concomitant administration of Pencillin G potassium and potassium-sparing diuretics (e.g., amiloride hydrochloride, triamterene) theoretically may increase the risk of hyperkalemia. The antibacterial activity of penicillins may occasionally be additive, synergistic, or antagonistic with Beta-lactam antibiotics, bacteriostatic anti-infectives (chloramphenicol, erythromycin, tetracyclines), rifampin, clavulanic acid, nonsteroidal anti-inflammatory agents, and colestipol. [AHFS Drug Information 1997; p 270-1] ADVERSE EFFECTS Adverse effects include hypersensitivity reactions including skin rashes, urticaria and reactions resembling serum sickness (e.g., chills, fever, edema, arthralgia, and prostration). Severe and occasionally fatal anaphylaxis has occurred. Rarely observed adverse reactions include hemolytic anemia, leucopenia, thrombocytopenia, nephropathy, and neuropathy. Cardiac arrhythmias and cardiac arrest may also occur. The Jarisch-Herxheimer reaction has been reported in patients treated for syphilis. [PDR 1997; p 2023-4] CONTRAINDICATIONS Contraindicated in patients with history of previous hypersensitivity reaction to any penicillin. [PDR 1997; p 2023] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Penicillin G is a natural penicillin produced by fermentation of Penicillium chrysogenum in a medium containing phenylacetic acid. Penicillin G potassium and sodium are frequently referred to as aqueous, crystalline forms of penicillin G. [AHFS Drug Information 1997; p 275] CHEMICAL/PHYSICAL DATA Molecular Formula: C16-H17-K-N2-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 372.49 [USPD 1998; p. 556] CHEMICAL/PHYSICAL DATA Elemental Comp: C51.59%, H4.60%, K10.50%, N7.52%, O17.18%, S8.61% (potassium) [Merck Index 1996; p. 1219] CHEMICAL/PHYSICAL DATA Solubility: Penicillin G potassium is very soluble in water, in 0.9% sodium chloride, and in dextrose solutions, and is sparingly soluble in alcohol. [PDR 1997; p 2022] CHEMICAL/PHYSICAL DATA Stability: Moderately hygroscopic, dry powders of the drug should be protected from moisture to prevent hydrolysis. Solutions of the drug retain substantially full potency for several days when stored at a temperature less than 15 C. [AHFS Drug Information 1997; p 275] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Colorless or white crystal or a white crystalline powder which is odorless, or practically so (potassium form). [PDR 1997; p 2022] SUBSTANCE DELIVERY DATA DOSAGE FORM: 1, 5, 10, and 20 million units (potassium) of dry powder in vials ready for reconstitution. [AHFS Drug Information 1997; p 278] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous, intramuscular, intrapleural, intraarticular, and other local instillations. [PDR 1997; p 2024; AHFS Drug Information 1997; p 276] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store dry powder below 86 F (30 C). Sterile solutions may be stored for seven days in a refrigerator. [PDR 1997; p 2024] MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Professional Information (800)438-1985 MANUFACTURERS 0000005385: Intervention provided by participating unit , Contact: Unspecified (800)438-1985 REFERENCES MED/97005660. Meynard JL, Barbut F, Blum L, Guiguet M, Chouaid C, Meyohas MC, Picard O, Petit JC, Frottier J. Risk factors for isolation of Streptococcus pneumoniae with decreased susceptibility to penicillin adult from patients infected with human immunodeficiency virus. Clin Infect Dis. 1996 Mar;22(3):437-40. MED/95214689. Gourevitch MN, Klein RS, Schoenbaum EE. Neurosyphillis in patients with human immunodeficiency virus infection [letter]. N Engl J Med. 1995 Apr 27;332(17):1170; discussion 1170-1. MED/95214687. Rodriquez-Bano J, Izquierdo G, Muniain MA. Neurosyphillis in patients with human immunodeficiency virus infection [letter]. N Engl J Med. 1995 Apr 27;332(17):1169; discussion 1170-1. MED/96035377. McGowan JE Jr, Metchock BG. Penicillin-resistant pneumococci--an emerging threat to successful therapy. J Hosp Infect. 1995 Jun;30 Suppl:472-82. MED/95059250. Gordon SM, Eaton ME, George R, Larsen S, Lukehart SA, Kuypers J, Marra CM, Thompson S. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection [see comments]. N Engl J Med. 1994 Dec 1;331(22):1469-73. MED/94361089. Poles MA, McMeeking AA, Scholes JV, Dieterich DT. Actinomyces infection of a cytomegalovirus esophageal ulcer in two patients with acquired immunodeficiency syndrome. Am J Gastroenterol. 1994 Sep;89(9):1569-72. MED/94213962. Kastner RJ, Malone JL, Decker CF. Syphilitic osteitis in a patient with secondary syphilis and concurrent human immunodeficiency virus infection. Clin Infect Dis. 1994 Feb;18(2):250-2. MED/93239909. Ishii N, Ichiyama S, Nakajimi H, Ito A. Sexually transmitted diseases in a HIV infected patient. J Dermatol. 1993 Mar;20(3):171-4. MED/92272489. Deschenes J, Seamone CD, Baines MG. Acquired ocular syphilis: diagnosis and treatment. Ann Ophthalmol. 1992 Apr;24(4):134-8. MED/93023483. Gleich LL, Linstrom CJ, Kimmelman CP. Otosyphilis: a diagnostic and therapeutic dilemma [see comments]. Laryngoscope. 1992 Nov;102(11):1255-9. ENTRY MONTH 199111 LAST REVISION DATE 20000801 219 UNIQUE IDENTIFIER DRG-0127 NAME OF SUBSTANCE Trichosanthin [Merck Index 1996; p. 1645] REGISTRY NUMBER 60318-52-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 106A PHARMACOLOGICAL ACTION MODE OF ACTION: Trichosanthin is a ribosomal inhibitory protein which, in vitro, inhibits HIV replication in lymphocytes and macrophages, and specifically kills HIV infected macrophages. GLQ-223 induces a humoral immune response in patients with AIDS and ARC. Frequency and time to development of an IgG response appear to be dose related. IgG antibodies to GLQ-223 do not appear to cause adverse clinical events, may result in decreased severity and frequency of side effects, and do not seem to abrogate effects of GLQ-223 on immunologic parameters. After IV administration GLQ-223 undergoes rapid distribution followed by a slower elimination phase with a half-life of approximately 3 hours. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 101 (abstract no PuB 7314); Int Conf AIDS 1991 Jun 16-21;7(2); 224 (abstract no W.B. 2171); Antimicrob Agents Chemother 1994 Feb;38(2); p 260-67] DISEASES STUDIED/TREATED Antiviral treatment. [Facts and Comparisons 1995; p 814; Antimicrob Agents Chemother 1994 Feb;38(2); p 260-67] CLASSIFICATION CODE Investigational - Antiviral [Facts and Comparisons 1995; p 814] OTHER MAJOR USES Treatment of trophoblastic tumors. Abortifacient. [Nucleic Acids Res 1991 Nov 25;19(22); p 6309-12] SUBSTANCE INTERACTIONS In patients failing zidovudine response, with decreasing CD4 cell levels, the addition of trichosanthin has been shown to reverse this trend. [Int Conf AIDS 1991 Jun 16-21;7(2); 224 (abstract no. W.B. 2171)] ADVERSE EFFECTS Adverse effects include flu-like syndrome characterized by fever, headache, myalgias, and pharyngitis; and allergic reactions characterized primarily by rash, pruritis, and rare hypertension. Transient confusion is seen rarely, and transient elevations in creatinine kinase have been noticed. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 97 (abstract no. PuB 7290); Antimicrob Agents Chemother 1994 Feb;38(2); p 260-67] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Plant single-chain ribosome-inactivating protein purified from fresh root tubers of Trichosanthas kirilowii. GLQ-223 (Compound Q) is a highly purified form of trichosanthin. [Int Conf AIDS 1991 Jun 16-21;7(2); 108 (abstract no. W.A.1064)] CHEMICAL/PHYSICAL DATA Molecular Weight: 26,000 (relative) [Merck Index 1996; p. 1645] CHEMICAL/PHYSICAL DATA Solubility: Poorly soluble in acetone and hexane. [CRC Handbook of Antibiotic Compounds Vol XIV, Pt 1, 1987] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystals. [CRC Handbook of Antibiotic Compounds Vol XIV, Pt 1, 1987] SUBSTANCE DELIVERY DATA DOSAGE FORM: Injection. [Antimicrob Agents Chemother 1994 Feb;38(2); p 260-67] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion, intramuscular. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 101 (abstract no PoB 7314); Antimicrob Agents Chemother 1994 Feb;38(2); p 260-67] MANUFACTURERS 0000001236: Genelabs Technologies Inc 505 Penobscot Dr Redwood City, CA 940634738 Contact: Arlene Kunz (415)369-9500 REFERENCES MED/98069990. Mulot S, Chung KK, Li XB, Wong CC, Ng TB, Shaw PC. The antigenic sites of trichosanthin, a ribosome-inactivating protein with multiple pharmacological properties. Life Sci 1997; 61(23):2291-303. MED/97462316. Tang NL, Chan WL, Ke YO, Mak MK, Lai FM, Tam SC. Acute renal failure and proximal tubule lesions after trichosanthin injection in rats. Exp Mol Pathol. 1997 Apr; 64(2):78-89. MED/97194936. Ke YB, Chen JK, Nie HL, He XH, Ke XY, Wang YH. Structure-function relationship of trichosanthin. Life Sci. 1997; 60(7):465-72. ICA10/94370923. Kahn J, Gorelick K. Results of a randomized study of GLQ223 in AIDS and ARC. Int Conf AIDS. 1994 Aug 7-12;10(1):8 (abstract no. 006B). MED/94347466. Byers VS, Levin AS, Malvino A, Waites L, Robins RA, Baldwin RW. A phase II study of effect of addition of trichosanthin to zidovudine in patients with HIV disease and failing antiretroviral agents. AIDS Res Hum Retroviruses. 1994 Apr;10(4):413-20. MED/94249998. Kahn JO, Gorelick KJ, Gatti G, Arri CJ, Lifson JD, Gambertoglio JG, Bostrom A, Williams R. Safety, activity, and pharmacokinetics of GLQ223 in patients with AIDS and AIDS-related complex. Antimicrob Agents Chemother. 1994 Feb;38(2):260-7. MED/94104738. Garcia PA, Bredesen DE, Vinters HV, Graefin von Einsiedel R, Williams RL, Kahn JO, Byers VS, Levin AS, Waites LA, Messing RO. Neurological reactions in HIV-infected patients treated with trichosanthin. Neuropathol Appl Neurobiol. 1993 Oct;19(5):402-5. ICA8/92404575. Kunz AY, Kahn JO, Gorelick KJ, Chew T, Lang W, Williams R. Safety of GLQ223 in patients with AIDS and ARC. Int Conf AIDS. 1992 Jul 19-24;8(3):97 (abstract no. PuB 7290). ICA8/92403359. Lifson J, Kahn JO, Chew T, Gorelick KJ, Lang W, Williams R. Anti-GLQ223 antibodies in treated patients with AIDS and ARC. Int Conf AIDS. 1992 Jul 19-24;8(3):101 (abstract no. PuB 7314). ICA7/3217191. Byers V, Levin AS, Waites L, Malvino A, Robins RA, Baldwin RW. A phase II study of the effect of trichosanthin treatment in combination with zidovudine in HIV disease. Int Conf AIDS. 1991 Jun 16-21;7(2):224 (abstract no. W.B.2171). ENTRY MONTH 199110 LAST REVISION DATE 20000801 220 UNIQUE IDENTIFIER DRG-0126 NAME OF SUBSTANCE Lamivudine [USPD 1998; p. 408] REGISTRY NUMBER 134678-17-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-,(2R-cis)- [USPD 1998; p 408] SYNONYMS (component of) Combivir [USP DI 2000; p. 1888] SYNONYMS (component of) Trizivir [Protocol ID: 308A ] SYNONYMS Epivir [USP DI 2000; p. 3453] PROTOCOL ID NUMBERS Complete CC 00 I-0053 PROTOCOL ID NUMBERS Complete FDA 246G PROTOCOL ID NUMBERS Complete CC 91 CC-0019 PROTOCOL ID NUMBERS Complete NIAID ACTG 298 PROTOCOL ID NUMBERS Complete NIAID ACTG 300 PROTOCOL ID NUMBERS Complete NIAID ACTG 302 PROTOCOL ID NUMBERS Complete NIAID ACTG 306 PROTOCOL ID NUMBERS Complete NIAID ACTG 315 PROTOCOL ID NUMBERS Complete NIAID ACTG 320 PROTOCOL ID NUMBERS Complete NIAID ACTG 330 PROTOCOL ID NUMBERS Complete NIAID ACTG 340 PROTOCOL ID NUMBERS Complete NIAID ACTG 343 PROTOCOL ID NUMBERS Complete NIAID ACTG 347 PROTOCOL ID NUMBERS Complete NIAID ACTG 373 PROTOCOL ID NUMBERS No longer recruiting FDA 039E PROTOCOL ID NUMBERS No longer recruiting FDA 129B PROTOCOL ID NUMBERS No longer recruiting FDA 129C PROTOCOL ID NUMBERS No longer recruiting FDA 129D PROTOCOL ID NUMBERS No longer recruiting FDA 200E PROTOCOL ID NUMBERS No longer recruiting FDA 225C PROTOCOL ID NUMBERS No longer recruiting FDA 225D PROTOCOL ID NUMBERS No longer recruiting FDA 228B PROTOCOL ID NUMBERS No longer recruiting FDA 228C PROTOCOL ID NUMBERS No longer recruiting FDA 228F PROTOCOL ID NUMBERS No longer recruiting FDA 229D PROTOCOL ID NUMBERS No longer recruiting FDA 229F PROTOCOL ID NUMBERS No longer recruiting FDA 229H PROTOCOL ID NUMBERS No longer recruiting FDA 229N PROTOCOL ID NUMBERS No longer recruiting FDA 229P PROTOCOL ID NUMBERS No longer recruiting FDA 232D PROTOCOL ID NUMBERS No longer recruiting FDA 232E PROTOCOL ID NUMBERS No longer recruiting FDA 232J PROTOCOL ID NUMBERS No longer recruiting FDA 238D PROTOCOL ID NUMBERS No longer recruiting FDA 238L PROTOCOL ID NUMBERS No longer recruiting FDA 238T PROTOCOL ID NUMBERS No longer recruiting FDA 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285A PROTOCOL ID NUMBERS No longer recruiting FDA 285C PROTOCOL ID NUMBERS No longer recruiting FDA 298A PROTOCOL ID NUMBERS No longer recruiting FDA 316A PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-198 PROTOCOL ID NUMBERS No longer recruiting NCI 92 C-96D PROTOCOL ID NUMBERS No longer recruiting NCI 94 C-35 PROTOCOL ID NUMBERS No longer recruiting NCI 95 C-163 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 328 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 332 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 338 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 353 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 354 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 370 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 377 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 380 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 395 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5014 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5051 PROTOCOL ID NUMBERS No longer recruiting FDA ATLANTIC STUDY PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 013 PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PROTOCOL ID NUMBERS Recruiting FDA 246T PROTOCOL ID NUMBERS Recruiting FDA 246U PROTOCOL ID NUMBERS Recruiting FDA 259H PROTOCOL ID NUMBERS Recruiting FDA 285G PROTOCOL ID NUMBERS Recruiting FDA 316B PROTOCOL ID NUMBERS Recruiting CC 97 I-082 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 345 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 356 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 358 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 386 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5072 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-04-008 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-08-002 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended FDA 300B PROTOCOL ID NUMBERS Suspended NIAID ACTG P1022 PROTOCOL ID NUMBERS Terminated CC 99 I-0062 PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PHARMACOLOGICAL ACTION MODE OF ACTION: Lamivudine is phosphorylated to its active 5'-triphosphate metabolite which has an intracellular half-life of 10.5 to 15.5 h. The principal mode of action of this metabolite is inhibition of HIV reverse transcription via viral DNA chain termination. The metabolite also inhibits the RNA- and DNA- dependent DNA polymerase activities of reverse transcriptase. The pharmacokinetics of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single IV doses ranging from 0.25 to 8 mg/kg, as well as single and multiple oral doses ranging from 0.25 to 10 mg/kg. The drug is rapidly absorbed after oral doses. Absolute bioavailability in adults was 86% for the tablet dosage form and 87% for an oral solution. After oral doses of 2 mg/kg twice daily to 9 adults with HIV, the peak serum levels were 1.5 mcg/ml. The AUC and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg. The drug may be administered with or without food. Apparent volume of distribution after IV administration in 20 patients was 1.3 l/kg, suggesting that lamivudine distributes into extravascular spaces. The volume of distribution was independent of dose and did not correlate with body weight. Binding to human plasma proteins is less than 36%. Metabolism is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite. Within 12 h after a single oral dose in 6 adults, 5.2% of the metabolite was excreted in the urine. The majority of lamivudine is eliminated unchanged in urine. In 20 patients given a single IV dose, renal clearance was 0.22 liter/(hr*kg), representing 71% of total clearance of the drug. In most single-dose studies in infected patients the mean elimination half-life ranged from 5 to 7 h. Adult patients with renal impairment need dosage modifications. Lamivudine-resistant isolates of HIV-1 have been selected in vitro. In patients receiving lamivudine alone or combined with zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients with zidovudine-resistant virus, phenotypic sensitivity to zidovudine by 12 weeks of treatment was restored. [PDR 1999; p 1112] DISEASES STUDIED/TREATED Lamivudine has been approved (1995) by the FDA for use in combination with AZT in HIV+ patients under the accelerated approval regulations. Lamivudine has demonstrated antiviral activity in combination with many other antiretrovirals including nucleoside analogues such as stavudine and protease inhibitors. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 47] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1885] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 624] OTHER MAJOR USES Nucleoside analogues, such as lamivudine and famciclovir, are showing promise as antiviral agents for chronic hepatitis B virus (HBV) infection. Lamivudine therapy should be considered for the treatment of HBV reactivation and might play a future role as preemptive therapy of HBV reactivation in patients with prior hepatitis B or chronic hepatitis B with inactive viral replication. [Am J Gastroenterol 1999 Jan;94(1); p 249-51; ] SUBSTANCE INTERACTIONS Coadministration of lamivudine and zidovudine resulted in an increase in Cmax of zidovudine. Coadministration of lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) resulted in an increase in lamivudine AUC, a decrease in lamivudine oral clearance, and a decrease in lamivudine renal clearance. [PDR 1999; p 1113] ADVERSE EFFECTS Lamivudine appears to be well tolerated. Peripheral neuropathy has been reported in adults receiving lamivudine but has rarely resulted in interruption or discontinuance of treatment. Paresthesia and peripheral neuropathies have been reported in 13% of children (in one study) receiving lamivudine monotherapy. Pancreatitis has occurred in 14-15% of pediatric patients on lamivudine. Treatment should be discontinued in any patient when clinical or laboratory signs of pancreatitis appear. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported - particularly in women - with the use of antiretroviral nucleoside analogues. Treatment with lamivudine should be suspended in any patients who develop clinical or laboratory findings of lactic acidosis or hepatotoxicity. [AHFS Drug Information 1999; p 592; PDR 1999; p 1113-4] CONTRAINDICATIONS In pediatric patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis, the combination of lamivudine and AZT should be used with extreme caution and only if there is no satisfactory alternative therapy. Treatment with lamivudine should be stopped immediately if clinical or laboratory abnormalities suggestive of pancreatitis occur. [PDR 1999; p 1113-4] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lamivudine, a synthetic antiretroviral agent, is a dideoxynucleoside reverse transcriptase inhibitor. Lamivudine is the negative enantiomer of a dideoxy analogue of cytidine, and is structurally similar to zalcitabine (2',3'-dideoxycytidine, ddC). Lamivudine differs structurally from zalcitabine in that the 3'-carbon of the ribose ring is replaced with sulfur, forming an oxathiolane ring. The absense of a free 3'-hydroxy group on the oxathiolane ring results in the inability of lamivudine to form phosphodiester linkages at this position. [AHFS Drug Information 1999; p 591] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H11-N3-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 229.26 [USPD 1998; p. 404] CHEMICAL/PHYSICAL DATA Melting Point: 160-162 C [Merck Index 1996; p. 914] CHEMICAL/PHYSICAL DATA Elemental Comp: C41.91%, H4.84%, N18.33%, O20.94%, S13.99% [Merck Index 1996; p. 914] CHEMICAL/PHYSICAL DATA Solubility: Approximately 70mg/ml in water at 20 C. [PDR 1999; p 1112] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline solid. [PDR 1999; p 1112] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, 150 mg and oral solution, 10 mg/ml. [PDR 1999; p 1115] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 1112] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store tablets between 2 C and 30 C(36 F and 86 F) in tightly closed bottles. Store oral solution between 2 C and 25 C (36 F and 77 F) in tightly closed bottles. [PDR 1999; p 1115] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Medical & Consumer Relations (919)483-9959 REFERENCES MED/99432083. Clarke JR, Braganza R, Mirza A, Stainsby C, Ait-Khaled M, Wright A, Lyall H, Parker D, McClure MO, Weber JN, Taylor GP. Rapid development of genotypic resistance to lamivudine when combined with zidovudine in pregnancy. J Med Virol 1999 Nov;59(3):364-8. MED/99393476. Feng JY, Shi J, Schinazi RF, Anderson. Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP. FASEB 1999 Sep;13(12):1511-7. MED/99367564. Dore GJ, Cooper DA, Barrett C, Goh LE, Thakrar B, Atkins M. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis 1999 Sep;180(3):607-13. MED/99367570. Hirsch M, Steigbigel R, Staszewski S, Mellors J, Scerpella E, Hirschel B, Lange J, Squires K, Rawlins S, Meibohm A, Leavitt R. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy. J Infect Dis 1999 Sep;180(3):659-65. MED/99398656. Sarafianos SG, Das K, Clark AD Jr, Ding J, Boyer PL, Hughes SH, Arnold E. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci U S A 1999 Aug 31;96(18):10027-32. MED/99342914. Poggi C, Profizi N, Djediouane A, Chollet L, Hittinger G, Lafeuillade A. Long-term evaluation of triple nucleoside therapy administered from primary HIV-1 infection. AIDS 1999 Jul 9;13(10):1213-20. MED/99318556. Michelet C, Bellissant E, Ruffault A, Arvieux C, Delfraissy JF, Raffi F, Bazin C, Renard I, Sebille V, Chauvin JP, Dohin E, Cartier F. Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine. Clin Pharmacol Ther 1999 Jun;65(6):661-71. MED/99143934. Johnson MA, Moore KH, Yuen GJ, Bye A, Pakes GE. Clinical pharmacokinetics of lamivudine. Clin Pharmacokinet 1999 Jan;36(1):41-66. Review. MED/99059856. Miller MD, Anton KE, Mulato AS, Lamy PD, Cherrington JM. Human immunodeficiency virus type 1 expressing the lamivudine-associated M184V mutation in reverse transcriptase shows increased susceptibility to adefovir and decreased replication capability in vitro. J Infect Dis 1999 Jan;179(1):92-100. MED/97307101. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997 May 17;349(9063):1413-21. ENTRY MONTH 199110 LAST REVISION DATE 20000801 221 UNIQUE IDENTIFIER DRG-0125 NAME OF SUBSTANCE Pyridoxine hydrochloride [USPD 1998; p. 617] REGISTRY NUMBER 58-56-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3,4-Pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Beesix [USP DI 2000; p. 2603] SYNONYMS Rodex [USP DI 2000; p. 2603] PROTOCOL ID NUMBERS Complete NIAID ACTG 177 PROTOCOL ID NUMBERS Complete NIAID ACTG 222 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 309 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 004 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 005 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 008 PHARMACOLOGICAL ACTION MODE OF ACTION: Vitamin B6 (pyridoxine) acts as a coenzyme in the metabolism of protein, carbohydrates and fat. In protein metabolism, it participates in the decarboxylation of amino acids; conversion of tryptophan to niacin or serotonin (5-hydroxytryptamine); and deamination, transamination, and transulfuration of amino acids. In carbohydrate metabolism, it is responsible for the breakdown of glycogen to glucose-1-phosphate. The half-life appears to be 15 to 20 days. It is degraded to 4-pyridoxic acid in the liver and this metabolite is excreted in the urine. [Physicians GenRx 1997; p II-1797] DISEASES STUDIED/TREATED Indicated to prevent or treat peripheral neuritis caused by drugs that act as pyridoxine antagonist (eg. isoniazid) and/or increase its excretion in the urine. [Drug Evaluations Annual 1995; p 2296] CLASSIFICATION CODE Antidote (to tuberculosis drug poisoning) [USP DI 2000; p. 2601] CLASSIFICATION CODE Nutritional supplement [USP DI 2000; p. 2601] OTHER MAJOR USES Pyridoxine is indicated to prevent or treat peripheral neuritis caused by certain drugs (eg, cycloserine, hydralazine, penicillamine). Pyridoxine deficiency, including: inadequate diet, drug-induced deficiency, inborn errors of metabolism. Reported to improve symptoms such as cheilosis, seborrheic dermatitis, glossitis, and stomatitis, that do not respond to thiamine, riboflavin, and niacin and to relieve the symptoms associated with premenstrual tension. [USP DI 1995; p 2352; Drug Evaluations Annual 1995; p 2296] SUBSTANCE INTERACTIONS Interacts with levodopa, INH, cycloserine, penicillamine, hydralazine, oral contraceptives, phenobarbital, phenytoin, and tiopronin. [Drug Evaluations Annual 1995; p 2296-97] ADVERSE EFFECTS Pyridoxine is usually nontoxic; however, chronic administration of large dosages has been associated with adverse neurologic effects. Nausea, headache, paresthesia, somnolence, and increased serum AST (SGOT) and decreased seurm folic acid concentrations have been reported. Burning or stinging at the injection site may occur following intramuscular or subcutaneous injection. Seizures have occurred following intravenous administration of very large doses. Allergic reactions have been reported occasionally in patients receiving the vitamin. [AHFS Drug Information 1997; p 2816] CONTRAINDICATIONS Contraindicated in patients with sensitivity to pyridoxine or to any of the ingredients in the drug. [Physicians GenRx 1997; p II-1797] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Water-soluble vitamin. One of the vitamins of the B6 complex. [AHFS Drug Information 1997; p 2815] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H11-N-O3.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 205.64 [USPD 1998; p. 617] CHEMICAL/PHYSICAL DATA Melting Point: 160 C (Free base) [Merck Index 1996; p. 1372] CHEMICAL/PHYSICAL DATA Elemental Comp: C46.73%, H5.88%, Cl17.24%, N6.81%, O23.34% [Merck Index 1996; p. 1372] CHEMICAL/PHYSICAL DATA Solubility: One gram dissolves in about 4.5 ml water, 90 ml alcohol. Soluble in propylene glycol, sparingly soluble in acetone, insoluble in ether, chloroform. [Merck Index 1996; p 1372] CHEMICAL/PHYSICAL DATA Stability: Reasonably stable in light and air. Acidic aqueous solutions are stable and may be heated for 30 min at 120 with decomposition. [Merck Index 1996; p 1372] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to practically white crystals or crystalline powder. Slightly bitter, salty taste. [AHFS Drug Information 1997; p 2815] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (500 mg); capsules, extended release (100, 150 mg); tablets (10, 25, 50, 100, 200, 250, 500 mg); tablets, extended release (500 mg); injection (100 mg/ml). [AHFS Drug Information 1997; p 2817] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; however, the drug may be given by intramuscular, intravenous, or subcutaneous injection when oral administration is not feasible. [AHFS Drug Information 1997; p 2816] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Protect from light and store in well-closed containers at a temperature less than 40 C, preferably between 15-30 C; freezing of the injection should be avoided. [AHFS Drug Information 1997; p 2815] MANUFACTURERS 0000005215: Forest Pharmaceuticals Inc 13600 Shoreline Drive St Louis, MO 63045 Contact: Unspecified (800)678-1605 MANUFACTURERS 0000005385: Intervention provided by participating unit , Contact: Unspecified (800)528-3144 MANUFACTURERS 0000005219: Legere Pharmaceuticals 7326 East Evans Road Scottsdale, AZ 85260 REFERENCES MED/94257925. Baum M, Cassetti L, Bonvehi P, Shor-Posner G, Lu Y, Sauberlich H. Inadequate dietary intake and altered nutrition status in early HIV-1 infection. Nutrition. 1994 Jan-Feb;10(1):16-20. MED/94134319. Rall LC, Meydani SN. Vitamin B6 and immune competence. Nutr Rev. 1993 Aug;51(8):217-25. ICA9/93336838. Baum MK, Shor-Posner G, Quesada J, Cure N, Fletcher MA, Page BJ. Nutritional abnormalities in intravenous drug users (IVDUs): impact of HIV-1 status. Int Conf AIDS. 1993 Jun 6-11;9(2):703 (abstract no. PO-C15-2917). ICA9/93337307. Valdespino JL, Garcia ML, Daniels E, Zacarias F, Weissenbacher M, Peruga A, Palacios M, Garcia-Sancho C, Loo E, Cruz C, et al. Outcomes of the pilot study of TB chemoprophylaxis trials. Int Conf AIDS. 1993 Jun 6-11;9(2):781. (abstract no. PO-C35-3387). ICA9/93334653. Garcia ML, Valdespino JL, Garcia-Sancho C, Weissenbacher M, Daniels E, Peruga A, Palacios M, Loo E, Cruz C, Luna JL, et al. Compliance and side effects to chemoprophylaxis for TB in HIV+. Mexican experience. Int Conf AIDS. 1993 Jun 6-11;9(1):324 (abstract no. PO-B07-1133). MED/93323670. Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection [see comments]. Lancet. 1993 Jul 31;342(8866):268-72. ICA8/92401437. Shor-Posner G, Blaney N, Feaster D, Manteroatienza E, et al. Anxiety and depression in early HIV-1 infection and its association with vitamin B6 status. Int Conf AIDS. 1992 Jul 19-24;8(2):B209 (abstract no. PoB 3711). MED/92334748. Vitamin B6 and immune function in the elderly and HIV-seropositive subjects. Nutr Rev. 1992 May;50(5):145-7. MED/92092175. Baum MK, Mantero-Atienza E, Shor-Posner G, Fletcher MA, Morgan R, Eisdorfer C, Sauberlich HE, Cornwell PE, Beach RS. Association of vitamin B6 status with parameters of immune function in early HIV-1 infection. J Acquir Immune Defic Syndr. 1991;4(11):1122-32. ICA6/40312390. Mantero-Atienza E, Baum M, Beach R, Javier J, Morgan R, Eisdorfer C. Vitamin B6 and immune function in HIV infection. Int Conf AIDS. 1990 Jun 20-23;6(2):432 (abstract no. 3123). ENTRY MONTH 199110 LAST REVISION DATE 20001107 222 UNIQUE IDENTIFIER DRG-0124 NAME OF SUBSTANCE Pyrazinamide [USPD 1998; p. 616] REGISTRY NUMBER 98-96-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Pyrazinecarboxamide [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS component of Rifater [USP DI 2000; p. 3519] PROTOCOL ID NUMBERS Complete NIAID ACTG 177 PROTOCOL ID NUMBERS Complete NIAID ACTG 222 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 309 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 004 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PHARMACOLOGICAL ACTION MODE OF ACTION: May be bacteriostatic or bactericidal, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. It is a highly specific agent and is active only against Mycobacterium tuberculosis. In vitro and in vivo, the drug is active only at a slightly acid pH. The exact mechanism has not been fully elucidated, but the antimycobacterial activity appears to partly depend on conversion of the drug to pyrazinoic acid (POA). Susceptible strains of M. tuberculosis produce pyrazinamidase, an enzyme that deaminates pyrazinamide to POA, and the in vitro susceptibility of a given strain of the organism appears to correspond to its pyrazinamidase activity. In vitro studies indicate that POA has specific antimycobacterial activity against M. tuberculosis. In addition, the fact that POA lowers the pH of the environment below that which is necessary for growth of M. tuberculosis appears to contribute to the drug's antimycobacterial activity in vitro. Pyrazinamide is well absorbed from the GI tract; it reaches peak plasma concentrations after an oral dose in 2 hours and is widely distributed throughout the body, including in cerebrospinal fluid (100% of serum concentrations in normal and inflamed meninges). Half-life is 9-10 hours in plasma. It is primarily metabolized by the liver; metabolites and about 4-14% of unchanged drug are excreted in urine. [AHFS Drug Information 1997; p 429; Protocol ID: ACTG 177 ; Facts and Comparisons 1995; p 391] DISEASES STUDIED/TREATED An oral antituberculosis drug used in combination regimens. Prophylaxis against Mycobacterium tuberculosis (MTb) in persons dually infected with HIV and MTb. (Used in conjuction with rifampin to help overcome drug resistance.) [Protocol ID: ACTG 177 ] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 2594] OTHER MAJOR USES Used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis. [AHFS Drug Information 1997; p 429] SUBSTANCE INTERACTIONS May interact with allopurinol, colchicine, probenecid, or sulfinpyrazone, increasing serum uric acid concentrations. Cyclosporine serum levels may be decreased by concomitant pyrazinamide. [USP DI 1995; p 2348] ADVERSE EFFECTS The most frequent adverse effect of pyrazinamide is hepatoxicty. Transient increases in serum aminotransferase (transaminase) concentrations, jaundice, hepatitis, and a syndrome of fever, anorexia, malaise, liver tenderness, hepatomegaly, and splenomegaly have been reported. Rarely, acute yellow atrophy of the liver and death have occurred. Hepatotoxicity appears to be dose related and may occur at any time during therapy. Other reactions include hyperuricemia, acute gout, nongouty polythralgia, maculopapular rash, arthralgia, fever, acne, porphyria, dysuria, photosensitivity with reddish-brown discoloration of exposed skin, urticaria and pruritus, nausea, vomiting, thrombocytopenia, sideroblastic anemia with erythroid hyperplasia, vaculolation of erythrocytes, and increased serum iron binding capacity and serum iron concentrations. [PDR 1995; p 1426-27; AHFS Drug Information 1997; p 429; Protocol ID: ACTG 177 ] CONTRAINDICATIONS Contraindicated in persons with severe hepatic damage, those who have shown hypersensitivity to the drug, and those with acute gout. Should be used with caution in patients with renal failure, history of gout, or diabetes. [PDR 1997; p 1442; AHFS Drug Information 1997; p 429] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The pyrazine analogue of nicotinamide. [PDR 1997; p 1442] CHEMICAL/PHYSICAL DATA Molecular Formula: C5-H5-N3-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 123.11 [USPD 1998; p. 616] CHEMICAL/PHYSICAL DATA Melting Point: 189-191 C [Merck Index 1996; p. 1368] CHEMICAL/PHYSICAL DATA Elemental Comp: C48.78%, H4.09%, N34.13%, O13.00% [Merck Index 1996; p. 1367] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in water and slightly soluble in alcohol. [AHFS Drug Information 1997; p 428] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Drug occurs as a white to practically white, odorless or practically odorless, crystalline powder. [AHFS Drug Information 1997; p 428] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (500 mg). [PDR 1997; p 1443] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1443] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store in a well-closed container at controlled room temperature of 15-30 C. [PDR 1997; p 1443] MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr Amy Baim (914)732-2147 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Dr John Riefler (914)732-2035 REFERENCES MED/97015631. Espinal MA, Reingold AL, Perez G, Camilo E, Soto S, Cruz E, Matos N, Gonzalez G. Human immunodeficiency virus infection in children with tuberculosis in Santo Domingo, Dominican Republic: prevalence, clinical findings, and response to antituberculosis treatment. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Oct 1;13(2):155-9. MED/97048231. Humma LM. Prevention and treatment of drug-resistant tuberculosis. Am J Health Syst Pharm. 1996 Oct 1;53(19):2291-8;quiz 2335-6. MED/97030413. Fisher M, Tomlinson DR, Coker RJ. The management of mycobacterial infections in HIV serpositive individuals. Jefferiss Wing Therapeutics and Protocols Group. Int J STD AIDS. 1996 Jul;7(4):244-9;quiz 249-51. MED/95166277. Perriens JH, St. Louis ME, Mukadi YB, Brown C Prignot J, Pouthier F, Portaels F, Willame JC, Mandala JK, Kaboto M, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months [see comments]. N Engl J Med. 1995 Mar 23;332(12):779-84. MED/95165491. Elliott AM, Halwiindi B, Hayes RJ, Luo N, Mwinga AG, Tembo G, Machiels L, Steebergen G, Pobee JO, Nunn PP, et al. The impact of human immunodeficiency virus on response to treatment and recurrence rate in patients treated for tuberculosis: two-year follow-up of a cohort in Lusaka, Zambia. J Trop Med Hyg. 1995 Feb 98(1):9-21. MED/95385410. Stevens JP, Daniel TM. Chemoprophylaxis of multidrug-resistant tuberculous infection in HIV-uninfected individuals using ciprofloxacin and pyrazinamide. A decision analysis. Chest. 1995 Sep;108(3):712-7. AIDS/95920039. Halsey N, Coberly J, Losikoff P, Atkinson J, Moulton L, Cantave M, Johnson M, Chaisson R, Geiter L, Huebner R, et al. Twice weekly INH vs RIF and PAZ for TB prophylaxis in HIV infected adults. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:55. MED/94011118. Paramasivan CN, Herbert D, Prabhakar R. Bactericidal action of pulsed exposure to rifampicin, ethambutol, isoniazid & pyrazinamide on Mycobacterium tuberculosis in vitro. Indian J Med Res. 1993 Jul;97:145-50. ICA9/93334741. Gutierrez MC, Cavalcante SC, Veloso VG, Grinsztejn B, Moreira RB, Coletti Junior C. Tuberculosis and AIDS: adverse reactions to treatment. Int Conf AIDS. 1993 Jun 6-11;9(1):337 (abstract no. PO-B07-1211). MED/93313179. Jain A, Mehta VL, Kulshrestha S. Effect of pyrazinamide on rifampicin kinetics in patients with tuberculosis. Tuber Lung Dis. 1993 Apr;74(2):87-90. ENTRY MONTH 199110 LAST REVISION DATE 20001107 223 UNIQUE IDENTIFIER DRG-0123 NAME OF SUBSTANCE Isoniazid [USPD 1998; p. 397] REGISTRY NUMBER 54-85-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Pyridinecarboxylic acid hydrazide [Merck Index 1996; p 5204] SYNONYMS component of Rifamate [USP DI 2000; p. 3519] SYNONYMS component of Rifater [USP DI 2000; p. 3519] SYNONYMS Laniazid [USP DI 2000; p. 1861] SYNONYMS Nydrazid [USP DI 2000; p. 1861] PROTOCOL ID NUMBERS Complete NIAID ACTG 177 PROTOCOL ID NUMBERS Complete NIAID ACTG 222 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 309 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 004 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 005 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 008 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PHARMACOLOGICAL ACTION MODE OF ACTION: May be bacteriostatic or bactericidal depending on the concentration attained at the site of infection and the susceptibility of the infecting organism. INH activity is limited to mycobacterium; it is bacteriostatic for resting bacilli and bactericidal for rapidly dividing organisms. Although not fully elucidated, several mechanisms of action including interference with metabolism of bacterial proteins, nucleic acids, carbohydrates and lipids have been proposed. One principal action of the drug appears to be inhibition of mycolic acid synthesis in susceptible bacteria which results in loss of acid-fastness and disruption of the bacterial cell wall. Isoniazid is active against susceptible bacteria only when they are undergoing cell division. Susceptible bacteria may undergo 1 or 2 divisions before multiplication is arressted. INH is completely and rapidly absorbed orally and parenterally and peaks in blood levels within 1 to 2 hours. These levels decline by less than or equal to 50% within 6 hours. Absorption rate and extent are decreased by food. It diffuses readily into all body fluids (including cerebrospinal, pleural and ascitic), tissues, organs, and excreta (saliva, sputum, feces). It passes through the placental barrier and into breast milk in concentrations comparable to those in plasma. The half-life is widely variable and dependent on acetylator status (i.e., one hour in fast acetylators to three hours in slow acetylators). The average concentration of active INH in the circulation of fast acetylators is about 30 to 50% of the concentration in persons who acetylate the drug slowly. Isoniazid is primarily acetylated by the liver; the process is genetically controlled and dependent on race, but not on age or sex (i.e., approximately 50% of Blacks and Caucasians are slow acetylators and the rest are rapid acetylators and the majority of Eskimos and Orientals are rapid acetylators). Liver disease can prolong the clearance of isoniazid. Several minor metabolites have been identified and one (monoacetylhydrazine is suspected) may be more reactive and responsible for liver damage. Acetylation rate does not alter the effectiveness of the drug. Slow acetylation may lead to increased blood levels and thus more toxic reactions. Fast acetylators may be more likely to develop hepatitis since hepatotoxicity is caused by the acetylated metabolite of INH, but this remains controversial. 75-96% of a 5 mg/kg oral dose is excreted as unchanged drug and metabolites by kidneys within 24 hours; but elimination is independent of renal function. However, slow inactivators may develop toxic levels in the presence of impaired renal function. [AHFS Drug Information 1997; p 423-4; Protocol ID: ACTG 177 ; Facts and Comparisons 1995; p 382] DISEASES STUDIED/TREATED An antibiotic which, in combination regimens, is standard for the treatment and prophylaxis of tuberculosis in the HIV infected patient. Administered concurrently with pyridoxine (vitamin B6) to prevent the peripheral neuropathy as well as nearly all other nervous system disorders attributable to isoniazid (INH). [AHFS Drug Information 1997; p 424-5; Protocol ID: ACTG 177 ] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 1855] OTHER MAJOR USES Isoniazid is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis. Isoniazid is usually used alone in certain patients to prevent the development of clinical tuberculosis. [AHFS Drug Information 1997; p 424-6] SUBSTANCE INTERACTIONS Interacts with alcohol, aluminum salts, anticoagulants (oral), benzodiazepines, carbamazepine, cycloserine, disulfiram, enflurane, halothane, hydantoins, ketoconazole, meperidine, phenytoin, BCG vaccine, and rifampin. [Facts and Comparisons 1995; p 383] ADVERSE EFFECTS The most frequent reactions are those affecting the nervous system and the liver. Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those prediposed to neuritis (e.g. alcoholics and diabetics), and is usually preceded by paresthesias of the feet and hands. Elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, jaundice and occasionally severe and sometimes fatal hepatitis. Other reactions include nausea, vomiting, epigastric distress, agranulocytosis, hemolytic, sideroblastic, aplastic anemia, thrombocytopenia, eosinophilia, fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, vasculitis, pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, gynecomastia, rheumatic syndrome, and systemic lupus, erythematosus-like syndrome, and local irritation at the site of intramuscular injection. [Physicians GenRx 1997; p II-1182-3] CONTRAINDICATIONS Contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; also contraindicated in those with previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid, such as fever, chills, and arthritis; and acute liver disease of any etiology. [Physicians GenRx 1997; p II-1182] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic, isonicotinic acid-derivative. [AHFS Drug Information 1997; p 423] CHEMICAL/PHYSICAL DATA Molecular Formula: C6-H7-N3-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 137.14 [USPD 1998; p. 397] CHEMICAL/PHYSICAL DATA Melting Point: 171.4 C [Merck Index 1996; p. 885] CHEMICAL/PHYSICAL DATA Elemental Comp: C52.55%, H5.14%, N30.64%, O11.67% [Merck Index 1996; p. 885] CHEMICAL/PHYSICAL DATA Solubility: Approximately 125 mg/ml in water and 20 mg/ml in alcohol at 25 C. [AHFS Drug Information 1997; p 423] CHEMICAL/PHYSICAL DATA Stability: At low temperatures, isoniazid in solution tends to crystallize and should be warmed to room temperature to redissolve the crystals prior to use. [AHFS Drug Information 1997; p 423] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Colorless or white crystals or as a white, crystalline powder. [AHFS Drug Information 1997; p 423] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (300 mg), injection (100 mg/ml), syrup (50 mg/5ml). [Physicians GenRx 1997; p II-1182] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, injection. [Physicians GenRx 1997; p II-1183] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Isoniazid preparations should be protected from light, air, and excessive heat. Isoniazid tablets should be stored in well-closed, light-resistant containers at a temperature less than 40 C, preferably between 15-30 C. Isoniazid injection should be protected from light and stored at a temperature less than 40 C, preferably between 15-30 C; freezing should be avoided. [AHFS Drug Information 1997; p 423] MANUFACTURERS 0000002568: Schein Pharmaceuticals Inc 100 Campus Drive Florham Park, NJ 07932 Contact: Dr William McIntyre (914)278-3742 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 MANUFACTURERS 0000001241: Lannett Co Inc 9000 State Rd Philadelphia, PA 19136 Contact: Unspecified (888)242-9321 MANUFACTURERS 0000001092: Barr Laboratories Inc 2 Quaker Rd / PO Box D-2900 Pomona, NY 10970 Contact: Unspecified (800)325-9994 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Vlad Mikijanic (215)333-9000 MANUFACTURERS 0000001241: Lannett Co Inc 9000 State Rd Philadelphia, PA 19136 Contact: Unspecified (914)362-1100 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Medical Information (800)633-1610 REFERENCES MED/97056013. Krance MB, Fisher MA. Prophylaxis of mycobacterial infections in immunocompromised patients. Am Fam Physician. 1996 Nov 1;54(6):1981-8,1991-2. MED/97042403. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, Quinn TC, Halsey NA. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med. 1996 Oct;154(4):Pt 1,1034-8. MED/97030413. Fisher M, Tomlinson DR, Coker RJ. The management of mycobacterial infections in HIV serpositive individuals. Jefferiss Wing Therapeutics and Protocols Groups. Int J STD AIDS. 1996 Jul;7(4):244-9; quiz 249-51. ICA11/96923711. Okwera a, Loughlin A, Johnson JL, Whalen C, Mugerwa R, Ellner J. Peripheral neuropathy in HIV-1 infected Ugandans in a placebo-controlled randomized MTB preventive therapy trial. Int Conf AIDS. 1996 Jul 7-12;11(2):120 (abstract no.We.B.3362). AIDS/96701786. Anonymous. Isoniazid TB prophylaxis effective in drug users with HIV. J Int Assoc Physicians AIDS Care. 1996 Jun 2(6):51. MED/96300907. Saenghirunvattana S. Effect of isoniazid prophylazis on incidence of active tuberculosis among Thai HIV-infected individuals. J Med Assoc Thai. 1996 May;79(5):285-7. MED/96370312. Graham NM, Galai N, Nelson KE, Astemborski J, Bonds M, Rizzo RT, Sheeley L, Vlahov D. Effect of isoniazid chemoprophylaxis on HIV-related mycobacterial disease. Arch Intern Med. 1996 Apr 22;156(8):889-94. AIDS/96920208. Okwera A, Vjecha M, Johnson J, Whalen C, Nsubuga P, Loughlin A, Mugerwa R, Ellner J. Preventive therapy for tuberculosis in HIV-infected Ugandans. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:91. MED/96048752. Ozick LA, Jacob L, Comer GM, Lee TP, Ben-Zvi J, Donelson SS, Felton CP. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients [see comments]. Am J Gastroenterol. 1995 Nov;90(11):1978-80. MED/95165491. Elliott AM, Halwiindi B, Hayes RJ, Luo N, Mwinga AG, Tembo G, Machiels L, Steenbergen G, Pobee JO, Nunn PP, et al. The impact of human immunodeficiency virus on response to treatment and recurrence rate injuries patients treated for tuberculosis: two-year follow-up of a cohort in Lusaka, Zambia. J Trop Med Hyg. 1995 Feb;98(10:9-21. ENTRY MONTH 199110 LAST REVISION DATE 20000801 224 UNIQUE IDENTIFIER DRG-0122 NAME OF SUBSTANCE Interleukin-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 080A PHARMACOLOGICAL ACTION MODE OF ACTION: IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) share common binding capacities on hemopoietic cells. Both molecules compete for binding with an equally high affinity to a dual GM-CSF/IL-3 receptor type that was found to be present on acute myeloblastic leukemia (AML) cells and normal monocytes and may explain overlapping biologic effects. There is evidence for IL-3-induced phosphorylation of several cellular proteins including theputative IL-3R subunits. IL-3 is also a specific inductor of enzymes involved in DNA/RNA turnover, cell metabolism, and differentiation, in particular 20-alpha steroid-dehydrogenase and histidine- and ornithine decarboxylase. Recent data have shown that IL-3 directly counteracts a number of mechanisms including growth inhibition and cell death; thus, a number of different effects of IL-3 on cell function and metabolism result in induction of growth, survival, and differentiation of the target cells. In hemopoiesis, IL-3 exerts functional and proliferative effects on multiple cell lineages, including neutrophilic, eosinophilic, basophilic, monocytic, and thrombopoietic lineages. Within the hemopoietic ontogeny, IL-3 acts on proliferation of early multipotential progenitor cells such as CFU-GEMM, and on more committed progenitor cells including CFU-GM, BFU-E, and CFU-MK. Human trials indicated a rapid clearance of IL-3. The half-life ranged from 13.4 to 53 minutes. This short half-life suggests that IL-3 should be given by prolonged IV infusion; alternatively, SC or IM administration may be useful, as administration by these routes results in prolonged serum levels. [Cancer 1991 May 15;67(10) supplement; p 2712; Drug Evaluations Annual 1995; p 2520-21; J Clin Oncol 1991 February; p S47] DISEASES STUDIED/TREATED Subcutaneous treatment of HIV associated cytopenia. [AmfAR Treat Dir 1995;7(4); p 66] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p. 3308] OTHER MAJOR USES Promotion of erythropoiesis in Diamond-Blackfan anemia (congenital pure cell aplasia); for sequential administration with sargramostin to accelerate neutrophil and platelet recovery in autologous bone marrow transplantation in Hodgkin's and non-Hodgkin's lymphoma. [USP DI 1997; p 3109] SUBSTANCE INTERACTIONS Interacts with systemic chemotherapy, medications with known myelosuppressive effects such as ganciclovir, trimethoprim / sulfamethoxazole, dapsone, or AZT. Exhibits synergistic activity with other hematopoietic growth factors such as EPO, GM-CSF, and G-CSF. [AmfAR Treat Dir 1993;6(4); p 61] ADVERSE EFFECTS Side effects can include fever, headache, flushing, and local erythema at the site of injection. [AmfAR Treat Dir 1995;7(4); p 66; Drug Evaluations Annual 1995; p 2521] CONTRAINDICATIONS Contraindicated in the presence of hepatic or renal dysfunction, documented allergic disorder such as asthma, history of anaphylaxis, atopy, serum sickness, or bronchospasm. [Protocol ID: 080A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: IL-3 is one of several colony-stimulating factors which regulate the proliferation and differentiation of hematopoietic and lymphoid cells. IL-3 is the recombinantly produced protein. [AmfAR Treat Dir 1995;7(4); p 66] CHEMICAL/PHYSICAL DATA Molecular Formula: C670-H1074-N186-O199-S5 [USPD 1998; p. 490] CHEMICAL/PHYSICAL DATA Molecular Weight: 15,079.45 [USPD 1998; p. 490] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Recombinant IL-3 produced by bacteria is not glycosylated but still exhibits biological activities similar to those of naturally produced IL-3. [J Clin Oncol 1991 February; p S45] SUBSTANCE DELIVERY DATA DOSAGE FORM: Injection. [Drug Evaluations Annual 1995; p 2521] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection. [AmfAR Treat Dir 1995;7(4); p 66] MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 REFERENCES MED/98122917. Difalco MR, Dufresne L, Congote LF. Efficacy of an insulin-like growth factor-interleukin-3 fusion protein in reversing the hematopoietic toxicity associated with azidothymidine in mice. J Pharmacol Exp Ther. 1998 Feb;284(2):449-54. MED/98049180. Scadden DT. Cytokine use in the management of HIV disease (see comments). J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16 Suppl 1:S23-9. MED/97479878. Thatte U, Dahanukar S. Apoptosis: clinical relevance and pharmacological manipulation. Drugs. 1997 Oct;54(4):511-32. MED/97464472. Wang XY, McCubrey JA. Differential effects of retroviral long terminal repeats on interleukin-3 gene expression and autocrine transformation. Leukemia. 1997 Oct;11(10):1711-25. MED/97243437. Lantero S, Sacco O, Scala C, Rossi GA. Stimulation of blood mononuclear cells of atopic children with the relevant allergen induces the release of eosinophil chemotaxins such as IL-3, IL-5, and GM-CSF. J Asthma. 1997;34(2):141-52. MED/97047822. Rameshwar P, Denny TN, Gascon P. Enhanced HIV-1 activity in bone marrow can lead to myelopoietic suppression partially contributed by gag p24. J Immunol. 1996 Nov 1;157(9):4244-50. MED/96035980. Gallicchio VS, Hughes NK. Influence of human granulocyte-macrophage colony stimulating factor/interleukin-3 fusion protein (PIXY321) on the hematopoietic toxicity associated with anti-viral drugs (zidovudine and didanosine) in vitro using normal human marrow cells. Life Sci. 1995;57(18):PL265-73. MED/96071143. Jurlander J, de Nully Brown P, Skov PS, Henrichsen J, Heron I, Obel N, Mortensen BT, Hansen MM, Geisler CH, Nielsen HJ. Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia. Leukemia. 1995 Nov;9(11):1902-9. MED/96078234. Scadden DT, Levine JD, Bresnahan J, Gere J, McGrath J, Wang Z, Resta DJ, Young D, Hammer SM. In vivo effects of interleukin 3 in HIV type 1-infected patients with cytopenia. AIDS Res Hum Retroviruses. 1995 Jun;11(6):731-40. ICDB/94600014. Von Roenn JH, Gordon LI, Grace W, Anderson J, Eickhoff C. Phase I trial of rIL-3 plus zidovudine (ZDV) in HIV positive patients with neutropenia (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol. 1994;13:A17. MED/94318202. Scadden DT, Wang A, Zsebo KM, Groopman JE. In vitro effects of stem-cell factor or interleukin-3 on myelosuppression associated with AIDS. AIDS. 1994 Feb;8(2):193-6. ENTRY MONTH 199108 LAST REVISION DATE 20000801 225 UNIQUE IDENTIFIER DRG-0121 NAME OF SUBSTANCE Bacitracin zinc/Polymyxin B sulfate [PDR 2000; p. 3167] REGISTRY NUMBER 1405-89-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Polymyxin B Sulfate bacitracin zinc [PDR 1997; p 1140] SYNONYMS Polysporin [PDR 2000; p. 3167] PROTOCOL ID NUMBERS Complete NIAID ACTG 172 PHARMACOLOGICAL ACTION MODE OF ACTION: A wide range of antibacterial action is provided by the overlapping spectra of bacitracin and polymyxin B sulfate. Bacitracin is bactericidal for a variety of gram-positive and gram-negative organisms. It interferes with bacterial cell wall synthesis by inhibition of the regeneration of phospholipid receptors involved in peptidoglycan synthesis. Polymyxin B is bactericidal for a variety of gram-negative organisms. It increases the permeability of the bacterial cell membrane by interacting with the together are considered active against the following microorganisms: Staphylococcus aureus, streptococci including Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Klebsiella/Enterobacter species, Neisseria species, and Pseudomonas aeruginosa. [AHFS Drug Information 1997; p 1140] DISEASES STUDIED/TREATED Applied over trifluridine in a clinical study of the effectiveness of trifluridine for HZV infection in AIDS patients (ACTG 172). [Protocol ID: ACTG 172 ] CLASSIFICATION CODE Antibacterial [USP DI 1998; p. 2106] OTHER MAJOR USES Treatment of superficial infections of the external eye and its adnexa caused by susceptible bacteria. Such infections encompass conjunctivitis, keratitis, and keratoconjunctivitis, blepharitis and blepharoconjunctivitis. [PDR 1997; p 1140] SUBSTANCE INTERACTIONS Topical corticosteroids, when used in combination with topical anti-infectives including bacitracin and polymyxin B, may mask clinical signs of bacterial, fungal or viral infections, or may suppress hypersensitivity reactions to the antibiotics or other ingredients in the formulation. [AHFS Drug Information 1997; p 2100, 2108] ADVERSE EFFECTS Adverse reactions have occurred with anti-infective components of Polysporin ophthalmic ointment. Reactions occur most often are allergic sensitization reactions including itching, swelling, and conjunctival erythema. More serious hypersensitivity reactions, including anaphylaxis, have been reported rarely. Local irritation on instillation has also been reported. WARNING: Polysporin ophthalmic ointment is not indicated for injection into the eye. It should not be directly introduced into the anterior chamber of the eye. Opthalmic ointment may retard corneal wound healing. [AHFS Drug Information 1997; p 1140-1] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to bacitracin zinc, polymyxin B sulfate, or any ingredients in the formulation. [PDR 1997; p 1140] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Polysporin ophthalmic ointment is a steril antimicrobial ointment for ophthalmic use. Each gram of ointment contains bacitracin zinc equivalent to 500 bacitracin units, polymyxin B sulfate equivalent to 10,000 polymyxin B units, and white petrolatum, q.s. Bacitracin zinc is the zinc salt of bacitracin, a mixture of related cyclic polypeptides (mainly bacitracin A) produced by the growth of and organism of the licheniformis group of Bacillus subtilis var Tracy. It has potency of not less than 40 bacitracin units per mg. Polymyxin B sulfate is the sulfate salt of polymyxin B1 and B2 which are produced by the growth of Bacillus polymyin (Prazmowski) Migula (Fam. Bacillaceae). It has a potency of not less than 6,000 polymyxin B units per mg, calculated on an anhydrous basis. [PDR 1997; p 1140] CHEMICAL/PHYSICAL DATA Solubility: Bacitracin zinc is sparingly soluble in water. Polymyxin B sulfate is freely soluble in water and in 0.9% sodium chloride injection and is slightly soluble in alcohol. [AHFS Drug Information 1997; p 2100, 2107] CHEMICAL/PHYSICAL DATA Stability: Bacitracin is stable in petrolatum, paraffins, white, and lanolin but not in water miscible bases. [AHFS Drug Information 1997; p 2100] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Ointment consisting of a special white petrolatum base where each gram contains polymyxin B sulfate 10,000 units and bacitracin zinc 500 units. [PDR 1997; p 1140] SUBSTANCE DELIVERY DATA DOSAGE FORM: Ophthalmic ointment in tube of 1/8 oz (3.5 g) with ophthalmic tip. [PDR 1997; p 1140-1] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical. [PDR 1997; p 1140] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-25 C (59-77 F). [PDR 1997; p 1141] MANUFACTURERS 0000001225: Warner-Lambert 201 Tabor Rd Morris Plains, NJ 07950 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/91268113. Walton MA, Carino E, Herndon DN, Heggers JP. The efficacy of Polysporin First Aid Antibiotic Spray (polymyxin B sulfate and bacitracin zinc) against clinical burn wound isolates [published erratum appears in J Burn Care Rehabil 1991 Jul-Aug;12(4):384]. J Burn Rehabil 1991 Mar-Apr;12(2):116-9. MED/91214242. Hansbrough JF, Zapata-Sirvent RL, Cooper ML. Effects of topical antimicrobial agents on the human neutrophil respiratory burst. Arch Surg 1991 May;126(5):603-8. MED/91288368. Eedy DJ, McMillan JC, Bingham EA. Anaphylactic reactions to topical antibiotic combinations. Postgrad Med J 1990 Oct;66(780):858-9. MED/90240981. Sharma S, Srinivasan M, George C. Acanthamoeba keratitis in non-contact lens wearers [see comments]. Arch Ophthalmol 1990 May;108(5):676-8. Comment in: Arch Opthamol 1991 Apr;109(4):463-4. MED/90189842. Cooper ML, Boyce ST, Hansbrough JF, Foreman TJ, Frank DH. Cytotoxicity to cultured human keratinocytes of topical antimicrobial agents. J Surg Res 1990 Mar;48(3):190-5. ENTRY MONTH 199108 LAST REVISION DATE 20000801 226 UNIQUE IDENTIFIER DRG-0120 NAME OF SUBSTANCE Trifluridine [USPD 1998; p. 758] REGISTRY NUMBER 70-00-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME alpha-alpha-alpha-trifluorothymidine [PDR 1997; p 1177] SYNONYMS Viroptic [USP DI 2000; p. 3545] PROTOCOL ID NUMBERS Complete NIAID ACTG 172 PROTOCOL ID NUMBERS No longer recruiting FDA 062B PHARMACOLOGICAL ACTION MODE OF ACTION: Exact mechanism of antiviral activity has not been fully elucidated but appears to involve inhibition of viral replication. Trifluridine, instead of thymidine, is incorporated into viral DNA during replication, which results in the formation of defective proteins and an increased mutation rate. Trifluridine also reversibly inhibits thymidylate synthetase, an enzyme required for DNA synthesis. [AHFS Drug Information 1997; p 2115] DISEASES STUDIED/TREATED Used experimentally for the treatment of acyclovir-resistant and foscarnet-resistant HZV infection. Herpes simplex, mucocutaneous (at nasal, oral, vaginal, and anal openings). [AmfAR Treat Dir 1995;7(4); p 71; Protocol ID: ACTG 172 ] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 3054] OTHER MAJOR USES Treatment of primary keratocon juncitivitis and recurrent epithelial keratitis due to Herpes simplex virus, types 1 and 2; treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred; treatment of epithelial kerattis in patients found to be resistant to the topical vidarabine. [PDR 1997; p 1177] ADVERSE EFFECTS The most common adverse effects of ophthalmic trifluridine are mild, transient burning or stinging upon instillation and palpebral (eyelid) edema. Other adverse reactions in decreasing order of reported frequency were superficial punctate keratopathy, epithelial keratopathy, hypersensitivity reaction, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure. [PDR 1997; p 1177] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity reactions or chemical intolerance to trifluridine. [PDR 1997; p 1177] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A pyrimidine nucleoside, structurally related to idoxuridine and thymidine. Trifluridine differs structurally from thymidine in the presence of 3 fluorine atoms in place of 3 hydrogen atoms in the methyl group of the latter compound. [AHFS Drug Information 1997; p 2115] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H11-F3-N2-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 296.20 [USPD 1998; p. 758] CHEMICAL/PHYSICAL DATA Melting Point: 186-189 C [Merck Index 1996; p. 1650] CHEMICAL/PHYSICAL DATA Elemental Comp: C40.55%, H3.74%, F19.24%, N9.46%, O27.01% [Merck Index 1996; p. 1650] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water and in alcohol. [AHFS Drug Information 1997; p 2115] CHEMICAL/PHYSICAL DATA Stability: Trifluridine ophthalmic solution should be store at 2-8 C. [AHFS Drug Information 1997; p 2115] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, crystalline powder. [AHFS Drug Information 1997; p 2115] SUBSTANCE DELIVERY DATA DOSAGE FORM: Ophthalmic solution 1%. [PDR 1997; p 1177] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical; instill one drop of 1% ophtalmic solution onto the cornea of the affected eye. [PDR 1997; p 1177] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C (36-46 F). [PDR 1997; p 1177] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97006454. Amin AR, Robinson MR, Smith DD, Swenson CF, Luque AE. Trifluorothymidine 0.5% ointment in the treatment of aciclovir-resistant mucocutaneous herpes simplex in AIDS [letter]. AIDS. 1996 Aug;10(9):1051-3. MED/96279844. Kessler HA, Hurwitz S, Farthing C, Benson CA, Feinberg J, Kuritzkes DR, Bailey TC, Safin S, Steigbigel RT, Cheeseman SH, et al. Pilot study of topical trifluridine for the treatment of acyclovir-resistant mucocoutaneous herpes simplex disease in patients with AIDS (ACTG 172). AIDS Clinical Trials Group. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Jun;12(2):147-52. AIDS/95920323. Ives DV, Stanat SC, Biron KK, Harris S. Successful treatment of acyclovir-resistant zoster with topical trifluorothymidine (TFT). Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:108. MED/94149559. Balfour HH Jr, Benson C, Braun J, Cassens B, Erice A, Friedman-Kien A, Klein T, Polsky B, Safrin S. Management of acyclovir-resistant herpes simplex and varicella-zoster virus infections. J Acquir Immune Defic Syndr. 1994 Mar;7(3):254-60. MED/92300076. Birch CJ, Tyssen DP, Tachedjian G, Doherty R, Hayes K, Mijch A, Lucas CR. Clinical effects and in vitro studies of trifluorothymidine combined with interferon-alpha for treatment of drug-resistant and -sensitive herpes simplex virus infections. J Infect Dis. 1992 Jul;166(1):108-12. MED/92095334. Rosenwasser GO, Greene WH. Simultaneous herpes simplex types 1 and 2 keratitis in acquired immunodeficiency syndrome [letter]. Am J Ophthalmol. 1992 Jan 15;113(1):102-3. MED/90067545. Young TL, Robin JB, Holland GN, Hendricks RL, Paschal JF, Engstrom RE Jr, Sugar J. Herpes simplex keratitis in patients with acquired immune deficiency syndrome. Ophthalmology. 1989 Oct;96(10):1476-9. ENTRY MONTH 199108 LAST REVISION DATE 20000801 227 UNIQUE IDENTIFIER DRG-0119 NAME OF SUBSTANCE Valacyclovir hydrochloride [USPD 1998; p. 772] REGISTRY NUMBER 124832-27-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)m- ethoxy]ethyl ester, monohydrochloride [USPD 1998; p 772] SYNONYMS Valtrex [USP DI 2000; p. 3543] PROTOCOL ID NUMBERS Complete NIAID ACTG 204 PROTOCOL ID NUMBERS No longer recruiting FDA 104A PROTOCOL ID NUMBERS No longer recruiting FDA 104B PROTOCOL ID NUMBERS No longer recruiting FDA 104C PROTOCOL ID NUMBERS No longer recruiting FDA 291A PROTOCOL ID NUMBERS Terminated NIAID ACTG 253 PHARMACOLOGICAL ACTION MODE OF ACTION: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir has in vivo and in vitro inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV). In cell culture, acyclovir's highest antiviral activity is against HSV-1, followed in decreasing order of potency against HSV-2 and VZV. The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV, VZV, and EBV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. Binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. Following administration of radiolabeled valacyclovir to healthy subjects, 45.60% and 47.12% of radioactivity was recovered in the urine and feces over 96 hours, respectively. Acyclovir accounted for 88.6% of the radioactivity in the urine. In some patients with advanced HIV disease, the pharmacokinetics were no different from those observed in healthy volunteers. [PDR 1999; p 1239] DISEASES STUDIED/TREATED Oral valacyclovir is used for the treatment of acute, localized herpes zoster (shingles) and for the treatment of initial episodes of genital herpes infections in immunocompetent adults. Efficacy for the treatment of disseminated herpes zoster in immunocompromised adults has not been established. [AHFS Drug Information 1999; p 558] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 3084] OTHER MAJOR USES Treatment of herpes zoster (shingles) in immunocompetent adults; episodic treatment of recurrent genital herpes in immunocompetent adults. [PDR 1999; p 1239] SUBSTANCE INTERACTIONS Acyclovir may act synergistically with AZT. An additive increase in acyclovir AUC and Cmax was observed when Valtrex was administered to healthy volunteers who were taking cimetidine, probenecid, or a combination of both cimetidine and probenecid. The administration of cimetidine and probenecid, separately or together, reduced the rate but not the extent of conversion of valacylovir to acyclovir. The renal clearance of acyclovir was reduced, resulting in a higher concentration of acyclovir in plasma. [AmfAR Treat Dir 1993;6(4); p 15] ADVERSE EFFECTS Safe and well tolerated in immunocompetent individuals. The most common adverse events include headache, nausea, vomiting and diarrhea. WARNINGS: There have been reports of renal insufficiency and thrombotic microangiopathy (TMA) or thrombotic thrombocytopenia purpura when valacyclovir was administered to immunocompromised patients (advanced HIV disease or allogeneic bone marrow transplant or renal transplant) at a dose of 8 grams/day for prolonged periods. Results of a study at this dosage level show that 15 percent of subjects developed complications of cytomegalovirus disease. Gastrointestinal complaints occurred more often and earlier with subjects using valacyclovir rather than acyclovir. Signs of TMA occurred significantly more often in valacyclovir versus acyclovir users. Reduced survival rates compared to acyclovir were noted. [PDR 1999; p 1239; Protocol ID: DMID 98-022 ; Treat Update 1998 Mar;10(1) TU 85; p 4-6] CONTRAINDICATIONS Contraindicated in patients with advanced HIV disease and with known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation. [Burroughs Wellcome Fact sheet June 1995; PDR 1999; p 1239] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Valtrex is the hydrochloride salt of L-valyl ester of the antiviral drug acyclovir. [PDR 1999; p 1239] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H20-N6-O4.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 360.80 [USPD 1998; p. 772] CHEMICAL/PHYSICAL DATA Elemental Comp: C48.14%, H6.22%, N25.91%, O19.73% (base) [Merck Index 1996; p. 1689] CHEMICAL/PHYSICAL DATA Solubility: The maximum solubility in water at 25C is 174mg/ml. [Merck Index 1996; p 1689] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white powder. [PDR 1999; p 1239] SUBSTANCE DELIVERY DATA DOSAGE FORM: Caplets, 500 mg and 1 g. [PDR 1999; p 1241] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 1239] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-25 C (59-77 F). [PDR 1999; p 1241] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/99183825. Zerr DM, Frenkel LM. Advances in antiviral therapy. Curr Opin Pediatr 1999 Feb;11(1):21-7. MED/99152431. Wald A. New therapies and prevention strategies for genital herpes. Clin Infect Dis 1999 Jan;28. MED/99070083. Wood MJ, Shukla S, Fiddian AP, Crooks RJ. Treatment of acute herpes zoster: effect of early (<48 h) versus late (48-72 h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis 1998 Nov;178 Suppl 1:S81-4. MED/98396698. Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, Chambers LO, Robinson JM, Corey L. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J Infect Dis 1998 Sep;178(3):603-10. AIDS/98703828. High-dose valaciclovir linked to problems. Treat Update 1998 Mar;10(1):4-6. AIDS/97926650. Currier JS, Williams P, Feinberg J, Becker S, Owens S, Benson CA. ACTG 815: a prospective study of bacterial infections in advanced HIV disease. 4th Conf Retro and Opportun Infect 1997 Jan 22-26;:131 (abstract no. 364). AIDS/97926664. Wu AW, Jacobson D, Clark B, Brookmeyer R, Feinberg J. Quality of life associated with valacyclovir vs. high and low-dose acyclovir for prophylaxis against cytomegalovirus in AIDS. 4th Conf Retro and Opportun Infect 1997 Jan 22-26:119 (abstract no. 297). MED/97125603. Bowen EF, Griffiths PD, Davey CC, Emery VC, Johnson MA. Lessons from the natural history of cytomegalovirus. AIDS 1996 Nov;10 Suppl 1:S37-41. AIDS/98927580. De Bony F, Bidault R, Tod M, On N, Rolan P. Interaction of cimetidine and probenecid with valaciclovir and its metabolite acyclovir. Intersci Conf Antimicrob Agents Chemother 1996 Sep 15-18:6 (abstract no. A32). AIDS/98927862. Weinberg A, Schneider SA, Clark JC. Acyclovir (ACV) and valacyclovir (VAL) prophylaxis of AIDS patients does not alter cytomegalovirus (CMV) susceptibility to ganciclovir (GCV) or foscarnet (FOS). Program Abstr Intersci Conf Antimicrob Agents Chemother 1996 Sep 15-18:202 (abstract no. I87). ENTRY MONTH 199108 LAST REVISION DATE 20000801 228 UNIQUE IDENTIFIER DRG-0118 NAME OF SUBSTANCE Alvircept sudotox [USPD 1998; p. 41] REGISTRY NUMBER 137487-62-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 201 PROTOCOL ID NUMBERS No longer recruiting FDA 084A PROTOCOL ID NUMBERS No longer recruiting CC 91 I-155 PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro, CD4-PE40 selectively kills cells expressing gp120. It is inactive against cells latently infected with HIV and uninfected cells. Addition of CD4-PE40 to chronically infected HIV lymphocytes inhibited protein synthesis, an indication that the cells were highly sensitive to the hybrid toxin. CD4-PE40 (10nM) selectively kills chronically HIV-infected monocyte/macrophages (U1 cell line) and inhibits HIV-1 spread in primary macrophage cultures. The size of the CD4-PE40 molecule (60 kD) may be too large to cross the blood-brain barrier. Following an 80 mcg/m2 IV dose, peak serum concentrations of 65-130 ng/ml were reached. The drug's half-life was 3.6 hours. The volume of distribution approximated the volume of plasma (1.5 L/m2) with a clearance rate of 0.2-0.3 L/h/m2. [AmfAR Treat Dir 1995;7(4); p 22; J Infect Dis 1994 Nov;170(5); p 1180-88] DISEASES STUDIED/TREATED Primary HIV infection. [AmfAR Treat Dir 1995;7(4); p 22] CLASSIFICATION CODE Investigational - Antiviral [USPD 1998; p. 41] SUBSTANCE INTERACTIONS A strong synergistic activity exists between CD4(178)-PE40 and AZT in blocking HIV spread; a similar synergistic antiviral activity exists with ddI. [Int Conf AIDS 1990 Jun 20-23;6(1); 182 (abstract no. Th.A.248)] ADVERSE EFFECTS Fatigue and reversible hepatic toxicity have been noted in patients receiving up to 160 micrograms/m2. [AmfAR Treat Dir 1995;7(4); p 23; J Infect Dis 1994 Nov;170(5); p 1180-88] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Biotechnologically-derived chimeric protein engineered to link the first 178 amino acids of the extracellular domain of CD4 via two linker residues to amino acids 1-3 and 253-613 of Pseudomonas exotoxin A. [USAN 1997; p 39-40] CHEMICAL/PHYSICAL DATA Molecular Formula: C2600-H4130-N748-O812-S10 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 59,187 daltons [USPD 1998; p. 41] SUBSTANCE DELIVERY DATA DOSAGE FORM: IV Injection. [J Infect Dis 1994 Oct;170(4); p 1009-13] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [AmfAR Treat Dir 1995;7(4); p 22; J Infect Dis 1994 Oct;170(4); p 1009-13] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 REFERENCES AIDS/95920120. Fiscus S, Wathen L, Alston B, Flexner C, Kumar P, Lertura J, Meehan P, Mitsuyasu R, Wood K, Batts D, et al. Safety and efficacy of soluble CD4-pseudomonas exotoxin 40 in HIV infected individuals (ACTG 201). Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:70. MED/95052836. Davey RT Jr, Boenning CM, Herpin BR, Batts DH, Metcalf JA, Wathen L, Cox SR, Polis MA, Kovacs JA, Falloon J, et al. Use of recombinant soluble CD4 Pseudomonas exotoxin, a novel immunotoxin, for treatment of persons infected with human immunodeficiency virus. J Infect Dis. 1994 Nov;170(5):1180-8. MED/95016001. Ramachandran RV, Katzenstein DA, Wood R, Batts DH, Merigan TC. Failure of short-term CD4-PE40 infusions to reduce virus load in human immunodeficiency virus-infected persons. J Infect Dis. 1994 Oct;170(4):1009-13. MED/94145743. Winters MA, Merigan TC. Continuous presence of CD4-PE40 is required for antiviral activity against single-passage HIV isolates and infected peripheral blood mononuclear cells. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1091-6. ICA9/93335797. Alston B, Mitsuyasu R, Lertora J, Flexner C, Timpone J, van der Horst C. Phase I study of sCD4-PE40 in HIV infected persons: (ACTG 201). Int Conf AIDS. 1993 Jun 6-11;9(1):498 (abstract no. PO-B29-2178). ICA9/93335661. Davey RT Jr, Boenning CM, Herpin BR, Batts DH, Metcalf JA, Wathen L. A phase I multi-dose trial of CD4-Pseudomonas exotoxin (sCD4-PE40) in HIV-1-infected individuals. Int Conf AIDS. 1993 Jun 6-11;9(1):478 (abstract no. PO-B26-2060). MED/93297133. Kennedy PE, Moss B, Berger EA. Primary HIV-1 isolates refractory to neutralization by soluble CD4 are potently inhibited by CD4-Pseudomonas exotoxin. Virology. 1993 Jan;192(1):375-9. ICA8/92400069. Davey RT Jr, Boenning CM, Herpin BR, Batts DH, Walker RE, Polis MA, Falloon J, Kovacs JA, Masur H, Metcalf JA, et al. A phase I study of recombinant CD4-Pseudomonas exotoxin (CD4-PE40) in HIV-infected individuals. Int Conf AIDS. 1992 Jul 19-24;8(1):Mo8 (abstract no. MoB 0020). MED/93049387. Verhoef J, Gekker G, Erice A, Peterson PK, Balfour HH. Quantitative assay for testing susceptibility of HIV isolates to zidovudine and sCD4 (178)-PE40. Eur J Clin Microbiol Infect Dis. 1992 Aug;11(8):715-21. MED/92214927. Rubino KL, Tarpley WG, Nicholas JA. Effects of a soluble CD4 and CD4-Pseudomonas exotoxin A chimeric protein on human peripheral blood lymphocytes: lymphocyte activation and anti-HIV activity in vitro. Antiviral Res. 1991 Oct;16(3):267-79. ENTRY MONTH 199108 LAST REVISION DATE 20000801 229 UNIQUE IDENTIFIER DRG-0117 NAME OF SUBSTANCE Pentoxifylline [USPD 1998; p. 561] REGISTRY NUMBER 6493-05-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3,7-Dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-pu- rine-2,6-dione [Merck Index 1996; p 1228] SYNONYMS Trental [USP DI 2000; p. 2435] PROTOCOL ID NUMBERS Complete NIAID ACTG 160 PROTOCOL ID NUMBERS No longer recruiting FDA 118A PHARMACOLOGICAL ACTION MODE OF ACTION: Pentoxifylline and its metabolites improve the flow property of blood by decreasing its viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the affected microcirculation and enhances tissue oxygenation. The precise mode of action of this drug and the sequence of events leading to clinical improvement are still to be defined. Pentoxifylline administration has been shown to produce dose-related hemorrheologic effects, lowering blood viscosity, and improving erythrocyte flexibility. It has been shown to increase leukocyte deformability and to inhibit neurophil adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by therapeutic doses of this drug in patients with peripheral arterial disease. [PDR 1997; p 1292] DISEASES STUDIED/TREATED Under investigation for the treatment of HIV infection and Kaposi's sarcoma. [AmfAR Treat Dir 1997;8(3); p 76] CLASSIFICATION CODE Blood viscosity-reducing agent [USP DI 2000; p. 2433] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Indicated for the treatment of patients with intermittent claudication on the basis of occlusive arterial disease of the limbs. [PDR 1997; p 1292] SUBSTANCE INTERACTIONS Concomitant administration of pentoxifylline and anticoagulants or drugs that inhibit platelet aggregation may cause bleeding and/or prolonged prothrombin times in patients. [AHFS Drug Information 1997; p 1157] ADVERSE EFFECTS Adverse effects include fevers, nausea, vomiting, dizziness, bloating, flushing, arrhythmia, angina, diarrhea, headache, and insomnia. [PDR 1997; p 1292; AmfAR Treat Dir 1997;8(3); p 56] CONTRAINDICATIONS The drug should not be used in patients with recent cerebral and/or retinal hemorrhage or in patients who have previously exhibited intolerance to this product or methylxanthines such caffeine, theophylline, and theobromine. [PDR 1997; p 1292] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A tri-substituted xanthine derivative. [PDR 1997; p 1291] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H18-N4-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 278.31 [USPD 1998; p. 561] CHEMICAL/PHYSICAL DATA Melting Point: 105 C [Merck Index 1996; p. 1228] CHEMICAL/PHYSICAL DATA Elemental Comp: C56.10%, H6.52%, N20.13%, O17.25% [Merck Index 1996; p. 1228] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, benzene, ethanol, sparingly soluble in toluene. [PDR 1997; p 1292] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Bitter tasting, colorless needles from methanol. [Merck Index 1996; p 1228] SUBSTANCE DELIVERY DATA DOSAGE FORM: Pink, film-coated oblong tablets (400 mg). [PDR 1997; p 1293] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1291] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature (59-86 F). Protect from light. [PDR 1997; p 1293] MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Unspecified (888)242-9321 REFERENCES MED/97285081. Reeves GE, Ferguson JK, Dobson P, Boyle MJ. Pentoxifylline to treat Mycobacterium avium complex exacerbation in late-stage HIV infection [letter]. Med J Aust, 1997 Apr 21; 166:(8),446. ASHM8/97153601. Reeves G, Ferguson JK, Boyle MJ, Dobson P. Improved control of symptomatic Mycobacterium avium infection (MAI) with oxpentifylline (trental). Annu Conf Australes Soc HIV Med, 1996 Nov 14-17;(8):45 (abstract no. 19). ICA11/96921456. Hermida-Escobedo EC, Rivera-Leon L, Escobedo-de la Pena J. A double-blinded clinical trial to assess the effect of pentoxifylline in the inhibition of tumor necrosis factor production in patients with AIDS. Int Conf AIDS, 1996 Jul 7-12;11(1):123 (abstracr no.Mo.B.1394). ICA11/96924571. Piconi S, Fusi ML, Ruzzante S, Rizzardini G, Capetti A, Milazzo F, Clerici M. Immunologic evaluation of the effects of in vivo treatment with pentoxifylline in HIV seropositive individuals. Int Conf AIDS, 1996 Jul 7-12;11(2):281 (abstract no. Th.B.4177). MED/96314093. Navarro J, Punzon MC, Pizarro A, Fernandez-Cruz E, Fresno M, Munoz-Fernandez MA. Pentoxifylline inhibits acute HIV-1 replication in human T cells by a mechanism not involving inhibition of tumour necrosis factors synthesis or nuclear factor-kappa B activation. AIDS, 1996 May;10(5):469-75. MED/95287063. Dezube BJ, Lederman MM, Sprizler JG, Chapman B, Korvick JA, Flexner C, Dando S, Mattiacci MR, Ahlers CM, Zhang L, et al. High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. National Insitute of Allergy and Infection Diseases AIDS Clinical Trial Group. J Infect Dis. 1995 Jun; (6):1628-32. MED/96234442. Dezube BJ, Ledermann MM. Pentoxiffine for the treatment of HIV infection and its complication. J Cardiovasc Pharmacol. 1995;25 Suppl 2:S139-42. ICA10/94371004. Sonnabend J, Buimovici-Klein E, Freeman K, Smith B, Mohan V, Harrington M. Pentoxifylline (PTX) as a TNF inhibitor in HIV+ individuals. Int Conf AIDS. 1994 Aug 7-12:10(2):101(abstract no. PA0285). ICA10/94369607. Navarro A, Pizzaro A, Herranz P, Aguayo M, Leon M, Pujol E. Treatment of aphthous oral ulcers with pentoxifylline. Int Conf AIDS. 1994 Aug 7-12;10(10):183 (abstract no. PB0158). MED/94331513. Landmans D, Sarai A, Sathe SS. Use of pentoxifylline therapy for patients with AIDS-related wasting: pilot study. Clin Infect Dis. 1994 Jan;18(1):97-9. ENTRY MONTH 199106 LAST REVISION DATE 20000801 230 UNIQUE IDENTIFIER DRG-0116 NAME OF SUBSTANCE Nevirapine [USPD 1998; p. 505] REGISTRY NUMBER 129618-40-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 6H-Dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one- , 11-cyclopropyl-5,11-dihydro-4-methyl- [USPD 1998; p 505] SYNONYMS Viramune [USP DI 2000; p. 3545] PROTOCOL ID NUMBERS Complete NIAID ACTG 164 PROTOCOL ID NUMBERS Complete NIAID ACTG 165 PROTOCOL ID NUMBERS Complete NIAID ACTG 168 PROTOCOL ID NUMBERS Complete NIAID ACTG 180 PROTOCOL ID NUMBERS Complete NIAID ACTG 193A PROTOCOL ID NUMBERS Complete NIAID ACTG 208 PROTOCOL ID NUMBERS Complete NIAID ACTG 241 PROTOCOL ID NUMBERS Complete NIAID ACTG 244 PROTOCOL ID NUMBERS Complete NIAID ACTG 245 PROTOCOL ID NUMBERS Complete NIAID ACTG 250 PROTOCOL ID NUMBERS Complete NIAID ACTG 373 PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS No longer recruiting FDA 200B PROTOCOL ID NUMBERS No longer recruiting FDA 200C PROTOCOL ID NUMBERS No longer recruiting FDA 200D PROTOCOL ID NUMBERS No longer recruiting FDA 200E PROTOCOL ID NUMBERS No longer recruiting FDA 200F PROTOCOL ID NUMBERS No longer recruiting FDA 200G PROTOCOL ID NUMBERS No longer recruiting FDA 229C PROTOCOL ID NUMBERS No longer recruiting FDA 285B PROTOCOL ID NUMBERS No longer recruiting FDA 285D PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-192 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 316 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 316A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 316B PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 338 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 341 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 377 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 403 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5014 PROTOCOL ID NUMBERS No longer recruiting FDA ATLANTIC STUDY PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 012 PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 023 PROTOCOL ID NUMBERS Recruiting CC 97 I-082 PROTOCOL ID NUMBERS Recruiting CC 98 C-0041 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 356 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5093 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5103 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended NIAID ACTG P1022 PROTOCOL ID NUMBERS Terminated FDA 292D PHARMACOLOGICAL ACTION MODE OF ACTION: Nevirapine inhibits replication of HIV-1 by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). It binds directly to herodimeric HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor; it appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme. The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization, in a deep pocket lying between beta sheets of the palm and at the base of the thumb subdomains of the enzyme's p66 subunit. In the absence of nevirapine, the binding of deoxynucleoside triphosphate to the reverse transcriptase-template complex results in a change in the conformation of reverse transcriptase. This conformational change is followed by a magnesium-dependent chemical reaction in which deoxynucleoside triphosphate is incorporated into the newly forming viral DNA; the conformational change appears to be the rate-limiting step of the reverse transcriptase catalysis of viral DNA formation. Nevirapine appears to have no appreciable effect on the rate of equilibrium constant for the conformational change but may slow the chemical reaction, which then becomes the rate-limiting step in the catalytic sequence. When nevirapine binds to the reverse transcriptase-template complex, changes may occur in the position of aspartic acid carboxyl groups in reverse transcriptase so that magnesium ions are not in proper alignment for the chemical reaction to occur efficiently, and the reaction is slowed. Therefore, although the nevirapine-reverse transcriptase template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it appears to do so at a slower rate. HIV isolates with reduced susceptibility (100-250 fold) to nevirapine emerge in vitro. Time to emergence of nevirapine resistance in vitro was not altered when selection included nevirapine in combination with several other NNRTIs. Nevirapine is readily absorbed after oral administration. Peak plasma concentrations were attained 4 hours after a single 200-mg dose. Nevirapine is highly lipophilic and essentially nonionized at physiologic pH. It readily crosses the placenta and is found in breast milk. Nevirapine is extensively biotransformed via cytochrome P450 metabolism to form several hydroxylated metabolites, which are primarily eliminated via urinary excretion. [AHFS Drug Information 1999; p 602; PDR 1999; p 2766-7] DISEASES STUDIED/TREATED HIV infection. FDA approved 6/24/96 for use in combination with approved nucleoside analogues for treatment of HIV-infected adults who have experienced clinical and/or immunologic deterioration. [AmfAR Treat Dir 1997;8(3); p 33; Boehringer Ingelheim Pharmaceuticals Inc ] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 2247] CLASSIFICATION CODE Nonnucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 635] SUBSTANCE INTERACTIONS No dosage adjustments are required when nevirapine is taken with nucleoside analogues such as ZDV, ddI, or ddC. Also no dosage adjustments are needed when nevirapine is taken with ritonavir. Coadministration of nevirapine and indinavir led to decrease in availability of the indinavir. Lowered availability of saquinavir resulted when it was given with nevirapine. Nevirapine and ketoconazole should not be administered concomitantly. Nevirapine plasma concentrations were elevated when it was given with cimetidine or macrolides (known inhibitors of cytochrome P450 isozymes from the CYP3A family). Therefore, careful monitoring is recommended of the effectiveness of other CYP3A-metabolized drugs when they are given with nevirapine. [PDR 1999; p 2767] ADVERSE EFFECTS The most frequently reported adverse events related to therapy were rash, fever, nausea, headache, and abnormal liver function tests. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face, and extremities. The majority of severe rashes occurred within the first 28 days of treatment; 25% of the patients with severe rashes required hospitalization; and one patient required surgical intervention. All patients recovered. Overall 7% of patients discontinued treatment due to rash. Monitoring of liver function should be considered during drug therapy due to frequent asymptomatic elevations in GGT levels. [PDR 1999; p 2769] CONTRAINDICATIONS Nevirapine is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the tablet. Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens-Johnson syndrome. The drug must be discontinued in patients developing a severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise. [PDR 1999; p 2768] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Nevirapine is a dipyridodiazepinone derivative that acts as a nonnucleoside reverse transcriptase inhibitor. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 37] CHEMICAL/PHYSICAL DATA Molecular Formula: C15-H14-N4-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 266.30 [USPD 1998; p. 505] CHEMICAL/PHYSICAL DATA Melting Point: 247-249 C [Merck Index 1996; p. 1114] CHEMICAL/PHYSICAL DATA Elemental Comp: C67.65%, H5.30%, N21.04%, O6.01% [Merck Index 1996; p. 1114] CHEMICAL/PHYSICAL DATA Solubility: Solubility in water 0.1 mg/ml at neutral pH; highly soluble at PH<3. [Merck Index 1996; p 1114] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder. [Boehringer Ingelheim Pharmaceuticals Inc ; PDR 1997; p 2368] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, 200 mg. [PDR 1999; p 2769] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration. [PDR 1999; p 2769] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). The bottles should be kept tightly closed. [PDR 1999; p 2769] MANUFACTURERS 0000001072: Roxane Laboratories Inc 1809 Wilson Rd / PO Box 16532 Columbus, OH 432288601 Contact: Clinical and Medical Info (800)327-4865 MANUFACTURERS 0000002793: Boehringer Ingelheim Pharmaceuticals Inc 900 Ridgebury Rd / PO Box 368 Ridgefield, CT 068770368 Contact: General Information (800)595-5494 MANUFACTURERS 0000001072: Roxane Laboratories Inc 1809 Wilson Rd / PO Box 16532 Columbus, OH 432288601 Contact: Information (800)520-1631 MANUFACTURERS 0000002793: Boehringer Ingelheim Pharmaceuticals Inc 900 Ridgebury Rd / PO Box 368 Ridgefield, CT 068770368 Contact: Patient Assistance (800)274-8651 REFERENCES MED/99408509. Vazquez-Rosales G, Garcia Lerma JG, Yamamoto S, Switzer WM, Havlir D, Folks TM, Richman DD, Heneine W. Rapid screening of phenotypic resistance to nevirapine by direct analysis of HIV type 1 reverse transcriptase activity in plasma. AIDS Res Hum Retroviruses 1999 Sep 1;15(13):1191-1200. MED/99413730. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999 Sep 4;354(9181):795-802. MED/99413731. Marseille E, Kahn JG, Mmiro F, Guay L, Musoke P, Fowler MG, Jackson JB. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet 1999 Sep 4;354(9181):803-9. MED/99297587. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS 1999 May 28;13(8):957-62. MED/99208690. Murphy RL, Sommadossi JP, Lamson M, Hall DB, Myers M, Dusek A. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J Infect Dis 1999 May;179(5):1116-23. MED/99211233. Musoke P, Guay LA, Bagenda D, Mirochnick M, Nakabiito C, Fleming T, Elliott T, Horton S, Dransfield K, Pav JW, Murarka A, Allen M, Fowler MG, Mofenson L, Hom D, Mmiro F, Jackson JB. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999 Mar 11;13(4):479-86. MED/99087766. Zhou XJ, Sheiner LB, D'Aquila RT, Hughes MD, Hirsch MS, Fischl MA, Johnson VA, Myers M, Sommadossi JP. Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Antimicrob Agents Chemother 1999 Jan;43(1):121-8. MED/99125804. Floridia M, Bucciardini R, Ricciardulli D, Fragola V, Pirillo MF, Weimer LE, Tomino C, Giannini G, Galluzzo CM, Andreotti M, et al. A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease. J Acquir Immune Defic Syndr Hum Retrovirol 1999 Jan 1;20(1):11-9. MED/99113641. Pollard RB, Robinson P, Dransfield K. Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection. Clin Ther 1998 Nov-Dec;20(6):1071-92. Review. MED/98204327. Montaner JS, Reiss P, Cooper D, Veila S, Harris M, Conway B, Wainberg MA, Smith D, Robinson P, Hall D, Myers M, Lange JM. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial, Italy, The Netherlands, Canada and Australia Study. JAMA 1998 Mar 25;279(12):930-7. ENTRY MONTH 199105 LAST REVISION DATE 20000801 231 UNIQUE IDENTIFIER DRG-0115 NAME OF SUBSTANCE Octreotide [USPD 1998; p. 525] REGISTRY NUMBER 83150-76-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-t- ryptophyl-L-lysyl-L-thr eonyl-N-(2-hydroxy-1-(hydroxymethyl)propyl)-, cyclic (2->7)-disulfide, (R-(R*,R*))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Sandostatin [USP DI 2000; p. 2293] PROTOCOL ID NUMBERS No longer recruiting FDA 102A PROTOCOL ID NUMBERS No longer recruiting FDA 102B PHARMACOLOGICAL ACTION MODE OF ACTION: Exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin; it suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide; it also suppresses secretion of TSH. [PDR 1997; p 2421] DISEASES STUDIED/TREATED Under investigation for the treatment of cryptosporidiosis and HIV-related diarrhea. [AmfAR Treat Dir 1997;8(3); p 68] CLASSIFICATION CODE Antisecretory (gastric) [USPD 2000 p. 514] OTHER MAJOR USES Reduction of serum levels of growth hormone and IGF-I in acromegaly; symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease; treatment of the profuse watery diarrhea associated with VIP-secreting tumors. [PDR 1997; p 2422] SUBSTANCE INTERACTIONS Sandostatin has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection; patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance may require dose adjustments of these therapeutic agents. [PDR 1997; p 2422] ADVERSE EFFECTS Adverse effects include gallbladder abnormalities, especially stones and /or biliary sludge, frequently develop in patients on chronic treatment; sinus bradycardia, conduction abnormalities, and arrhythmias may develop in acromegalics; diarrhea, loose stools, nausea, abdominal discomfort and less frequently vomiting, flatulence, abnormal stools, abdominal distention, and constipation were reported in acromegalics; hypoglycemia, hyperglycemia, hypothryroidism, goiter in acromegalics; pain on injection; headache;dizziness. [PDR 1997; p 2422-3] CONTRAINDICATIONS Contraindicated in patients with known sensitivity to the drug or any of its components. [PDR 1997; p 2422] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Long-acting synthetic octapeptide analog of somatostatin that mimics the inhibitory action of the naturally occurring hormone somatostatin. [PDR 1997; p 2421] CHEMICAL/PHYSICAL DATA Molecular Formula: C49-H66-N10-O10-S2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 1019.26 [USPD 1998; p. 525] CHEMICAL/PHYSICAL DATA Elemental Comp: C57.74%, H6.53%, N13.74%, O15.70%, S6.29% [Merck Index 1996; p. 1162] CHEMICAL/PHYSICAL DATA Stability: Stable for 14 days at room temperature if protected from light. [PDR 1997; p 2423] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Clear solution. [PDR 1997; p 2421] SUBSTANCE DELIVERY DATA DOSAGE FORM: Ampules (50, 100, 500 mcg/ml); vials (200 and 1,000 mcg/ml). [PDR 1997; p 2423] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Deep subcutaneous (intrafat) or intravenous injection. [PDR 1997; p 2421] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: For prolonged storage, ampuls and multi-dose vials should be stored at 2-8 C (36-46 F) and protected from light. The drug is stable for 14 days at room temperature (20-30 C or 70-86 F) if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple dose vials should be discarded within 14 days. Ampuls should be opened just prior to administration and the unused portion discarded. [PDR 1997; p 2423] MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (888)669-6682 REFERENCES MED/96100583. Harris AG, Caroli-Bosc FX, Demarquay JF, Hastier P, Delmont J. Acute pancreatitis in an octreotide-treated AIDS patients-suggested alternative mechanisms [letter;comment]. Pancreas. 1995 Oct;11(3):318-9. MED/95286014. Kotler DP. Octreotide therapy for human immunodeficiency virus-associated diarrhea: pitfalls in drug development [editorial;comment]. Gastoenterology. 1995 Jun;108(6):1939-41. MED/95285990. Simon DM, Cello JP, Valenzuela J, Levy R, Dickerson G, Goodgame R, Brown M, Lyche K, Fessel WJ, Grendell J, et al. Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associate diarrhea [see comments] [published erratum appears in Gastroenterology 1995 Sep; 109(3):1024]. Gastroenterology. 1995 Jun;108(6):1753-60. MED/96397994. Beaugerie L, Baumer P, Chaussade S, Berard H, Rozenbaum W, Pialoux G, Le Quintrec Y, Schwartz JC, Lecomte JM. Treatment of refractory diarrhea in AIDS with acetorphan and octreotide: a randomized crossover study. Eur J Gastorenterol Hepatol. 1996 May;8(5):485-9. MED/95234258. Montaner JS, Harris AG. Octreotide therapy in AIDS-related refractory diarrhea: results of a multicentre Canadian-European study. Octreotide International Multicentre AIDS-Diarhea Study [letter]. AIDS. 1995 Feb;9(2):209-10. MED/95151233. Garcia Compean D, Ramos Jimenez J, Guzman de la Garza F, Saenz C, Maldonado H, Barragan RF, Michel H. Octreotide therapy of large-volume refractory AIDS-associated diarrhea: a randomized controlled trial. AIDS. 1994 Nov;8(11):1563-7. ICA10/94369623. Miranda-Ruiz R, Feregrino-Goyos M, Alvarado Diez R, Castanon GJ, Gallegos-Perez J, Eid-Lidt G. Experience of two years in therapy of AIDS hypersecretory diarrhea with octreotide. Int Conf AIDS. 1994 Aug 7-12;10(1):187 (abstract no. PB0177). MED/94317668. Mosdell KW, Visconti JA. Emerging indications for octreotide therapy, Part 1. Am J Hosp Pharm. 1994 May 1;51(9):1184-92. MED/94311336. Kovelesky RA, Minor JR. Octreotide for HIV-related diarrhea. Am J Hosp Pharm. 1994 Apr 15;51(8):996, 1001. MED/93221726. Manfredi R, Vezzadini P, Costigliola P, Ricchi E, Fanti MP, Chiodo F. Elevated plasma levels of vasoactive intestinal peptide in AIDS patients with refractory idiopathic diarrhea. Effects of treatment with octreotide. AIDS. 1993 Feb;7(2):223-6. ENTRY MONTH 199104 LAST REVISION DATE 20001107 232 UNIQUE IDENTIFIER DRG-0114 NAME OF SUBSTANCE Ranitidine hydrochloride [USPD 1998; p. 629] REGISTRY NUMBER 66357-59-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,1-Ethenediamine, N-(2-(((5-((dimethylamino)methyl)-2-furanyl)m- ethyl)thio)ethyl)-N'-me thyl-2-nitro-, monohydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Zantac [USP DI 2000; p. 3547] PROTOCOL ID NUMBERS Complete NIAID ACTG 136 PROTOCOL ID NUMBERS No longer recruiting FDA 135A PHARMACOLOGICAL ACTION MODE OF ACTION: Ranitidine competitively inhibits the action of histamine on the H2 receptors of parietal cells, reducing gastric acid secretion under daytime and nocturnal basal conditions and also when stimulated by food, insulin,amino acids, histamine, or pentagastrin. [AHFS Drug Information 1997; p 2305] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection / enhancement of drug interactions. [Antimicrob Agents Chemother 1992 Oct;36(10); p 2075-9; AmfAR Treat Dir 1995;7(4); p 23] CLASSIFICATION CODE Antiulcer agent [USP DI 2000; p. 1704] CLASSIFICATION CODE Gastric acid secretion inhibitor [USP DI 2000; p. 1704] CLASSIFICATION CODE Histamine (H2) receptor antagonist [USP DI 2000; p. 1704] OTHER MAJOR USES Short-term treatment and maintenance therapy of active duodenal ulcer. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis). Short-term treatment and maintenance therapy of active, benign gastric ulcer. Treatment of GERD. Treatment and maintenance therapy of endoscopically diagnosed erosive esophagitis. [PDR 1997; p 1183] SUBSTANCE INTERACTIONS Concomitant administration of ranitidine and an aluminum and magnesium hydroxides antacid (Mylanta-II) resulted in a 33% decrease in the absorption of rantidine; propantheline bromide appears to delay the absorption and increase the peak serum concentration of ranitidine, probably by delaying gastric emptying and prolonging transit time; cigarette smoking reportedly adversely effects the healing of duodenal ulcers and also appears to decrease the efficacy of ranitidine; increased or decreased prothrombin time has been reported during concomitant therapy with warfarin; ranitidine reportedly produced dose-dependent inhibition of acetaminophen metabolism in one in vitro study, although the clinical importance is not known; concomitant administration of rantidine may increase the concentration-time curve for nifedipine by about 30%. [Antimicrob Agents Chemother 1992 Oct;36(10); p 2075-9] ADVERSE EFFECTS Transient pain at the site of intramuscular injection; transient local burning or itching with IV injections. Headache, sometimes severe, seems to be related to Zantac administration. Other adverse effects rarely reported include CNS effects such as malaise, dizziness, somnolence, insomnia, vertigo, reversible mental confusion, agitation, depression, and hallucination, arrhythmias such as tachycardia, bradycardia, asystole, atrioventricular block, premature ventricular beats; constipation, diarrhea, nausea/vomiting, abdominal disconfort/pain, and pancreatitis; hepatitis, hepatocellular or hepatocanalicular or mixed, with or without jaundice; arthralgias and myalgias; blood count change, usually reversible; gynecomastia, and loss of libido in male patients; rash. [PDR 1997; p 1181, 1184; Physicians GenRx 1997; II-1819] CONTRAINDICATIONS Contraindicated in patients with known hyper sensitivity to drug or any of the ingredients. [PDR 1997; p 1181, 1183] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A histamine H2-receptor antagonist. [PDR 1997; p 1180] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H22-N4-O3-S.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 350.87 [USPD 1998; p. 629] CHEMICAL/PHYSICAL DATA Melting Point: 133-134 C [Merck Index 1996; p. 1395] CHEMICAL/PHYSICAL DATA Elemental Comp: C49.66%, H7.05%, N17.82%, O15.27%, S10.20% (base) [Merck Index 1996; p. 1395] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water and acetic acid, soluble in methanol sparingly soluble in ethanol, practically insoluble in chloroform. [Merck Index 1996; p 8288] CHEMICAL/PHYSICAL DATA Stability: Ranitidine injection is stable for up to 48 hours at room temperature when added to or diluted with most IV solutions. Pharmacy IV admixtures prepared from the bulk package should be used within 24 hours. [AHFS Drug Information 1997; p 2305] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to pale yellow, granular substance with a slightly bitter taste and sulfur-like odor. The injectable solution is a clear, colorless to yellow liquid. [AHFS Drug Information 1997; p 2304-5] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, capsules, granules, syrup, Injection, Injection Premixed, and Injection pharmacy bulk package. [Physicians GenRx 1997; p II-1817] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection, IV injection (intermittent Bolus, intermittent infusion or continuous infusion), oral ingestion. [PDR 1997; p 1181-2, 1184] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store single-dose and multidose Injection vials, and Injection pharmacy bulk packages between 4-30 C, store Injection Premixed between 2-25 C, and protected from light. Store tablets between 15-30 C, store capsules between 2-25 C, store granules between 2-30 C, store syrup between 4-25 C, in a dry place, and protected from light. [PDR 1997; p 1182, 1184] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES ASHM8/97153766. Mijch A, Tee W. High grade mucosal associated lymphoid tissue lymphoma (MATLTOMA) in HIV patients. Annu Conf Australas Soc HIV Med. 1996 Nov 14-7;8:142 (abstract no.185). MED/96162732. Fletcher CV, Henry WK, Noormohamed SE, Rhames FS, Balfour HH Jr. The effect of cimetidine and ranitidine administration with zidovudine. Pharmacotherapy. 1995 Nov-Dec;15(6):701-8. MED/96071143. Jurlander J, de Nully Brown P, Skov PS, Henrichsen J, Heron I, Obel N, Mortensen BT, Hansen MM, Geisler CH, Nielsen HJ. Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia. Leukemia. 1995 Nov;9(11):1902-9. AIDS/95920541. Bartlett JA, Berry PS, Bockmon KW, Stein A, Johnson J, Quinn JB, Weinhold KJ. A placebo controlled trial of ranitidine in HIV infection. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:149. MED/93073744. Knupp CA, Graziano FM, Dixon RM, Barbhaiya RH. Pharmacokinetic-interaction study of didanosine and ranitidine in patients seropositive for human immunodeficiency virus. Antimicrob Agents Chemother. 1992 Oct;36(10):2075-9. MED/92006421. Hartman NR, Yarchoan R, Pluda JM, Thomas RV, Wyvill KM, Flora KP, Broder S, Johns DG. Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications. Clin Pharmacol Ther. 1991 Sep;50(3):278-85. MED/91217917. Nielson HJ, Svenningsen A, Moesgaard F, Georgsen J, Pedersen C, Mathiesen L, Dickmeiss E, Nielsen JO, Kehlet H. Ranitidine improves certain cellular immune responses in asymptomatic HIV-infected individuals. J Acquir Defic Syndr. 1991;4(6):577-84. ICA6/30047090. Hartman NR, Yarchoan R, Thomas RV, Pluda JM, Marczyk KS, Broder S, Johns DG. Effect of different oral preparations and presence of other medications on the pharmacokinetics of 2',3'-dideoxyinosine. Int Conf AIDS. 1990 Jun 20-23;6(3):203 (abstract no. S.B.470). ENTRY MONTH 199104 LAST REVISION DATE 20000801 233 UNIQUE IDENTIFIER DRG-0113 NAME OF SUBSTANCE Hypericin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 548-04-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,3,4,6,8,13-Hexahydroxy-10,11-dimethylphenan- thro (1,10,9,8,-opqra)perylene-7,14-dione [Merck Index 1996; p 835] PROTOCOL ID NUMBERS Complete NIAID ACTG 150 PROTOCOL ID NUMBERS Complete NIAID ACTG 258 PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro, hypericin inhibits the assembly and budding of virions from infected cells, possibly by direct inactivation of virions or by interfering with shedding of assembled virus particles at the cell membrane. Hypericin and pseudohypericin inhibit protein kinase C (PKC) in vitro. The antiretroviral activity of the compounds may be attributable to the inhibition of phosphorylation by PKC during viral infection of cells. The inactivation of HIV by hypericin is dependent on the presence of light. In one study natural hypericin was provided in a single dose to mice 24 hours after experimental infection with Friend leukemia virus (FV). The treated mice survived more than 240 days after infection as compared with 15 to 30 days for untreated controls. It has been shown that synthetic hypericin enters lymphocytes and macrophages in vitro. In addition, hypericin decreases HIV in vitro in whole blood obtained from HIV infected individuals. A phase I dose escalatory trial of synthetic hypericin showed the serum half-life of the compound was shorter than expected (about 24 hours). Oral formulation of hypericin has also been tested. Preliminary pharmacokinetic data indicates that oral bioavailability ranges from 14%-22%. A long-term (48-72 months) clinical trial of hypericin with HIV positive patients showed decline in viral load in most patients. In some patients there was an increase of viral load without effect on the clinical conditions of viral CMV (cytomegalovirus), herpes, or EBV (Epstein-Barr Virus) complications. [Int Conf AIDS 1996 Jul 7-12;11(1):18; p 120 (abstract no.Mo.B.1377); Proc Natl Acad Sci USA 1993 Jan 1;90(1); p 158-62] DISEASES STUDIED/TREATED HIV infection. [AmfAR Treat Dir 1995;7(4); p 44; Am J Hosp Pharm 1994 Feb 15;51(4); P 2251-67] CLASSIFICATION CODE Investigational - Virucidal agent [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Antidepressant, astringent and diuretic, anticancer agent [Merck Index 1989; p 773; Martindale: The Extra Pharmacopoeia 1993; p 1378] ADVERSE EFFECTS Dose-limiting reversible photosensitivity, requiring withdrawal of some patients, was observed at 0.5 mg/kg. This reaction manifests itself as a tingling or burning sensation in the skin, or hypersensitivity to cold or hot. Reversible elevated liver function tests have been associated with over-the-counter hypericin containing extracts (St. Johns wort). [AmfAR Treat Dir 1995;7(4); p 44] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An aromatic polycyclic dione, extracted from the herb Hypericum triquetrifolium Turra (St. John's Wort) by several successive extractions followed by chromatographic procedures. [AmfAR Treat Dir 1995;7(4); p 44] CHEMICAL/PHYSICAL DATA Molecular Formula: C30-H16-O8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 504.45 [Merck Index 1996; p. 835] CHEMICAL/PHYSICAL DATA Elemental Comp: C71.43%, H3.20%, O25.37% [Merck Index 1996; p. 835] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in pyridine and other organic bases; almost insoluble in most other organic solvents. Soluble in alkaline aqueous solutions. [Merck Index 1996; p 835] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Solvated blue-black needles from pyridine and methanolic HCL. [Merck Index 1996; p 835] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous, oral. [AmfAR Treat Dir 1995;7(4); p 44] MANUFACTURERS 0000001222: VIMRx Pharmaceuticals Inc 9 Parker Avenue Irvine, CA 92618 Contact: Unspecified (302)998-1734 REFERENCES MED/98002853. Sattler S, Schaefer U, Schneider W, Hoelzl J, Lehr CM. Binding, uptake, and transport of hypericin by Caco-2 cell monolayers. J Pharm Sci 1997 Oct;86(10):1120-6. MED/98002175. Brockmoller J, Reum T, Bauer S, Kerb R, Hubner WD, Roots I. Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 1997 Sep;30 Suppl 2:94-101. MED/97142490. Dewilde A, Pellieux C, Hajjam S, Wattre P, Pierlot C, Hober D, Aubry JM. Virucidal activity of pure singlet oxygen generated by thermolysis of a water-soluble naphthalene endoperoxide. J Photochem Photobiol B 1996 Oct;36(1):23-9. ICA11/96921439. Vonsover A, Steinbeck KA, Rudich C, Mazur Y, Lavie D, Mandel M, Lavie G. HIV-1 virus load in the serum of AIDS patients undergoing long term therapy with hypericin. Int Conf AIDS. 1996 Jul 7-12;11(1):120 (abstract no.Mo.B.1377). ICA11/96922328. Pitisuttithum P, Migasena S, Suntharasamai P, Sutthan R, Perathamanond P, Wasi C, Shikan U, Peeters P, Tobia AJ. Hypericin: safety and antiretroviral activity in Thai HIV-positive volunteers. Inf Conf AIDS. 1996 Jul 7-12;11(1):285 (abstract no.Tu.B.2121). ICA11/96924501. Sandmann M, Bottcher J, Schmutz G, Hower M, Gehring P, Baier JE. Complementary therapies in HIV-infected patients-a multicenter study. Int Conf AIDS. 1996 Jul 7-12;11(2):269 (abstract no.Th.B.4099). MED/96044410. Diwu Z. Novel therapeutic and diagnostic applications of hypocrellins and hypericins. Photochem Photobiol 1995 Jun;61 (6):529-39. MED/95252512. Dwyer JT, Salvato-Schille AM, Coulston A, Casey VA, Cooper WC, Selles WD. The use of unconventional remedies among HIV-positive men living in California. J Assoc Nurses AIDS Care. 1995 Jan-Feb;6(1):17-28. MED/95062597. Hudson JB, Zhou J, Chen J, Harris L, Yip L, Towers GH. Hypocrellin, from Hypocrella bambuase, is phototoxic to human immunodeficiency virus. Photochem Photobiol. 1994 Sep;60(3):253-5. ICA9/93335618. Steinbeck-Klose A, Wernet P. Successful long term treatment over 40 months of HIV-patients with intravenous Hypericin. Int Conf AIDS. 1993 Jun 6-11;9(1):470 (abstract no. PO-B26-2012). ENTRY MONTH 199104 LAST REVISION DATE 20000801 234 UNIQUE IDENTIFIER DRG-0112 NAME OF SUBSTANCE Amikacin sulfate [USPD 1998; p. 46] REGISTRY NUMBER 39831-55-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME D-Streptamine, O-3-amino-3-deoxy-alpha-D-glucopyranosyl-(1-6- )-O-(6-amino-6-deoxy-al pha-D-glucopyranosyl-(1-4))-N(sup 1)-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-, (S)-, sulfate (1:2)(salt) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Amikin [USP DI 2000; p. 84] PROTOCOL ID NUMBERS Complete NIAID ACTG 135 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PHARMACOLOGICAL ACTION MODE OF ACTION: Antibacterial. Rapidly absorbed after intramuscular injection and well tolerated. Mean serum half life of slightly over 2 hours. Excreted primarily by glomular filtration. Following administration of recommended dose, therapeutic levels are found in bone, heart, gall bladder and lung, as well as significant concentrations in urine, bile, sputum, bronchial secretions, interstitial, synovial, and pleural fluids. Amikacin is active in vitro against the gram negative organisms from the Pseudomonas species, Escherichia coli, Proteus species, Providencia species, Klebsiella-Enterobacter-Serratia species, Acinetobacter species, and Citrobacter freundii. It is also active in vitro against the gram positive organisms from the penicillinase- and non-penicillinase- producing Staphylococcus species. Aminoglycosides in general have low activity against other gram positive organisms. Amikacin resists degradation by most aminoglycoside inactivating enzymes. [PDR 1998; p 536-7; 900] DISEASES STUDIED/TREATED Under investigation in combination therapy for Mycobacterium avium complex (MAC). [AmfAR Treat Dir 1997 Dec; p 50] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 79] OTHER MAJOR USES Indicated in the short term treatment of serious infections due to susceptible strains of gram-negative bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (Mima-Herellea) species. [PDR 1998; p 900] SUBSTANCE INTERACTIONS The concurrent or serial use of other ototoxic or nephrotoxic agents should be avoided because of the potential for additive effects. Increased nephrotoxicity has been reported following concurrent use of aminoglycoside antibiotics and cephalosporins. In vitro, mixing of aminoglycosides and beta-lactam antibiotics (pencillins or cephalosporins) results in significant mutual deactivation. [PDR 1998; p 900-1] ADVERSE EFFECTS May possibly induce auditory/vestibular dysfunction, renal toxicity, and neuromuscular blockade. May cause irreversible deafness in children when given to pregnant women. May cause nausea, vomiting, anemia, and rash. [PDR 1998; p 901; Protocol ID: ACTG 238 ] CONTRAINDICATIONS Aminoglycosides can cause fetal harm when administered to pregnant women. Elderly patients may have reduced renal functions. Monitoring of renal functions in these patients during amikacin treatment is important. Amikacin should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism. Cross-allergenicity among the aminoglycoside antibiotics has been demonstrated. Contraindicated in patients with history of hypersensitivity to amikacin or with history of hypersensitivity or serious toxic reactions to aminoglycosides. [PDR 1998; p 900-1] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semisynthetic aminoglycoside antibiotic derived from kanamycin A (free base). [Merck Index 1996; p 72] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H43-N5-O13.2H2-S-O4 [USPD 1998; p. 46] CHEMICAL/PHYSICAL DATA Molecular Weight: 781.77 [USPD 1998; p. 46] CHEMICAL/PHYSICAL DATA Elemental Comp: C45.12%, H7.40%, N11.96%, O35.52% (base) [Merck Index 1996; p. 72] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in water. [AHFS Drug Information 1997; p 62] CHEMICAL/PHYSICAL DATA Stability: Stable at room temperature for 24 hours at concentrations of 0.25 and 5 mg/ml in certain solutions (e.g., 5% Dextrose Injection, USP). Undiluted are stable for 2 yrs. [AHFS Drug Information 1997; p 62] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystaline powder [AHFS Drug Information 1997; p 62] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 100 and 500 mg/2 ml or 1 g/4 ml and disposable syringes containing 50 mg/2 ml. [PDR 1998; p 538,901] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: IV or IM injection. [PDR 1998; p 901] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Room temperature. [PDR 1998; p 538, 901] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/98088807. Itokazu GS, Weinstein RA. Aerosolized antimicrobials: another look (editorial; comment). Crit Care Med 1998 Jan;26(1):5-6. MED/98084900. Okhravi N, Towler HM, Hykin P, Matheson M, Lightman S. Assessment of a standard treatment protocol on visual outcome following presumed bacterial endophthalmitis (see comments). Br J Ophthalmol 1997 Sep;81(9):719-25. MED/97070524. Rastogi N, Goh KS, Bryskier A, Devallois A. Spectrum of activity of levofloxacin against nontuberculous mycobacteria and its activity against the Mycobacterium avium complex in combination with ethambutol, rifampin, roxithromycin, amikacin, and clofazimine. Antimicrob Agents Chemother. 1996 Nov;40(11):2483-7. AIDS/98927999. Chambers HF, Turner J, Wagner C, Schecter G, Hopewell P. Imipenem (Imi) + amikacin (AK) in combination chemotherapy of multiple-drug resistant (MDR) tuberculosis (TB). Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18; :285 (abstract no. LM27). MED/97030413. Fisher M, Tomlinson DR, Coker RJ. The management of mycobacterial infections in HIV seropositive individuals. Jefferiss Wing Therapeutics and Protocols Group (see comments). Int J STD AIDS. 1996 Jul;7(4):244-9; quiz 249-51. MED/97012627. Pellegrin I, Maugein J, Lapeyre C, Barbeau P, Leng B, Pellegrin JL. Activity of rifabutin, clarithromycin, ethambutol, sparfloxacin and amikacin, alone and in combination, against Mycobacterium avium complex in human macrophages. J Antimicrob Chemother. 1996 Mar;37(3):501-10. MED/97004293. Yajko DM, Sanders CA, Madej JJ, Cawthon VL, Hadley WK. In vitro activities of rifabutin, azithromycin, ciprofloxacin, clarithromycin, clofazimine, ethambutol, and amikacin in combinations of two, three, and four drugs against Mycobacterium avium. Antimicrob Agents Chemother. 1996 Mar;40(3):743-9. MED/95314203. Fattorini L, Li B, Piersimoni C, Tortoli E, Xiao Y, Santoro C, Ricci ML, Orefici G. In vitro and ex vivo activities of antimicrobial agents used in combination with clarithromycin, with or without amikacin, against Mycobacterium avium. Antimicrob Agents Chemother. 1995 Mar;39 (3):680-5. AIDS/95920040. Parent D, Ellner J, Hafner R, Williams M, Jacobs P, Hojczyk P. A phase II/III trial of Rifampin (RIF) Ciprofloxach (CIPRO), Clofazimine (CLOF), Ethambutol (ETH), +/- Amikacin (AK) in the treatment (RX) of Disseminated Mycobacterium avium (MA) infection in HIV-infected individuals (PTS). Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:56. AIDS/96700801. Ferreira T. Disseminated MAC: current treatment strategies. STEP Perspect. 1995 Summer;7(2):15-6. ENTRY MONTH 199104 LAST REVISION DATE 20001107 235 UNIQUE IDENTIFIER DRG-0111 NAME OF SUBSTANCE Ethambutol hydrochloride [USPD 1998; p. 287] REGISTRY NUMBER 1070-11-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Butanol, 2,2'-(1,2-ethanediyldiimino)bis-, dihydrochloride, (S-(R*,R*))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Myambutol [USP DI 2000; p. 1484] PROTOCOL ID NUMBERS Complete NIAID ACTG 135 PROTOCOL ID NUMBERS Complete NIAID ACTG 222 PROTOCOL ID NUMBERS Complete NIAID ACTG 223 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting FDA 048D PROTOCOL ID NUMBERS No longer recruiting FDA 048E PROTOCOL ID NUMBERS No longer recruiting FDA 214A PROTOCOL ID NUMBERS No longer recruiting FDA 226B PROTOCOL ID NUMBERS No longer recruiting FDA 275A PROTOCOL ID NUMBERS No longer recruiting CC 92 I-165 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 309 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 007 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 027 PHARMACOLOGICAL ACTION MODE OF ACTION: Diffuses into actively growing mycobacterium cells such as tubercle bacilli and appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. About 75-80% of an oral dose is rapidly absorbed from the gastrointestinal tract. Following a single oral dose of 25 mg/kg of body weight, the drug attains a peak of 2 to 5 micrograms/mL in serum 2 to 4 hours after administration. The serum level of the drug falls below detectable levels by 24 hours after the last dose except in some patients with abnormal renal function. In patients with normal renal function the plasma half-life is about 3.3 hours. In patients with renal failure the half-life may be 7 hours or more. Approximately 50% of the initial dose is excreted in the urine, while an additional 8% to 15% appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehyde intermediate, followed by conversion to a dicarboxylic acid. From 20-22% of the initial dose is excreted in the feces as unchanged drug. [PDR 1997; p 1432; AHFS Drug Information 1997; p 420-1] DISEASES STUDIED/TREATED Approved as an anti-mycobacterial antibotic used in combination regimens for tuberculosis. Under investigation in combination therapy for Mycobacterium avium complex (MAC). Should be used in conjunction with at least one other antituberculous drug. Drugs used with ethambutol have included isoniazid, streptomycin, cycloserine, ethionamide, pyrazinamide, viomycin, and aminosalicylic acid. [AmfAR Treat Dir 1997;8(3); p 70; Protocol ID: ACTG 135 ; AHFS Drug Information 1995; p 377-80] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 1480] OTHER MAJOR USES Myambutol is indicated for the treatment of pulmonary tuberculosis in conjunction with other antituberculous drugs (at least one). [PDR 1997; p 1432] SUBSTANCE INTERACTIONS Concurrent administration of ethambutol with other neurotoxic drugs, e.g, stavudine, zalcitabine, etc., may increase the potential for neurotoxicity such as optic and peripheral neuritis. [USP DI 1995; p 1279] ADVERSE EFFECTS The most important adverse effect is optic neuritis with decreases in visual acuity, constriction of visual fields, central and peripheral scotomas, and loss of red-green color discrimination. The extent of ocular toxicity appears to be related to the dose and duration of ethambutol therapy. Other adverse effects include dermatitis, pruritis, headache, malaise, dizziness, fever, mental confusion, disorientation, possible hallucinations, joint pain, and rarely anaphylactic reactions. GI upset, abdominal pain, nausea, vomiting, and anorexia have occured occasionally; peripheral neuritis, with numbness and tingling of the extremities, infrequently; increased serum uric acid concentrations and precipitation of acute gout; transient impairment of liver functions; and cholestatic jaundice. [AHFS Drug Information 1997; p 421] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to ethambutol hydrochloride and those with known optic neuritis unless clinical judgement determines that it can be used. [PDR 1997; p 1432] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic, bacteriostatic antituberculosis agent. [AHFS Drug Information 1997; p 420] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H24-N2-O2.2Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 277.24 [USPD 1998; p. 287] CHEMICAL/PHYSICAL DATA Melting Point: 201.8-202.6 C [Merck Index 1996; p. 635] CHEMICAL/PHYSICAL DATA Elemental Comp: C58.79%, H11.84%, N13.71%, O15.66% (base) [Merck Index 1996; p. 635] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water, DMSO; sparingly soluble in ethanol; soluble with difficulty in acetone, chloroform. [Merck Index 1996; p 635] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, crystalline powder. [AHFS Drug Information 1997; p 420] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (100 and 400 mg). [PDR 1997; p 1433] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1432-3] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature 15-30 C (59-86 F). Tablets should be protected from light, moisture, and excessive heat and should be well-closed. [PDR 1997; p 1433; AHFS Drug Information 1997; p 420] MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr Amy Baim (914)732-2147 MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr John Riefler (914)732-2035 REFERENCES MED/97206889. Chaisson RE;, Keiser P, Pierce M, Fessel WJ, Ruskin J, Lahart C, Benson CA, Meek K, Siepman N, Craft JC. Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex diease in patients with HIV infection. AIDS, 1997 Mar:11(3):311-7. MED/97247099. French AL, Benator DA, Gordin FM. Nontuberculous mycobacterial infection. Med Clin North Am, 1997 Mar;81(2):361-79. MED/97221882. Peloquin CA. Mycobacterium avium complex infection. Pharmacokinetic and pharmacodynamic considerations that improve clinical outcomes. Clin Pharmacokinet, 1997 Feb;32(2):132-44. MED/97099171. Rooney G, Nelson MR, Gazzard B. Mycobacterium kansasii: its presentation, treatment and outcome in HIV infected patients. J Clin Pathol. 1996 Oct;49(10):821-3. MED/97042403. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, Quinn TC, Halsey NA. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med. 1996 Oct;154:4 Pt 1;1034-8. MED/96293367. Shafran SD, Singer J, Zarowny DP, Phillips P, Salit I, Walmsley SL, Fong IW, Gill IW, Gill MJ, Rachlis AR, Lalonde RG, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group [see comments]. N Engl J Med. 1996 Aug 8;335(6):377-83. ICA11/96922552. Singer J, Thorne A, Raboud JM, Fanning M, Toma E, Turgeon F, Duperval R, Schlech WF, Cameron DW, Smaill FM, et al. The canadian randomized open-label trial of combination therapy for MAC bacteremia: quality of life outcomes. Int Conf AIDS. 1996 Jul 7-12;11(1):325 (abstract no.Tu.B.2350). AIDS/96920206. Dube M, Sattler F, Torriani F, See D, Havlir D, Kemper C, Dezfuli M, Bozzette S, Bartok A, Leedom J. Prevention of relapse of MAC bacteremia in AIDS: a randomized study of clarithromycin plus clofazimine, with or without ethambutol. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:91. MED/94284631. Kemper CA, Havlir D, Haghighat D, Dube M, Bartok AE, Sison JP, Yao Y, Yangco B, Leedom JM, Tilles JG, et al. The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS. J Infect Dis. 1994 Jul;170(1):157-64. AIDS/96920603. Chaisson RE, Keiser P, Pierce M, Fessel WJ, Ruskin J, Lahart C, Meek K. Controlled trial of clarithromycin/ethambutol with or without clofazimine for Mycobacterium avium complex bacteremia in AIDS. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:164. ENTRY MONTH 199104 LAST REVISION DATE 20000801 236 UNIQUE IDENTIFIER DRG-0110 NAME OF SUBSTANCE Ciprofloxacin hydrochloride [USPD 1998; p. 171] REGISTRY NUMBER 86393-32-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-quinolinecarboxylic acid [Merck Index 1996; p 389] SYNONYMS Ciloxan [USP DI 2000; p. 899] SYNONYMS Cipro [USP DI 2000; p. 1654] PROTOCOL ID NUMBERS Complete NIAID ACTG 135 PHARMACOLOGICAL ACTION MODE OF ACTION: Antibacterial against a wide range of gram- positive and gram-negative organisms; bactericidal action results from interference with the enzyme DNA gyrase needed for the synthesis of bacterial DNA. The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously. The serum elimination half-life is approximately 5-6 hours and the total clearance is around 35 liter/hour. After intravenous administration, approximately 50-70% of the dose is excreted in the urine as unchanged drug; three metabolites of ciprofloxacin have been identified in urine which together account for approximately 10% of the intravenous dose; approximately 15% of the IV dose is recovered from the feces within 5 days after dosing; drug accumulation is not observed in patients. [PDR 1997; p 588, 590-1] DISEASES STUDIED/TREATED Approved as an oral antibiotic used for treatment of several common bacterial infections; under investigation for combination therapy of Mycobacterium avium infection. [AmfAR Treat Dir 1997;8(3); p 69] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 1556] OTHER MAJOR USES Cipro I.V. is indicated for the treatment of mild, moderate, severe, and complicated urinary tract infections; mild to moderate lower respiratory tract infections; mild to moderate skin and skin structure infections; and mild to moderate bone and joint infections. [PDR 1997; p 588, 591] SUBSTANCE INTERACTIONS Concurrent administration of theophylline may lead to elevated plasma concentrations of theophylline and increase the risk of theophylline adverse reactions. Ciprofloxacin absorption may be decreased by antacids containing magnesium, aluminum or calcium, by sucralfate or by divalent and trivalent cations such as iron in multivitamin and mineral preparations. Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly. Quinolones have also enhanced the effects of warfarin or other coumarin derivatives and therefore prothrombin times should be monitored. Caffeine metabolism may be affected, increasing its serum half-life. In vitro, ciprofloxacin exhibits synergism with aminoglycosides and beta-lactam antibiotics; however, clinical effects vary. Probenecid interferes with renal tubular secretion of ciprofloxacin. [PDR 1997; p 589, 592] ADVERSE EFFECTS The most frequently reported events, without regard to drug relationship, among patients treated with intravenous ciprofloxacin were nausea, diarrhea, central nervous system disturbance, local intravenous site reactions, abnormalities of liver associated enzymes, eosinophilia, headache, restlessness, and rash. [PDR 1997; p 589, 592] CONTRAINDICATIONS Contraindicated in patients with history of hypersensitivity to ciprofloxacin or any member of the quinolone class of antimicrobial agents. [PDR 1997; p 588, 591] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fluorinated quinolone with the fluorine at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position. [PDR 1997; p 587] CHEMICAL/PHYSICAL DATA Molecular Formula: C17-H18-F-N3-O3.Cl-H.H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 385.82 [USPD 1998; p. 171] CHEMICAL/PHYSICAL DATA Melting Point: 318-320 C [Merck Index 1996; p. 390] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.62%, H5.48%, F5.73%, N12.68%, O14.49% (base) [Merck Index 1996; p. 389] CHEMICAL/PHYSICAL DATA Solubility: Soluble in 0.1N hydrochloric acid and practically insoluble in water and ethanol. [PDR 1997; p 587, 590] CHEMICAL/PHYSICAL DATA Stability: Ciprofloxacin injection 1% (10 mg/ml), when diluted with appropriate intravenous solutions to concentrations of 0.5 to 2.0 mg/ml, is stable for up to 14 days at refrigerated or room temperature. [PDR 1997; p 590, 593] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Faint to light yellow crystalline powder. [PDR 1997; p 587, 590] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials (Cipro I.V.; 200 mg/20 ml, and 400 mg/40ml); flexible containers (Cipro I.V.; 200 mg/100 ml, and 400 mg/200 ml); tablets (Cipro; 250, 500, 750 mg). [PDR 1997; p 590, 593] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous (Cipro I.V.; Ciprofloxacin); and oral (Cipro tablets; Ciprofloxacin hydrochloride). [PDR 1997; p 590, 592] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Vials should be stored between 5-30 C (41-86 F), flexible containers should be stored between 5-25 C (41-77 F), and protected from light, excessive heat (a temperature exceeding 40 C), and freezing. Tablets should be stored in tight containers at a temperature less than 30 C, and protected from intense UV light. [PDR 1997; p 590, 593; AHFS Drug Information 1997; p 574] MANUFACTURERS 0000001074: Miles Inc Pharmaceutical Division 400 Morgan Lane West Haven, CT 06516 Contact: Dr Kenneth Kashkin (203)937-2468 MANUFACTURERS 0000005293: Alcon Laboratories Inc 6201 South Freeway Fort Worth, TX 761342099 Contact: Unspecified (800)288-8371 MANUFACTURERS 0000005230: Bayer Corporation 400 Morgan Lane West Haven, CT 065164175 Contact: Unspecified (800)288-8371 REFERENCES MED/97244227. Singh G, Thomas PD, Blackwell AL. An audit of the problems in management of patients with gonorrhea. Int J STD AIDS. 1997 Mar; 8(3):208-9. MED/97221882. Peloquin CA. Mycobacterium avium complex infection. Pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes. Clin Pharmacokinet. 1997 Feb; 32(2):132-44. MED/97070461. Sesin GP, Manzi SF, Pacheco R. New trends in the drug therapy of localized and disseminated Mycobacterium avium complex infection. Am J Health Syst Pharm, 1996 Nov 1; 53:(21), 2585-90. MED/96293367. Shafran SD, Singer J, Zarowny DP, Phillips P, Salit I, Walmsley SL, Fong IW, Gill MJ, Rachlis AR, Lalonde RG, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group [see comments]. N Engl J Med. 1996 Aug 8;335(6):377-83. ICA11/96923579. Verdier RI, Pape JW. Comparative therapy for Coccidia species. Int Conf AIDS. 1996 Jul 7-12;11(2):95 (abstract no.We.B.3226). ICA11/96924249. Malonza I, Tyndall M, Hawken M, Bukusi E, MacDonald K, Maclean I, Perriens J, Ronald AR, Ndinya-Achola JO, Moses S. Randomized, double-blind, placebo-controlled clinical trial of erythromycin and ciprofloxacin in the treatment of chancroid. Int Conf AIDS. 1996 Jul 7-12;11(2);219 (abstract no.Th.B.111). ICA11/96922552. Singer J, Thorne A, Raboud JM, Fanning M, Toma E, Turgeon F, Duperval R, Schlech WF, Cameron DW, Smaill FM, et al. The canadian randomized open-label trial of combination therapy for MAC bacteremia: quality of life outcomes. Int Conf AIDS. 1996 Jul 7-12;11(1):325 (abstract no.Tu.B.2350). MED/96309052. Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, Ngowi FI, Ramsay AR, Saruni AO, Sam N, et al. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis. 1996 May;22(5):827-33. MED/96156285. Porco FV, Visconte EB. Pseudomonas aeruginosa as a cause of infectious diarrhea successfully treated with oral ciprofloxacin. Ann Pharmacother. 1995 Nov;29(11):1122-3. MED/95385410. Stevens JP, Daniel TM. Chemoprophylaxis of multidrug-resistant tuberculous infection in HIV-uninfected individuals using ciprofloxacin and pyrazinamide. A decision analysis. Chest. 1995 Sep;108(3):712-7. ENTRY MONTH 199104 LAST REVISION DATE 20000801 237 UNIQUE IDENTIFIER DRG-0109 NAME OF SUBSTANCE Rifampin [USPD 1998; p. 637] REGISTRY NUMBER 13292-46-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3-(((4-Methyl-1-piperazinyl)imino)-methyl)rif- amycin [Merck Index 1996; p 1413] SYNONYMS component of Rifater [USP DI 2000; p. 3519] SYNONYMS Rifadin [USP DI 2000; p. 2672] SYNONYMS Rifadin I.V. [USP DI 2000; p. 2673] SYNONYMS Rimactane [USP DI 2000; p. 2672] PROTOCOL ID NUMBERS Complete NIAID ACTG 135 PROTOCOL ID NUMBERS Complete NIAID ACTG 177 PROTOCOL ID NUMBERS Complete NIAID ACTG 222 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 309 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 004 PHARMACOLOGICAL ACTION MODE OF ACTION: Inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Readily absorbed from the GI tract. Peak blood levels in normal adults vary widely from individual to individual. The peak level averages 7 micrograms/ml but may vary from 4 to 32 micrograms/ml. Absorption of rifampin is reduced when the drug is ingested with food. In normal subjects, the biological half-life of rifampin in serum averages about 3 hours after a 600 mg oral dose, with increases up to 5.1 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2-3 hours. It does not differ in patients with renal failure at doses not exceeding 600 mg daily. After absorption, rifampin is rapidly eliminated in the bile, and an enterohepatic circulation ensues. During this process, rifampin undergoes progressive deacetylation so that nearly all the drug in the bile is in this form in about 6 hours. Up to 30% of the dose is excreted in the urine, with about half of this being unchanged drug. Rifampin is 80% protein bound during oral or intravenous administration. After intravenous administration of a 300 or 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers (n=11), mean peak plasma concentrations were 9.0 and 17.5 micrograms/ml, respectively. [PDR 1997; p 1276] DISEASES STUDIED/TREATED Approved as an anti-mycobacterial drug for the treatment of tuberculosis. Under investigation in combination regimens as treatment for Mycobacterium avium infection and prophylaxis for tuberculosis. Frequently used regimens are rifampin and isoniazid; rifampin, isoniazid, and pyrazinamide; rifampin, isoniazid, and ethambutol; and rifampin and ethambutol. [AmfAR Treat Dir 1995;7(4); p 70; PDR 1997; p 1277] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 2665] OTHER MAJOR USES A standard treatment for tuberculosis in combination drug therapy; it is being investigated for tuberculosis prophylaxis. Also indicated for asymptomatic carriers of Neisseria meningitidis, and not to be used for the treatment of meningococcal infections. [PDR 1997; p 1277; AmfAR Treat Dir 1997;8(3); p 1278] SUBSTANCE INTERACTIONS Has liver enzyme-inducing properties and may reduce the activity of a number of drugs, including anticoagulants, corticosteroids, cyclosporine, cardiac glycosides, quinidine, oral contraceptives, oral hypoglycemic agents (sulfonylureas), dapsone, narcotics, and analgesics. May diminish the effects of concurrently administered methadone, barbiturates, diazepam, verapamil, beta-adrenergic blockers, clofibrate, progestins, disopyramide, mexiletine, theophylline, chloramphenicol, and anticonvulsants. Paraaminosalicylic acid has been reported to decrease rifampin blood levels. Probenecid has been reported to increase rifampin blood levels. Halothane, when given concomitantly with rifampin, has been reported to increase the hepatotoxicity of both drugs. Ketoconazole, when given concomitantly with rifampin, has been reported to diminish the serum concentrations of both drugs. An interaction has also been reported with rifampin-isoniazid and vitamin D. [PDR 1997; p 1277] ADVERSE EFFECTS Adverse effects include the following, gastrointestinal: heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea; hematologic, thrombocytopenia, cerebral hemorrhage and fatalities after appearance of purpura, transient leukopenia, hemolytic anemia, and decreased hemoglobin; central nervous system: headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, generalized numbness, myopathy rarely; ocular: visual disturbances; endocrine: menstrual disturbances; renal: elevations in BUN and serum uric acid, and rarely hemolysis, hemoglobinuria, hematuria, interstitial nephritis, renal insufficiency, and acute renal failure; dermatologic: flushing, itching with or without a rash; hypersensitivity reactions: pruritus, urticaria, rash, pemphigoid reaction, eosinophilia, sore mouth, sore tongue, and conjunctivitis. Other adverse effects may include edema of the face and extremities, flu symptoms (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. [PDR 1997; p 1277] CONTRAINDICATIONS Contraindicated in patients with history of hypersensitivity to any of the rifamycins or impaired liver function. [PDR 1997; p 1277] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semisynthetic antibiotic derivative of rifamycin B. Rifampin is obtained by reacting 3-formylrifamycin SV with 1-amino-4-methylpiperazine in tetrahydrofuran. [PDR 1997; p 1276] CHEMICAL/PHYSICAL DATA Molecular Formula: C43-H58-N4-O12 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 822.96 [USPD 1998; p. 637] CHEMICAL/PHYSICAL DATA Elemental Comp: C62.76%, H7.10%, N6.81%, O23.33% [Merck Index 1996; p. 1414] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in CH3Cl, DMSO; soluble in ethyl acetate, methanol, tetrahydrofuran; slightly soluble in water, acetone, carbon tetrachloride. [Merck Index 1996; p 1414] CHEMICAL/PHYSICAL DATA Stability: The reconstituted solution for injection is stable at room temperature for 24 hrs. When added to the recommended dextrose 5% for injection infusion the solution is stable for 4 hours. Extemporaneously prepared oral suspensions are stable for 4 wks at room temperature or when refrigerated at 2-8 C. [PDR 1997; p 1278] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Red brown crystalline powder. [PDR 1997; p 1276] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (150,300 mg) or lyophilized powder (600 mg) in glass vials. [PDR 1997; p 1278] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: IV infusion; oral ingestion [PDR 1997; p 1278] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Keep capsules in tightly closed containers in a dry place; avoid excessive heat. Keep lyophilized powder away from excessive heat (temperature above 40C or 104F), and protected from light. [PDR 1997; p 1278] MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Unspecified (888)242-9321 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Unspecified (888)242-9321 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Medical Information (800)633-1610 REFERENCES MED/97247099. French AL, Benator DA, Gordin FM. Nontuberculous mycobacterial infections. Med Clin North Am. 1997 Mar;81(2)361-79. MED/97221882. Peloquin CA. Mycobacterium avium complex infection. Pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes. Clin Pharmcokinet. 1997 Feb;32(2):132-44 MED/97215051. Pozniak A. Tuberculous meningitis [letter]. Int J STD AIDS. 1997 Feb;8(2):139-40. AIDS/97926449. Gallicano K; Sahai J; Foster B; Bouchard J; Cameron DW. Rifampin (R) decreases zidovudine (Z) plasma concentrations in HIV infected patients. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:177 (abstract no. 612). AIDS/97926688. Whalen C, Okwera A, Johnson J, Nsubuga P, Hom D, Loughlin A, Myanja H, Mugerwa R, Ellner J. Preventive therapy for tuberculosis in HIV-infected Ugandans. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:131 (abstract no. 363). AIDS/97926836. Pedral-Sampaio DB, Netto EM, Alcantara AP, Souza J, Moura L, Silva N, Bina JC, Brites C, Badaro R. Increased frequency of adverse reactions with standard therapy for tuberculosis in HIV patients. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:186 (abstract no. 659a). AIDS/97702171. Anonymous. Treating concurrent HIV and TB. Centers for Disease Control and Prevention. AIDS Clin Care. 1996 Dec; 8(12):87-100, 104. MED/97015631. Espinal MA, Reingold AL, PaEerez G, Camilo E, Soto S, Cruz E, Matos N, Gonzalez G. Human immunodeficiency virus infection in children with tuberculosis in Santo Domingo, Dominican Republic: prevalance, clinical findings, and response to antituberculosis treatment. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Oct 1;13(2):155-9. MED/97042403. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, Quinn TC, Halsey NA. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med. 1996 Oct;154(4):Pt 1 1034-8. MED/95166277. PerriAens JH, St. Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portaels F, Willame JC, Mandala JK, Kaboto M, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months [see comments]. N Engl J Med. 1995 Mar 23;332(12):779-84. ENTRY MONTH 199104 LAST REVISION DATE 20000801 238 UNIQUE IDENTIFIER DRG-0108 NAME OF SUBSTANCE Pentosan polysulfate sodium [USPD 1998; p. 560] REGISTRY NUMBER 116001-96-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME beta-D-Xylan, (1->4), 2,3-bis(hydrogen sulfate), sodium salt [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Elmiron [USP DI 2000; p. 2429] PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-69 PHARMACOLOGICAL ACTION MODE OF ACTION: Pentosan is cleared from the body via desulfation in the liver and spleen, and depolymerization in the kidney, with excretion in the urine of desulfated, lower molecular weight material. A little of the drug (4-8%) is excreted unchanged in the urine so it appears that the drug is eliminated mainly by a metabolic process. There is some evidence that the desulfation and depolymerization mechanisms can be saturated at pharmacologically relevant doses. Elimination follows a bimodal distribution, with an initial rapid clearance of an IV dose (90% cleared by 80 mins) followed by a slower second phase. Terminal half-life of this second phase is between 24 and 193 hours. Because of saturation of degradation pathways, the possibility exists of increased drug accumulation with prolonged administration. Peak levels appear to be related to the administered parental dose in a linear fashion. Peak levels obtained 60-80 mins following SC administration were 1/10 obtained following the same dose IV. Oral absorption has been found to be < 10% (and likely is substantially less). Studies have shown pentosan to possess anti-retroviral activity in vitro. One hypothesis of the mechanism for this anti-retroviral activity was inhibition of reverse transcriptase. However, it is currently believed that it acts by a mechanism other than this. It is also believed the mechanism of action is a CD4-independent mechanism. It has been discovered that pentosan inhibits the activities of protein tyrosine kinases from lymphocytes and rat lung in a concentration dependent manner. These results suggest that the ability of pentosan polysulfate to inhibit various protein serine/threonine and tyrosine kinases may be one of the mechanisms by which this compound exerts its inhibitory effect of HIV-1 replication. Pentosan is also reported to have anti-tumor activity. Two mechanisms for this activity have been proposed 1) antagonizes the binding of FGF to its cell surface receptors in certain cell lines (but unlikely this is the sole mechanism because pentosan exhibits antitumor activity against cell lines which do not respond to FGF and full inhibition requires greater than 7 days); and 2) inhibits EGF tyrosine kinase activity in cell lysate but not in intact cells. [Mol Cell Biochem 1993 Mar 24;120(2); p 127-33; Int Conf AIDS 1990 Jun 20-23;6(1); 179 (abstract no Th.A.238); Protocol ID: 90 C-69 p 3-4] DISEASES STUDIED/TREATED Primary HIV infection; Kaposi's sarcoma. [Protocol ID: 90 C-69 ; Martindale: The Extra Pharmacopoeia 1993; p 233-34] CLASSIFICATION CODE Anti-inflammatory (interstitial nephritis) [USP DI 2000; p. 2428] CLASSIFICATION CODE Investigational - Virion receptor binding antagonist [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Anticoagulant, especially during the immediate post-operative period. Orphan drug indication for interstitial cystitis. [USP DI 1995; p 2989-90; Protocol ID: 90 C-69 p 3] SUBSTANCE INTERACTIONS May react synergistically with AZT. [AIDS Res Hum Retroviruses 1990 May;6(5); p 679-89] ADVERSE EFFECTS Use as an anticoagulant has been associated with relatively little toxicity. Elevations of hepatic transaminases have been reported, as well as decreases in hemoglobin and thrombocytopenia. Animal studies with long term administration (>3 mos) have revealed abnormalities of the spleen, liver, kidney, thyroid, adrenal and pituitary glands, especially at high doses. Sterile abscesses were seen at SC injection sites, again mainly at higher doses. Side effects which occur rarely include the following: headache, dizziness, nausea, diarrhea, dyspepsia, peripheral edema and skin rash. [Protocol ID: 90 C-69 p 4] CONTRAINDICATIONS Contraindicated in patients with a history of bleeding diasthesis that was not self-limited, history of hepatic cirrhosis or present hepatic dysfunction, hypersensitivity to pentosan or other sulfated polysaccharides. Also contraindicated in pregnant women. [Protocol ID: 90 C-69 p 7] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semi-synthetic sulfated polyanion composed of beta-D-xylopyranose residues with properties similar to heparin (polysulfate); synthesized by treatment of hemicellulose from beech wood; chemically related to the drug suramin, a sulfated naphthylurea. [Merck Index 1996; p 1227] CHEMICAL/PHYSICAL DATA Molecular Formula: (C5-H6-Na2-O10-S2)n (n=6 to 12) [USPD 1998; p. 560] CHEMICAL/PHYSICAL DATA Molecular Weight: 4000 to 6000 [USP DI 2000; p. 2428] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water. [Merck Index 1996; p 1228] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White odorless powder, slightly hygroscopic (polysulfate sodium). [Merck Index 1996; p 1228] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular (IM), intravenous (IV), subcutaneous (SC) and oral (although absorption is poor with oral dosage form). [Int Conf AIDS 1989 Jun 4-9;5; p 401 (abstract no. W.B.P. 299); Protocol ID: 90 C-69 ; USP DI 1995; p 2990] MANUFACTURERS 0000003417: Natl Cancer Institute 9000 Rockville Pike / Clinical Ctr Bethesda, MD 20892 Contact: Jill Lietzau (800)772-5464 MANUFACTURERS 0000003966: Baker Norton Pharmaceuticals 4400 Biscayne Blvd Miami, FL 33137 Contact: Kathy Wyvill (800)772-5464 REFERENCES MED/97046048. Schwartsmann G, Sprinz E, Kalakun L, Yamagushi N, Sander E, Grivicich I, Koya R, Mans DR. Phase II study of pentosan polysulfate (PPS) in patients with AIDS-related Kaposi's sarcoma. Tumori. 1996 Jul-Aug;82(4):360-3. MED/94139798. Hampson SJ, Woodhouse CR. Sodium pentosanpolysulphate in the management of haemorrhagic cystitis: experience with 14 patients. Eur Urol. 1994;25(1):40-2. MED/94127472. Tardy-Poncet B, Tardy B, Grelac F, Reynaud J, Mismetti P, Bertrand JC, Guyotat D. Pentosan polysulfate-induced thrombocytopenia and thrombosis. Am J Hematol. 1994 Mar;45(3):252-7. MED/95118877. Goad KE, Horne MK 3rd, Gralnick HR. Pentosan-induced thrombocytopenia: support for an immune complex mechanism. Br J Haematol. 1994 Dec;88(4):803-8. MED/94016647. Pluda JM, Shay LE, Foli A, Tannenbaum S, Cohen PJ, Goldspiel BR, Adamo D, Cooper MR, Broder S, Yarchoan R. Administration of pentosan polysulfate to patients with human immunodeficiency virus-associated Kaposi's sarcoma. J Natl Cancer Inst. 1993 Oct 6;85(19):1585-92. ICDB/93694418. Schwartsmann G, Sander E, Prolla G, Sprinz E, Zampese M, Vinholes J, Jung F, Kronfeld M, Kalakun L, Mans DA, et al. Phase II trial of pentosan polysulfate (PPS) in patients (pts) with AIDS-related Kaposi's sarcoma (KS) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol. 1993;12:A18. MED/93347328. Parsons CL, Benson G, Childs SJ, Hanno P, Sant GR, Webster G. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate. J Urol. 1993 Sep;150(3):845-8. MED/92054617. Maffrand JP, Herbert JM, Bernat A, Defreyn G, Delebassee D, Savi P, Pinot JJ, Sampol J. Experimental and clinical pharmacology of pentosan polysulfate. Semin Thromb Hemost. 1991;17 Suppl 2:186-98. ENTRY MONTH 199104 LAST REVISION DATE 20001107 239 UNIQUE IDENTIFIER DRG-0107 NAME OF SUBSTANCE Env 2-3 [AmfAR Treat Dir 1997;8(3); p 58] PROTOCOL ID NUMBERS Complete NIAID ACTG 214 PROTOCOL ID NUMBERS Complete NIAID AVEG 005A/B PROTOCOL ID NUMBERS Complete NIAID AVEG 005C PROTOCOL ID NUMBERS Complete NIAID AVEG 008 PROTOCOL ID NUMBERS Complete NIAID AVEG 103 PHARMACOLOGICAL ACTION MODE OF ACTION: It is theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cellular immune responses. Researchers have shown Env 2-3 to stimulate production of antibodies against the envelope glycoprotein, gp120 of HIV. Evidence of CD4 cell priming and lymphoproliferative responses have also been observed. [AmfAR Treat Dir 1997;8(3); p 58; Protocol ID: AVEG 005 ] DISEASES STUDIED/TREATED Primary HIV infection. [AmfAR Treat Dir 1997;8(3); p 58] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 008 ] SUBSTANCE INTERACTIONS Interacts with immunosuppressive medications. [Protocol ID: AVEG 005 p 10] ADVERSE EFFECTS ENV 2,3 alone is well tolerated. Researchers have shown that 40% of patients who received ENV 2,3 with MTP-PE experienced severe local or systemic reactions including malaise, myalgia, headache and moderate fever. Those who received vaccine without adjuvant experienced severe local or systemic reactions at a rate of 7-8%. [AmfAR Treat Dir 1997;8(3); p 59] CONTRAINDICATIONS Contraindicated in patients with history of immunodeficiency, chronic illness, or autoimmune disease. [Protocol ID: AVEG 005 p 10] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: ENV 2,3 is a non-glycosylated, fully denatured recombinant polypeptide modeled on envelope glycoprotein gp120. It is derived from the SF-2 strain of HIV-1 and propagated in yeast cells. [AmfAR Treat Dir 1997;8(3); p 58] CHEMICAL/PHYSICAL DATA Molecular Weight: 55 kd [Protocol ID: AVEG 005 p 4] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Clear solution. [Protocol ID: AVEG 005 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Single dose vials in a sterile aqueous solution of 0.35 ml per vial. Can be administered alone, but also has been administered with a combination of muramyl tripeptide (MTP- PE) and an emulsion (MF59). [AmfAR Treat Dir 1997;8(3); p 58; Protocol ID: AVEG 005 p 9] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: IM injection. [AmfAR Treat Dir 1997;8(3); p 58] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Keep frozen below -10 C. Thaw at 45 C for one hour to solubilize the antigen contents. Bring the vial to room temperature. Vortex lightly for about 5 seconds. Before use, make sure the solution is clear (or slightly opalescent) with no visible particulates. Inject as soon as possible, but no longer than 4 hours after preparation. [Protocol ID: AVEG 005 p 9] MANUFACTURERS 0000001094: BIOCINE Co 4560 Horton St Emeryville, CA 946082916 Contact: Dr David Chernoff (510)601-2775 REFERENCES ICA9/93335769. Corey L, McElrath J, Keefer M, Paxton W, Sposto R, Chernoff D. A phase I HIV-1 vaccine trial in asymptomatic HIV-infected individuals using ENV 2,3 in MF59 with or without MTP-PE. Int Conf AIDS. 1993 Jun 6-11;9(1):494 (abstract no. PO-B28-2152). ICA9/93334143. McElrath J, Keefer M, Greenberg P, Sposto R, Chernoff D, Steimer K. Evaluation of a nonglycosylated yeast-derived envelope vaccine on HIV-1 specific immunity in a randomized, blinded, controlled HIV-1 seropositive trial. Int Conf AIDS. 1993 Jun 6-11;9(1):246 (abstract no. PO-A28-0670). ICA8/92400162. Haigwood N, Yoshiyama H, McClure J, Ho DD, Steimer KS. Neutralization of primary HIV-1 isolates by sera from primates immunized with recombinant HIV-SF2 gp120. Int Conf AIDS. 1992 Jul 19-24;8(1):Tu27 (abstract no. TuA 0504). ICA8/92400528. Dolin R, Corey L, Graham B, Wright P, McElrath J, Keefer M, Matthews T, Stablein D, Dekker C. Safety and immunogenicity of an HIV vaccine candidate, env 2-3, in combination with MTP-PE/MF59. Int Conf AIDS. 1992 Jul 19-24;8(2):A40 (abstract no. PoA 2226). MED/91108143. Wintsch J, Chaignat CL, Braun DG, Jeannet M, Stalder H, Abrignani S, Montagna D, Clavijo F, Moret P, Dayer JM, et al. Safety and immunogenicity of a genetically engineered human immunodeficiency virus vaccine. J Infect Dis. 1991 Feb;163(2):219-25. ENTRY MONTH 199105 LAST REVISION DATE 20000801 240 UNIQUE IDENTIFIER DRG-0106 NAME OF SUBSTANCE MTP-PE/MF59 [Int Conf AIDS 1992 Jul 19-24;8(2); A40 (abstract no. PoA 2226)] STANDARD CHEMICAL NAME L-Alaninamide, N-(N-acetylmuramoyl)-L-alanyl-D-alpha- glutaminyl-N- (4-hydroxy-10--oxo-7((1-oxohexadecyl)oxy)-3,5- ,9- trioxa-4-phosphapen tacos-1-yl)--, P-oxide, (R)- [CHEMLINE ] PROTOCOL ID NUMBERS Complete NIAID AVEG 005A/B PROTOCOL ID NUMBERS Complete NIAID AVEG 007A/B PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PROTOCOL ID NUMBERS Complete NIAID AVEG 103 PHARMACOLOGICAL ACTION MODE OF ACTION: A biological response modifier, with immunomodulating activities, that is believed to act by the mechanism of macrophage-monocyte activation. Used as an adjuvant or substance that augments the immune response to vaccines. A recent trial combining ENV 2-3/MTP-PE/MF59 showed this combination of virus and adjuvant emulsion is reactogenic and stimulates high rates of serum antibody responses as detected by WB and ELISA. [Int Conf AIDS 1992 Jul 19-24;8(2); A40 (abstract no. PoA 2226); Protocol ID: AVEG 005 p 1-2] DISEASES STUDIED/TREATED Primary HIV-infection - as a vaccine adjuvant for enhancement of the immune response. [AmfAR Treat Dir 1993;6(4); p 37-38] CLASSIFICATION CODE Immunologic adjuvant [Protocol ID: AVEG 015 ] OTHER MAJOR USES Vaccine adjuvant. Treatment of osteosarcoma [Protocol ID: AVEG 005 p 3; J Clin Oncol 1995 April; p 93-9] ADVERSE EFFECTS Adverse effects include mild to moderate local pain at the site of injection, mild erythema at the site of injection, fatigue, myalgia, eyelid burning, feverishness, buzzing in the head, limb pain, indisposition, headache, back pain, dysuria, ear pressure. Laboratory evidence may include transient increase in leukocytes (absolute neutrophili) starting at 4-6 hours post injection, but never rising above the normal range, transient increase in fibrinogen at 48 hours, increased sedimentation rate, transient drop in serum iron at 24 hours. [Int Conf AIDS 1996 Jul 7-12;11(1); Mo9 (abstract no. MoB 0025); Protocol ID: AVEG 005 p 3] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A muramyl tripeptide (MTP) linked covalently with dipalmitoyl phosphatidylethanolamine (PE). The active ingredient is a fully synthetic lipophilic derivative of the naturally occurring muramyl dipeptide (MDP). Used as an adjuvant emulsion, MTP-PE/MF59. Prepared by the emulsion process titled MF59. The emulsifier system, consisting of polysorbate 80 (Tween 80, polyoxyethylene sorbitan monooleate) and sorbitan trioleate (Span 85, Arlacel 85), prevents coalescence of the dispersed droplets. Emulsification, by high pressure homogenization, results in a physically stable emulsion with a mean droplet size of less than 200 nm. In this oil-in-water emulsion, squalene constitutes the oil phase. MTP-PE is expected to be situated at the interface of the aqueous and oil phases and act as a weak co-emulsifier. [Int Conf AIDS 1996 Jul 7-12;11(1); Mo9 (Abstract no. MoB 0025)] SUBSTANCE DELIVERY DATA DOSAGE FORM: Used in an oil-in-water emulsion. [Protocol ID: AVEG 005 p 7] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection (IM). [Int Conf AIDS 1992 Jul 19-24;8(2); A40 (abstract no. PoA 2226)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refrigerate. [Protocol ID: AVEG 005 p 9] MANUFACTURERS 0000001094: BIOCINE Co 4560 Horton St Emeryville, CA 946082916 Contact: Dr David Chernoff (510)601-2775 REFERENCES MED/96301139. Graham BS, Keefer MC, McElrath MJ, Gorse GJ, Schwartz DH, Weinhold K, Esterlitz JR, Sinangil F, Fast PE. Safety and immunogenicity of a candidate HIV-1 vaccine in health adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. Ann Intern Med. 1996 Aug 15;125(4):270-9. ICA11/96923724. Duliege AM, Sinangil F, Walker C, Dekker C, Boggio K, Clements ML, McElrath J, Kahn J, Graham B, Excler JL, et al. Recombinant HIV subunit vaccines development: a collaborative effort. Int Conf AIDS. 1996 Jul 7-12;11(2):122 (abstract no.We.B.3376). ICA11/96920850. McElrath MJ, Montefiori D, Wolff M, Clements M, Gorse G, Keefer M, Graham B, Duliege AM, Francis D, Matthews T. Safety, immunity, and risk behavior in HIV-1 uninfected volunteers representing diverse risk populations following recombinant envelope vaccinations: a three-year follow-up. Int Conf AIDS. 1996 Jul 7-12;11(1):10 (abstract no.Mo.A.284). MED/96303587. Keefer MC, Graham BS, McElrath MJ, Matthews TJ, Stablein DM, Corey L, Wright PF, Lawrence D, Fast PE, Weinhold K, et al. Safety and immunogenicity of Env 2-3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP-PE/MF59. NIAID AIDS Vaccine Evaluation Group. AIDS Res Hum Retrovirsuses, 1996 May 20;12(8):683-93. AIDS/95920551. Lambert JS, McNamara J, Katz S, Livingston R, Fenton T, Geheb H, Duliege AM, Francis D, Volvowitz F, Hawkins E, et al. Safety and immunogenicity of recombinant envelope HIV vaccines in asymptomatic HIV infected children. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:151. MED/95274866. Langenberg AG, Burke RL, Adair SF, Sekulovich R, Tigges M, Dekker CL, Corey L. A recombinant glycoprotein vaccine for herpes simplex type 2: safety and efficacy. Ann Intern Med. 1995 Jun 15;122(12):889-98. MED/95208659. Kleinerman ES, Gano JB, Johnston DA, Benjamin RS, Jaffe N. Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma. Am J Clin Oncol 1995 Apr;18(2):93-9. MED/95052854. Kahn JO, Sinangil F, Baenziger J, Murcar N, Wynne D, Coleman RL, Steimer KS, Dekker CL, Chernoff D. Clinical and immunologic responses to human immunodeficiency virus (HIV) type 1SF2 gp120 subunit vaccine combined with MF59 adjuvant with or without muramyl tripeptide dipalmitoyl phosphatidylethanolamine in non-HIV-infected human volunteers. J Infect Dis. 1994 Nov;170(5):1288-91. MED/94293161. Bui T, Dykers T, Hu SL, Faltynek CR, Ho RJ. Effect of MTP-PE liposomes and interleukin-7 on induction of antibody and cell-mediated immune responses to a recombinant HIV-envelope protein. J Acquir Immune Defic Syndr. 1994 Aug;7(8):799-806. ICA9/93336304. Kahn J, Chernoff D, Sinangil F, Baenziger J, Murcar N, Steimer K. Phase 1 study of an HIV-1 gp 120 vaccine combined with MF59 and with dose escalation of MTP-PE, in sero-negative adults. Int Conf AIDS. 1993 Jun 6-11;9(1):70 (abstract no. WS-B27-2). ENTRY MONTH 199104 LAST REVISION DATE 20000801 241 UNIQUE IDENTIFIER DRG-0105 NAME OF SUBSTANCE L-697,661 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 184 PROTOCOL ID NUMBERS No longer recruiting CC 91 I-112 PROTOCOL ID NUMBERS No longer recruiting CC 91 I-74 PHARMACOLOGICAL ACTION MODE OF ACTION: L-697,661 is a non-nucleoside pyridinone derivative with in vitro activities comparable to other non-nucleoside reverse transcriptase inhibitors (nevirapine, BHAP compounds, and TIBO derivatives). However, all these compounds have unique structures. L-697,661 inhibits HIV-1 reverse transcriptase through direct binding with the enzyme. HIV-1 variants highly resistant to L-697,661 were found to emerge rapidly during treatment. In a 6 week trial, patients had a rapid dose-related decrease in p24 antigen levels; however, this response virtually disappeared in some patients, coincidentally with the emergence of resistant viruses. This change in susceptibility was more frequent in patients receiving higher doses (500 mg orally every 12 h) and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene. Researchers have since identified other non-nucleoside reverse transcriptase inhibitors which inhibit virus resistance to L-697,661. A randomized controlled clinical trial of 135 patients (CD4+ T cell count < or = 500/mm3), compared zidovudine (500 mg/day) versus L-697,661 (50, 300, or 1,000 mg daily). At 1 week, patients treated with either 300 or 1,000 mg daily of L-697,661 showed significant decreases from baseline in plasma standard and ICD p24 antigen and QC-PCR-determined HIV-1 RNA levels. Whereas viral load decreases seen with zidovudine were sustained for the duration of treatment, plasma viral markers often returned to pretreatment levels despite ongoing L-697,661 treatment, with evidence of the emergence of drug-resistant virus. [AmfAR Treat Dir 1993;6(4); p 45-46; N Engl J Med 1993 Oct 7;329(15); P 1065-72; J Acquir Immune Defic Syndr Hum Retrovirol 1995 Oct 1;10(2); p 139-49] DISEASES STUDIED/TREATED Primary HIV infection. [AmfAR Treat Dir 1993;6(3); p 45-46] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE INTERACTIONS The manufacturer suggests that combination treatment with AZT may delay the development of resistance to L-697,661. Possibly interacts with experimental drugs and antiretroviral drugs. [AmfAR Treat Dir 1993;6(4); p 45-46] ADVERSE EFFECTS Adverse effects include headaches, fatigue, and moderate transaminase elevations. L-697,661 is safe and well tolerated. [AmfAR Treat Dir 1993;6(4); p 45-46; N Engl J Med 1993 Oct 7;329(15); p 1065-72] CONTRAINDICATIONS Contraindicated in the presence of a recent history of fever. [Protocol ID: 91 I-74 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Non-nucleoside pyridinone compound. [AmfAR Treat Dir 1993;6(4); p 45-46] CHEMICAL/PHYSICAL DATA Molecular Formula: C16-H15-Cl2-N3-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 352.22 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (100 mg). [Protocol ID: ACTG 184 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1991 April; p 25; N Engl J Med 1993 Oct 7;329(15); P 1066] MANUFACTURERS 0000003415: Merck Research Laboratories 126 East Lincoln Ave Rahway, NJ 07065 Contact: Carol Sable REFERENCES MED/97111302. Lee LL, Herold ML, Zacchei AG. High-performance liquid chromatographic method for the determination of an HIV-1 non-nucleoside reverse transcriptase inhibitor (L-696,229) in plasma samples from animals. J Chromatogr B Biomed Appl. 1996 Oct 25;685(2):323-8. MED/97037957. Perrin L, Rakik A, Yerly S, Baumberger C, Kinloch-de Loes S, Pechere M, Hirschel B. Combined therapy with zidovudine and L-697,661 in primary HIV infection. AIDS. 1996 Sep;10(11):1233-7. MED/96261388. Kilby JM, Saag MS. Clinical experience with non-nucleoside reverse transcriptase inhibitors: L-697,661 and nevirapine. Adv Exp Med Biol. 1996;394:291-8. MED/96007275. Kappes JC, Saag MS, Shaw GM, Hahn BH, Chopra P, Chen S, Emini EA, McFarland R, Yang LC, Piatak M Jr, et al. Assessment of antiretroviral therapy by plasma viral load testing: standard and ICD HIV-1 p24 antigen and viral RNA (QC-PCR) assays compared. J Acquir Immune Defic Syndr Hum Retroviral. 1995 Oct 1;10(2):139-49. MED/95271050. Staszewski S, Massari FE, Kober A, Gohler R, Durr S, Anderson KW, Schneider CL, Waterbury JA, Bakshi KK, Taylor VI, et al. Combination therapy with zidovudine prevents selection of human immunodeficiency virus type 1 variants expressing high-level resistance to L-697,661, a nonnucleoside reverse transcriptase inhibitor. J Infect Dis. 1995 May;171(5):1159-65. MED/95191048. Lineberger DW, Kessler JA, Waterbury JA, Byrnes VW, Massari F, Staszewski S, Emini EA. Turnover of circulating virion RNA and of cell-associated viral DNA reflects active viral replication in human immunodeficiency virus type 1-infected individuals. J Virol. 1995 Apr;69(4):2637-9. MED/93382466. Saag MS, Emini EA, Laskin OL, Douglas J, Lapidus WI, Schleif WA, Whitley RJ, Hildebrand C, Byrnes VW, Kappes JC, et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med. 1993 Oct 7;329(15):1065-72. ICA9/93335589. Kuritzkes DR, Curtis S, Rosandich M, Stein DS, Schooley RT. Delayed emergence of resistance to L-697,661 in patients receiving concomitant zidovudine. Int Conf AIDS. 1993 Jun 6-11;9(1):467 (abstract no. PO-B26-1994). ICA9/93334823. Byrnes VW, et al. Combination therapy with AZT prevents selection of HIV-1 variants that are highly resistant to the nonnucleoside reverse transcriptase inhibitor L-697,661. Int Conf AIDS. 1993 Jun 6-11: (abstract no. WS-A19-5). MED/93297956. Goldman ME, O'Brien JA, Ruffing TL, Schleif WA, Sardana VV, Byrnes VW, Condra JH, Hoffman JM, Emini EA. A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency virus type 1 isolates resistant to related inhibitors. Antimicrob Agents Chemother. 1993 May;37(5):947-9. ENTRY MONTH 199105 LAST REVISION DATE 20000801 242 UNIQUE IDENTIFIER DRG-0104 NAME OF SUBSTANCE Azithromycin [USPD 1998; p. 75] REGISTRY NUMBER 83905-01-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-Oxa-6-azacyclopentadecan-15-one, 13-((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-- L-ribo-hexopyranosyl)ox y)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14- -heptamethyl-11-((3,4,6 -trideoxy-3-(dimethylamino)-beta-D-xylo-hexop- yranosyl)oxy)-, [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Zithromax [USP DI 2000; p. 513] PROTOCOL ID NUMBERS Complete NIAID ACTG 135 PROTOCOL ID NUMBERS Complete NIAID ACTG 156 PROTOCOL ID NUMBERS No longer recruiting FDA 058C PROTOCOL ID NUMBERS No longer recruiting FDA 058D PROTOCOL ID NUMBERS No longer recruiting FDA 058F PROTOCOL ID NUMBERS No longer recruiting FDA 058H PROTOCOL ID NUMBERS No longer recruiting FDA 058I PROTOCOL ID NUMBERS No longer recruiting FDA 058J PROTOCOL ID NUMBERS No longer recruiting FDA 226A PROTOCOL ID NUMBERS No longer recruiting FDA 226B PROTOCOL ID NUMBERS No longer recruiting FDA 226C PROTOCOL ID NUMBERS No longer recruiting FDA 226D PROTOCOL ID NUMBERS No longer recruiting FDA 275A PROTOCOL ID NUMBERS No longer recruiting CC 91 CC-100 PROTOCOL ID NUMBERS No longer recruiting CC 92 I-165 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 341 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 362 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 048 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 001 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 254 PROTOCOL ID NUMBERS Recruiting NIAID DAIDS R001 PHARMACOLOGICAL ACTION MODE OF ACTION: Similar to erythromycin, which binds to the 50 S ribosomal subunits of susceptible bacteria and suppresses protein synthesis. Azithromycin appears to bind to the same receptor as erythromycin. These drugs may be bactericidal or bacteriostatic. The in vitro spectrum of azithromycin is greater than that of erythromycin. It retains the erythromycin spectrum (eg, gram-positive coverage) while showing significant improvement in activity against gram-negative organisms. Appears to have a better side effect profile and greater acid stability than erythromycin. Azithromycin is well absorbed in humans and has a remarkable affinity for tissue. The half-life of the drug in humans appears to vary between 5 and 11 hours, depending on the dose. Peak concentrations are attained between 1.5 and 3.3 hours after oral administration. The drug is protein bound in serum and appears to be eliminated slowly, possibly because of low serum clearance and extensive distribution in the tissues. Thus, detectable levels of the drug can be found in the urine 7 to 14 days after the administration of a single dose. The relatively long half life, affinity for tissues, and the slow elimination of azithromycin indicate potential for once-a-day dosing. Biliary excretion, predominantly as unchanged drug, is a major route of elimination. Over a 7 day period, about 6% of the administered dose appears as unchanged drug in the urine. In patients with non-inflamed meninges only very low concentrations were noted in the CSF (less than 0.01 mcg/ml). Studies suggest that the drug attains active concentrations in the inflamed central nervous system. In one study involving ten healthly male volunteers, a single 500 mg oral dose resulted in a peak concentration of 0.4 mg/l. The mean serum concentrations were < 50% than those after an IV dose. Oral bioavailability is 37%. Within 72 hours after dosing, 4.5% (oral) and 12.2% (IV) was excreted in the urine. The half-life depended on the sampling time and was quite variable, ranging from 11 to 57 hours when sampling 8 hours to 6 days post-dose. Serum protein binding varied by drug concentration ranging from 51% at 0.02 micrograms/ml to 7% at 2.0 micrograms/ml. Concentrations of azithromycin varied between 1 and 9 mg/kg in various tissues and were 10 to 100 times higher than serum sample after a 500 mg dose. Concentrations were lowest in fat, muscle, bone, and gastric mucosa. Food decreases absorption of azithromycin; the Cmax can be lowered by 50% and the AUC by 43%. [PDR 1998; p 2222-3; Facts and Comparisons 1995; p 342m; Antimicrob Agents Chemother 1988 May; Araujo, et al., 32(5):755-757] DISEASES STUDIED/TREATED FDA approved, 6/12/96, for the prevention of disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infection. [Pfizer Inc U S Prescribing Information; No date was given.] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 511] OTHER MAJOR USES Used to treat bacterial upper and lower respiratory tract infections, skin and skin structure infections, and sexually transmitted diseases. [PDR 1998; p 2225-6] SUBSTANCE INTERACTIONS Aluminum- and magnesium-containing antacids reduce the peak serum levels but not the extent of azithromycin absorption. Concurrent use of macrolides and theophylline has been associated with increased serum concentrations of theophyline. Monitoring of prothrombin time is indicated in patients receiving azithromycin and warfarin. Dose adjustments are not indicated when azithromycin and zidovudine, didanosine or rifabutin are coadministered. Careful monitoring is needed when azithromycin is used with digoxin, ergotamine, triazolam, or drugs that are metabolized by the cytochrome P450 system, such as carbamazepine, cyclosporine, hexobarbital and phenytoin. [PDR 1998; p 2224-5] ADVERSE EFFECTS Adverse effects include diarrhea/loose stools (5%), nausea (3%), abdominal pain (3%). The remaining side effects were seen at an occurrence rate of less than 1%: palpitations, chest pain, dyspepsia, flatulence, vomiting, melena, cholestatic jaundice, monilia, vaginitis, nephritis, dizziness, headache, vertigo, somnolence, fatigue, rash, photosensitivity, and angioedema. [PDR 1998; p 2225] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to azithromycin, erythromycin, or any other macrolide antibiotics. Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for outpatient oral therapy. Should be used with caution in patients with impaired liver or kidney functions. [PDR 1998; p 2224] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: sn azalide, a subclass of macrolide antibiotics. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. [PDR 1998; p 2218] CHEMICAL/PHYSICAL DATA Molecular Formula: C38-H72-N2-O12 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 749.00 [Merck Index 1996; p. 157] CHEMICAL/PHYSICAL DATA Melting Point: 113-115 C [Merck Index 1996; p. 157] CHEMICAL/PHYSICAL DATA Elemental Comp: C60.94%, H9.69%, N3.74%, O25.63% [Merck Index 1996; p. 157] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, crystalline powder (dihydrate). [PDR 1998; p 2218] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg gelatin capsules. Lyophilized form (for injection) in evacuated vials. 600 mg tablets. [PDR 1998; p 2225,2229] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, i.v.injection. [PDR 1998; p 2225,2229] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Capsules should be stored below 30 C. Solution for injection is stable for 7 days refrigerated at 5 C (41F), or for 24 hours at or below room temperature (30C or 86F). [PDR 1998; p 2225,2229] MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Professional Information (800)438-1985 MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Unspecified (800)438-1985 REFERENCES MED/98109337. Bermudez LE, Petrofsky M, Kolonoski P, Kolonoski P, Young LS. Emergence of Mycobacterium avium populations resistant to macrolides during experimental chemotherapy. Antimicrob Agents Chemother. 1998 Jan;42(1):180-3. MED/98119561. Holmberg SD, Moorman AC, Von Bargen JC, Palella FJ, Loveless MO, Ward DJ, Navin TR. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. HIV Outpatient study (HOPS) Investigators. JAMA. 1998 Feb 4;279(5):384-6. MED/98023032. Cohn DL. Prevention strategies for Mycobacterium avium-intracellulare complex (MAC) infection. A review of recent studies in patients with AIDS. Drugs. 1997;54 Suppl 2:8-15; discussion 28-9. MED/98023031. Dautzenberg B. Rationale for the prevention of disseminated Mycobacterium avium-intracellulare complex disease. Drugs. 1997;54 Suppl 2:1-7; discussion 28-9. MED/97445691. Brettle RP. Mycobacterium avium intracellulare infection in patients with HIV or AIDS. J Antimicrob Chemother. 1997 Aug;40(2):156-60. MED/98025616. Tartaglione T. Treatment of nontuberculous mycobacterial infections: role of clarithromycin and azithromycin. Clin Ther. 1997 Jul-Aug;19(4):626-38; discussion 603. MED/97372359. Handsfield HH. Azithromycin in gonorrhoea (letter; comment) Int J STD AIDS. 1997 Jul;8(7):472-3. AIDS/98927577. Vincent J, Foulds G, Apseloff G, Laboy-Goral L, Gerber N. Interaction of rifabutin (RIF) with the macrolides azithromycin (AZM) and clarithromycin (CLA). Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:6 (abstract no.A29). AIDS/98927597. Clemons KV, Minn AY, Aristizabal BH, Stevens DA. Efficacy of fluconazole (FCZ) alone or in combination with azithromycin (AZI) or rifabutin (RIF) against systemic murine Cryptococcosis. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:30 (abstract no. B50). AIDS/98927645. Ellis LC, Rashad AL, Loveless MO, Sykes R, Jacobs S. Effect of dimethylsulfoxide (DMSO) on the susceptibility of Mycobacterium avium complex (MAC) to azithromycin (AZ), clarithromycin (CLA), and erthromycin (ERY)> Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:93 (abstract no. E65). ENTRY MONTH 199104 LAST REVISION DATE 20001107 243 UNIQUE IDENTIFIER DRG-0103 NAME OF SUBSTANCE rgp120/HIV-1 SF-2 [Protocol ID: AVEG 015 ] PROTOCOL ID NUMBERS Complete NIAID ACTG 214 PROTOCOL ID NUMBERS Complete NIAID ACTG 218 PROTOCOL ID NUMBERS Complete NIAID AVEG 007A/B PROTOCOL ID NUMBERS Complete NIAID AVEG 007C PROTOCOL ID NUMBERS Complete NIAID AVEG 008 PROTOCOL ID NUMBERS Complete NIAID AVEG 010 PROTOCOL ID NUMBERS Complete NIAID AVEG 012A PROTOCOL ID NUMBERS Complete NIAID AVEG 015 PROTOCOL ID NUMBERS Complete NIAID AVEG 022 PROTOCOL ID NUMBERS Complete NIAID AVEG 022A PROTOCOL ID NUMBERS Complete NIAID AVEG 024 PROTOCOL ID NUMBERS Complete NIAID AVEG 026 PROTOCOL ID NUMBERS Complete NIAID AVEG 029 PROTOCOL ID NUMBERS Complete NIAID AVEG 201 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 230 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 032 PROTOCOL ID NUMBERS No longer recruiting NIAID AVEG 202 PROTOCOL ID NUMBERS Terminated NIAID ACTG 233 PHARMACOLOGICAL ACTION MODE OF ACTION: rgp120(CHO) is a recombinant form of envelope glycoprotein gp120 derived from HIV-1 strain SF-2. The molecule is fully glycosylated, allowing it to closely simulate the three-dimensional structure of naturally occurring gp120. rgp120 (CHO) is expressed in Chinese hamster ovary cells. rgp120(CHO) has been administered with a combination of adjuvant muramyl tripeptide (MTP-PE) and an emulsion (MF-59). MF59 may also have some adjuvant properties. It has been theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cellular immune responses. Steimer et al report that conformation-dependent antibodies to gp120 neutralize divergent strains of HIV-1. The conformational similarity of rgp120 CHO to the native gp120 may have positive implications for its ability to block primary infection of diverse HIV-1 strains. Kahn et al report that rgp120 (CHO) has stimulated antibodies to gp120 that have persisted at least three months. Forty-two HIV-negative patients were randomized to six arms, corresponding to increasing doses of MTP-PE, ranging from 0-300 micrograms. Within each arm, six patients received 25 micrograms rgp120 (CHO) in MF59 emulsion and two patients received MTP-PE alone. Three injections were administered. The best responses appear to be correlated with higher doses of MTP-PE. A five arm study (ACTG 240) of 128 HIV+ with CD4+ counts > 500 cells/cubic mm has been completed. Recombinant gp120 products stimulate less binding antibody but more HIV-1 neutralizing antibody than rgp120 products. Four doses of vaccine spaced over 12 months stimulated higher titers of HIV-1 neutralizing antibody than an accelerated schedule of four monthly immunizations. A fifth dose of rgp120 boosted antibody levels at approximately post fourth dose levels but no higher than post dose 4. Another set of phase I and II trials of candidate AIDS vaccines, used 2099 uninfected subjects. Nineteen vaccinated subjects acquired HIV-1 infection during the trials indicating that immunization with the vaccines is less than 100% effective in preventing or rapidly clearing infection. Laboratory analysis suggested that vaccine-induced immune respones did not significantly affect the genotypic or phenotypic characteristics of transmitted virus or the early clinical course of HIV-1 infection. There are no longer any gp 120 vaccines under study as therapeutic interventions in HIV disease. The sponsors have discontinued research for this indication due to unimpressive trial results. [J Infect Dis 1998 Feb;177(2); p 310-9; AmfAR Treat Dir 1997 Dec; p 48; Conf Adv AIDS Vaccine Dev 1996 Feb 11-15; p 107] DISEASES STUDIED/TREATED Primary HIV infection / prevention. [AmfAR Treat Dir 1997 Dec; p 48] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 034 ] SUBSTANCE INTERACTIONS Interacts with corticosteroids or other known immunosuppressive drugs and any experimental agents. [Protocol ID: AVEG 008 ] ADVERSE EFFECTS Mild myalgia, headache, and low-grade fever are the most common adverse effects. [AmfAR Treat Dir 1997;8(3); p 59] CONTRAINDICATIONS Contraindicated in the presence of prior history of clinically significant cardiac, pulmonary, hepatic, renal or autoimmune disease (other than HIV infection); pregnancy; and breastfeeding. [AmfAR Treat Dir 1991 April; p 19; AmfAR Treat Dir 1995;7(4); p 137-38] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: SF-2 rgp 120/HIV-1 is a recombinant form of envelope glycoprotein gp120 derived from HIV-1 strain SF-2. [AmfAR Treat Dir 1997 Dec; p 48] SUBSTANCE DELIVERY DATA DOSAGE FORM: Single dose vials as a solution. [Protocol ID: AVEG 015 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection (IM). [AmfAR Treat Dir 1993;6(3); p 26; AmfAR Treat Dir 1991 April; p 19; AmfAR Treat Dir 1995;7(4); p 137-38] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store frozen at -70 C or colder. [Protocol ID: AVEG 015 ] MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 REFERENCES MED/98125992. Graham BS, McElrath MJ, Connor RI, Schwartz DH, Gorse GJ, Keefer MC, Mulligan MJ, Matthews TJ, Wolinsky SM, Montefiori DC, et al. Analysis of intercurrent human immunodeficiency virus type 1 infections in phase I and II trials of candidate AIDS vaccines. AIDS Vaccine Evaluation Group, and the Correlates of HIV Immune Protection Group. J Infect Dis. 1998 Feb;177 (2):310-9. AIDS/97927176. Gorse GJ, Patel GB, Mandava M, Berman PW, Belshe RB, Binding antibody against primary HIV-1 isolates induced in recipients of recombinant envelope glycoprotein HIV-1 candidate vaccines (MN/rgp120 and IIIB/rgp120). Conf Adv AIDS Vaccine Dev. 1997 May 4-7;:212 (Poster 107). MED/97378939. Barnett SW, Rajasekar S, Legg H, Doe B, Fuller DH, Haynes JR, Walker CM, Steimer KS. Vaccination with HIV-1 gp120 DNA induces immune responses that are boosted by a recombinant gp120 protein subunit. Vaccine. 1997 Jun;15(8):869-73. AIDS/97920693. Belshe RB, Bolognesi D, Clements ML, Corey L, Fast P, Graham B, Keefer M, Mestecky J, Mulligan M. Candidate HIV-1 vaccines: what is available for expanded clinical trials? Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:107. MED/97120481. Cleland JL, Barron L, Daugherty A, Eastman D, Kensil C, Lim A, Weissburg RP, Wrin T Vennari J, Powell MF. Development of a single-shot subunit vaccine for HIV-1. 3. Effect of adjuvant and immunization schedule on the duration of the humoral immune response to recombinant MN gp120. J Pharm Sci. 1996 Dec;85(12):1350-7. MED/97071928. Gorse GJ, Yang EY, Belshe RB, Berman PW. Salivary binding and antibodies induced by human immunodeficiency virus type 1 recombinant gp120 vaccine. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Nov;3(6):769-73. MED/96400824. Gorse GJ, Patel GB, Newman FK, Belshe RB, Berman PW, Gregory TJ, Matthews TJ. Antibody to native human immunodeficiency virus type 1 envelope glycoproteins induced by IIIB and MN recombinant gp120 vaccines. The NIAID AIDS Vaccine Evaluation Group. Clin Diagn Lab Immunol. 1996 Jul;3(4):378-86. MED/96003456. VanCott TC, Bethke FR, Burke DS, Redfield RR, Birx DL. Lack of induction of antibodies specific for conserved discontinuous epitopes of HIV-1 envelopes glycoprotein by candidate AIDS vaccines. J Immunol. 1995 Oct 15;155(8):4100-10. AIDS/97920693. Belshe RB, Bolognesi D, Clements ML, Corey L, Fast P, Graham B, Keefer M, Mestecky J, Mulligan M. Candidate HIV-1 vaccines: what is available for expanded clinical trials? Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15;:107. AIDS/95920551. Lambert JS, McNamara J, Katz S, Livingston R, Fenton T, Geheb H, Duliege AM, Francis D, Volvowitz F, Hawkins E, et al. Safety and immunogenicity of recombinant envelope HIV vaccines in asymptomatic HIV infected childern. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:151. ENTRY MONTH 199105 LAST REVISION DATE 20000801 244 UNIQUE IDENTIFIER DRG-0102 NAME OF SUBSTANCE Mitoxantrone hydrochloride [USPD 1998; p. 480] REGISTRY NUMBER 70476-82-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,4-Dihydroxy-5, 8-bis ((2-((2-hydroxyethyl)amino) ethyl) amino)-9,10-anthracenedione dihydrochloride [PDR 1995; p 1170] SYNONYMS Novantrone [USP DI 2000; p. 2169] PROTOCOL ID NUMBERS No longer recruiting FDA 055A PROTOCOL ID NUMBERS No longer recruiting FDA 055B PHARMACOLOGICAL ACTION MODE OF ACTION: Although its mode of action is not fully elucidated, mitoxantrone is a DNA reactive agent and inhibitor of both RNA and DNA synthesis. Mitoxantrone appears to be most active in the late S phase of cell division, but is not cycle-phase-specific. Although the exact mechanism is unknown, evidence seems to indicate involvement of two effects - binding to DNA by intercalation between base pairs, and a nonintercalative electrostatic interaction - resulting in inhibition of DNA and RNA synthesis. Mitoxantrone also has antiviral, antibacterial, antiprotozoal, and immunosuppressant effects. Distribution is rapid and extensive; largest concentrations are in the thyroid, liver, heart, and red blood cells. Protein binding is high (78%). Biotransformation is hepatic. The mean alpha half-life of mitoxantrone (after a single iv administration) is 6-12 minutes; the mean beta half-life is 0.1-3.1 hours and the mean gamma (terminal or elimination) half-life is extensive. Mitoxantrone is 78% bound to plasma proteins. Metabolism and elimination are not well characterized. Some 11% of the dose is recovered in the urine, and 25% or less in the feces within 5 days of drug administration. Extensive tissue uptake and binding accounts for most of the dose, which is then thought to be gradually released. Because of extensive tissue binding, it is unlikely to be significantly removed by hemodialysis or peritoneal dialysis. [PDR 1998; p 1285; USP DI 1997; p 2060] DISEASES STUDIED/TREATED Under investigation for the treatment of Kaposi's sarcoma and lymphoma. [AmfAR Treat Dir 1997;8(3); p 75] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 2166] OTHER MAJOR USES Myelogenous, promyelocytic, monocytic and erythroid acute leukemias, advanced hormone-refractory prostate cancer. [PDR 1998; p 1286] SUBSTANCE INTERACTIONS Possibly interacts with allopurinol, colchicine, probenecid, sulfinpyrazone, blood dyscrasia-causing medications, bone marrow depressants, radiation therapy, daunorubicin, doxorubicin, killed or live virus vaccines, and previously administered anthracyclines. [USP DI 1997; p 2061] ADVERSE EFFECTS Adverse effects include cardiotoxicity including decreased left ventricular ejection fraction, congestive heart failure, cough or shortness of breath (which may be associated with heart failure), ECG changes, arrhythmias such as tachycardia and rarely, myocardial infarction. Other adverse effects may include blood problems, loss of hair, gastrointestinal bleeding, leukopenia or infection, stomatitis or mucositis, stomach pain, conjunctivitis, jaundice, renal failure, seizures, thrombocytopenia, allergic reaction, local irritation, phlebitis, extravasation. Urine may have a blue green color and whites of eyes may have a blue color during treatment. Mitoxantrone can result in chromosomal aberrations in animals and is mutagenic in bacterial systems. May cause hyperuricemia and transient elevations of AST and ALT. When used in doses indicated for treatment of leukemia, severe myelosuppression will occur. May cause fetal harm when administered to pregnant women. [PDR 1998; p 1286-88; USP DI 1997; p 2060-61] CONTRAINDICATIONS Contraindicated in the presence of preexisting myelosuppression, chickenpox (recent or existing), herpes zoster, history of gout or urate renal stones, heart disease, hepatic function impairment, infection, sensitivity to mitoxantrone, pregnancy or breastfeeding. [PDR 1998; p 1286-88; USP DI 1997; p 2060-61] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic, antineoplastic anthracenedione. [PDR 1998; p 1285] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H28-N4-O6.2Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 517.41 [USPD 1998; p. 480] CHEMICAL/PHYSICAL DATA Melting Point: 203-205 C [Merck Index 1996; p. 1064 (from ethanol/water)] CHEMICAL/PHYSICAL DATA Elemental Comp: C59.45%, H6.35%, N12.60%, O21.60% (base) [Merck Index 1996; p. 1064] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in water; slightly soluble in methanol; practically insoluble in acetonitrile, chloroform, acetone. [Merck Index 1996; p 1064] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Dark blue aqueous solution. [PDR 1995; p 1169] SUBSTANCE DELIVERY DATA DOSAGE FORM: Mitoxantrone hydrochloride concentrate is supplied in 10, 12.5, and 15 mg vials in sterile aqueous solutions containing 2 mg base/ml. [PDR 1998; p 1288] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [PDR 1998; p 1288] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15-25 C (59-77F). Do not freeze. Open vials may be stored no longer than 7 days at 15-25 C or 14 days under refrigeration. [PDR 1998; p 1288] MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Dr Jan Agosti (206)389-4321 MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Unspecified (800)466-8639 REFERENCES MED/98111279. Bellosillo B, Colomer D, Pons G, Gil J. Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol 1998 Jan;100(1):142-6. MED/98103879. Iino Y, Yokoe T, Sugamata N, Maemura M, Takei H, Horiguchi J, Takeyoshi I, Ohwada S, Morishita Y, et al. A combination chemoendorine therapy of mitoxantrone, doxifluridine, and medroxyprogesterone acetate for anthracycline-resistant advanced breast cancer. Cancer Chemother Pharmacol 1998;41 (3):243-7. MED/98121642. Feldman EJ. High-dose mitoxantrone in acute leukaemia: New York Medical College experience. Eur J Cancer Care (Engl) 1997 Dec;6(4 Suppl):27-32. MED/98121641. Keating MJ, McLaughlin P, Cabanillas F. Low-grade non-Hodgkin's lymphoma--development of a new effective combination regimen (fludarabine, mitoxantrone and dexamethasone;FND). Eur J Cancer Care (Engl) 1997 Dec;6(4 Suppl):21-6. MED/98121637. Powles TJ. Evolving clinical strategies: innovative approaches to the use of mitoxantrone--introduction. Eur J Cancer Care (Engl) 1997 Dec;6(4 Suppl):1-3. MED/98067429. Weaver CH, Greco FA, Hainsworth JD, Zhen B, Baldwin P, Wittlin F, Lewis M, West WH, Schwartzberg L, Buckner CD. A phase I-II study of high-dose melphalan, mitoxantrone and carboplatin with peripheral blood stem cell support in patients with advanced ovarian or breast carcinoma. Bone Marrow Transplant 1997 Nov;20 (10):847-53. MED/98090593. Le Donne M, Messina G, Buda C, Corrado F, Pettineo G, Salimbeni V, Irato S. Intraperitoneal chemotherapy with mitoxanthrone in ovarian cancer. Tumori 1997 Sept-Oct;83(5) :837-40. MED/98071692. Morabito F, Callea I, Console G, Stelitano C, Sculli G, Filangeri M, Oliva B, Musolino C, Iacopino P, Brugiatelli M. The in vitro cytotoxic effect of mitoxantrone in combination with fludarabine or pentostatin in B-cell chronic lymphocytic leukemia. Haematologica 1997 Sep-Oct;82(5):560-5. ICDB/97626139. Spina M, Valentini M, Fedele P, Bernardi D, Nasti G, Simonelli C, Santarossa S, Sandri S, Talamini R, Tirelli U. Randomized comparison of granisetron vs ondansetron in patients (pts) with HIV-related non-Hodgkin's lymphoma (HIV-NHL) receiving moderately emetogenic chemotherapy (CT) regimens (Meeting abstract). Anti-Cancer Treatment, Sixth International Congress, p. 91. Paris, France, February 6-9, 1996. ICDB/97632417. Shostak L, McCormack J, Zon G. Interactions of phosphorothioate oligodeoxynucleotides with DNA binding agents (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res; 36:A2417 1996. ENTRY MONTH 199104 LAST REVISION DATE 20000801 245 UNIQUE IDENTIFIER DRG-0101 NAME OF SUBSTANCE L-697,639 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 135525-77-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2(1H)-Pyridinone, 3-(((4,7-dimethyl-2-benzoxazolyl)methyl)amino- )-5-ethyl-6-methyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed Nov 6, 2000.] PROTOCOL ID NUMBERS No longer recruiting CC 91 I-41 PHARMACOLOGICAL ACTION MODE OF ACTION: L-697,639 and its congeners are specifically active against the reverse transcriptase of HIV-1, but not against the reverse transcriptases of HIV-2 or any other retroviruses. Nor are they active against any of the cellular DNA polymerases. These HIV-1-specific reverse transcriptase inhibitors seem to interact with a specific target site (YQYMDDLY) at positions 181-188, which is distinct from, but functionally and spatially related to, the substrate (dNTP) binding site. The tyrosine residues Y181 and Y188 play a crucial role in the interaction of L-697,639 and its congeners with their target site. The HIV-1-specific reverse transcriptase inhibitors have proven to inhibit the replication of various HIV-1 strains, including AZT-resistant HIV-1 strains in different cell culture systems, including peripheral blood lymphocytes and monocyte/macrophages. In vitro they exhibit selectivity indexes of up to 5 orders of magnitude, which means that they are inhibitory to virus replication in cell culture at concentrations that are up to 100,000 times lower than the concentrations at which they are toxic to the host cells. As a rule, the HIV-1-specific reverse transcriptase inhibitors are orally bioavailable, as has been demonstrated in rats, dogs, monkeys, and humans. They sustain plasma drug levels that are well above the concentration required to inhibit virus replication in cell culture. L-697,639 inhibited HIV-1 reverse transcriptase activity in a concentration-dependent manner with IC50 values in the 20-600 nM range, depending upon the template-primer substrate. At 300 muM, however, these compounds did not inhibit ten other enzyme activities. These molecules were reversible dead-end inhibitors which gave mixed-type inhibition patterns with respect to dGTP and TTP as well as to rC.dG and rA.dT. L-697,639 inhibited by at least 95% the spread of HIV-1 infection at concentrations of 25-200 nM. The potential clinical usefulness of this compound as a monotherapeutic agent may be limited by the selection of inhibitor-resistant viral variants. [Med Res Rev 1993 May;13(3); p 229-58; Antimicrob Agents Chemother 1993 May;37(5); p 947-9; J Med Chem 1992 Oct 16;35(21); p 3792-802] DISEASES STUDIED/TREATED Primary HIV infection. [Med Res Rev 1993 May;13(3); p 229-58] CLASSIFICATION CODE Investigational - Nonnucleoside reverse transcriptase inhibitor [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE INTERACTIONS Interacts with other experimental drugs and antiretroviral drugs. [Protocol ID: 91 I-41 ] ADVERSE EFFECTS When administered to healthy male volunteers to investigate the pharmacokinetics and tolerability of single doses ranging from 25 to 500 mg, and multiple doses of up to 100 mg every 12 h for ten days, L-697,639 produced no clinically important adverse events. It was well tolerated for up to ten days at doses that resulted in mean steady state trough concentrations that exceed their in-vitro susceptibilities. Some patients have complained of headaches. Possible toxic effects following 8 weeks of oral 25 mg twice daily therapy were reported in a patient. These effects included tinnitus, retinal cotton wool spots, testicular and tonsillar ulcerative lesions. [AmfAR Treat Dir 1991 April; p 24; AIDS 1992 June;6(6); p 597-99; Int J Clin Pharmacol Res 1994;14(2); p 45-50] CONTRAINDICATIONS Contraindicated in the presence of a recent history of fever. [Protocol ID: 91 I-41 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Pyridinone derivative; part of a novel series of potent and selective HIV-1 non-nucleoside reverse transcriptase inhibitors developed from a screening lead through a synthetic program and judicious SAR analysis. [Antimicrob Agents Chemother 1993 May;37(5); p 947-9] CHEMICAL/PHYSICAL DATA Molecular Formula: C18-H21-N3-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 311.39 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1991 April; p 24] MANUFACTURERS 0000003415: Merck Research Laboratories 126 East Lincoln Ave Rahway, NJ 07065 Contact: Carol Sable REFERENCES MED/95137735. Van Hecken A, Depre M, De Leperleire I, Laskin O, Au T, Woolf E, Yeh KC, De Schepper PJ. Human pharmacokinetics and tolerability of L-697,639, a non-nucleoside HIV-1 reverse transcriptase inhibitor. Int J Clin Pharmacol Res. 1994;14(2):45-50. MED/93140499. O'Brien JA, Ostovic D, Schorn TW, Smith SJ, Ruffing TL, Siegl PK, Goldman ME. A rapid bioassay for the determination of non-nucleoside HIV-1 reverse transpritase inhibitor plasma levels. Life Sci. 1993;52(3):243-9. MED/93247318. De Clercq E. HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Med Res Rev. 1993 May;13(3):229-58. MED/93059212. Saari WS, Wai JS, Fisher TE, Thomas CM, Hoffman JM , Rooney CS, Smith AM, Jones JH, Bamberger DL, Goldman ME, et al. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one. J Med Chem. 1992 Oct 16;35(21):3792-802. MED/92388095. Sardana VV, Emini EA, Gotlib L, Graham DJ, Lineberger DW, Long WJ, Schlabach AJ, Wolfgang JA, Condra JH. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem. 1992 Sep 5;267(25):17526-30. MED/92378238. Condra JH, Emini EA, Gotlib L, Graham DJ, Schlabach AJ, Wolfgang JA, Colonno RJ, Sardana VV. Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob Agents Chemother. 1992 Jul;36(7):1441-6. MED/91333034. Nunberg JH, Schleif WA, Boots EJ, O'Brien JA, Quintero JC, Hoffman JM, Emini EA, Goldman ME. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol. 1991 Sep;65(9):4887-92. ICA7/3101291. Nunberg JH, Quintero JC, Schleif WA, Emini EA, Friedman PA, Raison JM. HIV-1 specific pyridinone reverse transcriptase inhibitors: III. Synergism in the combined in vitro use with nucleoside analogs. Int Conf AIDS. 1991 Jun 16-21;7(2):95 (abstract no. W.A.1012). MED/91319784. Goldman ME, Nunberg JH, O'Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai JS, Hoffman JM, et al. Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci USA. 1991 Aug 1;88(15):6863-7. ICA7/2006791. Goldman ME, O'Brien JA, Ruffing TL, Stern AM, Gaul SL, Saari WS, Wai JS, Hoffman J, Rooney CS, Quintero JC, et al. HIV-1 specific pyridinone RT inhibitors: I. Preclinical biological characterization of two investigational new drugs. Int Conf AIDS. 1991 Jun 16-21;7(1):74 (abstract no. TU.A. 67). ENTRY MONTH 199105 LAST REVISION DATE 20001106 246 UNIQUE IDENTIFIER DRG-0100 NAME OF SUBSTANCE Acetylcysteine [USPD 1998; p. 20] REGISTRY NUMBER 616-91-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Cysteine, N-acetyl-, L- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Mucomyst [USP DI 2000; p. 19] SYNONYMS Mucosil [USP DI 2000; p. 19] PROTOCOL ID NUMBERS No longer recruiting CC 91 I-68 PHARMACOLOGICAL ACTION MODE OF ACTION: Acetylcysteine is deacetylated by the liver to cysteine and subsequently metabolized. Recent studies have demonstrated that human immunodeficiency virus (HIV)-infected individuals have lower levels of serum acid-soluble thiols, lower levels of intracellular glutathione (GSH) in peripheral blood mononuclear cells (PBMCs), and that asymptomatic HIV-seropositivie individuals have dramatically reduced GSH levels in lung epithelial lining fluid and in blood plasma. These findings have been related to the regulation of HIV replication by demonstration that increased intracellular thiol levels block the stimulation of HIV by phorbol 12- myristate 13-acetate (PMA) and tumor necrosis factor alpha (TNF-alpha). TNF-alpha exerts some of its toxic effects by stimulating production of reactive oxidative intermediates (ROIs). PMA, which mimics lymphokine activities, also stimulates ROI production. Intracellular GSH protects cells by scavenging ROIs; however, the oxidant-buffering capacity of cellular GSH can be overcome by excessive stimulation with TNF-alpha. Thus drugs, like acetylcysteine, that replenish intracellular GSH may protect against the toxic effects of TNF-alpha and other agents that cause oxidative damage. The latest findings show NAC not only increases glutathione levels and suppresses HIV replication (presumably via suppression of the activation of transcription factor NF-kappa B), but also is an effective enhancer of T cell function and a remarkable enhancer of growth. Following inhalation or intratracheal instillation, most of the administered NAC appears to participate in the sulfhydryl-disulfide reaction; the remainder is absorbed from the pulmonary epithelium, deacetylated by the liver to cysteine, and subsequently metabolized. Following oral administration (e.g., when used as an antidote for acetaminophen overdosage), NAC is absorbed from the GI tract. [Int Immunol 1993 Jan;5(1); p 97-101; AHFS Drug Information 1997; p 2096; Proc Natl Acad Sci USA 1990; Roederer, et al, 87(6):4884-8] DISEASES STUDIED/TREATED Primary HIV infection. [Pharmacology 1993;46(2); p 61-5] CLASSIFICATION CODE Antidote (to acetaminophen overdose) [USP DI 2000; p. 18] CLASSIFICATION CODE Antioxidant [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Treatment of acetaminophen overdose to protect against hepatotoxicity. Treatment of various lung diseases requiring mucolysis. [USP DI 1997; p 16-19; AHFS Drug Information 1995; p 1856-57] SUBSTANCE INTERACTIONS Acetylcysteine has been shown to be incompatible, when mixed in the same solution, with amphotericin B, erythromycin lactobionate, ampicillin sodium, or tetracycline antibiotics. These agents should be administered in separate solutions. Acetylcysteine is also incompatible with iodized oil, hydrogen peroxide, chymotrypsin and trypsin. [USP DI 1997; p 18] ADVERSE EFFECTS Appears to have a wide margin of safety. Adverse effects may include stomatitis, nausea (disagreeable odor may contribute), vomiting, drowsiness, clamminess, rhinorrhea, generalized urticaria, fever and chills, elevations in liver function test results, dermal eruptions, irritation of the tracheal and bronchial tracts and hemoptysis, chest tightness, bronchoconstriction, increased airway obstruction, shortness of breath, wheezing. [AHFS Drug Information 1997; p 2097; USP DI 1997; p 17, 19] CONTRAINDICATIONS Monitor use closely in asthmatic patients, in geriatric or debilitated patients with severe respiratory insufficiency, in those with conditions predisposing to gastric hemorrhage including esophageal varices, peptic ulceration and in nursing mothers. Use only when clearly needed in pregnant women. Contraindicated in patients hypersensitive to the drug. [AHFS Drug Information 1997; p 2097; USP DI 1995; p 17] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: N-acetyl derivative of the naturally occurring amino acid L- cysteine. [AHFS Drug Information 1997; p 2096] CHEMICAL/PHYSICAL DATA Molecular Formula: C5-H9-N-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 163.20 [USPD 1998; p. 20] CHEMICAL/PHYSICAL DATA Melting Point: 109-110 C [Merck Index 1996; p. 16] CHEMICAL/PHYSICAL DATA Elemental Comp: C36.80%, H5.56%, N8.58%, O29.41%, S19.65% [Merck Index 1996; p. 16] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water and alcohol. [AHFS Drug Information 1997; p 2096] CHEMICAL/PHYSICAL DATA Stability: Reducing agent which is incompatible with oxidizing agents; solutions of acetylcysteine become discolored and liberate hydrogen sulfide upon contact with rubber and some metals (particularly iron, nickel, copper), and/or when subject to autoclaving. [AHFS Drug Information 1997; p 2096] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: A white, crystalline powder with a slight acetic odor; commercially available as aqueous solutions of the sodium salt, prepared with the aid of sodium hydroxide, are colorless, and have odor and taste of hydrogen sulfide. [AHFS Drug Information 1997; p 2096] SUBSTANCE DELIVERY DATA DOSAGE FORM: 10 or 20% solution; or 10-20% solution diluted. [AHFS Drug Information 1997; p 2098] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral (nebulization, direct application, intratracheal instillation) and intraveneous. [USP DI 1997; p 16-19] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Unopened vials should be stored at 15-30 C in a tight container. Opened vials should be stored in a refrigerator and discarded after 96 hours. [USP DI 1997; p 18, 20] MANUFACTURERS 0000001233: Zambon Corp 1 Meadowlands Plaza East Rutherford, NJ 07073 Contact: Unspecified (201)896-2200 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000005214: Dey 2751 Napa Valley Corporate Drive Napa, CA 94558 Contact: Unspecified (800)755-5560 REFERENCES AIDS/97702484. Lands L. NAC, glutamine, and alpha lipoic acid. (interview by John S. James) AIDS Treat News. 1997 Apr 4; (No 268):2-7. AIDS/97702533. James JS. Stanford NAC study: glutathione level predicts survival. AIDS Treat News. 1997 Mar 7; (No 266):1-5. MED/97203170. Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, Herzenberg LA. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA. 1997 Mar4;94(5):1967-72. MED/97172440. Omara FO, Blakley BR, Bernier J, Fournier M. Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro. Toxicology. 1997 Jan 15; 116(1-3):219-26. AIDS/97926715. Walmsley S, Djurdjev O, Singer J, Khorasheh S. A randomized, multicenter, controlled trial of the use of N'acetylcysteine (NAC) for the prevention of trimethoprim-sulfamethoxazole (TMP-SMX) hypersensitivity reactions in HIV. 4th Conf Retro and Opportun Infect. 1997 Jan 22-26;:118(abstract no.291). MED/97051086. Droge W, Gross A, Hack V, Kinscherf R, Schykowski M, Bockstette M, Mihm S, Galter D. Role of cysteine and glutathione in HIV infection and cancer cachexia: therapeutic intervention with N-acetylcysteine. Adv Pharmacol. 1997;38:581-600. MED/97102927. Kameoka M. Okada Y. Tobiume M. Kimura T. Ikuta K. Intracellular glutathione as a possible direct blocker of HIV type 1 reverse transcription. AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1635-8. MED/97017394. Weiss L, Hildt E, Hofschneider PH. Anti-hepatitis B virus activity of N-acetyl-L-cysteine (NAC:new aspects of a well-established drug. Antiviral Res. 1996 Aug;32(1):43-53. MED/96439637. Kinscherf R, Hack V, Fischbach T, Friedmann B, Weiss C, Edler L, Bartsch P, Droge W. Low plasma glutamine in combination with high glutamate levels indicate risk for loss of body cell mass in healthy individuals: the effect of N-acetyl-cysteine. J Mol Med. 1996 Jul;74(7):393-400. MED/97011261. Akerlund B, Jarstrand C, Lindeke B, Sonnerborg A, Akerblad AC, Rasool O. Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. Eur J Clin Pharmacol. 1996;50(6):457-61. ENTRY MONTH 199104 LAST REVISION DATE 20001107 247 UNIQUE IDENTIFIER DRG-0099 NAME OF SUBSTANCE Clarithromycin [USPD 1998; p. 174] REGISTRY NUMBER 81103-11-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 6-o-Methylerythromycin [PDR 1998; p 405] SYNONYMS Biaxin [USP DI 2000; p. 926] PROTOCOL ID NUMBERS Complete NIAID ACTG 157 PROTOCOL ID NUMBERS Complete NIAID ACTG 178 PROTOCOL ID NUMBERS Complete NIAID ACTG 196 PROTOCOL ID NUMBERS Complete NIAID ACTG 223 PROTOCOL ID NUMBERS Complete NIAID ACTG 237 PROTOCOL ID NUMBERS No longer recruiting FDA 048D PROTOCOL ID NUMBERS No longer recruiting FDA 124A PROTOCOL ID NUMBERS No longer recruiting FDA 200G PROTOCOL ID NUMBERS No longer recruiting FDA 214A PROTOCOL ID NUMBERS No longer recruiting FDA 226B PROTOCOL ID NUMBERS No longer recruiting FDA 275A PROTOCOL ID NUMBERS No longer recruiting CC 90 CC-04 PROTOCOL ID NUMBERS No longer recruiting CC 95 CC-102 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 283 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 001 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 007 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 027 PHARMACOLOGICAL ACTION MODE OF ACTION: Clarithromycin, is a 14-membered macrolide which demonstrates a broad in vitro antibacterial spectrum which includes staphylcocci, streptococci, Legionella, Haemophilus influenzae, Neisseria gonorrhoeae, Chlamydia and anaerobes. A derivative of erythromycin, it inhibits protein synthesis in susceptible organisms by binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. Clarithromycin differs from erythromycin by the substitution of a methoxy for a hydroxy group at position 6 of the macrolide ring and its metabolite, unlike that of erythromycin, has been shown to be microbiologically active. Clarithromycin has better bacteriologic activity than erythromycin and the presence of the methyl group at the 6-position confers greater acid stability to the erythronolide ring thereby preventing formation of the inactive 6,9-9,12-spiroketal derivative. Studies in animals indicate that clarithromycin is metabolized via three main pathways: N-demethylation, hydroxylation at the 14-position to form the R and S epimers and hydrolysis of the cladinose sugar. Clarithromycin is well absorbed orally and has a longer half-life in serum than erythromycin does. Since clarithromycin is more lipophilic, it may be able to penetrate the lipid coat of some bacteria more readily than erythromycin can. Clarithromycin has been reported to achieve high concentrations in tissue and to have high intracellular concentrations. Since clarithromycin is more acid stable than erythromycin, it is possible that it would remain active for a longer period of time than erythromycin in the acidic environment of the phagolysosome. [AHFS Drug Information 1997; p 239-241; Antimicrob Agents Chemother 1989; Sept 33(9):1531-4; Drug Metab Dispos 1990; 18(4): 441] DISEASES STUDIED/TREATED FDA approved 12/23/93 (Biaxin) as a treatment for disseminated mycobacterium avium complex (MAC). FDA approved 10/12/95 for the prevention of disseminated Mycobacterium avium Complex (MAC) in patients with advanced HIV infection. Under investigation in combination therapy for toxoplasmosis. [Abbott Laboratories Drug Information Packet, Oct 1985; AmfAR Treat Dir 1997;8(3); p 69; AHFS Drug Information 1997; p 239-41] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 923] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 923] OTHER MAJOR USES Treatment of common bacterial infections of the upper and lower respiratory tract, and the skin. [PDR 1998; p 406] SUBSTANCE INTERACTIONS Interacts with theophylline, carbamazepine, digoxin, anticoagulants, ergotamine, triazolam, cyclosporine, hexobarbital, phenytoin, warfarin, anti-infective agents, and drugs metabolized by the cytochrome P450 system (may cause elevation of serum levels of these drugs). Clarithromycin increases terfenadine plasma levels 3-fold. Simultaneous administration of clarithromycin and zidovudine decreased bioavailability of the latter. Coadministration of clarithromycin and didanosine did not result in significant changes to the didanosine pharmacokinetics. [PDR 1998; p 407-8] ADVERSE EFFECTS The most frequently reported side effects were diarrhea, nausea, abnormal taste, dyspepsia, abdominal pain/discomfort and headache. Most of these events were described as mild or moderate in severity. Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have occurred. Rare cases of severe hepatic dysfunctions also have been reported. There have also been rare cases of association between clarithromycin and ventricular arrhythmias. [PDR 1998; p 408] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics. Should not be used in pregnancy and with caution in patients with renal or hepatic dysfunction. [PDR 1998; p 407] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semisynthetic macrolide antibiotic. [PDR 1998; p 405] CHEMICAL/PHYSICAL DATA Molecular Formula: C38-H69-N-O13 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 747.97 [USPD 1998; p. 174] CHEMICAL/PHYSICAL DATA Melting Point: 217-220 C [Merck Index 1996; p. 395] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.02%, H9.30%, N1.87%,O27.81% [Merck Index 1996; p. 395] CHEMICAL/PHYSICAL DATA Solubility: Soluble in acetone, slightly soluble in methanol, ethanol and acetonitrile, and practically insoluble in water. [PDR 1998; 405] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Colorless needles from chloroform + diisopropyl ether (1:2); also reported as crystals from ethanol. [Merck Index 1996; p 395] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (250 and 500 mg), oral suspension (125 and 250 mg/5ml). [PDR 1998; p 409] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1998; p 408] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be stored in tight containers at a temperature less than 40 C, preferably between 15-30 C (59-86F). Do not refrigerate oral suspension. Protect from light. [PDR 1998; p 409] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/98140823. Hocqueloux L, Lesprit P, Herrmann JL, de La Blanchardiere A, Zagdanski AM, Decazes JM, Modai J. Pulmonary Mycobacterium avium complex disease wihout dissemination in HIV-infected patients. Chest. 1998 Feb;113(2):542-8. MED/98127898. Preston SL, M Postelnick M, Purdy BD, Petrolati J, Aasi H, Stein DS, Drug interactions in HIV-positive patients initiated on protease inhibitor therapy (letter). AIDS. 1998 Jan 22;12(2):228-30. MED/98116710. Goujard C, Lebrun L, Doucet-Populaire F, Vincent V, Nordmann P. Clarithromycin-resistant Mycobacterium avium strain in a clarithromycin-naive AIDS patient. Clin Infect Dis. 1998 Jan;26(1):186. MED/98109337. Bermudez LE, Petrofsky M, Kolonoski P, Young LS. Emergence of Mycobacterium avium populations resistant to macrolides during experimental chemotherapy. Antimicrob Agents Chemother. 1998 Jan;42(1):180-3. MED/98059474. Burman WJ, Reves RR, Rietmeijer CA, Cohn DL. A retrospective comparison of clarithromycin versus rifampin in combination treatment for disseminated Mycobacterium avium complex disease in AIDS: clarithromycin decreases transfusion requirements. Int J Tuberc Lung Dis. 1997 Apr;1(2):163-9. MED/98119561. Holmberg SD, Moorman AC, Von Bargen JC, Palella FJ, Loveless MO, Ward DJ, Navin TR. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. HIV Outpatient Study (HOPS) Investigators. JAMA. 1998 Feb 4;279(5):384-6. MED/98079010. Shafran SD, Singer J, Zarowny DP, Deschenes J, Phillips P, Turgeon F, Aoki FY, Toma E, Miller M, Duperval R, et al. Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group. J Infect Dis. 1998 Jan;177(1):252-5. MED/98023033. Jablonowski H, Fatkenheuer G, Youle M, Newell T, Lines S, Craft JC. Ancillary benefits of Mycobacterium avium-intracellulare complex prophylaxis with clarithromycin in HIV-infected patients. Drugs. 1997;54 Suppl 2:16-22; discussion 28-9. MED/98023031. Dautzenberg B. Rationale for the prevention of disseminated Mycobacterium avium-intracellulare complex disease. Drugs. 1997;54 Suppl 2:1-7; discussion 28-9. AIDS/98927645. Ellis LC, Rashad AL, Loveless MO, Sykes R, Jacobs S. Effect of dimethylsulfoxide (DMSO) on the susceptibility of Mycobacterium avium complex (MAC) to azithromycin (AZ), clarithromycin (CLA), and erythromycin (ERY). Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18;:93 (abstract no.E65). ENTRY MONTH 199105 LAST REVISION DATE 20000801 248 UNIQUE IDENTIFIER DRG-0098 NAME OF SUBSTANCE Fialuridine [USPD 1998; p. 309] REGISTRY NUMBER 69123-98-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-(2-deoxy-2-fluoro-beta-arabinofuranosyl)-5-- iodouracil [MeSH ] PROTOCOL ID NUMBERS Complete NIAID ACTG 122 FIAU PHARMACOLOGICAL ACTION MODE OF ACTION: The pyrimidine nucleoside analog FIAC and its primary deaminated uracil metabolite FIAU are highly and specifically active compounds in vitro against several herpes group viruses, particularly herpes simplex virus (HSV) types 1 and 2, varicella zoster (VZV), cytomegalovirus (CMV) and hepatitis B virus (HBV). While the specific mechanism of action of FIAC/FIAU is unknown, it appears to exert its effect by serving as substrate for viral DNA polymerase. A single dose study of FIAC in man documented a conversion of a majority of the compound to FIAU, which was then eliminated by renal excretion and further biotransformation (deiodinization and glucuronic conjugation). After IV administration of 50 or 100 mg/m2 (approx 1.2 or 2.5 mg/kg) the plasma T 1/2 values for FIAC and FIAU were 1.3 and 4.2 hours respectively. After oral dosing with either 50 or 100 mg/m2, peak concentrations of FIAC and FIAU were noted at one to two hours and eight hour plasma levels averaged more than twice those observed after IV administration (1.16 mcm versus 0.44 mcm, respectively). [Int Conf AIDS 1991 Jun 16-21;7(2); 254 (abstract no. W.B. 2290); Protocol ID: ACTG 122 FIAU ] DISEASES STUDIED/TREATED Cytomegalovirus infections. [AmfAR Treat Dir 1993;6(3); p 48] CLASSIFICATION CODE Investigational - Antiviral [USPD 1998; p. 309] OTHER MAJOR USES Demonstrated along with its parent compound, FIAC, to be a highly and specifically active compound in vitro against several herpes group viruses, particularly herpes simplex virus (HSV) types 1 and 2, variella zoster (VZV) and hepatitis B virus (HBV). [Int Conf AIDS 1991 Jun 16-21;7(2); 254 (abstract no. W.B. 2290); USP DI 1995; p 2977] ADVERSE EFFECTS Although short term studies reported minor side effects, longer term hepatitis B trials (3 months) resulted in 4 fatalities in 20 patients and resulted in discontinuance of human studies. In addition other fatalities due to hepatotoxicity have been reported. FIAU toxicity was due to marked mitochondrial dysfunction as shown by disturbances in cellular energy metabolism and micro- and macrovesicular steatosis in liver cells. [Lancet 1994 June 11;343; p 1494; J Clin Invest 1995 Feb;95(2); p 555-563; J NIH Res 1995 Sep;5(9); p 33-35] CONTRAINDICATIONS Contraindicated in patients exhibiting HIV wasting syndrome; presenting clinical or x-ray evidence of bronchitis, pneumonitis, pulmonary edema, effusion, or suspected active tuberculosis; or having any unstable medical condition (including serious infections or cardiovascular, oncologic, renal or hepatic conditions) or any cytomegalovirus end organ disease. [Protocol ID: ACTG 122 FIAU ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Primary deaminated uracil metabolite of the pyrimidine nucleoside analog 1-(2'deoxy-2'fluoro-1-B-D-arabinofurano- syl)-5-iodocytosine (FIAC). [AmfAR Treat Dir 1993;6(3); p 48] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H10-F-I-N2-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 372.09 [USPD 1998; p. 309] CHEMICAL/PHYSICAL DATA Melting Point: 216-217 C [Merck Index 1996; p. 689] CHEMICAL/PHYSICAL DATA Elemental Comp: C29.05%, H2.71%, F5.11%, I34.11%, N7.53%, O21.50% [Merck Index 1996; p. 688] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water (Parent compound) [Protocol ID: ACTG 122 FIAU ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral syrup. [Protocol ID: ACTG 122 FIAU ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Int Conf AIDS 1991 Jun 16-21;7(2); 254 (abstract no. W.B. 2290)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15-30 C (59-86 F). [Protocol ID: ACTG 122 FIAU ] MANUFACTURERS 0000001180: Oclassen Pharmaceuticals Inc 311 Bonnie Circle Corona, CA 928802882 Contact: Dr Syd Dromgoole (415)258-4558 REFERENCES AIDS/96700717. Grodeck B. A, B, C, D, E...any school child can tell you not to mess with viral hepatitis. Posit Aware. 1995 Sep/Oct;:12-5. MED/96071467. Lewis W. Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995 May;1(5):417-22. MED/95232136. Dusheiko GM. Treatment and prevention of chronic viral hepatitis. Pharmacol Ther. 1995 Jan;65(1):47-73. MED/94260796. Brahams D. Death in US fialuridine trial [news]. Lancet. 1994 Jun 11;343(8911):1494-5. ICA8/92400966. Pottage JC, Kessler HA, Kapell K, Benson CA. Acyclovir resistant (ACV-R) herpes simplex: susceptibility to alternative antiviral agents. Int Conf AIDS. 1992 Jul 19-24;8(2):B126 (abstract no. PoB 3238). ICA7/3229091. Tartaglione T, Hooton TM, Jones T, Smiles K, Corey L. Actg 122: phase II tolerance study of oral FIAU in HIV-infected persons. Int Conf AIDS. 1991 Jun 16-21;7(2):254 (abstract no. W.B.2290). MED/97030931. Fletcher CV. Pharmacologic considerations for antiviral drug development (see comments). MED/97056749. Ahluwalia GS. Driscoll JS. Ford H Jr. Johns DG. Comparison of the DNA incorporation in human MOLT-4 cells of two 2'-beta-fluoronucleosides, 2'-beta-fluoro-2', 3'-dideoxyadenosine and fialuridine. J Pharm Sci. 1996 Apr; 85(4): 454-5. MED/96117917. De Man RA. Heijtink RA. Niesters HG. Schalm SW. New developments in antiviral therapy for chronic hepatitis B infection. Scand J Gastroenterol Suppl. 1995; 212:100-4. ENTRY MONTH 199104 LAST REVISION DATE 20000801 249 UNIQUE IDENTIFIER DRG-0097 NAME OF SUBSTANCE Alovudine [USPD 1998; p. 36] REGISTRY NUMBER 25526-93-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting FDA 054A PROTOCOL ID NUMBERS No longer recruiting FDA 054B PROTOCOL ID NUMBERS No longer recruiting FDA 054C PHARMACOLOGICAL ACTION MODE OF ACTION: FLT inhibits HIV replication in vitro. By inhibiting reverse transcriptase activity, premature DNA chain termination occurs. Absorption of FLT is rapid, peak plasma concentration (Cmax) was reached in all subjects within 90 minutes. There was up to a three-fold difference in C-max among subjects at the same dose level. The area under the concentration-time curve (AUC) was less variable, with coefficients of variation ranging from 14% to 21%. Increase in Cmax and AUC were proportional to the increment in dose; mean Cmax's were 234, 529, 1130, 1662 ng/ml for subjects at four dose levels, 0.13, 0.3, 0.67, or 1.3 mg/kg. AUC's were 612, 1110, 2493, and 5190 ng*hr/ml for each group respectively. The elimination half-life of FLT ranged from 2.5 to 6.3 hours (mean 3.1 to 4.3 hours), independent of dose and three-fold longer than the half-life of AZT. In another study, the anti-HIV-1 activity of 3'-deoxy-3'-fluorothymidine was assessed. Of 14 patients enrolled in this study, seven of these had significant (greater than or equal to eight-fold) decrease in HIV-1 titer isolated from PBMC and/or plasma. Six had a greater or equal to 50% reduction in antigenemia. [Int Conf AIDS 1992 Jul 19-24;8(2); B91 (abstract no. PoB 3025); Int Conf AIDS 1991 Jun 16-21;7(2); 210 (abstract no. W.B. 2114); AmfAR Treat Dir 1991 April; p 18] DISEASES STUDIED/TREATED HIV infection. [Int Conf AIDS 1992 Jul 19-24;8(2); B91 (abstract no PoB 3025)] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS When FLT was administered in a single dose, no side effects were observed. Hematologic toxicity effects were reported in a multiple dose study to assess hematologic toxicity. [Int Conf AIDS 1996 Jul 7-12;11(1); We47 (abstract no. WeB 1012); Int Conf AIDS 1991 Jun 16-21;7(2); 210 (abstract no. W.B. 2114)] CONTRAINDICATIONS Contraindicated in patients who are intolerant to zidovudine (AZT), have oral hairy leukoplakia at any time, or are pregnant or breastfeeding. [Protocol ID: 054A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: FLT is a synthesized 3'fluor-substituted derivative of 3'-deoxythymidine, a pyrimidine nucleoside analogue. FLT is structurally similar to AZT, differing only at the 2' and 3' positions of the ribose. AZT is characterized by an azido group at the 3' position, FLT has a fluoro group at this position. [AmfAR Treat Dir 1991 April; p 18] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H13-F-N2-04 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 244.22 [USPD 1998; p. 36] SUBSTANCE DELIVERY DATA DOSAGE FORM: Liquid. [Int Conf AIDS 1991 Jun 16-21;7(2); 102 (abstract no. W.A. 1041)] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Int Conf AIDS 1991 Jun 16-21;7(2); 102 (abstract no. W.A. 1041)] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/96316002. Faraj A, Schinazi RF, Xie MY, Gosselin G, Perigaud C, Imbach JL, Sommadossi JP. Selective protection of toxicity of 2'3'-dideoxypyrimidine nucleoside analogs by beta-D-uridine in human granulocyte-macrophage progenitor cells. Antiviral Res. 1996 Mar;29(2-3):261-7. MED/96431793. Sundseth R, Joyner SS, Moore JT, Dornsife RE, Dev IK. The anti-human immunodeficiency virus agent 3'-fluorothymidine induces DNA damage and apoptosis in human lymphoblastoid cells. Antimicrob Agents Chemother. 1996 Feb;40(2):331-5. MED/95018073. Kumar R, Wang L, Wiebe LI, Knaus EE. Synthesis and antiviral (HIV-1, HBV) activities of 5-halo-6-methoxy (or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidin- e diastereomers. Potential prodrugs to 3'-fluoro-3'-deoxythymidine. J Med Chem. 1994 Oct 14;37(21):3554-60. MED/95088418. Flexner C, van der Horst C, Jacobson MA, Powderly W, Duncanson F, Ganes D, Barditch-Crovo PA, Petty BG, Baron PA, Armstrong D, et al. Relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials. J Infect Dis. 1994 Dec;170(6):1394-403. MED/93362563. Cox SW, Albert J, Ljungdahl-Stahle E, Wahren B. Effect of resistance on combination chemotherapy for human immunodeficiency virus infection. Adv Enzyme Regul. 1993;33:27-36. MED/94012340. Clumeck N. Current use of anti-HIV drugs in AIDS. J Antimicrob Chemother. 1993 Jul;32 Suppl A:133-8. ICA9/93335735. Flexner C, Polsky B, van der Horst C, Jacobson M, Powderly W, Duncanson F. Relationship between antiretroviral drug exposure and activity in patients receiving 3'-deoxy-3'-fluorothymidine (FLT). Int Conf AIDS. 1993 Jun 6-11;9(1):489 (abstract no. PO-B26-2123). ICA8/92401659. Polsky B, Barditch-Crovo P, van der Horst C, Flexner C, Raasch R, Duncanson F, Kuye O, Armstrong D. Anti-HIV-1 activity of FLT: preliminary results from a clinical trial. Int Conf AIDS. 1992 Jul 19-24;8(2):B91 (abstract no. PoB 3025). ICA8/92400251. Barditch-Crovo P, Ganes D, Duncanson F, van der Horst C, Polsky B, Petty B, Faulkner R, Kuye O, Yacobi A, Lietman P, et al. Early markers of hematologic toxicity with FLT therapy. Int Conf AIDS. 1992 Jul 19-24;8(1):We47 (abstract no. WeB 1012). MED/92385161. Pan XZ, Qiu ZD, Baron PA, Gold JW, Polsky B, Chou TC, Armstrong D. Three-drug synergistic inhibition of HIV-1 replication in vitro by 3'-fluoro-3'-deoxythymidine, recombinant soluble CD4, and recombinant interferon-alpha. AIDS Res Hum Retroviruses. 1992 May;8(5):589-95. ENTRY MONTH 199105 LAST REVISION DATE 20000801 250 UNIQUE IDENTIFIER DRG-0096 NAME OF SUBSTANCE Amphotericin B Lipid Complex [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 1397-89-3 STANDARD CHEMICAL NAME Amphotericin B lipid complex [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Abelcet [USP DI 2000; p. 117] SYNONYMS AmBisome [USP DI 2000; p. 119] PROTOCOL ID NUMBERS Complete FDA 051A PROTOCOL ID NUMBERS No longer recruiting NCI 92 C-47 PROTOCOL ID NUMBERS No longer recruiting NCI 97 C-0013 PHARMACOLOGICAL ACTION MODE OF ACTION: Amphotericin B is a polyene antibiotic whose mechanism of action is related to its capacity to bind to membrane sterols, thereby forming transmembrane pores that allow vital intracellular constituents to leak out, eventually leading to cell death. Amphotericin B therapy is associated with side effects such as fever, chills, hypotension, azotemia, hypokalemia and normocytic anemia. In laboratory animals, incorporation of amphotericin B in phospholipid vesicles (liposomes) resulted in a decreased number of toxic reactions and enhanced therapeutic activity in a variety of experimentally produced fungal infections. The mechanisms of activity of liposomal amphotericin B seem to be related to tissue targeting, altered interactions between yeast and mammalian cells, and possible intracellular delivery to phagocytic cells. In rodents and humans, liposomes are taken up preferentially by the liver, spleen, lung, kidneys and bone marrow - organs that are rich in mononuclear phagocytes and that are also target for fungal infections. When incubated in vitro with yeast cells, liposomal amphotericin B retains the antifungal potency of amphotericin B but is not toxic to red blood cells. Liposomes are avidly taken up by circulating and tissue phagocytes, suggesting the possibility of a second carrier and a reservoir for the drug. Other mechansims such immunostimulation and capillary leakage caused by fungal endothelial invasion may also play a role. [Arch Intern Med 1989; November; Vol 148, p 2533-6] DISEASES STUDIED/TREATED Disseminated fungal infections including cryptococcal meningitis, systemic candidiasis, coccidioidomycosis, and aspergillosis. FDA approved 11/20/95 for patients with aspergillosis who are refractory to or intolerant of conventional amphotericin B. [AmfAR Treat Dir 1995;7(4); p 61; FDA Bulletin ] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 115] SUBSTANCE INTERACTIONS Interacts with corticosteroids, salicylates or other drugs known to interfere with prostaglandin synthesis, interferon, interleukin-2, isoprinosine. [Protocol ID: 051A ] ADVERSE EFFECTS ABLC has been associated with treatment increases in transaminases, transient renal toxicity, fever and chills. [AmfAR Treat Dir 1995;7(4); p 61] CONTRAINDICATIONS Contraindicated in the presence of history of hypersensitivity/anaphylactoid reaction attributed to amphotericin B; pregnancy; breastfeeding. [Protocol ID: 051A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A molecule containing two lipids (DMPC/DMPG) and amphotericin B. Liposome encapsulation delivers the drug in a vehicle that tends to be taken up by organs rich in reticuloendothelial cells, the site of most disseminated fungal infections. [AmfAR Treat Dir 1993;6(3); p 45] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Polyene antibiotic (Amphotericin B). [Merck Index 1989; p 93] MANUFACTURERS 0000003334: Liposome Co Inc 1 Research Way Princeton, NJ 085406619 Contact: Medical Information (800)422-5279 MANUFACTURERS 0000003335: Fujisawa Healthcare Inc Parkway Center North / 3 Parkway North Deerfield, IL 600152548 Contact: Medical Information (800)727-7003 MANUFACTURERS 0000003334: Liposome Co Inc 1 Research Way Princeton, NJ 085406619 Contact: Unspecified (800)335-5476 MANUFACTURERS 0000003335: Fujisawa Healthcare Inc Parkway Center North / 3 Parkway North Deerfield, IL 600152548 Contact: Unspecified (800)727-7003 REFERENCES MED/96435303. Sharkey PK, Graybill JR, Johnson ES, Hausrath SG, Pollard RB, Kolokathis A, Mildvan D, Fan-Harvard P, Eng RH, Patterson TF, et al. Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS [see comments]. Clin Infect Dis, 1996 Feb; 22(2): 315-21. MED/95258069. Reblin T, Meyer A, Albrecht H, Greten H. Disseminated cryptococcosis in a patient with AIDS. Mycoses. 1994 Jul-Aug;37(7-8):275-9. MED/94375920. Leake HA, Appleyard MN, Hartley JP. Successful treatment of resistant cryptococcal meningitis with amphotericin B lipid emulsion after nephrotoxicity with conventional intravenous amphotericin B. J Infect. 1994 May;28(3):319-22. MED/94204189. Davidson RN, Di Martino L, Gradoni L, Giacchino R, Russo R, Gaeta GB, Pempinello R, Scott S, Raimondi F, Cascio A, et al. Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med. 1994 Feb;87(2):75-81. MED/94350503. Viviani MA, Rizzardini G, Tortorano AM, Fasan M, Capetti A, Roverselli AM, Gringeri A, Suter F. Lipid-based amphotericin B in the treatment of cryptococcosis. Infection. 1994 Mar-Apr;22(2):137-42. MED/93371711. Coker RJ, Viviani M, Gazzard BG, Du Pont B, Pohle HD, Murphy SM, Atouguia J, Champalimaud JL, Harris JR. Treatment of cryptococcosis with liposomal amphotericin B (AmBisome) in 23 patients with AIDS. AIDS. 1993 Jun;7(6):829-35. MED/94092867. Torre-Cisneros J, Villanueva JL, Kindelan JM, Jurado R, Sanchez-Guijo P. Successful treatment of antimony-resistant visceral leishmaniasis with liposomal amphotericin B in patients infected with human immunodeficiency virus [see comments]. Clin Infect Dis. 1993 Oct;17(4):625-7. ICA8/92400867. al-Haddadin D, Fan-Havard P, Boghossian J, Marton R, Vincent-Graber D, Dungo L, Eng RH, Johnson ES. Amphotericin B-lipid complex (ABLC) in treatment of cryptococcal meningitis in AIDS. Int Conf AIDS. 1992 Jul 19-24;8(2):B109 (abstract no. PoB 3132). ICA8/92401070. Lazanas M, Tsekes G, Papandreou S, Harhalakis N, Nikiphorakis E, Saraglou G. Liposomal amphotericin B for leishmaniasis treatment of AIDS patients unresponsive to antimonium compounds. Int Conf AIDS. 1992 Jul 19-24;8(2):B143 (abstract no. PoB 3341). ICA7/3217791. Lazar JT, Ksionski GE. Efficacy and safety of amBisome (liposomal amphotericin B) in primary episodes of cryptococcosis in patients with HIV infection. Int Conf AIDS. 1991 Jun 16-21;7(2):226 (abstract no. W.B.2177). ENTRY MONTH 199105 LAST REVISION DATE 20001107 251 UNIQUE IDENTIFIER DRG-0095 NAME OF SUBSTANCE p24 Vaccine, Recombinant [Int Conf AIDS 1996 Jul 7-12;11(1); Tu39 (abstract no. TuB 0562)] PROTOCOL ID NUMBERS No longer recruiting CC 90 I-170 PHARMACOLOGICAL ACTION MODE OF ACTION: Infection with HIV has been demonstrated to elicit antibody responses to HIV-specific proteins, including the p24 core and gp160 envelope proteins, although there are variations in responses to the different structural proteins from patient to patient. While antibody titers to envelope protein tend to remain high throughout all stages of infection, antibody titers to the major core antigen, p24, tend to be higher in asymptomatic individuals and lower or falling p24 antibody titers are associated with clinical progression. The in vivo HIV antigen load is bimodal, characterized by a rise after initial infection, a period of latency of variable time, and an increase again which correlates with progressive stages of infection, as determined by various methods of viral detection including isolation of virus from peripheral blood mononuclear cells and detection of free viral core p24 protein. A decline in p24 antibody has been shown to precede the reappearance of p24 antigenemia by as long as 18 months. While it is possible that this observation could be explained by viral events alone, it is also possible that in vivo HIV expression is initially regulated by an effective immune response directed against HIV in natural infection. If the persistence or decline of immune mechanisms such as p24 antibody level determine whether or not HIV-infected individuals have clinical progression of disease, it may be possible to stimulate an anamnestic response using an immunogen such as p24 to enhance or prolong the asymptomatic state and delay or prevent the development of clinical disease. RGP160 (VaxSyn) and p24 vaccines when given by intradermal injection are safe but did show significant local side effects as well as discomfort due to the route of administration. Significant improvements in mean and median CD4+ cell counts were observed through month 12 in patients receiving GP160 alone. A similar trend was not observed in the GP160/p24 combination group. While numbers were small, the difference in trends lead to the unblinding and the discontinuation of administration of p24 and injection of vaccine through the intradermal route. [Int Conf AIDS 1996 Jul 7-12;11(1); Tu39 (abstract no. TuB 0562); Protocol ID: 90 I-170 ; Int Conf AIDS 1993 Jun 6-11;9(1); p 490] DISEASES STUDIED/TREATED Primary HIV infection. [Int Conf AIDS 1996 Jul 7-12;11(1); Tu39 (abstract no. TuB 0562)] CLASSIFICATION CODE Vaccine [Protocol ID: 90 I-170 ] ADVERSE EFFECTS Adverse effects may include inflammation at the site of injection and effects associated with immunizations in general. [Protocol ID: 90 I-170 ; AmfAR Treat Dir 1990 Dec; p31] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to insect cells or baculovirus, leukopenia, anemia, thrombocytopenia, significant hepatic or renal dysfunction, malignancy (other than Kaposi's sarcoma), clinically significant CNS dysfunction as assessed by neurologic exam, and pregnant or nursing women. [Protocol ID: 90 I-170 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Noninfectious subunit vaccine derived from synthetic Human Immunodeficiency Virus Type I (HIV-1) core protein (p24) produced in insect cells. A baculovirus expression vector containing the entire HIV-1 p24 protein, gag, is used to program cultured insect cells to produce the synthetic HIV-1 core protein. The HIV-1 p24 is harvested and purified from cultures of Lepidopteran (insect) cells following exposure to recombinant baculovirus vector. The protein contained in the vaccine is at least 95% pure and contains no more than 5% insect cell and baculovirus proteins. [AmfAR Treat Dir 1990 Dec; p 31] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular (IM) injection. Intradermae. [Protocol ID: 90 I-170 ; Int Conf AIDS 1993 Jun 6-11;9(1); p 490] MANUFACTURERS 0000001169: MicroGeneSys Inc 1000 Research Parkway Meriden, CT 06450 Contact: Unspecified REFERENCES MED/96183598. Levine AM, Groshen S, Allen J, Munson KM, Carlo DJ, Daigle AE, Ferre F, Jensen FC, Richieri SP, Trauger RJ, et al. Initial studies on active immunization of HIV-infected subjects using a gp120-depleted HIV-1 Immunogen: long-term follow-up. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Apr 1;11(4):351-64. MED/94328232. Gringeri A, Santagostino E, Mannucci PM, Tradati F, Cultraro D, Buzzi A, Criscuolo M, David A, Guillemot L, Barre-Sinoussi F, et al. A randomized, placebo-controlled, blind anti-AIDS clinical trial: safety and immunogenicity of a specific anti-IFN alpha immunization. J Acquir Immune Defic Syndr. 1994 Sep;7(9):978-88. ICA9/93335746. Blick G, Crook S, Buchanan S, Pelke I, Smith G, Volvovitz F. A phase I/II trial evaluating the combination use of recombinant GP160 (VaXSyn) and P24 vaccines vs. GP160 and placebo by intradermal injection. Int Conf AIDS. 1993 Jun 6-11;9(1):490 (abstract no. PO-B27-2128). ICA9/93335745. Blick G, Crook S, Buchanan S, Smith G, Volvovitz F. A phase I/II trial evaluating the combination use of recombinant gp160 (VaxSyn) and P24 vaccines in HIV-seropositive individuals regardless of initial CD4+ cell counts. Int Conf AIDS. 1993 Jun 6-11;9(1):490 (abstract no. PO-B27-2131). MED/93103803. Zunich KM, Lane HC, Davey RT, Falloon J, Polis M, Kovacs JA, Masur H. Phase I/II studies of the toxicity and immunogenicity of recombinant gp160 and p24 vaccines in HIV-infected individuals. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1335. ICA8/92400492. Martin SJ, Weber J, Roitt I, Matear P, Jones K, Vyakarnam A. Recombinant HIV-1 gag p24-Ty virus-like particles (VLP's) induce HIV-1 p24-specific T helper cells in seronegative volunteers vaccinated with these particles. Int Conf AIDS. 1992 Jul 19-24;8(2):A35 (abstract no. PoA 2194). ICA8/92400220. Blick G, Buchanan S, Crook S, Diamond M, Smith G, Volvovitz F. A phase I/II study of the toxicity, immunogenicity and efficacy of recombinant gp160 and p24 vaccines (VAXSYN) in HIV-infected individuals regardless of CD4+ cell count. Int Conf AIDS. 1992 Jul 19-24;8(1):Tu39 (abstract no. TuB 0562). ICA7/1134391. Blick G, Buchanan S, Diamond M, Smith G, Volvovitz F. Active immunization of recombinant gp160/p24 vaccine (VAXSYN(R)) in HIV-infected individuals: a community-based phase I/II trial of toxicity and immunogenicity. Int Conf AIDS. 1991 Jun 16-21;7(1):177 (abstract no. M.A.1343). ENTRY MONTH 199104 LAST REVISION DATE 20000801 252 UNIQUE IDENTIFIER DRG-0094 NAME OF SUBSTANCE Sevirumab [USPD 2000 p. 647] REGISTRY NUMBER 138660-96-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 266 PROTOCOL ID NUMBERS Complete NIAID ACTG 294 PROTOCOL ID NUMBERS No longer recruiting FDA 071A PROTOCOL ID NUMBERS No longer recruiting FDA 071B PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro, it has been shown to bind to the surface membrane of CMV-infected cells. It is an IgG1 with high neutralizing activity against CMV strains and no cross reactivity with other herpes viruses. It is well tolerated with a T 1/2 approaching native immunoglobulin in HIV seropositive recipients. An initial study of MSL-109 in patients with AIDS showed that it was well tolerated, the development of antibody was not observed, and that at the higher dose levels, peak and trough serum levels greatly exceed the in vitro sensitivity of CMV to the antibody preparation. [AmfAR Treat Dir 1991 April; p 64; Int Conf AIDS 1990 Jun 20-23;6; Petersen et al., Abstract No Th.B.442] DISEASES STUDIED/TREATED Cytomegalovirus infection. [AmfAR Treat Dir 1993;6(3); p 51] CLASSIFICATION CODE Monoclonal antibody (antiviral) [USPD 2000 p. 647] SUBSTANCE INTERACTIONS Interacts with amphotericin B; fluconazole; and biologicals including immunoglobulin therapy, granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin alpha, or any interleukin. [Protocol ID: 071A ] ADVERSE EFFECTS No adverse effects related to MSL-109 have been noted in animals or bone-marrow transplant patients. In a pharmacokinetics and toxicity study, no laboratory abnormalities, evidence for immune complex formation or development of antiidiotypic antibody were noted. [AmfAR Treat Dir 1993;6(3); p 51; Int Conf AIDS 1990 Jun 20-23;6; Petersen et al., Abstract No Th.B.442] CONTRAINDICATIONS Contraindicated in patients with previous history of or evidence of idiopathic thrombocytopenia purpura, agammaglobulinemia, or hypogammaglobulinemia; significant pulmonary dysfunction; uncontrolled or unstable diabetes; significant cardiovascular disease including uncontrolled hypertension, congestive heart failure, cardiac arrhythmia, angina pectoris, or history of myocardial infarction (within one year); coagulation or hemorrhagic disorders; active severe opportunistic infection; severe concomitant clinical condition; prior treatment with monoclonal antibodies derived from any animal species; pregnant; or breastfeeding. [Protocol ID: 071A ; Protocol ID: 071B ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An antiviral monoclonal antibody produced in a stable hybridoma cell line after in vitro stimulation with CMV. [AmfAR Treat Dir 1993;6(3); p 51] CHEMICAL/PHYSICAL DATA Molecular Weight: approx. 150,000 daltons [USPD 2000 p. 647] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: IV. [Int Conf AIDS 1990 Jun 20-23;6; Petersen et al., Abstract No Th.B.442] MANUFACTURERS 0000003372: Protein Design Laboratories 34801 Campus Drive Fremont, CA 94555 Contact: Medical & Regulatory Affairs (415)903-3700 REFERENCES MED/95030975. Nokta M, Tolpin MD, Nadler PI, Pollard RB. Human monoclonal anti-cytomegalovirus (CMV) antibody (MSL 109): enhancement of in vitro foscarnet-and ganciclovir-induced inhibition of CMV replication. Antiviral Res. 1994 May;24(1):17-26. ICA9/93336073. Tolpin M, Pollard R, Tierney M, Nokta M, Wood D, Hirsch M. Combination therapy of cytomegalovirus (CMV) retinitis with a human monoclonal anti-CMV antibody (SDZ MSL 109) and either ganciclovir (DHPG) or foscarnet (PFA). Int Conf AIDS. 1993 Jun 6-11;9(1):54 (abstract no. WS-B11-2). ICA8/92400967. Pollard R, Nokta MA, Pappas P, Holloway M, Borucki MJ, Wood DL, Zitelli AM, Tolpin MD, Nadler PI, Whitley RJ. An anti-cytomegalovirus human monoclonal antibody in individuals with AIDS: a phase I/IIA study. Int Conf AIDS. 1992 Jul 19-24;8(2):B126 (abstract no. PoB 3237). MED/91297780. Emanuel DJ. Uses of immunotherapy for control of human cytomegalovirus-associated diseases. Transplant Proc. 1991 Jun;23(3 Suppl 3):144-6. MED/91263218. Drobyski WR, Gottlieb M, Carrigan D, Ostberg L, Grebenau M, Schran H, Magid P, Ehrlich P, Nadler PI, Ash RC. Phase I study of safety and pharmacokinetics of a human anticytomegalovirus monoclonal antibody in allogeneic bone marrow transplant recipients. Transplantation. 1991 Jun;51(6):1190-6. MED/91245182. Aulitzky WE, Schulz TF, Tilg H, Niederwieser D, Larcher K, Ostberg L, Scriba M, Martindale J, Stern AC, Grass P, et al. Human monoclonal antibodies neutralizing cytomegalovirus (CMV) for prophylaxis of CMV disease: report of a phase I trial in bone marrow transplant recipients. J Infect Dis. 1991 Jun;163(6):1344-7. ICA6/10044290. Petersen E, Kaplan C, Fish D, Hersh E, Grayson J, Gray J, Masuho Y. Human monoclonal antibody to cytomegalovirus (TI-23); pharmacokinetics and toxicity study in HIV seropositive patients. Int Conf AIDS. 1990 Jun 20-23;6(1):232 (abstract no. Th.B.442). MED/90176942. Skarp-Orberg I, Hokeberg I, Olding-Stenkvist E, Tufveson G. Use of a human monoclonal anti-cytomegalovirus antibody for the treatment of severe cytomegalovirus after renal transplantation. Transplant Proc. 1990 Feb;22(1):234. ENTRY MONTH 199105 LAST REVISION DATE 20000801 253 UNIQUE IDENTIFIER DRG-0093 NAME OF SUBSTANCE Interleukin-2, Polyethylene Glycolated [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 141 PROTOCOL ID NUMBERS Complete NIAID ACTG 236 PROTOCOL ID NUMBERS No longer recruiting FDA 072A PROTOCOL ID NUMBERS No longer recruiting FDA 072B PHARMACOLOGICAL ACTION MODE OF ACTION: Interleukin-2 (IL-2) is a lymphokine which stimulates the proliferation of T-lymphocytes and thus amplifies immune response to an antigen; it also has actions on B-lymphocytes and induces the proliferation of interferon-gamma and activation of natural killer cells. However, recombinant IL-2 (rIL-2) when expressed in Escherichia coli is unglycosylated, has limited solubility, requires high doses and long term regimes for tumor regression and antibodies to rIL-2 have been found in patients undergoing clinical trials with rIL-2. These antibodies could potentially interfere with the effectiveness of the drug. Covalent attachment of polyethylene glycol (PEGylation) enhances solubility, increases circulatory life and eliminates the possibility of potential aggregates of rIL-2 which may elicit an immune response. In one clinical trial of PEG IL-2 all patients demonstrated high levels of lymphokine-activated killer cell activity by cells freshly removed from the circulation and in the absence of in vitro exposure to IL-2. Natural killer cell activity was also enhanced. Limiting dilution analysis revealed an increase in the frequency of IL 2-responsive cells from abnormally low to levels above normal during the course of injections. In a subgroup of four patients with greater or equal to 400 CD4+ T cells/microliter at entry, there was a trend to sustained increases in CD4+ T cell numbers. However, this increase did not reach statistical significance. This subset of patients also exhibited higher proliferation responses to phytohemagglutinin as mitogen. Several of these effects persisted for 3-6 months after cessation of therapy. In conclusion, the study reported low dose IL-2 regimens lead to sustained immune enhancement. [J Exp Med 1993 Feb 1;177(2); p 483-92; Martindale: The Extra Pharmacopoeia 1993; p 485; J Immunol 1990 Jan 1; Vol 144:209-213] DISEASES STUDIED/TREATED Investigated to determine the effects on the immune system, HIV virus and antibody titers. [J Exp Med 1993 Feb 1;177(2); p 483-92; Protocol ID: ACTG 141 ] CLASSIFICATION CODE Immunomodulator [AmfAR Treat Dir 1993;6(3); p 31] OTHER MAJOR USES Immunotherapy of various malignant neoplasms; treatment of a number of viral infections and mitogens. [Martindale: The Extra Pharmacopoeia 1993; p 485; Protocol ID: ACTG 042 p 13] SUBSTANCE INTERACTIONS Interacts with drugs used in chemotherapy, hormonal therapy or other immunotherapy, and with antihypertensives. [Protocol ID: ACTG 141 ] ADVERSE EFFECTS Side effects to interleukin-2 may include encephalopathy, fever, malaise, diarrhea and mild anorexia. Other side effects to interleukin-2 may also include adverse pulmonary, cardiovascular and hepatic reactions. Thrombocytopenia, proteinuria, hemoglobinuria, granulocytopenia, eosinophilia, lymphopenia, rash, exacerbation of polymositis and dermatomyositis, dose-related fatigue, arthralgia, myalgia, nausea, vomiting, anuria, and creatinine elevation have been reported. [J Infect Dis 1993 Mar;167(3); p 519-25; Protocol ID: ACTG 042 p 8-10,43] CONTRAINDICATIONS Contraindicated in the presence of major organ allograft, significant cardiac disease, central nervous system lesions, pregnancy or lactation. [Protocol ID: ACTG 141 ; Protocol ID: ACTG 042 p 35] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Human recombinant interleukin-2 expressed in Escherichia coli purified and chemically modified with a water soluble polymer, monomethoxy polyethylene glycol(PEG), to enhance solubility and extend in vivo circulation. [J Immunol 1990 Jan 1; Vol 144:209-213] CHEMICAL/PHYSICAL DATA Solubility: Covalent attachment of PEG to recombinant interleukin-2 (rIL-2) makes the molecule very hydrophilic, have a longer circulation life and completely soluble at any pH. [J Immunol 1990 Jan 1; Vol 144:209-213] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intraveneous infusion; intradermal. [J Exp Med 1993 Feb 1;177(2); p 483-92; Protocol ID: ACTG 141 ] MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 REFERENCES ICA11/96923197. Carr A, Lloyd A, Emery S, Hoy J, Garsia R, Stewart G, French M, Fyfe G, Cooper DA. A randomised, controlled trial of interleukin-2 (IL2) or polyethylene glycol IL2 (PEG-IL2) plus antiretroviral therapy (AR) versus AR alone in HIV-infected patients with 200 - 500 CD4+ cells microliter-1. Int Conf AIDS 1996 Jul 7-12;11:2-23 (abstract no.We.B.292). MED/96183643. Ramachandran R, Katzenstein DA, Winters MA, Kundu SK, Merigan TC. Polyethylene glycol-modified interleukin-2 and thymosin alpha 1 in human immunodeficiency virus type 1 infection. J Infect Dis. 1996 Apr;173(4):1005-8. MED/96075716. Cunningham-Rundles C, Kazbay K, Zhou K, Mayer L. Immunologic effects of low-dose polyethylene glycol-conjugated recombinant human interleukin-2 in common variable immunodeficiency. J Interferon Cytokine Res 1995 Mar;15(3):269-76. TOXBIB/96/057954. Bernsen MR, Dullens HF, Den Otter W, Heintz PM. Reevaluation of the superiority of polyethylene glycol-modified interleukin-2 over regular recombinant interleukin-2. J Interferon Cytokine Res; VOL 15, ISS 7, 1995, P641-5. MED/93179771. Wood R, Montoya JG, Kundu SK, Schwartz DH, Merigan TC. Safety and efficacy of polyethylene glycol-modified interleukin-2 and zidovudine in human immunodeficiency virus type 1 infection: a phase I/II study. J Infect Dis. 1993 Mar;167(3):519-25. MED/93147738. Teppler H, Kaplan G, Smith KA, Montana AL, Meyn P Cohn ZA. Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection. J Exp Med. 1993 Feb 1;177(2):483-92. MED/93132377. Teppler H, Kaplan G, Smith K, Cameron P, Montana A, Meyn P, Cohn Z. Efficacy of low doses of the polyethylene glycol derivative of interleukin-2 in modulating the immune response of patients with human immunodeficiency virus type 1 infection. J Infect Dis. 1993 Feb;167(2):291-8. ICA8/92403649. Waites L, Fyfe G, Senechek D, Husemann C, Santiago F, Lamborn K, Vollmer C. Polyethylene glycol modified interleukin-2 (PEG IL-2) therapy in HIV seropositive individuals. Int Conf AIDS. 1992 Jul 19-24;8(3):145 (abstract no. PuB 7580). ICA8/92401184. Teppler H, Montana A, Meyn P, Kaplan G, Cohn ZA. Prolonged immunostimulatory effect of low dose PEG interleukin-2 in HIV-infected individuals. Int Conf AIDS. 1992 Jul 19-24;8(2):B162(abstract no. PoB 3453). MED/92192088. Shih Y, Konrad MW, Warren MK, Childs A, Paradise C, Meyers FJ, Groves ES. Suppression and transient induction of lymphokines in cancer patients after administration of polyethylene glycolated interleukin-2. Eur J Immunol. 1992 Mar;22(3):727-33. ENTRY MONTH 199105 LAST REVISION DATE 20000801 254 UNIQUE IDENTIFIER DRG-0092 NAME OF SUBSTANCE Cryptosporidium Immune Whey Protein Concentrate (Bovine) [Protocol ID: 068A ] PROTOCOL ID NUMBERS Complete FDA 068A PROTOCOL ID NUMBERS No longer recruiting FDA 081A PHARMACOLOGICAL ACTION MODE OF ACTION: Cows are immunized with Cryptosporidium organisms and subsequently make antibodies which spill into milk the cows produce. Whey, collected from milk, is given to patients with cryptosporidiosis and is speculated to cause an antigen/antibody interaction. However, the exact mechanism of action is unknown. Safety and efficacy of colostrum-derived bovine immunoglobulin concentrate in the treatment of diarrhea caused by Cryptosporidium parvum in AIDS patients were evaluated. All patients were treated with the concentrate for 21 consecutive days. Medication was given in powder or capsule form. Patients with C. parvum who were treated with the concentrate in powder form experienced a sighnificant decrease in mean stool weight and frequency at the end of treatment, and 1 month thereafter. Patients who receiveed the capsule form and patients with diarrhea not caused by C. parvum showed no improvement. No serious side effects were observed, and the medication was well tolerated Bovine colostrum immunoglobulin concentrate, in powder form, appears promising in the treatment of severe diarrhea caused by C. parvum. The optimal dosage, duration of therapy, and overall efficacy need to be determined in placebo-controlled trials. [Stolle Milk Biologics International 1990 January Dr. Gergich; Martindale: The Extra Pharmacopoeia 1993; p 1276; J Acquir Immune Defic Syndr Hum Retrovirol 1996 Dec 1;13(4); p 348-54] DISEASES STUDIED/TREATED Under investigation for the treatment of cryptosporidiosis (cryptosporidium-associated diarrhea). [AmfAR Treat Dir 1995;7(4); p 62; Protocol ID: 068A ] CLASSIFICATION CODE Antidiarrheal [Protocol ID: 068A ] CONTRAINDICATIONS Contraindicated in patients with known allergy or intolerance to milk products. [Protocol ID: 068A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An immune-globulin product which has been concentrated and pasteurized in such a way that its natural antibodies are not destroyed. These antibodies may form a protective barrier on the intestines to prevent damage from such organisms as cryptosporidium. [AmfAR Treat Dir 1995;7(4); p 62] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Powdered cow's milk, specifically the whey portion, collected and dried from cows immunized with cryptosporidiosis. [Stolle Milk Biologics International 1990 January Dr. Gergich] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral, milk powder. [Stolle Milk Biologics International 1990 January Dr. Gergich] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1995;7(4); p 62] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Cool, dry place as with any milk-powder product. [Stolle Milk Biologics International 1990 January Dr. Gergich] MANUFACTURERS 0000002380: Univax Biologics Inc 12280 Wilkins Ave Rockville, MD 20852 Contact: Dr Louis Frief (301)770-3099 MANUFACTURERS 0000001207: Stolle Milk Biologic International 6954 Cornell Rd / Suite 400 Cincinnati, OH 45242 Contact: Lauren Macturk (301)770-3099 REFERENCES MED/97104215. Greenberg PD, Cello JP. Treatment of severe diarrhea caused by Cryptosporidium parvum with oral bovine immunoglobulin concentrate in patients wit AIDS. J Acquir Immune Defic Syndr Hum Retroviral. 1996 Dec 1;13(4):348-54. MED/94082709. Shield J, Melville C, Novelli V, Anderson G, Scheimberg I, Gibb D, Milla P. Bovine colostrum immunoglobulin concentrate for cryptosporidiosis in AIDS [see comments]. Arch Dis Child. 1993 Oct;69(4):451-3. MED/93200737. Plettenberg A, Stoehr A, Stellbrink HJ, Albrecht H, Meigel W. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clin Investig. 1993 Jan;71(1):42-5. MED/92292012. Flanigan T, Marshall R, Redman D, Kaetzel C, Ungar B. In vitro screening of therapeutic agents against Cryptosporidium: hyperimmune cow colostrum is highly inhibitory. J Protozool. 1991 Nov-Dec;38(6):225S-227S. MED/90351575. Nord J, Ma P, DiJohn D, Tzipori S, Tacket CO. Treatment with bovine hyperimmune colostrum of cryptosporidial diarrhea in AIDS patients. AIDS. 1990 Jun;4(6):581-4. MED/90108566. Ungar BL, Ward DJ, Fayer R, Quinn CA. Cessation of Cryptosporidium-associated diarrhea in an acquired immunodeficiency syndrome patient after treatment with hyperimmune bovine colostrum. Gastroenterology. 1990 Feb;98(2):486-9. ICA6/10052190. Hojlying N, Henriksen SA, Gaub J, Hjelt K, Mathiesen L, Jepsen S, Ladefoged K, Tzipori S. Cryptosporidium diarrhoea in AIDS patients treated with hyperimmune bovine colostrum. Int Conf AIDS. 1990 Jun 20-23;6(1):252(abstract no. Th.B.521). ICA5/00346889. Nord J, Ma P, Tacket CO, DiJohn D, Tzipori S, Sahner D, Shieb G. Treatment of AIDS associated cryptosporidiosis with hyperimmune colostrum from cows vaccinated with cryptosporidium. Int Conf AIDS. 1989 Jun 4-9;5:656 (abstract no. C.586). ICA5/00080189. Ma P. Cryptosporidiosis, isosporiasis and microsporidiosis. Int Conf AIDS. 1989 Jun 4-9;5:192 (abstract no. M.B.O.32). ICA5/00177389. Ungar B, Ward D, Fayer R, Quinn C. Successful use of hyperimmune bovine colostrum to treat Cryptosporidium infection in an AIDS patient. Int Conf AIDS. 1989 Jun 4-9;5:359 (abstract no. W.B.P.45). ENTRY MONTH 199105 LAST REVISION DATE 20000801 255 UNIQUE IDENTIFIER DRG-0091 NAME OF SUBSTANCE Chlorhexidine gluconate [USPD 1998; p. 154] REGISTRY NUMBER 18472-51-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2,4,11,13-Tetraazatetradecanediimidamide, N,N''-bis(4-chlorophenyl)-3,12-diimino-, di-D-gluconate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS (component of) Hibistat [PDR 2000; p. 2] SYNONYMS Dyna-hex [Facts and Comparisons p. 1621] SYNONYMS Hibiclens [Facts and Comparisons p. 1621] SYNONYMS Peridex [Facts and Comparisons p. 1202] SYNONYMS Periogard [Facts and Comparisons p. 1202] PROTOCOL ID NUMBERS No longer recruiting FDA 050A PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 025 PHARMACOLOGICAL ACTION MODE OF ACTION: Because of its positive charge, chlorhexidine is adsorbed during oral rinsing on the surfaces of teeth, plaque, and oral mucosa, which have a net negative charge. Subsequently, the adsorbed medication is gradually released from these sites by diffusion for up to 24 hours as the concentration of chlorhexidine in the saliva decreases. This release provides a continuing bacteriostatic effect. Chlorhexidine is adsorbed onto the cell walls of microorganisms, which causes leakage of intracellular components. At low concentrations, chlorhexidine is bacteriostatic; at higher concentrations, chlorhexidine is bactericidal. Pharmacokinetic studies indicate that approximately 30% of chlorhexidine is retained in the oral cavity following rinsing and subsequently is slowly released into the oral fluids. Studies using humans and animals have shown that chlorhexidine is poorly absorbed in the gastrointestinal tract. In humans, the mean plasma level of chlorhexidine reached a peak of 0.206 mcg per gram 30 minutes following an oral dose of 300 mg. Following oral doses of 30 mg, excretion was primarily through feces (approximately 90%); less than 1% was excreted in the urine. [PDR 1998; p 2306; USP DI 1997; p 798-9] DISEASES STUDIED/TREATED Oral candidiasis, gingivitis, prevention of thrush. [AmfAR Treat Dir 1995;7(4); p 69; AmfAR Treat Dir 1997;8(3); p 76] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 873] OTHER MAJOR USES Gingivitis, acute necrotizing ulcerative gingivitis, postoperative (prophylaxis) mouth infections, mouth infections in cancer patients (prophylaxis and treatment), denture stomatitis, aphthous stomatitis and dental plaque. Topical preparations are used as bactericidal skin wound cleansing agents. [USP DI 1997; p 798] ADVERSE EFFECTS May cause an increase in staining of teeth and other oral surfaces; an increase in calculus formation and an alteration in taste perception. Less frequent or rare are superficial desquamative lesions (mouth irritation) - reported mainly in children ages 10 to 18 (the lesions are transient and may be painless); tongue tip irritation and parotitis (inflammation or swelling of salivary glands). [PDR 1998; p 2306; USP DI 1997; p 798-9] CONTRAINDICATIONS Front-tooth fillings having rough surfaces or margins may develop permanent discoloration from chlorhexidine, necessitating replacement for comestic reasons. May be contraindicated in those patients with intolerance to chlorhexidine. May be contraindicated in those patients with periodontitis since it is not known whether the use of chlorhexidine results in an increase in subgingival calculus and since gingival inflammation and bleeding may occur with both periodontitis and gingivitis and chlorhexidine oral rinse may reduce these signs, the presence or absence of these signs should not be used as indicators of periodontitis after the patient has been treated with chlorhexidine. The oral rinse should not be used by patients who are known to be sensitive to chlorhexidine gluconate. [USP DI 1997; p 799; PDR 1998; p 2306] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Bisbiguanide with bacteriostatic activity. [Merck Index 1996; p 348] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H30-Cl2-N10.2C6-H12-O7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 897.77 [USPD 1998; p. 154] CHEMICAL/PHYSICAL DATA Elemental Comp: C52.28%, H5.98%, Cl14.03%, N27.71% (base) [Merck Index 1996; p. 348] CHEMICAL/PHYSICAL DATA Solubility: In water at 20 C. Miscible with water, with up to 5 parts alcohol, and with up to 3 parts acetone. [USP DI 1997; p 800] CHEMICAL/PHYSICAL DATA Stability: Avoid excessive heat (above 104 F) and keep away from flame or devices which may generate an electrical spark with Hibiclens and Hibistat products. [PDR 1998; p 3165-6] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Oral rinse (Peridex), hand rinse (Hibistat germicidal handwipe towelettes), skin cleanser (Hibiclens) [PDR 1998; p 838, 2305, 3165-6] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral rinse, skin cleanser, hand rinse, and towelette (handwipe). [PDR 1998; p 838, 2306, 3165-6] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral rinses not intended for ingestion and should be expectorated after use. Topical preparations for skin cleansing. [PDR 1998; p 838, 2306, 3165-6] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store above freezing at a temperature not exceeding 25 C (77 F) unless otherwise specified by manufacturer. Protect from light. [PDR 1998; p 2306; USP DI 1997; p 800] MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Cheryl Karol (508)366-1100 MANUFACTURERS 0000001188: Proctor and Gamble Co PO Box 5516 Cincinnati, OH 45201 Contact: Dr Jim Hull (513)626-0225 MANUFACTURERS 0000005224: Xttrium Laboratories 415 West Pershing Road Chicago, IL 60609 Contact: Unspecified (800)236-9933 MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Unspecified (800)358-8707 MANUFACTURERS 0000001188: Proctor and Gamble Co PO Box 5516 Cincinnati, OH 45201 Contact: Unspecified (773)268-5800 MANUFACTURERS 0000005213: Colgate Oral Pharmaceuticals Inc One Colgate Way Canton, MA 02021 Contact: Cheryl Karol (508)366-1100 REFERENCES AIDS/97229586. FDA panel finds insufficient data to approve antimicrobial glove [news]. AIDS Patient Care STDS. 1996 Oct;10(5):316. MED/95163490. Taha TE, Justesen A, Paterson K, Mtimavalye LA, Munthali P, Canner JK, Broadhead RL, Chiphangwi JD, Miotti PG, Biggar RJ. An intervention to reduce the risk of mother-to-infant HIV transmission: results of a pilot toxicity study. East Afr Med J. 1994 Nov;71(11):712-5. MED/95022577. Greenspan D. Treatment of oral candidiasis in HIV infection. Oral Surg Oral Med Oral Pathol. 1994 Aug;78(2):211-5. MED/94332853. Buckner RY, Kayrouz GA, Briner W. Reduction of oral microbes by a single chlorhexidine rinse. Compendium. 1994 Apr;15(4):512,514,516 passim; quiz 520. MED/94342648. Ciancio S. Expanded and future uses of mouthrinses. J Am Dent Assoc. 1994 Aug;125 Suppl 2:29S-32S. TOXBIB/94/342646. Fischman SL. A clinician's perspective on antimicrobial mouthrinses. J Am Dent Assoc. 1994 Aug;125 Suppl 2:20S-22S. MED/92388600. Modak S, Sampath L, Miller HS, Millman I. Rapid inactivation of infectious pathogens by chlorhexidine-coated gloves. Infect Control Hosp Epidemiol. 1992 Aug;13(8);463-71. MED/92342542. Rowan C. Peridex decreases oral mucositis. Oncol Nurs Forum. 1992 Jul;19(6):939. MED/92019664. Persson RE, Truelove EL, LeResche L, Robinovitch MR. Therapeutic effects of daily or weekly chlorhexidine rinsing on oral health of a geriatric population. Oral Surg Oral Med Oral Pathol. 1991 Aug;72(2):184-91. MED/90264699. Montefiori DC, Robinson WE Jr, Modliszewski A, Mitchell WM. Effective inactivation of human immunodeficiency virus with chlorhexidine antiseptics containing detergents and alcohol. J Hosp Infect. 1990 Apr;15(3):279-82. ENTRY MONTH 199105 LAST REVISION DATE 20001107 256 UNIQUE IDENTIFIER DRG-0090 NAME OF SUBSTANCE Interferon alfa-n3 [USPD 2000; p 373] STANDARD CHEMICAL NAME Interferons, alfa- [USPD 2000; p 373] SYNONYMS Alferon LDO [USPD 2000; p 373] SYNONYMS Alferon N [USP DI 2000; p 1815] SYNONYMS Alferon N Gel [USPD 2000; p 373] PROTOCOL ID NUMBERS Complete FDA 082A PROTOCOL ID NUMBERS No longer recruiting FDA 069A PROTOCOL ID NUMBERS No longer recruiting FDA 069B PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 022 PHARMACOLOGICAL ACTION The precise mechanism of action of interferon alfa-n3 is unknown. Generally, natural alfa interferons appear to produce their effects via a complex sequence of intracellular events that result in enzyme induction, inhibition of virus replication, suppression of cell proliferation, and modulation of the host immune response. Following intralesional injection of interferon alfa-n3, plasma concentrations are minimally detectable. However, minor systemic effects are reported, indicating some absorption of the drug into the systemic circulation. The pharmacokinetic profile of interferon alfa-n3 administered via systemic routes should resemble that of other natural human alfa interferons. Refer to Interferon alfa-n1 for more information. [PDR 2000; p 1439; PDR 2000; p 1439] DISEASES STUDIED/TREATED Interferon alfa-n3 is FDA-approved for the treatment of refractory or recurrent external condyloma acuminatum in patients 18 years of age or older. HIV/AIDS-related indications are unlabeled and largely investigational. They include the treatment of AIDS-associated Kaposi's sarcoma and the treatment of chronic, active hepatitis C in select populations 18 years of age or older. In addition, interferon alfa-n3 is included in a number of HIV clinical trials due to its antiproliferative and antiviral effects. [USP DI 2000; p 1810, 1815; Protocol ID: DATRI 022 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1810] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 1810] OTHER MAJOR USES Interferon alfa-n3 is FDA-approved for the treatment of refractory or recurrent external condyloma acuminatum in patients 18 years of age or older. Other indications are unlabeled and largely investigational. They include the treatment of chronic hepatitis C, laryngeal papillomatosis, hairy cell leukemia, chronic myelocytic leukemia, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, and various carcinomas. [USP DI 2000; p 1810, 1815] SUBSTANCE INTERACTIONS There are no reported food or drug interactions with intralesionally administered interferon alfa-n3. Following administration by systemic routes interferon alfa-n3 is likely to perform similarly to other natural human alfa interferons. Alfa interferons may inhibit the activity of hepatic cytochrome P450 isoenzymes. Caution should be used in the concomitant administration of similarly metabolized drugs, such as theophylline. Caution should also be used when combining interferon alfa and myelosuppressive agents. [AHFS Drug Information 2000; p 981] ADVERSE EFFECTS The most common adverse effect associated with the intralesional administration of interferon alfa-n3 is a flu-like syndrome. Myalgias, fever, headache, and fatigue are generally mild or moderate, transient, and do not interfere with treatment. Adverse reactions are typically more frequent and severe following systemic administration. Again, the most common adverse effect is a flu-like syndrome (chills, fever, myalgia/arthralgia, headache and fatigue). Gastrointestinal, CNS, and dermatologic side effects are also reported. For more information, refer to the side effect profile for Interferon alfa-n1. [PDR 2000; p 1440] CONTRAINDICATIONS Interferon alfa-n3 is contraindicated in patients allergic to alfa interferon or any component of the product. It is also contraindicated in patients with a history of anaphylaxis to mouse immunoglobulin (IgG), egg protein, or neomycin sulfate. [PDR 2000; p 1440] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Interferon alfa-n3 is a highly purified mixture of up to 14 natural human alfa interferon subtypes, which are obtained from human leukocytes following induction with Sendai virus. [USP DI 2000; p 1810-1] CHEMICAL/PHYSICAL DATA Molecular Weight: 16,000 to 27,000 [PDR 2000; p 1439] SUBSTANCE DELIVERY DATA DOSAGE FORM: Interferon alfa-n3 is supplied as a sterile injectable solution containing 5 million units per vial. [PDR 2000; p 1440; Protocol ID: DATRI 022 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Interferon alfa-n3 is administered by intralesional injection. [PDR 2000; p 1440; Protocol ID: DATRI 022 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The injectable solution should be stored at 2 to 8 C (36 to 46 F). Do not freeze or shake vial. [PDR 2000; p 1440] MANUFACTURERS 0000001018: Interferon Sciences Inc 783 Jersey Ave New Brunswick, NJ 089013660 Contact: Hilary Helmrich (908)249-3250 MANUFACTURERS 0000001018: Interferon Sciences Inc 783 Jersey Ave New Brunswick, NJ 089013660 Contact: Unspecified (888)728-4372 MANUFACTURERS 0000001018: Interferon Sciences Inc 783 Jersey Ave New Brunswick, NJ 089013660 Contact: Hilary Helmrich (908)249-3250 MANUFACTURERS 0000001018: Interferon Sciences Inc 783 Jersey Ave New Brunswick, NJ 089013660 Contact: Unspecified (888)728-4372 REFERENCES MED/20097662. Alston B, Ellenberg JH, Standiford HC, Muth K, Martinez A, Greaves W, Kumi J. A multicenter, randomized, controlled trial of three preparations of low-dose oral alpha-interferon in HIV-infected patients with CD4+ counts between 50 and 350 cells/mm(3). Division of AIDS Treatment Research Initiative (DATRI) 022 Study Group. J Acquir Immune Defic Syndr. 1999 Dec 1;22(4):348-57. MED/98359166. Sostegni R, Ghisetti V, Pittaluga F, Marchiaro G, Rocca G, Borghesio E, Rizzetto M, Saracco G. Sequential versus concomitant administration of ribavirin and interferon alfa-n3 in patients with chronic hepatitis C not responding to interferon alone: results of a randomized, controlled trial. Hepatology. 1998 Aug;28(2):341-6. MED/97463299. Zhao XX, Hua J, Smith T, Ferencz-Biro K, Liao MJ, Rashidbaigi A. Interferon-alpha neutralizing antibodies in HIV and chronic HCV patients treated with natural-source human leukocyte-derived interferon-alpha n3. Hum Antibodies. 1997;8(3):129-36. MED/97174228. Simon DM, Gordon SC, Kaplan MM, Koff RS, Regenstein F, Everson G, Lee YM, Weiner F, Silverman A, Plasse T, Fedorczyk D, Liao MJ. Treatment of chronic hepatitis C with interferon alfa-n3: a multicenter, randomized, open-label trial. Hepatology. 1997 Feb;25(2):445-8. MED/96403158. Mapou RL, Law WA, Wagner K, Malone JL, Skillman DR. Neuropsychological effects of Interferon Alfa-n3 treatment in asymptomatic human immunodeficiency virus-1-infected individuals. J Neuropsychiatry Clin Neurosci. 1996 Winter;8(1):74-81. MED/96208866. Skillman DR, Malone JL, Decker CF, Wagner KF, Mapou RL, Liao MJ, Testa D, Meltzer MS. Phase I trial of interferon alfa-n3 in early-stage human immunodeficiency virus type 1 disease: evidence for drug safety, tolerance, and antiviral activity. J Infect Dis. 1996 May;173(5):1107-14. MED/95335596. Shrestha R, McKinley C, Bilir BM, Everson GT. Possible idiopathic thrombocytopenic purpura associated with natural alpha interferon therapy for chronic hepatitis C infection. Am J Gastroenterol. 1995 Jul;90(7):1146-7. MED/95243361. Friedman-Kien A. Management of condylomata acuminata with Alferon N injection, interferon alfa-n3 (human leukocyte derived). Am J Obstet Gynecol. 1995 Apr;172(4 Pt 2):1359-68. MED/95087472. Fleshner PR, Freilich MI. Adjuvant interferon for anal condyloma. A prospective, randomized trial. Dis Colon Rectum. 1994 Dec;37(12):1255-9. MED/94145746. Fan SX, Skillman DR, Liao MJ, Testa D, Meltzer MS. Increased efficacy of human natural interferon alpha (IFN-alpha n3) versus human recombinant IFN-alpha 2 for inhibition of HIV-1 replication in primary human monocytes. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1115-22. ENTRY MONTH 199105 LAST REVISION DATE 20001010 257 UNIQUE IDENTIFIER DRG-0089 NAME OF SUBSTANCE Smallpox Vaccine [USPD 1998; p. 671] PROTOCOL ID NUMBERS Complete FDA 063A PROTOCOL ID NUMBERS Complete NIAID AVEG 014A/B PHARMACOLOGICAL ACTION MODE OF ACTION: Used to promote active immunity to smallpox in individuals exposed to the disease or virus. The vaccine contains vaccinia virus which is antigenically similar to variola virus, the causative agent of smallpox. Administration of vaccinia virus promotes the production of specific antibodies which confer immunity against smallpox. Following administration of vaccine, local replication of vaccinia virus occurs; replication of the vaccinia virus may occur in the regional lymph nodes. Protection that results from immunization is probably the result of both T and B cell-mediated antibodies. Following primary immunization, antibody appears in the serum within 4-5 days, peaks within 4 weeks, and persists for several years. The skin response to immunization appears within 3-5 days, peaks within 4 weeks, and may show evidence of change for up to 20 years following immunization. Appearance of antibody in serum without a skin response occurs rarely following primary immunization; however, absence of a skin response usually indicates an inadequate immune response to the vaccine. Immunization is highly protective, although the exact mechanism of protection has not been fully established. Nearly 100% of the individuals who receive vaccine are protected during the first 1-3 years following immunization. The duration of immunity has not been definitely established, but the vaccine generally provides substantial but waning immunity for 10 years or more. Individuals exposed to smallpox who were immunized more than 3 years before exposure may develop smallpox; however, the disease process is generally modified and nonfatal. This modification of disease following exposure may occur up to 20 years following immunization. [AHFS Drug Information 1997; p 2647] DISEASES STUDIED/TREATED Comparative study of HIVAC-1e and the smallpox vaccine in previously vaccinated and unvaccinated volunteers. Control in vaccine studies. [Protocol ID: 063A ] CLASSIFICATION CODE Vaccine [Protocol ID: 063A ] OTHER MAJOR USES Used only to promote active immunity to smallpox in individuals exposed to the disease or virus (e.g. laboratory workers directly involved with smallpox or closely related orthopox viruses and civilians producing or testing smallpox vaccine.). [AHFS Drug Information 1997; p 2647] SUBSTANCE INTERACTIONS In general, individuals receiving immunosuppressive therapy (e.g. corticotropin, corticosteroids, alkylating agents, antimetabolites, radiation therapy) may have a diminished response to smallpox vaccine and replication of the virus may be potentiated. Concomitant smallpox vaccination and dexamethasone therapy and concomitant smallpox vaccination and prednisone therapy have been reported to result in immunosuppression produced by corticosteroids and impairment of the response to smallpox vaccine, increasing the risk of generalized vaccinia. Concomitant indomethacin and smallpox vaccination has been reported to alter the response to smallpox vaccination. Concomitant methotrexate and smallpox vaccination has been reported to impair the immunologic response to smallpox vaccine and result in generalized vaccinia. [AHFS Drug Information 1995; p 2359] ADVERSE EFFECTS Adverse reactions following administration of smallpox vaccine range from mild to severe and may rarely result in death. Severe adverse reactions have been reported when the vaccine was administered to children younger than 1 year or when it was inadvertently administered to patients with immunological deficiencies. However, because the use of smallpox vaccine is restricted, most complications occur in recently vaccinated military personnel or their contacts who are infected by person-to-person spread of vaccinia virus. Primary immunization results in a typical skin response at the site of administration with swelling and tenderness, some regional lymphadenopathy and occasionally a low grade fever. Generalized vaccinia, manifested as an erythematous urticarial rash, frequently occurs 7-12 days following administration of the vaccine. The rash is self-limiting and usually persists for a few days; individuals are not acutely ill. Eczema vaccinatum may occur as a result of local spread and/or dissemination of vaccinia virus infections in individuals with a previous history of atopic dermatitis or eczema. Bullous erythema multiforme occurs rarely. Vaccinia necrosum, characterized by progressive necrosis of an apparently normal skin response to the vaccine has been reported rarely. Fever, headache and meningeal signs occur 1-2 weeks after immunization and may be followed by ataxia, muscular weakness, paralysis, lethargy, coma, and seizures; permanent brain damage may result. Secondary bacterial infections may occur at the vaccination site. Other adverse effects reported include myocarditis, thrombocytopenia, arthritis, pericarditis, lymphangitis, lymphadenitis, osteomyelitis and pneumonia. Adverse nervous system effects including encephalitis, encephalomyelitis, encephalopathy, transverse myelitis, neuromyelitis optica and acute infectious polyneuritis have occurred rarely following administration of smallpox vaccine. Malignant melanoma has developed rarely in the vaccination scar at the administration site. Acute erythema nodosum leprosum or lepra reactions have been reported following administration of smallpox vaccine to individuals with lepromatous leprosy. [AHFS Drug Information 1997; p 2647] CONTRAINDICATIONS Primary and booster immunizations with smallpox vaccine are generally contraindicated in infants with failure to thrive, premature infants, and small, weak debilitated children; individuals of any age with eczema, wounds, burns, poison ivy, impetigo, or other chronic form of dermatitis as well as siblings or other household contacts of these individuals; individuals with leukemia, lymphomas of any other type, or other malignant neoplasms affecting the bone marrow or lymphatic systems; individuals with known or suspected disorders of gamma globulin synthesis (e.g. dysgammaglobulinemia); and individuals receiving immunosuppressive therapy (e.g. corticotropin, corticosteriods, radiation therapy, certain antineoplastic agents). However, the manufacturer states that there are no absolute contraindications to the use of smallpox vaccine in direct contacts of patients with smallpox or in endemic areas. Vaccine should probably be administered with caution to those who have exhibited previous systemic allergic reactions to smallpox vaccine or any ingredient in the formulation (e.g. polymyxin B, dihydrostreptomycin, chlortetracycline tracycline, neomycin). The risk of severe adverse reactions appears to be greatest in children younger than 1 year of age. Administration of smallpox vaccine to pregnant women during weeks 3-24 of gestation may cause fetal vaccinia which usually results in fetal death. [AHFS Drug Information 1997; p 2647-8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lyophilized preparation of live vaccinia virus prepared from calf lymph and grown in the skin of a vaccinated bovine calf. [AHFS Drug Information 1997; p 2646] CHEMICAL/PHYSICAL DATA Stability: Lyophilized smallpox vaccine should be refrigerated at 2-8 C. Following reconstitution with the diluent provided, the vaccine may be used for 3 months when stored at less than 4 C (preferably less than 0 C). [AHFS Drug Information 1997; p 2647] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: The lyophilized vaccine occurs as a yellow to grayish pellet which may become fragmented upon shaking. [AHFS Drug Information 1997; p 2646] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lyophilized powder for reconstitution and diluent. [AHFS Drug Information 1995; p 2357, 2360] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Administered intradermally by the multiple pressure technique, preferably over the deltoid region of the arm. [AHFS Drug Information 1997; p 2649] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized smallpox vaccine should be refrigerated at 2-8 C. [AHFS Drug Information 1997; p 2647] MANUFACTURERS 0000004834: Wyeth - Lederle Vaccines and Pediatrics 1 Great Valley Parkway Malvern, PA 19355 Contact: Unspecified (610)647-9452 REFERENCES MED/96210576. McElrath MJ, Corey L, Greenberg PD, Matthews TJ, Montefiori DC, Rowen L, Hood L, Mullins JI. Human immunodeficiency virus type 1 infection despite prior immunization with a recombinant envelope vaccine regimen. Proc Natl Acad Sci USA. 1996 Apr 30;93(9):3972-7. MED/96137659. Moulin AM. [Historical development of vaccines. Introduction: Hazards and rationality in the vaccinal approach]. Pubbl Stn Zool Napoli II. 1995;17(1):5-29. MED/96183917. Demkowicz WE Jr, Littaua RA, Wang J, Ennis FA. Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J Virol. 1996 Apr;70(4):2627-31. MED/94118914. Siefkes D. The origin of HIV-1, the AIDS virus. Med Hypotheses. 1993 Oct;41(4):289-99. MED/93103838. Tartaglia J, Cox WI, Taylor J, Perkus M, Riviere M, Meignier B, Paoletti E. Highly attenuated poxvirus vectors. AIDS Res Hum Retroviruses 1992 Aug;8(8):1445-7. ICA7/5000191. Graham BS, Belshe R, Clements ML, Dolin R, Fernie B, Stablein D, Wright P, Koff W. HIV-GP160 recombinant vaccinia vaccination of vaccinia-naive adults followed by RGP160 booster immunization. Int Conf AIDS. 1991 Jun 16-21;7(2):88 (abstract no. F.A.1). MED/92144714. Baxby D. Smallpox. Int J STD AIDS. 1991;2 Suppl 1:8-12. ICA6/40113190. Graham B, Belshe R, Midthun K, Dolin R, Fernie B, Stablein D, Wright P, Koff W. HIV gp160 recombinant vaccinia in vaccinia-naive adults. Int Conf AIDS. 1990 Jun 20-23;6(2):346 (abstract no. 1131). ICA6/40105190. Keefer MC, Bonnez E, Roberts NJ Jr, Lambert J, Dolin R, Reichman R. HIV-1 rgp160-specific cellular immune responses by recipients of a live vaccinia-rgp160 vaccine. Int Conf AIDS. 1990 Jun 20-23;6(2):326 (abstract no. 1051). MED/87144451. Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med. 1987 Mar 12;316(11):673-6. ENTRY MONTH 199105 LAST REVISION DATE 20000801 258 UNIQUE IDENTIFIER DRG-0088 NAME OF SUBSTANCE Methoxsalen [USPD 1998; p. 463] REGISTRY NUMBER 298-81-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 7H-Furo(3,2-g)(1)benzopyran-7-one, 9-methoxy- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS 8-MOP [USP DI 2000; p. 3486] SYNONYMS Oxsoralen Lotion [USP DI 2000; p. 2108] SYNONYMS Oxsoralen Ultra [USP DI 2000; p. 2104] SYNONYMS Uvadex [USP DI 2000; p. 3286] PROTOCOL ID NUMBERS No longer recruiting FDA 049A PHARMACOLOGICAL ACTION MODE OF ACTION: Following photoactivation, methoxsalen forms covalent bonds with DNA to produce monofunctional (addition to a single bond of DNA) and bifunctional adducts (cross linking to both strands of DNA). Reactions with other proteins also occur. Since the half-life of the photoactivated methoxsalen is in the microsecond range, tissues not simultaneously exposed to both the drug and ultraviolet A are spared the toxic effects of the active form. Methoxsalen appears to be well, but variably absorbed from the GI tract following oral administration. When administered orally with food, the extent of absorption and peak serum concentration appear to increase. The drug appears to be preferentially taken up by epidermal cells; distributes into the lens of the eye in concentrations proportional to the serum concentrations. The drug is reportedly 75-91% bound to serum proteins, principally albumin. About 95% of the drug is excreted in urine within 24 hours as metabolites. UVAR system: Oral ingestion of methoxsalen is followed by withdrawal of blood from the patient. This blood is infused into the UVAR system and red cells and plasma are immediately returned to the patient. Before the leukocyte fraction is returned to the patient, it is exposed to UV radiation which activates the methoxsalen. Methoxsalen becomes an alkylating agent that deactivates when no longer exposed to the light. The treated white cells, unable to reproduce, are returned to the patient. [AHFS Drug Information 1997; p 2784; N Engl J Med 1987 Feb 5; 316:6, p 297; Facts and Comparisons 1995; p 741] DISEASES STUDIED/TREATED AIDS-Related Complex. [Dermatol Nurs 1993 Feb;5(1); p 39-41] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 2104] CLASSIFICATION CODE Antipsoriatic [USP DI 2000; p. 2104] OTHER MAJOR USES Idiopathic vitiligo, psoriasis. Cutaneous T-cell lymphoma. [AHFS Drug Information 1995; p 2784] SUBSTANCE INTERACTIONS Concomitant administration with other systemic or topical photosensitizing agents [e.g., anthralin, coal tar, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylamides (bacteriostatic soaps), sulfonamides, tetracyclines, or certain organic staining dyes] may produce additive photosenitizing effects. When administered with foods, the extent of absorption and the peak serum concentration appears to be increased. [AHFS Drug Information 1997; p 2786] ADVERSE EFFECTS Toxic topical reactions: severe erythema and blistering or nausea. Oral reaction: Gastric discomfort occasionally follows oral administration and is minimized by giving the drug with milk or meals. If overdose of drug occurs, patient should remain in a darkened room for eight hours or until cutaneous reactions subside. UVAR system: post-reinfusion temperature elevations. [PDR 1997; p 1303; N Engl J Med 1987 Feb 5; 316(6):301] CONTRAINDICATIONS Contraindicated in patients exhibiting idiosyncratic reactions to psoralens or with a history of a sensitivity reaction to the drug; those with diseases associated with photosensitivity; patients with aphakia (absence of lenses) because of the increased risk of retinal damage. Also contraindicated in patients with hepatic diseases or insufficiency, children 12 years of age and younger. FDA pregnancy category C. [PDR 1997; p 1294; AHFS Drug Information 1997; p 2785; USP DI 1997; p 1994-7] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Methoxsalen is a naturally occurring substance found in the seeds of the Ammi majus (Umbilliferae) plant; it belongs to a group of compounds known as the psoralens or furocoumarins. It is prepared synthetically for commercial use. Methoxsalen undergoes extracorporeal photoactivation by ultraviolet A light. [PDR 1997; p 1301] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H8-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 216.19 [USPD 1998; p. 463] CHEMICAL/PHYSICAL DATA Melting Point: 148 C [Merck Index 1996; p. 1026] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.67%, H3.73%, O29.60% [Merck Index 1996; p. 1026] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water; slightly soluble in alcohol and soluble in propylene glycol. [AHFS Drug Information 1997; p 2784] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Occurs as white to cream-colored fluffy, odorless, needle-like crystals. [AHFS Drug Information 1995; p 2492] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules 10 mg; lotion 1% (Oxsoralen; Oxsoralen-Ultra). [AHFS Drug Information 1997; p 2787] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical with area subsequently exposed to UVA radiation, oral administration is recommended for larger areas of involvement. [AHFS Drug Information 1997; p 2784] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature: 15 to 30 C (59-86 F), protect from light. [AHFS Drug Information 1997; p 2784] MANUFACTURERS 0000001014: ICN Pharmaceuticals Inc 3300 Hyland Ave Costa Mesa, CA 92626 Contact: Dennis DeCola (610)344-3323 MANUFACTURERS 0000001213: Therakos Inc 437 Creamery Way Exton, PA 19341 Contact: Jack Sholl (714)545-0100 MANUFACTURERS 0000001014: ICN Pharmaceuticals Inc 3300 Hyland Ave Costa Mesa, CA 92626 Contact: Unspecified (800)548-5100 MANUFACTURERS 0000001014: ICN Pharmaceuticals Inc 3300 Hyland Ave Costa Mesa, CA 92626 Contact: Jack Sholl (714)545-0100 MANUFACTURERS 0000001213: Therakos Inc 437 Creamery Way Exton, PA 19341 Contact: Unspecified (800)548-5100 REFERENCES MED/97231868. Zmudzka BZ, Strickland AG, Beer JZ, Ben-Hur E. Photosensitized decontamination of blood with the silicon phthalocyanine Pc 4: no activation of the human immunodeficiency virus promoter. Photochem Phtobiol. 1997 Mar;65(3):461-4. MED/96336928. Morison WL. PUVA therapy is preferable to UVB phototherapy in the management of HIV-associated dermatoses. Photochem Photobiol. 1996 Aug;64(2):267-8. MED/96319546. Wolf P, Mullegger R, Cerroni L, Aigner R, Fueger G, Hofler G, Derbaschnig J, Kerl H. Photoaccentuated erythroderma associated with CD4+ T lymphocytopenia: successful treatment with 5-methoxypsoralen and UVA, interferon alfa-2b, and extracorporeal photopheresis. J Am Acad Dermatol. 1996 Aug;35(2 Pt 2):291-4. MED/95156188. Miolo G, Tomanin R, De Rossi A, Dall'Acqua F, Zacchello F, Scarpa M. Antiretroviral activity of furocoumarins plus UVA light detected by a replication-defective retrovirus. J Photochem Photobiol B. 1994 Dec;26(3):241-7. ICDB/96618035. Anonymous. Extracorporeal photochemotherapy: clinical aspects and the molecular basis for efficacy. Extracorporeal Photochemtherapy: Clinical Aspects and the Molecular Basis for Efficacy. Gaspaorro FP, ed. (Medical Intelligence Unit) Austin, TX, RG landes Co., 139 p., 1994. ICDB/96612804. Santamaria L, Bianchi-Santamaria A. Carotenoids in tumor and AIDS: prevention and treatment (Meeting abstract). 2nd Denver Conference on Nutrition and Cancer, September 7-11, 1994, Denver, CO 1994. ICA10/943713673. Lightfoote M, Beer JZ, Smudzka B, Gregory N. Modulation of immune response and HIV antigen expression in UVB-treated psoriasis patients. Int Conf AIDS. 1994 Aug 7-12;10(2):184 (abstract no. PB0750). MED/93313210. Lin L, Londe H, Hanson CV, Wieshahn G, Isaacs S, Cimino G, Corash L. Photochemical inactivation of cell-associated human immunodeficiency virus in platelet concentrates. Blood. 1993 Jul 1;82(1):292-7. MED/93199925. Cahill C, Keyes B, Crater D, Meyer K, et al. Photopheresis for ARC: a nursing perspective. Dermatol Nurs. 1993 Feb;5(1):39-41. MED/93017138. Heald P, Rook A, Perez M, Wintroub B, et al. Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol. 1992 Sep;27(3):427-33. ENTRY MONTH 199105 LAST REVISION DATE 20001107 259 UNIQUE IDENTIFIER DRG-0087 NAME OF SUBSTANCE Anti-HIV Immune Serum Globulin (Human) [Protocol ID: 060A ] PROTOCOL ID NUMBERS Complete NIAID ACTG 273 PROTOCOL ID NUMBERS No longer recruiting FDA 060A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 185 PROTOCOL ID NUMBERS Terminated NIAID ACTG 131 PHARMACOLOGICAL ACTION MODE OF ACTION: HIVIG kinetics are typical of immune globulins. HIVIG is safe in persons with AIDS. A Phase I clinical trial of HIVIG in persons with AIDS showed mean antibody changes (pre to 24h post dose) after the 2 low and 2 high doses were, respectively: total IgG rise .64, 2.63 g/L and anti-p24, 5436, 19199. Mean T1/2 of anti-p24 after dose 4 was 15.9 days. CD4 count and beta-2 microglobulin pre 1st dose and 28d post 4th dose were, respectively, 54, 51 x10(6)/L; 3.24, 3.17 mug/L. In all 5 subjects who were HIV Ag pos pre 1st dose, HIV Ag became undetectable and the anti-p24 T1/2 was shorter. Paired plasma HIV cultures pre and 24h post dose were available for 37/48 doses: 20 were +/+, 5 +/-, 3 -/+, 12 -/-. Of 7 1st dose +/+ pairs, the post dose time to positivity was equal or longer in all (mean 8.9d to 17.9d). Evaluation of HIVIG PK in the initial HIV+ pregnant females & their newborns enrolled in ACTG 185, a controlled (IVIG) blinded trial of HIVIG to reduce perinatal HIV transmission. HIVIG PK in HIV+ pregnant females & in newborns is consistent with those of other immunoglobulins. Interpatient variability in PK parameters in pregnant females was greater than seen in HIV+ males in a phase I study. In HIVIG patients at trough Ab (serum p24 antibody) levels, no increase in Ag (ICD p24 antigen) was seen; Ag became & stayed non-detectable in all Ag+ HIVIG but no Ag+ IVIG pts. HIVIG PK in HIV+ pregnant females. [Int Conf AIDS 1990 Jun 20-23;6(3); p 211 (abstract no. S.B. 500); Protocol ID: 060A ; Natl Conf Hum Retrv Rela Inf (2nd) 1995; p 148] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection. Under investigation for prevention of maternal-fetal HIV transmission. Treatment of pediatric HIV infection. [Protocol ID: 060A ; Protocol ID: ACTG 185 ; USP DI 1996; p 3105] CLASSIFICATION CODE Immunomodulator [Protocol ID: 060A ] SUBSTANCE INTERACTIONS Possibly interacts with immunomodulating agents, steroids, and interferons. [Protocol ID: 060A ] ADVERSE EFFECTS Toxicities reported in a Phase I trial: lightheadedness, reversible pneumocystosis, and wasting. [Int Conf AIDS 1990 Jun 20-23;6(3); p 211 (abstract no. S.B. 500)] CONTRAINDICATIONS Contraindicated in the presence of HIV-induced neurological disease, or in patients who are IgA negative. [Protocol ID: 060A ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Anti-HIV immune serum globulin is derived from the plasma of asymptomatic patients who demonstrate HIV antigens and from plasma from HIV culture negative HIV infected persons with high anti-p24 antigen titer. The fraction is inactivated with 1% tri-N-butyl phosphate and cold alcohol and fractionated to produce the final HIVIG product. [Protocol ID: 060A ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Fraction of immune globulin (human). [Protocol ID: 060A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [Protocol ID: 060A ] MANUFACTURERS 0000002674: North American Biologicals Inc 16500 Northwest 15th Ave Miami, FL 33169 Contact: Dr Christine Sapan (305)625-5303 REFERENCES MED/97068248. Douvas A, Takehana Y, Ehresmann G, Chernyovskiy T, Daar ES. Neutralization of HIV type 1 infectivity by serum antibodies from a subset of autoimmune patients with mixed connective tissue disease. AIDS Res Hum Retroviruses. 1996 Nov 1;12(16):1509-17. AIDS/96920632. McKinney RE Jr. Ongoing and future trials of antiretroviral therapy in the pediatric AIDS clinical trials group (PACTG). 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:173. AIDS/96920071. Farzadegan H, Vlahov D, Chaplinskiene M, Nelson K, Lambert J, Halsey N, Bollinger R, Jackson B, Saah A, Reichelderfer P. Cross-neutralization of domestic and international HIV-1 isolates by autologous sera and HIVIG. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:66. AIDS/96156180. Lambert JS. The prevention of maternal-fetal HIV-1 infection through passive antibody products (HIVIG) and active immunization (AIDS vaccines). Pediatr AIDS HIV Infect. 1995 Oct;6(5):300-2. AIDS/95920533. Lambert J, Fletcher C, Mofenson L, Stiehm ER, Moye J, Meyer W, Nemo G, Mathieson B, Hirsch G. Pharmacokinetics (PK) of hyperimmune HIV immunoglobulin (HIVIG) in HIV+ pregnant females & newborns. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:148. MED/95074890. Wrin T, Loh TP, Vennari JC, Schuitemaker H, Nunberg JH. Adaptation to persistent growth in the H9 cell line renders a primary isolate of human immunodeficiency virus type 1 sensitive to neutralization by vaccine sera. J Virol. 1995 Jan;69(1):39-48. AIDS/95920715. Lamacchia M, Garratty E, Burton D, Baras C, Stiehm ER, Bryson YJ. Neutralization of a panel of primary infant HIV-1 isolates by HIVIG and HIV IgGB12 antibodies. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:35. MED/94358488. Pardridge WM, Buciak J, Yang J, Diagne A. Treatment of human immunodeficiency virus-infected lymphocytes with cationized human immunoglobulins. J Infect Dis. 1994 Sep;170(3):563-9. ICA10/94369771. Jelonek M, Maskrey J, Steimer K, Potts B, Higgins K, Keller M. Inhibition of the antibody response to an HIV vaccine by maternal antibody. Int Conf AIDS. 1994 Aug 7-12;10(1):220 (abstract no. PB0308). AIDS/95921133. Zolla-Pazner S, Burda S, Andrus L, Prince A. Augmented neutralization demonstrated by combining HIVIG and human monoclonal antibodies. Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:73. ENTRY MONTH 199105 LAST REVISION DATE 20000801 260 UNIQUE IDENTIFIER DRG-0086 NAME OF SUBSTANCE Filgrastim [USPD 1998; p. 310] REGISTRY NUMBER 121181-53-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Colony-stimulating factor (human clone 1034), N-L-methionyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Neupogen [USP DI 2000; p. 979] PROTOCOL ID NUMBERS Complete NIAID ACTG 149 PROTOCOL ID NUMBERS Complete NIAID ACTG 243 PROTOCOL ID NUMBERS Complete NIAID ACTG 285 PROTOCOL ID NUMBERS Complete NIAID ACTG 286 PROTOCOL ID NUMBERS No longer recruiting FDA 061A PROTOCOL ID NUMBERS No longer recruiting FDA 077A PROTOCOL ID NUMBERS No longer recruiting FDA 087A PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-01 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-207 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 380 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5072 PROTOCOL ID NUMBERS Terminated NIAID ACTG 252 PHARMACOLOGICAL ACTION MODE OF ACTION: Colony stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment, and some end-cell functional activation. Endogenous G-CSF is a lineage-specific colony stimulating factor with selectivity for the neutrophil lineage. G-CSF is not species specific and has been shown to primarily affect neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing, and the increased expression of some functions associated with cell surface antigens. In Phase I studies involving 96 patients with various myeloid malignancies, administration of G-CSF resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1-70 mcg/kg/day. Absorption and clearance of G-CSF follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area under the concentration time curves. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg resulted in maximum serum concentration and 4 and 49 ng/mL, respectively, within 2 to 8 hours. The volume of distribution averaged 150 mL/kg in both normal subjects and cancer patients. The elimination half-life, in both normal subjects and cancer patients was approximately 3.5 hours. Clearance rates were approximately 0.5-0.7 mL/min/kg. [PDR 1995; p 513] DISEASES STUDIED/TREATED Although not FDA approved, filgrastim is used to treat HIV-infected patients with neutropenia caused by the disease itself, by opportunistic infection, or by antiretroviral medications. [USP DI 2000; p. 975] CLASSIFICATION CODE Antineutropenic [USP DI 2000; p. 975] CLASSIFICATION CODE Hematopoietic stimulant [USP DI 2000; p. 975] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Filgrastim is indicated for use following chemotherapy-induced neutropenia and bone-marrow or stem cell transplantation. Off-label uses include the augmentation of neutrophil count in patients with myelodysplastic syndromes, severe chronic neutropenia, or drug-induced neutropenia. [USP DI 2000; p. 975-976] SUBSTANCE INTERACTIONS The safety and efficacy of concomitant doses of filgrastim and myelosuppressive antineoplastic agents has not been established. Because filgrastim stimulates the proliferation of neutrophil precursors and since many antineoplastic agents target rapidly proliferating cells, filgrastim should not be administered within 24 hours before or after a dose of one of these agents. Because transient decreases in platelet counts have been reported in some patients receiving filgrastim, the drug should be used with caution in patients receiving other agents that decrease platelet counts. Drugs which could possibly potentiate the myeloproliferative effect of filgrastim, e.g., lithium, should be used with caution. [AHFS Drug Information 1995; p 986] ADVERSE EFFECTS Medullary bone pain is the most common side effect. This side effect can be controlled in most patients with non-narcotic analgesics. This effect was seen less in patients who received the drug subcutaneously rather than intravenously. Spontaneously reversible elevations in uric acid, lactate dehydrogenase, and alkaline phosphatase occurred in 27% to 58% of 98 patients. These increases were generally mild to moderate. Splenomegaly has occasionally been reported in patients receiving chronic filgrastim, principally in those with congenital or cyclic neutropenia. Transient decreases in blood pressure have also been reported. Rare occurences of hematuria/proteinuria and osteoporosis have also been reported. [AHFS Drug Information 1995; p 985] CONTRAINDICATIONS Contraindicated in patients hypersensitive to E. coli-derived products. Contraindicated in the presence of previous hypersensitivity to myeloid growth factors; leukemic or preleukemic conditions; hairy cell leukemia because of possible increased incidence of Sweet Syndrome gout since elevations in uric acid levels may occur; psoriasis since exacerbation has been reported; however, some investigators feel there are no absolute contraindications to G-CSF. [N Engl J Med 1989; 320:1343-5; Ann Int Med 1989; 110 976-84] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Endogenous G-CSF: One of several hematopoietic growth factors secreted by T lymphocytes, monocytes, macrophages and other tissues which stimulate myeloid cell growth and differentiation. Recombinant: a single chain, 175 amino acid polypeptide, nonglycosylated, expressed by E.coli. [USAN 1996; p 297] CHEMICAL/PHYSICAL DATA Molecular Formula: C845-H1339-N223-O243-S9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 18,800 daltons [USPD 1998; p. 310] CHEMICAL/PHYSICAL DATA Stability: Filgrastim may aggregate if frozen. Solutions should not be shaken in order to avoid frothing or bubble formation. The injection is stable over a pH range of 3.8-4.2. To avoid adsorption to infusion containers or equipment, albumin human should be added to the admixtures. [AHFS Drug Information 1995; p 980] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 300 mcg filgrastim per 1 ml. [PDR 1995; p 516] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous and subcutaneous. [PDR 1995; p 515] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2 to 8 C prior to use; do not freeze. [PDR 1995; p 516] MANUFACTURERS 0000003330: Amgen Inc 1840 Dehavilland Dr Thousand Oaks, CA 913201799 Contact: Professional Services (800)772-6436 MANUFACTURERS 0000003330: Amgen Inc 1840 Dehavilland Dr Thousand Oaks, CA 913201799 Contact: Unspecified (800)772-6436 REFERENCES MED/97076184. Sparano JA, Wiernik PH, Hu X, Sarta T, Schwartz EL, Soeiro R, Henry DH, Mason B, Ratech H, Dutcher JP. Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma. J Clin Oncol. 1996 Nov;14(11):3026-35. MED/96420209. Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn G. Filgrastim (r-methHuG-CSF): the first 10 years. Blood. 1996 Sep;88(6):1907-29. ICA11/96921313. Routy JP, MacLeod J, Urbanek A. Bleomycin + vincristine/VP16 with or without G-CSF in AIDS patients with Kaposi's sarcoma. Int Conf AIDS. 1996 Jul 7-12;11(1):97 (abstract no.Mo.B.1249). ICA11/96923456. Grutzmeier S, Gerstoft J, Boje Hansen P, Sandstrom E. Filgrastim (G-CSF) use is associated with prolonged survival in AIDS-patients with leukopenia and CD4 cells less than 50 x 10 6/l. Int Conf AIDS. 1996 Jul 7-12;11(2):73 (abstract no.We.A.3094). ICA11/96924575. Pitrak DL, Mullane K, Bilek M, Skariah A, Porter L, Wong R, Namini h, Allen R, Stevens P. Filgrastim (r-methug-CSF) treatment of HIV-infected patients improves neutrophil function. Int Conf AIDS. 1996 Jul 7-12;11(2):282 (abstract no. Th.B.4181). MED/96371978. Hermans P. Haematopoietic growth factors as supportive therapy in HIV-infected patients. AIDS. 1995 Dec;9 suppl 2:S9-14. MED/95324425. Frampton JE, Yarker YE, Goa KL. Lenograstim. A review of its pharmacological properties and therapeutic efficacy in neutropenia and related clinical settings. Drugs. 1995 May;49(5):767-93. MED/95340935. Manders SM, Kostman JR, Mendez L, Russin VL. Thalidomide-resistant HIV-associated aphthae successfully treated with granulocyte colony-stimulating factor. J Am Acad Dermatol. 1995 Aug;33(2 Pt 2):380-2. MED/95287034. Vecchiarelli A, Monari C, Baldelli F, Pietrella D, Retini C, Tascini C, Francisci D, Bistoni F. Beneficial effect of recombinant human granulocyte colony-stimulating factor on fungicidal activity of polymorphonuclear leukocytes from patients with AIDS. J Infect Dis. 1995 Jun;171(6):1448-54. MED/95336959. Boogaerts M, Cavalli F, Cortes-Funes H, Gatell JM, Gianni AM, Khayat D, Levy Y, Link H. Granulocyte growth factors: achieving a consensus. Ann Oncol. 1995 Mar;6(3):237-44. ENTRY MONTH 199105 LAST REVISION DATE 20001107 261 UNIQUE IDENTIFIER DRG-0085 NAME OF SUBSTANCE Rifabutin [USPD 1998; p. 636] REGISTRY NUMBER 72559-06-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1',4-didehydro-1-deoxy-1,4-dihydro-5'- (2-methylpropyl)-1-oxorifamycin XIV- [PDR 1995; p 1893] SYNONYMS Mycobutin [USP DI 2000; p. 2665] PROTOCOL ID NUMBERS Complete NIAID ACTG 196 PROTOCOL ID NUMBERS Complete NIAID ACTG 223 PROTOCOL ID NUMBERS No longer recruiting FDA 048A PROTOCOL ID NUMBERS No longer recruiting FDA 048B PROTOCOL ID NUMBERS No longer recruiting FDA 048C PROTOCOL ID NUMBERS No longer recruiting FDA 048D PROTOCOL ID NUMBERS No longer recruiting FDA 048E PROTOCOL ID NUMBERS No longer recruiting FDA 109A PROTOCOL ID NUMBERS No longer recruiting FDA 226A PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-70 PROTOCOL ID NUMBERS No longer recruiting CC 95 CC-102 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 283 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 365 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 001 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 027 PHARMACOLOGICAL ACTION MODE OF ACTION: Like rifampin, rifabutin is believed to exert its primary bactericidal effect by inhibiting DNA-dependent RNA polymerase and is active against a wide variety of gram-positive and gram-negative bacteria in vitro. The drug is also active in vitro against a variety of mycobacteria, including both M. tuberculosis and atypical species. It is not known whether this activity is dependent on inhibition of DNA-dependent RNA polymerase. Rifabutin is readily absorbed from the GI tract. Plasma concentrations declined in an apparent biphasic manner. Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung to plasma concentration ratio, obtained at 12 hours, was found to be approximately 6.5 in four surgical patients administered oral doses. About 85% of the drug is bound in a concentration independent manner to plasma proteins. Binding does not seem to be influenced by renal or hepatic dysfunction. Renal and biliary clearance of unchanged drug each contribute about 5% to the mean systemic clearance. About 30% of the dose is excreted in the feces. About 53% of the oral dose (in one mass-balance study in healthy volunteers) was excreted in the urine, primarily as metabolites. Of the 5 metabolites that have been identified, 25-O-desacetyl and 31 hydroxy predominate. The former has an activity equal to the parent drug and contributes up to 10% of the total antimicrobial activity. Absolute bioavailability assessed in 5 HIV-positive patients who received both oral and IV doses, averaged 20%. At least 53% of orally administered rifabutin is absorbed from the GI tract. High-fat meals slow the rate without influencing the extent of absorption (capsule dosage form). Rifabutin steady-state kinetics in early symptomatic HIV-positive patients are similar to healthy volunteers. [Drug Evaluations Annual 1994; p 1659-70; PDR 1995; p 1893] DISEASES STUDIED/TREATED FDA approved 9/23/92 for prevention of Mycobacterium avium Complex (MAC) bacteremia and disseminated infections in patients with advanced HIV infection. Designated by the FDA as an orphan drug for this use. [AHFS Drug Information 1995; p 396] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 2000; p. 2661] OTHER MAJOR USES Most strains of M. tuberculosis are inhibited by rifabutin. However, it remains to be established whether rifabutin is effective for the prevention of M. tuberculosis infection. [AHFS Drug Information 1995; p 396] SUBSTANCE INTERACTIONS May act synergistically with ethambutol, ciprofloxacin, or erythromycin against strains of Mycobacterium avium complex isolated from AIDS patients. Rifampin, which is structurally related to rifabutin, is known to reduce the activity of many drugs due to its hepatic enzyme-inducing properties. Drug interaction data for rifabutin itself are not available but patients taking rifabutin concurrently with these drugs should be monitored. Steady-state plasma concentrations of zidovudine (AZT) were decreased after repeated rifabutin dosing (healthy volunteers and HIV-positive patients). However, population pharmacokinetic analysis of zidovudine concentration vs. time data showed a nonsignificant trend for rifabutin to increase the apparent renal clearance of zidovudine. In vitro studies show that rifabutin does not affect the inhibition of HIV by zidovudine. [Antimicrob Agents Chemother 1988 Sep; 32(9):1392-5] ADVERSE EFFECTS Rifabutin is generally well tolerated. The most common adverse effects are rash, GI intolerance, and neutropenia. In patients with severe HIV infection, adverse effects serious enough to discontinue treatment occurred in 16% of patients receiving rifabutin and 8% of patients on placebo. [AHFS Drug Information 1995; p 396] CONTRAINDICATIONS Contraindicated in patients who have clinically important hypersensitivity to this drug or any other rifamycin (e.g., rifampin). Preventive therapy with rifabutin should not be initiated in patients with active M. tuberculosis since use of the drug as sole antimycobacterial therapy in such patients would likely lead to development of tuberculosis that is resistant to both rifabutin and rifampin. Because uveitis may occur in patients receiving rifabutin, the drug should be discontinued temporarily on appearance of inflammatory ocular conditions. [AHFS Drug Information 1995; p 396] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semisynthetic ansamycin antibiotic that is derived from rifamycin S. [Drug Evaluations Annual 1994; p 1659-70] CHEMICAL/PHYSICAL DATA Molecular Formula: C46-H62-N4-O11 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 847.02 [USPD 1998; p. 636] CHEMICAL/PHYSICAL DATA Elemental Comp: C65.23%, H7.38%, N6.61%, O20.78% [Merck Index 1996; p. 1413] SUBSTANCE DELIVERY DATA DOSAGE FORM: Hard gelatin capsules. [PDR 1995; p 1895] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1995; p 1895] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature (15-30 C) (59-86 F). [PDR 1995; p 1895] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 REFERENCES MED/97081597. Pulik M, Leturdu F, Lionnet F, Genet P, Petitdidier C, Touahri T. Rifabutin prevents campylocacter infection in patients with AIDS [letter]. Clin Infect Dis. 1996 Nov;23(5):1197-8. MED/97134289. Petrowski JT 3rd. Uveitis associated with rifabutin therapy: a clinical alert. J Am Optom Assoc. 1996 Nov;67(11):693-6. MED/96293367. Shafran SD, Singer J, Zarowny DP, Phillips P, Salit I, Walmsley SL, Fong IW, Gill MJ, Rachlis AR, Lalonde RG, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group [see comments]. N Engl J Med. 1996 Aug;335(6):377-83. MED/96293369. Havlir DV, Dube MP, Sattler FR, Forthal DN, Kem per CA, Dunne MW, Parenti DM, Lavelle P, White AC Jr, Witt MD, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group [see comments]. N Engl J Med. 1996 Aug;335(6):329-8. MED/97131181. Stephenson JM, Williams IG, is rifabutin prophylaxis against Mycobacterium avium complex infection in HIV infection worthwile? The net impact on patients suggests not. Genitourin Med. 1996 Aug;72(4):272-6. MED/97030413. Fisher M, Tomlinson DR, Coker RJ. The manangement of mycobacterial infections in HIV seropositive individuals. Jefferiss Wing Therapeutics and Protocols Group. Int J STD AIDS. 1996 Jul;7(4):244-9, quiz 249-51. MED/96318620. Mandigo K, Hogg RS, Phillips P, Barber C, Le T, Bessuille E, Black W, O'Shaughnessy MV, Schechter MT, Montaner JS. Pattern of utilization of rifabutin for prophylaxis Mycobacterium avium complex among patients with advanced human immunodeficiency virus disease in a community setting. Tuber Lung Dis. 1996 Jun;77(3):233-8. MED/96362438. Dautzenberg B, Olliaro P, Ruf B, Esposito R, Opravil M, Hoy JF, Rozenbaum W, Carosi GP, Micoud M, L'Age M, et al. Rifabutin versus placebo in combination with three drugs in the treatment of nontuberculous mycobacterial infection in patients with AIDS. Clin Infect Dis. 1996 Apr;22(4):705-8. MED/96250353. Grassi C, Peona V. Use of rifabutin in the treatment of pulmonary tuberculosis. Clin Infect Dis. 1996 Apr;22 suppl 1:S50-4. MED/96250350. Dautzenberg B. Rifabutin in the treatment of Mycobacterium avium complex infection: experience in Europe. Clin Infect Dis. 1996 Apr;22 suppl 1:S33-6. ENTRY MONTH 199104 LAST REVISION DATE 20000801 262 UNIQUE IDENTIFIER DRG-0084 NAME OF SUBSTANCE Atovaquone [USPD 1998; p. 68] REGISTRY NUMBER 95233-18-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1,4-Naphthalenedione,2-[4-(4-chlorophenyl)cyc- lohexyl]- 3-hydroxy-,trans [CHEMLINE ] SYNONYMS Mepron [USP DI 2000; p. 497] PROTOCOL ID NUMBERS Complete NIAID ACTG 167 PROTOCOL ID NUMBERS Complete NIAID ACTG 227 PROTOCOL ID NUMBERS Complete NIAID ACTG 237 PROTOCOL ID NUMBERS No longer recruiting FDA 053B PROTOCOL ID NUMBERS No longer recruiting FDA 053D PROTOCOL ID NUMBERS No longer recruiting FDA 101A PROTOCOL ID NUMBERS No longer recruiting FDA 107A PROTOCOL ID NUMBERS No longer recruiting FDA 227B PROTOCOL ID NUMBERS No longer recruiting CC 90 CC-164 PROTOCOL ID NUMBERS No longer recruiting CC 90 CC-79 PROTOCOL ID NUMBERS No longer recruiting CC 91 CC-119 PROTOCOL ID NUMBERS No longer recruiting CC 91 CC-54 PROTOCOL ID NUMBERS No longer recruiting CC 93 I-36 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 277 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 254 PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of atovaquone's antiprotozoal activity has not been fully elucidated. It may be related principally to the drug's ability to inhibit selectively mitochondrial electron transport with consequent inhibition of de novo pyrimidine synthesis. Unlike mammalian cells, certain protozoa are unable to salvage preformed pyrimidines, thus accounting for the preferential susceptibility (e.g., relative to human hosts) of the protozoa to the drug. The site of action in the mitochondrial electron transport chain appears to be the cytochrome bc 1 complex. Atovaquone is highly lipophilic with low aqueous solubility. Studies show that the bioavailability of the drug is low, variable and decreases significantly with a single dose above 750 mg. Following a single dose administration of atovaquone, the plasma concentration - time profile displayed a distinct double peak - the first between 1 and 8 hours after dosing, and the second between 24 to 96 hours post-dose. This suggests that the drug in systemic circulation is excreted into the bile and is subsequently reabsorbed. Bioavailabity is increased 3-fold when the drug is administered with meals (especially fatty meals). There is significant difference in bioavailability between normal volunteers, HIV-positive individuals and AIDS patients. Steady-state atovaquone plasma concentrations in the AIDS patients are about one third to one half the levels achieved in the other individuals. [AHFS Drug Information 1995; p 554; PDR 1995; p 783] DISEASES STUDIED/TREATED FDA approved 11/25/92 for the treatment of mild to moderate PCP in patients intolerant to standard therapies. Treatment and suppression of T. gondii encephalitis. Primary prophylaxis of HIV-infected persons at high risk for developing this disease. Limited studies suggest that atovaquone may also be effective in the treatment of ocular and cerebral toxoplasmosis in AIDS patients. [FDA Talk Paper ; USP DI 1995; p 2964; Drug Evaluations Annual 1994; p 1727] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 495] OTHER MAJOR USES Potent anti-malarial. Good in vitro activity against Toxoplasma gondii. [Drugs Exp Clin Res 1991;17(9); p 427-35; USP DI 1995; p 401] SUBSTANCE INTERACTIONS Since atovaquone is highly bound to plasma protein, caution should be used when giving the drug concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur. The extent of plasma protein binding of atovaquone is not affected by the presence of therapeutic doses of phenytoin (15 microgram/ml), nor is the binding of phenytoin affected by the presence of atovaquone. [PDR 1995; p 764] ADVERSE EFFECTS Although adverse effects associated with atovaquone therapy are common, the drug generally appears to be well tolerated. The most frequent adverse effects include rash, GI effects, fever and headache. Because most HIV-infected patients receiving the drug to date have had serious underlying disease with multiple baseline symptomatology, many reported effects may not be directly attributed to atovaquone. Treatment-limiting adverse effects were substantially less common with atovaquone than with co-trimoxazole or pentamidine. [AHFS Drug Information 1995; p 555] CONTRAINDICATIONS Patients should be advised regarding pulmonary manifestation of possibly concurrent bacterial, viral, fungal or mycobacterial infections associated with HIV infection. Atovaquone is presently not recommended for severe P. carinii pneumonia nor in the prevention of P. carinii pneumonia. Efficacy of the drug in children has not been established. The drug should be used with caution in geriatric patients. The drug should be used during pregnancy only if potential benefits justify the possible risk to the fetus. It is not known whether atovaquone is distributed in human milk; the drug should be used with caution in nursing women. [AHFS Drug Information 1995; p 555-6] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic hydroxynaphthoquinone-derivative antiprotozoal agent. [AHFS Drug Information 1995; p 554] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H19-Cl-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 366.85 [USPD 1998; p. 68] CHEMICAL/PHYSICAL DATA Melting Point: 216-219 C [Merck Index 1996; p. 147] CHEMICAL/PHYSICAL DATA Elemental Comp: C72.03%, H5.22%, Cl9.66%, O13.08% [Merck Index 1996; p. 146] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water. [PDR 1995; p 783] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow crystalline solid. [PDR 1995; p 783] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg tablets; 150 mg/ml micronized suspension in 120 ml amber bottles. Suspension formulation FDA approved for adults 2/8/95. [PDR 1995; p 786; Protocol ID: ACTG 227 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1995; p 785] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store tablets and micronized suspension at 15-25 C (59-77 F); protect micronized suspension from light. [PDR 1995; p 786; Protocol ID: ACTG 227 ] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97028614. Katlama C, Mouthon B, Gourdon D, Lapierre D, Rousseau F. Atovaquone as long-term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance. Atovaquone Expanded Access Group. AIDS. 1996 Sep;10(10):1107-12. MED/96374589. Anwar-Bruni DM, Hogan SE, Schwartz DA, Wilcox CM,, Bryan RT, Lennox JL. Atovaquone is effective treatment for the symptoms of gastrointestinal microsporidiosis in HIV-1-infected patients. AIDS. 1996 Jun;10(6):619-23. HTA/96339251. Zarkin GA, Bala MV, Wood LL, Bennett CL, Simpson K, Dohn MN. Estimating the cost effectiveness of atovaquone versus intravenous pentamidine in the treatment of mild-to-moderate Pneymocystis carinii pneumonia. Pharmacoeconomics. 1996 Jun;9(6):525-34. MED/96008522. Anonymous. Drugs for AIDS and associated infections. Med Lett Drugs Ther. 1995 Oct;37(959):87-94. MED/96152186. Lee BL, Tauber MG, Sadler B, Goldstein D, Chambers HF. Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther. 1996 Jan;59(1):14-21. MED/96185167. Korraa H, Saadeh C. Options in the management of pneumonia caused by Pneumocystis carinii in patients with acquired immune deficiency syndrome and intolerance to trimethoprim/sulfamethoxazole. South Med J. 1996 Mar;89(3):272-7. MED/96065059. Shah GK, Cantrill HL, Holland EJ. Vortex keratopathy associated with atovaquone. Am J Ophthalmol. 1995 Nov;120(5):669-71. MED/95308204. White A, LaFon S, Rogers M, Andrews E, Brown N. Clinical experience with atovaquone on a treatment investigational new drug protocol for Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Jul 1;9(3):280-5. MED/95271069. Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis. 1995 May;171(5):1295-301. MED/94288398. Dohn MN, Weinberg WG, Torres RA, Follansbee SE, Caldwell PT, Scott JD, Gathe JC Jr, Haghighat DP, Sampson JH, Spotkov J, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med. 1994 Aug 1;121(3):174-80. ENTRY MONTH 199104 LAST REVISION DATE 20000801 263 UNIQUE IDENTIFIER DRG-0083 NAME OF SUBSTANCE Fat Emulsion 20% [USP DI 2000; p. 3477] REGISTRY NUMBER 112353-79-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Liposyn II [USP DI 2000; p. 3477] PROTOCOL ID NUMBERS No longer recruiting FDA 041A PROTOCOL ID NUMBERS No longer recruiting FDA 041B PHARMACOLOGICAL ACTION MODE OF ACTION: Infused fat particles cause a transient increase in plasma triglyceride concentrations. The triglycerides are then hydrolyzed to free fatty acids and glycerol by the enzyme lipoprotein lipase. The free fatty acids either enter the tissues (to be oxidized or resynthesized to triglycerides for storage) or circulate bound to albumin in the plasma, and subsequently may undergo hepatic oxidation or conversion to very low-density lipoproteins that re-enter the bloodstream. Fat emulsions also contain phosphatides (a component of which is choline) as an emulsifier, and glycerin to adjust tonicity. Phosphatides are involved in the formation of membrane structures; choline prevents deposition of fat in the liver; and glycerin is metabolized to carbon dioxide and glycogen or is used in the synthesis of fats. Study of the effects of lipid sources (such as Liposyn II) in total parenteral nutrition on whole body protein, kinetics and tumor growth showed that the source of lipid can influence tumor growth and host protein metabolism. A structured lipid composed of medium-chain triglycerides and fish oil seems to improve protein metabolism in host tissue without stimulating tumor growth. The effect of lipid-based parenteral nutrition was assessed in AIDS patients with weight loss of 10% or greater. In 2 months period, weight gain and improved well being were noted in all patients. There was no change in T-cell subsets; viral cultures and P24 serum levels remained unchanged. Lipid-based parenteral nutrition is safe and probably efficacious in AIDS patients. [USP DI 1997; p 1417-9; J Parenter Enteral Nutr 1992;16(6); p 545-51; J Parenter Enteral Nutr 1992;16(2); p 165-7] DISEASES STUDIED/TREATED Nutritional support. [Protocol ID: 041A ; Protocol ID: 041B ; AHFS Drug Information 1997; p 2015-6] CLASSIFICATION CODE Nutritional supplement [USP DI 1998; p. 1414] OTHER MAJOR USES Fatty acid deficiency (prophylaxis and treatment). Intravenous fat emulsions are used to prevent or reverse fatty acid deficiency and provide a source of calories for patients requiring parenteral nutrition. [USP DI 1997; p 1417; AHFS Drug Information 1997; p 2015] SUBSTANCE INTERACTIONS Drug stability and compatibility studies should be performed for all medications added to total nutrient admixtures (TNAs), before administration to patients. Thus, some histamine receptor antagonists such as ranitidine are stable in TNAs containing Liposyn II or Intralipid for 24 hours, but beyond this time administration of ranitidine may be unreliable because of poor stability. [J Parenter Enteral Nutr 1994;18(4); p 308-12] ADVERSE EFFECTS Acute adverse effects include allergic reactions, hyperlipemia, dyspnea cyanosis, flushing, dizziness, headache, sleepiness, nausea, vomiting, hyperthermia, sweating, chest and back pain, thrombocytopenia, hypercoa, galability and transient increases in liver enzymes. Chronic side effects include hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leucopenia, transient increases in liver function test, overloading syndrome and deposition of brown pigment (fat pigment) in the reticulo endothelial tissue of the liver. WARNING: Death in preterm infants after infusion of intravenous fat emulsions has been reported. Caution should be exercised in administering Liposyn II to patients with severe liver damage, pulmonary disease, anemia or blood coagulation disorders or when there is danger of fat embolism. The too rapid administration of Liposyn II can cause fluid and/or fat overloading resulting in dilution of serum electrolyte concentration, overhydration, congested states, pulmonary edema, impaired pulmonary diffusion capacity or metabolic acidosis. [Abbott Laboratories Drug Information Packet, Oct 1985; Lancet 1980 October 18; p 815-8; J Pediatr 1980 Nov; 97;800-5] CONTRAINDICATIONS Risk-benefit should be considered when the following medical problems exist: anemia; blood coagulation disorders; conditions in which there is disturbance in normal fat metabolism such as: uncompensated diabetes or pathologic hyperlipidemia, or lipid nephrosis, or acute pancreatitis if accompanied by hyperlipemia, or renal insufficiency; severe hepatic damage, immunocompromised patient (fat emulsions have been reported to alter immune response); jaundice; platelet dysfunction disorders; pulmonary disease; sensitivity to fat emulsions; sepsis. [USP DI 1997; p 1417] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: It is a mixture of safflower oil and soybean oil. The major component fatty acids of the 50/50 mixture are approximately 65.8% linoleic acid, 17.7% oleic acid, 8.8% palmitic acid, 3.4% stearic acid, and 4.2% linolenic acid. It contains egg phosphatides as an emulsifying agent and glycerin to adjust tonicity. [AHFS Drug Information 1997; p 2015] CHEMICAL/PHYSICAL DATA Stability: Fat particle-size distribution in and physical stability of Liposyn II and Intralipid before and after their use in total nutrient admixtures (TNAs) were studied. All the admixtures were stable in terms of pH and visual appearance. [Am J Hosp Pharm 1992;49(11); p 2749-55] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to slightly off-white emulsion. [Abbott Laboratories Drug Information Packet, Oct 1985] SUBSTANCE DELIVERY DATA DOSAGE FORM: Liposyn I 10% is supplied in 100, 200, and 500 ml single dose containers; Liposyn II 20% is supplied in 200 and 500 ml single dose containers. [Abbott Laboratories Drug Information Packet, Oct 1985] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous. [Abbott Laboratories Drug Information Packet, Oct 1985; AHFS Drug Information 1997; p 2015] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: It is recommended that the product be stored at room temperature (25 C). Protect from freezing. [Abbott Laboratories Drug Information Packet, Oct 1985; USP DI 1997; p 1418] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/95019023. Hatton J, Luer M, Hirsch J, Westrich T, Holstad S. Histamine receptor antagonists and lipid stability in total nutrient admixtures. JPEN J Parenter Enteral Nutr. 1994 Jul-Aug;18(4):308-12. IPA/95. /1064339. Lennon C, Davidson KW, Sadowski JA, Mason JB. The vitamin K content of intravenous lipid emulsions. JPEN J Parenter Enteral Nutr. 1993 Mar-Apr;17(2):142-4. MED/94280321. Saladino CF, Kowacolsky-Singer C, Fox R, Nethala V, Feffer SE, Jonas EA. The effect of parenteral lipid emulsion-induced hyperlipidemia on prostaglandin E1 modulation of platelet function. Artery. 1993;20(6):303-13. MED/92211808. Singer P, Rubinstein A, Askanazi J, Calvelli T, Lazarus T, Kirvela O, Katz DP. Clinical and immunologic effects of lipid-based parenteral nutrition in AIDS. JPEN J Parenter Enteral Nutr 1992 Mar-Apr;16(2):165-7. MED/92148993. Bullock L, Fitzgerald JF, Walter WV. Emulsion stability in total nutrient admixtures containing a pediatric amino acid formulation. JPEN J Parenter Enteral Nutr. 1992 Jan-Feb;16(1):64-8. MED/93156145. Mendez B, Ling PR, Istfan NW, Babayan VK, Bistrian BR. Effects of different lipid sources in total parenteral nutrition on whole body protein kinetics and tumor growth. JPEN J Parenter Enteral Nutr. 1992 Nov-Dec;16(6):545-51. MED/92208395. Mcleod HL, McGuire TR, Yee GC. Stability of cyclosporine in dextrose 5%, NaCl 0.9%, dextrose/amino acid solution, and lipid emulsion. Ann Pharmacother. 1992 Feb;26(2):172-5. MED/92208517. Nichoalds GE, Weinsier RL, Millikan WJ Jr, Smith DK. Lipid and lipoprotein levels in adults receiving Liposyn II. Nutrition 1991 Sep-Oct;7(5):329-32; discussion 333-4. MED/91325377. Buchman AL, Ament ME. Comparative hypersensitivity in intravenous lipid emulsion. JPEN J Parenter Enteral Nutr. 1991 May-Jun;15(3):345-6. MED/90036561. Update: October 1989 guidelines for nutrition support in AIDS. Task Force on Nutrition in AIDS. J Ark Med Soc. 1989 Nov;86(6):219-28. ENTRY MONTH 199104 LAST REVISION DATE 20000801 264 UNIQUE IDENTIFIER DRG-0082 NAME OF SUBSTANCE Fat Emulsion 2% [USP DI 2000; p. 3477] SYNONYMS Liposyn III [USP DI 2000; p. 3477] PROTOCOL ID NUMBERS No longer recruiting FDA 041A PROTOCOL ID NUMBERS No longer recruiting FDA 041B PHARMACOLOGICAL ACTION MODE OF ACTION: Liposyn III is a 2% intravenous fat emulsion solution, manufactured exactly the same as Liposyn II, which is a 20% solution. Refer to the record for Liposyn II for further information. [Abbott Laboratories Drug Information Packet, Oct 1985] DISEASES STUDIED/TREATED Nutritional support. [Protocol ID: 041A ; Protocol ID: 041B ] CLASSIFICATION CODE Nutritional supplement [USP DI 1998; p. 1414] OTHER MAJOR USES Is indicated as a source of calories for patients requiring parenteral nutrition. [Abbott Laboratories Drug Information Packet, Oct 1985] ADVERSE EFFECTS Refer to record for Liposyn II. [Abbott Laboratories Drug Information Packet, Oct 1985] CONTRAINDICATIONS Refer to record for Liposyn II. [Abbott Laboratories Drug Information Packet, Oct 1985] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Liposyn III is a 2% solution of the same materials as Liposyn II: a mixture of safflower oil and soybean oil. [Abbott Laboratories Drug Information Packet, Oct 1985] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to slightly off-white emulsion. [Abbott Laboratories Drug Information Packet, Oct 1985] SUBSTANCE DELIVERY DATA DOSAGE FORM: Refer to record for Liposyn II. [Abbott Laboratories Drug Information Packet, Oct 1985] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Refer to record for Liposyn II. [Abbott Laboratories Drug Information Packet, Oct 1985] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refer to record for Liposyn II. [Abbott Laboratories Drug Information Packet, Oct 1985] MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Dr David Nevalainen (708)937-0691 MANUFACTURERS 0000001080: Abbott Laboratories One Hundred Abbott Park Rd Abbott Park, IL 600643500 Contact: Unspecified (800)633-9110 REFERENCES MED/96111998. Chen X, Ruiz J, Boden G. Release, oxidation, and reesterification of fatty acids from infused triglycerides: effect of heparin. Metabolism. 1995 Dec;44(12):1590-5. MED/96007230. Boden G, Chen X, Rosner J, Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995 Oct;44(10):1239-42. MED/95198224. Li J, Caldwell KD. Structural studies of commercial fat emulsions used in parenteral nutrition. J Pharm Sci. 1994 Nov;83(11):1586-92. MED/95078297. Rodriguez JM, Arias-Diaz J, Figueredo MA, Torres-Melero J, Garcia-Carreras C, Escobar C, Gomez de la Concha E, Balibrea JL. [Lymphocyte subpopulations and surgery. The role of postoperative parenteral nutrition]. Nutr Hosp. 1994 Sep-Oct;9(5):324-30. MED/95058552. Kruger RA, Liu P. Photoacoustic ultrasound: pulse production and detection of 0.5% Liposyn. Med Phys. 1994 Jul;21(7):1179-84. MED/94280321. Saladino CF, Kosacolsky-Singer C, Fox R, Nethala V, Feffer SE, Jonas EA. The effect of parenteral lipid emulsion-induced hyperlipidemia on prostaglandin E1 modulation of platelet function. Artery. 1993;20(6):303-13. MED/92211808. Singer P, Rubinstein A, Askanazi J, Calvelli T, Lazarus T, Kirvela O, Katz DP. Clinical and immunologic effects of lipid-based parenteral nutrition in AIDS [see comments]. JPEN J Parenter Enteral Nutr. 1992 Mar-Apr;16(2):165-7. MED/90036561. Update: October 1989 guidelines for nutritional support in AIDS. Task Force on Nutrition in AIDS. J Ark Med Soc. 1989 Nov;86(6):219-28. MED/89263915. Crocker KS. Gastrointestinal manifestations of the acquired immunodeficiency syndrome. Nurs Clin North Am. 1989 Jun;24(2):395-406. MED/89237128. Probart CK. Guidelines for nutritional support in AIDS. J Sch Health. 1989 Apr;59(4):170-1. ENTRY MONTH 199104 LAST REVISION DATE 20000801 265 UNIQUE IDENTIFIER DRG-0081 NAME OF SUBSTANCE Etoposide [USPD 1998; p. 294] REGISTRY NUMBER 33419-42-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Furo(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6(5a- H)-one-, 9-((4,6-O-ethylidene-beta-D-glucopyranosyl)ox- y)5,8,8a,9-tetrahydro-5 -(4-hydroxy-3,5-dimethoxyphenyl), (5R-(5alpha,5abeta,8aalpha,9beta(R*)))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Etopophos (phosphate salt) [USP DI 2000; p. 1496] SYNONYMS Toposar [USP DI 2000; p. 1495] SYNONYMS VePesid [USP DI 2000; p. 1495] PROTOCOL ID NUMBERS Complete NIAID ACTG 110 PROTOCOL ID NUMBERS No longer recruiting FDA 055A PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 269 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PHARMACOLOGICAL ACTION MODE OF ACTION: Has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G2 portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 mcg/ml or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 mcg/ml), cells are inhibited from entering prophase. It does not interfere with microtubule assembly. The predominant macromolecular effect of the drug appears to be DNA synthesis inhibition. On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to 48 ml/min or 16 to 36 ml/min/m2 and, like the terminal elimination half-life, are independent of dose over a range of 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration versus time curves (AUC) and the maximum plasma concentation (Cmax) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days. Etoposide enters the CSF poorly. The exact mechanism of action of etoposide is not known, but the drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis. Etoposide appears to be cell-cycle dependent and cycle-phase specific, including G2-phase arrest and preferentially killing cells in the G2 and late S phase. [PDR 1995; p 686; AHFS Drug Information 1995; p 640] DISEASES STUDIED/TREATED Kaposi's sarcoma. [AHFS Drug Information 1995; p 642] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1492] OTHER MAJOR USES Etoposide is indicated, in combination with other antineoplastics, for treatment of refractory testicular tumors in patients who have already received appropriate surgical, chemotherapeutic, and radiation therapy. Etoposide is also indicated for treatment of small cell lung carcinoma. [PDR 1995; p 686] SUBSTANCE INTERACTIONS Blood dyscrasia causing medications, bone marrow depressants, killed virus vaccines, live virus vaccines, or any combinations containing any of these medications may cause negative reactions with etoposide. Additive bone marrow depression may occur with radiation therapy. Etoposide and cisplatin may be synergistic against some tumors. However, patients previously treated with cisplatin may have impaired elimination of etoposide. [USP DI 1995; p 1290-3] ADVERSE EFFECTS Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Nausea and vomiting are the major gastrointestinal toxicities. Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving the drug intravenously and in less than 1% of the patients treated with oral capsules. Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients. Other effects include aftertaste, fever, pigmentation, abdominal pain, constipation, dysphagia, transient cortical blindness, and optic neuritis. [PDR 1995; p 687] CONTRAINDICATIONS Contraindicated in the presence of chicken pox or existing or recent herpes zoster. Caution should be exercised in the presence of bone marrow depression, hepatic function impairment, general infection, renal function impairment, and in patients who have had previous cytotoxic drug therapy and radiation therapy. Etoposide is teratogenic and embryotoxic in mice and rats at doses of 1-3% of the recommended clinical dose based on body surface; therefore, although human studies have not been done, its use in pregnancy is contraindicated. Breastfeeding is not recommended while etoposide is being administered. Dental work during etoposide therapy is discouraged due to the bone marrow depressant effects which may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. [USP DI 1995; p 1291] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Etoposide is a semisynthetic derivative of podophyllin. [PDR 1995; p 687] CHEMICAL/PHYSICAL DATA Molecular Formula: C29-H32-O13 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 588.57 [USPD 1998; p. 294] CHEMICAL/PHYSICAL DATA Melting Point: 236-251 C [Merck Index 1996; p. 659] CHEMICAL/PHYSICAL DATA Elemental Comp: C59.18%, H5.48%, O35.34% [Merck Index 1996; p. 659] CHEMICAL/PHYSICAL DATA Solubility: Very soluble in methanol and in chloroform; slightly soluble in ethanol; sparingly soluble in water and in ether; made more miscible with water by means of organic solvents [PDR 1995; p 686] CHEMICAL/PHYSICAL DATA Stability: Unopened vials of VePesid Injection are stable for 24 months at room temperature (25 C). Vials diluted to a concentration of 0.2 or 0.4 mg/ml are stable for 96 and 48 hours, at room temperature under normal room fluorescent light in both glass and plastic containers. [PDR 1995; p 687] SUBSTANCE DELIVERY DATA DOSAGE FORM: 50 mg capsules; 5 ml vials containing 100 mg for injection. [AHFS Drug Information 1995; p 644] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous. [AHFS Drug Information 1995; p 644] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: VePesid capsules must be stored under refrigeration 2-8 C. [PDR 1995; p 687] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 REFERENCES MED/97076184. Sparano JA, Wiernik PH, Hu X, Sarta T, Schwartz El, Soeiro R, Henry DH, Mason B, Ratech H, Dutcher JP. Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma. J Clin Oncol. 1996 Nov;14(11):3026-35. MED/96303582. Patarca R, Freidlander A, Harrington WJ, Cabral L, Byrnes JJ, Fletcher MA. Peripheral blood T cell subsets as prognostic indicators of chemotherapy outcome in AIDS patients with large cell lymphoma. AIDS Res Hum Retroviruses. 1996 May;12(8):645-9. MED/96206033. Tirelli U, Errante D, Spina M, Gastaldi R, Nigra E, Nosari AM, Magnani G, Vaccher E. Second-line chemotherapy in human immunodeficieny virus-related non-Hodgkin's lymphoma: evidence of activity of a combination of etoposide, mitoxantrone, and prednimustine in relapsed patients. Cancer. 1996 May;77(10):2127-31. MED/96206030. Hentrich MU, Brack NG, Schmid P, Schuster T, Clemm C, Hartenstein RC. Testicular germ cell tumors in patients with human immunodeficiency virus infection. Cancer. 1996 May;77(10):2109-6. MED/96405517. Remick SC, Reddy M, Ekman K, Vyzula R, Hilstro J, Horton J. Continuous infusion etoposide in advanced AIDS-related kaposi sarcoma. J Infus Chemother. 1996 Spring;6(2):92-6. MED/96122066. Stein ME, Lachter J, Spencer D, Bezwoda WR. Chemotherapy for AIDS-related and endemic African Kaposi's sarcoma in southern Africa. Int J Dermatol. 1995 Oct;34(10):729-32. MED/95268882. Paredes J, Kahn HO, Tong WP, Feldstein ML, Lin S, Bennett JM, Metroka CE, Ratner L, Krown SE. Weekly oral etoposide in patients with Kaposi's sarcoma associated with human immunodeficiency virus infection: a phase I multicenter trial of the AIDS Clinical Trials Group. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Jun 1;9(2):138-44. MED/95399331. Jost LM, Jacky E, Dommannn-Scherrer C, Honegger HP, Maurer R, Sauter C, Stahel RA. Short-term weekly chemotherapy followed by high-dose therapy with autologous bone marrow transplantation for lymphoblastic and Burkitt's lymphomas in adult patients. Ann Oncol. 1995 May;6(5):445-51. MED/95218170. Kaplan LD, Shiramizu B, Herndier B, Hahn J, Meeker TC, Ng V, Volberding PA, McGrath MS. Influence of molecular characteristics on clinical outcome in human immunodeficiency virus-associated non-Hodgkin's lymphoma: identification of a subgroup with favorable clinical outcome. Blood. 1995 Apr 1;85(7):1727-35. ICA10/94369560. Mans D, Sprinz E, Sander I, Kalakun F, Jung G, Prolla G, Schwarstmann G. A phase II study of oral etoposide (VP-16) in AIDS-related Kaposi's sarcoma (KS). Int Conf AIDS. 1994 Aug 7-12;10(1):173 (abstract no. PB0118). ENTRY MONTH 199104 LAST REVISION DATE 20000801 266 UNIQUE IDENTIFIER DRG-0080 NAME OF SUBSTANCE Dinitrochlorobenzene [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 97-00-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-chloro-2,4-dinitrobenzene [Merck Index 1989; p 329] PROTOCOL ID NUMBERS No longer recruiting FDA 047A PROTOCOL ID NUMBERS No longer recruiting FDA 265A PHARMACOLOGICAL ACTION MODE OF ACTION: Dinitrochlorobenzene (DNCB) is a contact sensitizing agent that enhances the function of antigen-presenting cells (APCs) via induction of delayed-type hypersensitivity. Topical application of DNCB was previously shown to be safe in a small number of patients with early HIV disease. One study has followed the clinical course and examined alterations of lymphocyte subsets in this same group of patients over a longer period of time. The researchers concluded that prolonged use of topical DNCB is associated with a stable clinical course in most patients, despite a significant decrease in CD4 T-cells. Lack of disease progression is associated with a stable CD8 CD38 count, and may be related to a persistent increase in natural killer cells. This increase is probably due to DNCB-induced delayed-type hypersensitivity that may be beneficial in HIV disease. DNCB also appears to be effective in the treatment of cutaneous Kaposi's angiosarcoma. In 13 patients receiving topical DNCB over 14-44 months increases in natural killer cells and activated/cytotoxic CD8-T cells were noted. In the same study, in noncompliant patients, these cellular immune related lymphocyte subsets decreased. [Int Conf AIDS 1992 Jul 19-24;8(2); B163 (abstract no PoB 3461); J Am Acad Dermatol 1994 Sep;31(3Pt2); p 462-66; ImmunoFacts 1993; p 506] DISEASES STUDIED/TREATED Local treatment for cutaneous Kaposi's angiosarcoma; stimulation of immune system. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 109 (abstract no. PuB 7361; Int Conf AIDS 1992 Jul 19-24;8(2); B163 (abstract no. PoB 3461)] CLASSIFICATION CODE Contact allergen [Merck Index 1996; p. 356] OTHER MAJOR USES Test for cellular immunity in patients with neoplastic and immunologic disorders. Treatment of alopecia areata and persistent verruca vulgaris. [Martindale: The Extra Pharmacopoeia 1993; p 1362] SUBSTANCE INTERACTIONS Cross-reacts with chloramphenicol. [Br Med J 1976; 2:1130] ADVERSE EFFECTS Treated areas have become erythematous and bullous, with pruritis and burning. A 10% adverse reaction rate was reported following topical DNCB in patients with early HIV disease. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 109 (abstract no PuB 7361); Immunol Lett 1993 Apr;36(1); p 1-6] CONTRAINDICATIONS Contraindicated in patients with benign dermatoses. [Arch Dermatol 1985; 121:330] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A contact sensitizing agent. [Int Conf AIDS 1993 Jun 6-11;9(1); 492 (abstract no. PO-B28-2140] CHEMICAL/PHYSICAL DATA Molecular Formula: C6-H3-Cl-N2-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 202.55 [Merck Index 1996; p. 356] CHEMICAL/PHYSICAL DATA Elemental Comp: C35.58%, H1.49%, Cl17.50%, N13.83%, O31.60% [Merck Index 1996; p. 356] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water; sparingly soluble in cold alcohol; freely soluble in hot alcohol; soluble in ether, benzene, CS2. [Merck Index 1989; p 329] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow crystals. [Merck Index 1989; p 329] SUBSTANCE DELIVERY DATA DOSAGE FORM: 2% solution of DNCB in acetone. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 109 (abstract no PuB 7361); ImmunoFacts 1993; p 506] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Topical. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); 109 (abstract no PuB 7361); ImmunoFacts 1993; p 506] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES ICA11/96924576. Stricker RB, Goldberg B, Mills LB, Epstein WL. Decrease in viral load associated with topical dinitrochlorobenzene (DNCB) therapy of HIV disease. Int Conf AIDS. 1996 Jul 7-12;11(2):282 (abstract no.Th.B.4182). ICA11/96924569. Traub A, Margulis SB. Use of dinitrochlorobenzene-DNCB as an immunomodulator in HIV-positive patients -- two years of follow-up. Int Conf AIDS. 1996 Jul 7-12;11(2):281 (abstract no.Th.B.4174). MED/95366690. Stricker RB, Goldberg B. Host-directed therapy for AIDS [letter, comment]. Ann Intern Med. 1995 Sep;123(6):471-2. MED/95403745. Stricker RB, Goldberg B, Mills LB, Epstein WL. Improved results of delayed-type hypersensitivity skin testing in HIV-infected patients treated with topical dinitrochlorobenzene. J Am Acad Dermatol. 1995 Oct;33(4):608-11. MED/94358210. Stricker RB, Elswood BF, Goldberg B, Dumlao C, Van Elk J, Henry J, Winger EE, Epstein WL. Clinical and immunologic evaluation of HIV-infected patients treated with dinitrochlorobenzene. J Am Acad Dermatol. 1994 Sep;31(3 Pt 1):462-6. ICA9/93335757. Stricker RB, Elswood BF, Goldberg B, Dumlao C, Van Elk J, Berger TG, Epstein WL. Analysis of lymphocyte subsets in HIV-infected patients treated with topical dinitrochlorobenzene (DNCB). Int Conf AIDS. 1993 Jun 6-11;9(1):492 (abstract no. PO-B28-2140). MED/93346057. Stricker RB, Zhu YS, Elswood BF, Dumlao C, Van Elk J, Berger TG, Tappero J, Epstein WL, Kiprov DD. Pilot study of topical dinitrochlorobenzene (DNCB) in human immunodeficiency virus infection. Immunol Lett. 1993 Apr;36(1):1-6. MED/93266906. Stricker RB, Elswood BF. Topical dinitrochlorobenzene in HIV disease. J Am Acad Dermatol. 1993 May;28(5 Pt 1):796-7. ICA8/92403411. Micheletti GA Jr, Adams A, Garland J, Stool E, Gathe J Jr, Manner C. Topical treatment of cutaneous Kaposi's angiosarcoma with DNCB. Int Conf AIDS. 1992 Jul 19-24;8(3):109 (abstract no. PuB 7361). MED/92120736. Stricker RB, Elswood BF, Abrams DI. Dendritic cells and dinitrochlorobenzene (DNCB): a new treatment approach to AIDS. Immunol Lett. 1991 Aug;29(3):191-6. ENTRY MONTH 199104 LAST REVISION DATE 20000801 267 UNIQUE IDENTIFIER DRG-0079 NAME OF SUBSTANCE Diclazuril [USPD 1998; p. 231] REGISTRY NUMBER 101831-37-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzeneacetonitrile, 2,6-dichloro-alpha-(4-chlorophenyl)-4-(4,5-di- hydro-3,5-dioxo-1,2,4-t riazin-2(3H)-yl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 038A PROTOCOL ID NUMBERS No longer recruiting FDA 038B PHARMACOLOGICAL ACTION MODE OF ACTION: Diclazuril completely interrupts the life cycle of coccidial microorganisms. It has potent activity against various stages: oocyst, schizonts, merozuites, micro and macro gametocytes. It is believed that it will interrupt the life cycle of the microorganism at a very early stage. In one study of diclazuril pharmacokinetics eleven patients were tested. Mean peak plasma concentrations of 0.16 mg/1 were reached at 12 hours for all but two subjects (DCL peak at 8 hours). The mean terminal half-life was 84.8 hours. Diclazuril was not detected in the CSF samples. This data suggest slow absorption, low peak serum levels, and a long half-life. Currently research is focusing on letrazuril, an oral fluorine-based congener of diclazuril. In preclinical studies, the drug is more readily absorbed than diclazuril. [AmfAR Treat Dir 1997;8(3); p 73; Int Conf AIDS 1991 Jun 16-21;7(2); p 261 (abstract no. W.B. 2318); Lancet 1989 Jun 17;1] DISEASES STUDIED/TREATED Successfully used to treat isospora and cryptosporidium infection in HIV patients. [Int Conf AIDS 1991 Jun 16-21;7(2); p 261 (abstract no. W.B. 2318)] CLASSIFICATION CODE Antiprotozoal [Lancet 1989 Jun 17;1] OTHER MAJOR USES Veterinary uses, coccidiostat in poultry. [USAN 1997; p 227] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: New benzeacetonitrile with anticoccidial activity. [Lancet 1989 Jun 17;1] CHEMICAL/PHYSICAL DATA Molecular Formula: C17-H9-Cl3-N4-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 407.64 [USPD 1998; p. 231] CHEMICAL/PHYSICAL DATA Melting Point: 290.5 C [Merck Index 1996; p. 521] CHEMICAL/PHYSICAL DATA Elemental Comp: C50.09%, H2.23%, Cl26.09%, N13.74%, O7.85% [Merck Index 1996; p. 521] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules. [Protocol ID: 038A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Int Conf AIDS 1991 Jun 16-21;7(2); p 261 (abstract W.B. 2318)] MANUFACTURERS 0000001153: Janssen Research Foundation 1125 Trenton-Harbourton Rd Titusville, NJ 085600200 Contact: Professional Services (800)526-7736 REFERENCES MED/97155108. Fung HB, Kirschenbaum HL. Treatment regimens for patients with toxoplasmic encephalitis. Clin Ther. 1996 Nov-Dec;18(6):1037-56. MED/96252383. Haberkorn A. Chemotherapy of human and animal coccidioses: state and perspectives. Parasitol Res. 1996;82(3):193-9. MED/95244742. Limson-Pobre RN, Merrick S, Gruen D, Soave R. Use of diclazuril for the treatment of isosporiasis in patients with AIDS [letter]. Clin Infect Dis. 1995 Jan;20(1):201-2. MED/93179810. Lemeteil D, Roussel F, Favennec L, Ballet JJ, Brasseur P. Assessment of candidate anticryptosporidial agents in an immunosuppressed rat model. J Infect Dis. 1993 Mar;167(3):766-8. ICA7/3231891. Moretti MV, Menichetti F, Pauluzzi S. Diclazuril (DCL) pharmacokinetic in patients with HIV infection. Int Conf AIDS. 1991 Jun 16-21;7(2):261 (abstract no. W.B. 2318). ICA7/1103491. Foster BC, Wilson DL, Tryphonas H, Whitehouse LW, Khan SR. A pre-clinical in vitro toxicological model using human lymphocytes. Int Conf AIDS. 1991 Jun 16-21;7(1):100 (Abstract no. M.A.1034). MED/91143753. Menichetti F, Moretti MV, Marroni M, Papili R, Di Candilo F. Diclazuril for cryptosporidiosis in AIDS [letter]. Am J Med. 1991 Feb;90(2):271-2. MED/90373070. Connolly GM, Youle M, Gazzard BG. Diclazuril in the treatment of severe cryptosporidial diarrhoea in AIDS patients [letter]. AIDS. 1990 Jul;4(7):700-1. ICA6/10052090. Soave R, Dieterich D, Kotler D, Gassyuk E, Tierney AR, Liebes L, Legendre R. Oral diclazuril therapy for cryptosporidiosis. Int Conf AIDS. 1990 Jun 20-23;6(1):252 (abstract no. Th.B.520). ICA6/40212290. Connolly G, Youle M, Gazzard B. Diclazuril in the treatment of cryptosporidial diarrhoea in AIDS. Int Conf AIDS. 1990 June 20-23;6(2):384 (abstract no. 2122). MED/89280914. Kayembe K, Desmet P, Henry MC, Stoffels P. Diclazuril for Isospora belli infection in AIDS [letter]. Lancet. 1989 Jun 17;1(8651):1397-8. ENTRY MONTH 199104 LAST REVISION DATE 20001107 268 UNIQUE IDENTIFIER DRG-0078 NAME OF SUBSTANCE SCH 39304 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 121650-83-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 125 PHARMACOLOGICAL ACTION MODE OF ACTION: SCH 39304 appears to effectively penetrate into the cerebrospinal fluid (CSF), expressing its activity against Cryptococcus neoformans infection. SCH 39304 is slowly eliminated following oral administration of 50-200 mg, having a plasma half-life of about 60 hours which is dose independent. About 75% of the drug is eliminated unchanged in the urine, with clearance kinetics being dose independent. Dose proportionality has been observed in plasma peak levels, the area under the plasma level-time curve, and the amount of drug excreted in the urine. Maximum drug plasma levels at steady state were 2.45, 4.73, 8.36, and 15.49 mcg/ml at doses of 25, 50, 100, and 200 mg, respectively. Animal studies indicate that the drug effectively penetrates into the CSF, achieving concentrations active against many opportunistic fungi and sustaining drug concentrations in the CSF for at least 24 hours. [Protocol ID: ACTG 125 ] DISEASES STUDIED/TREATED Cryptococcal meningitis, oropharyngeal candidiasis. [Antimicrob Agents Chemother 1992 Dec;36(12); p 2790-3; Protocol ID: ACTG 125 ] CLASSIFICATION CODE Antifungal [Antimicrob Agents Chemother 1992 Dec;36(12); p 2790-3] SUBSTANCE INTERACTIONS Preliminary results of a drug interaction study of the drug with Mylanta/cimetidine indicate that the absorption of SCH 39304 is not inhibited by these drugs. [Protocol ID: ACTG 125 ] ADVERSE EFFECTS May cause headaches, nausea, diarrhea and rash in humans. Slight, not clinically significant elevations in liver enzymes have been reported. Animal toxicity studies in rodents, dogs, and primates have been conducted. [Protocol ID: ACTG 125 ; J Acquir Immune Defic Syndr 1992;5(6); p 600-04] CONTRAINDICATIONS Contraindicated in patients who have a history of hypersensitivity to imidazole or azole compounds, and in pregnant or lactating women. [Protocol ID: ACTG 125 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Triazole derivative. [Protocol ID: ACTG 125 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H15-F2-N3-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystalline powder. [Protocol ID: ACTG 125 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (100 mg) [Protocol ID: ACTG 125 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Antimicrob Agents Chemother 1992 Dec;36(12); p 2790-3] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature (15-30 C). [Protocol ID: ACTG 125 ] MANUFACTURERS 0000001199: Schering - Plough Research 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Professional Information (800)526-4099 REFERENCES MED/94343183. Hostetler JS, Catanzaro A, Stevens DA, Graybill JR, Sharkey PK, Larsen RA, Tucker RM, al-Haidary AD, Rinaldi MG, Cloud GA, et al. Treatment of coccidioidomycosis with SCH 39304. J Med Vet Mycol. 1994;32(2):105-14. MED/94154101. Anaissie EJ, Konotyiannis DP, Vartivarian S, Kantarjian HM, O'Brien S, Giralt SA, Andersson BS, Karl C, Champlin RE, Bodey GP. Effectiveness of an oral triazole for opportunistic mold infections in patients with cancer: experience with SCH 39304. Clin Infect Dis 1993 Dec;17(6):1022-31. MED/94062049. Graybill JR. Treatment of coccidioidomycosis. Curr Top Med Mycol. 1993;5:151-79. MED/93128895. Hardin TC, Sharkey PK, Lam YF, Wallace JE, Rinaldi MG, Graybill JR. Pharmacokinetics of SCH-39304 in human immunodeficiency virus-infected patients following chronic oral dosing. Antimicrob Agents Chemother. 1992 Dec;36(12):2790-3. MED/92269114. Lee BL, Padula AM, Tauber MG, Chambers HF, Sande MA. Oral SCH 39304 as primary, salvage, and maintenance therapy for cryptococcal meningitis in AIDS. J Acquir Immune Defic Syndr. 1992;5(6):600-4. MED/93075877. Anaissie E, Gokaslan A, Hachem R, Rubin R, Griffin G, Robinson R, Sobel J, Bodey G. Azole therapy for trichosporonosis: clinical evaluation of eight patients, experimental therapy for murine infection, and review. Clin Infect Dis. 1992 Nov;15(5):781-7. MED/90072982. Perfect JR, Wright KA, Hobbs MM, Durack DT. Treatment of experimental cryptococcal meningitis and disseminated candidiasis with SCH39304. Antimicrob Agents Chemother. 1989 Oct;33(10):1735-40. ENTRY MONTH 199104 LAST REVISION DATE 20000801 269 UNIQUE IDENTIFIER DRG-0077 NAME OF SUBSTANCE Fiacitabine [USPD 1998; p. 309] REGISTRY NUMBER 69123-90-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2(1H)-Pyrimidinone, 4-amino-1-(2-deoxy-2-fluoro-beta-D-arabinofur- anosyl)-5-iodo- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 122 FIAC PHARMACOLOGICAL ACTION MODE OF ACTION: FIAC is rapidly and virtually completely absorbed after a single oral dose, and principally converted into its primary deaminated uracil metabolite (fialuridine, FIAU), which is then eliminated by renal excretion and further biotransformation via deiodinization and glucuronic conjugation. While the specific mechanism of action of FIAC is unknown, it appears to exert its effect on cytomegalovirus by serving as substrate for viral DNA polymerase. Both FIAC and FIAU demonstrate potent and nearly identical in vitro activities against HSV-1, HSV-2, VZV, CMU, and HBV. Following intravenous injection of 50 or 100 mg/sq meter (about 1.2 or 2.5 mg/kg, respectively), the plasma half-lives of FIAC and FIAU were 1.36 and 3.91 hours, respectively. Peak plasma levels of FIAC and FIAU were observed 1-2 hours after oral dosing, and plasma levels of FIAU were equal or greater than the cytomegalovirus in vitro ED-50 at 8 hours in all 3 patients given 50 or 100 mg/sq meter (about 1.2 or 2.5 mg/kg, respectively); 8-hour plasma levels in these patients (after oral administration) averaged more than twice those observed after intravenous injection of FIAC (hence, daily oral doses of as little as 100 mg/sq meter (about 2.5 mg/kg) given at 8-hour intervals might be expected to provide plasma levels of FIAC and FIAU that continuously exceed the in vitro minimum inhibitory levels for cytomegalovirus). Investigators report that toxicities seen with FIAC may be due to metabolism. [AmfAR Treat Dir 1993;6(3); p 48; Int Conf AIDS 1991 Jun 16-21;7(2); p 254 (abstract no. W.B. 2290); Protocol ID: ACTG 122 ] DISEASES STUDIED/TREATED Treatment of cytomegalovirus infections. Phase I studies of fiacitabine have been discontinued due to gastrointestinal toxicity and severe fatigue. [AmfAR Treat Dir 1993;6(3); p 48; Protocol ID: ACTG 122 ] CLASSIFICATION CODE Investigational - Antiviral [USPD 1998; p. 309] ADVERSE EFFECTS Phase I studies of FIAC have been discontinued due to gastrointestinal toxicity, bone marrow suppression, and severe fatigue. May cause mild to moderate nausea, hematologic toxicity, thrombocytopenia, irregular pancytopenia, alteration of leukocyte and platelet levels, elevation of SGOT, gastrointestinal intolerance, reversible central nervous system symptoms (confusion, myoclonic jerking, and seizures), and possible hypotension with increased pulmonary edema. [AmfAR Treat Dir 1993;6(3); p 48; Protocol ID: ACTG 122 ] CONTRAINDICATIONS Should not be used in patients exhibiting HIV wasting syndrome, presenting clinical or x-ray evidence of bronchitis, pneumonitis, pulmonary edema, effusion, or suspected active tuberculosis, or having any unstable medical condition (including serious cardiovascular, infections, oncologic, renal, or hepatic conditions), or any cytomegalovirus end organ disease. [Protocol ID: ACTG 122 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fluorinated pyrimidine nucleoside analog. [Transplant Proc 1991 Jun;23 (3 Supp 3); p 168-70] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H11-F-I-N3-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 371.11 [USPD 1998; p. 309] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water. [Protocol ID: ACTG 122 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystalline powder. [Protocol ID: ACTG 122 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Powder dissolved in USP Purified Water (4 mg/ml). [Protocol ID: ACTG 122 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AmfAR Treat Dir 1993;6(3); p 48] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store powder between 15-30 C (59-86 F); store reconstitued aqueous solution under refrigeration (36-46 F). [Protocol ID: ACTG 122 ] MANUFACTURERS 0000001180: Oclassen Pharmaceuticals Inc 311 Bonnie Circle Corona, CA 928802882 Contact: Dr Syd Dromgoole (415)258-4558 REFERENCES MED/95377331. Andrei G, Snoeck R, Reymen D, Liesnard C, Goubau P, Desmyter J, De Clercq E. Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. Eur J Clin Microbiol Infect Dis. 1995 Apr;14(4):318-29. ICA8/92400966. Pottage JC, Kessler HA, Kapell K, Benson CA. Acyclovir resistant (ACV-R) herpes simplex: susceptibility to alternative antiviral agents. Int Conf AIDS. 1992 Jul 19-24;8(2):B126 (abstract no. PoB 3238). ICA7/3229091. Tartaglione T, Hooton TM, Jones T, Smiles K, Corey L. ACTG 122: phase II tolerance study of oral FIAU in HIV-infected persons. Int Conf AIDS. 1991 Jun 16-21;7(2);254 (abstract no. W.B.2290). MED/91297786. King DH. Fluorinated pyrimidines: a new change for old drugs. Transplant Proc. 1991 Jun;23(3 Suppl 3):168-70. ICDB/92669953. Resta S, Wolitz R, Merigan TC. CMV Retinitis in the AIDS Patient. AIDS Updates; 3(3): 1-12 1990. MED/87000003. Gold JW, Leyland-Jones B, Urmacher C, Armstrong D. Pulmonary and neurologic complications of treatment with FIAC (2'fluoro-5-iodo-aracytosine) in patients with acquired immune deficiency syndrome. AIDS Res. 1983-84;1(4):243-52. ENTRY MONTH 199104 LAST REVISION DATE 20001107 270 UNIQUE IDENTIFIER DRG-0076 NAME OF SUBSTANCE CD4-IgG [Int Conf AIDS 1992 Jul 19-24;8(2); p 1391 (abstract no. PoB 3028)] PROTOCOL ID NUMBERS Complete NIAID ACTG 121 PROTOCOL ID NUMBERS Complete NIAID ACTG 134 PROTOCOL ID NUMBERS Complete NIAID ACTG 139 PROTOCOL ID NUMBERS Complete NIAID ACTG 146 PROTOCOL ID NUMBERS Complete NIAID IRP 011 PROTOCOL ID NUMBERS No longer recruiting FDA 076A PROTOCOL ID NUMBERS No longer recruiting NCI 89 C-CD4 PROTOCOL ID NUMBERS No longer recruiting CC 90 I-15 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 351 PROTOCOL ID NUMBERS Terminated CC 90 I-114 PHARMACOLOGICAL ACTION MODE OF ACTION: rCD4-IgG blocks the cytopathic effect of HIV in T cell lines and blocks the infection of H-9 or U937 cells. It has been shown that CD4-IgG can mediate antibody-dependent cytotoxicity directed against HIV infected target cells. In vitro studies in animals have demonstrated no evidence of CD4-IgG related toxicity. rCD4-IgG crosses the human placenta to the same extent IgG does. Following IV therapy in a 12 week dose escalating study the mean peak serum level was 8.28 mcg/ml with a serum half-life of 32 h. The protein (CD4-IgG2) binds with nanomolar affinity to purified gp120 from both a laboratory-adapted strain and a primary isolate of HIV-1. Pharmockinetic studies in rabbits demostrated that CD4-IgG2 has a plasma terminal half-life greater than 1 day, compared with 15 min for soluble CD4 (sCD4). CD4-IgG2 does not bind to Fc receptors on the surface of U937 monocyte/macrophage cells. Compared to molecules that incorporate the Fc portion of IgG1, CD4-IgG2 molecule inhibited syncytium formation more effectively than monomeric sCD54 or a dimeric CD4-gamma 2 fusion protein. This suggests the protein will block cell-to-cell transmission of HIV-1. Moreover, CD4-IgG2 effectively neutralized a panel of laboratory-adapted strains and primary isolates of HIV-1, including strains with different tropisms and isolates from different stages of the disease, at concentrations that should be readily achieved in vivo. [Int Conf AIDS 1992 Jul 19-24;8(2); p 1391 (abstract no. PoB 3028); J Acquir Immune Defic Syndr Hum Retrovirol 1995 Feb 1; 8(2); p 154-60; AIDS Res Hum Retroviruses p 11] DISEASES STUDIED/TREATED Being developed as an immunoprophylactic agent to reduce the probability of infection following HIV-1 exposure, in settings such as occupational or perinatal exposure to the virus. [AIDS Res Hum Retroviruses p 533-9] CLASSIFICATION CODE Immunomodulator [Protocol ID: ACTG 121 ] CLASSIFICATION CODE Investigational - Virion receptor binding antagonist [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS So far rCD4-IgG is well tolerated, with no important clinical or immunologic toxicities noted. In pregnant women neither the mother or infants have shown evidence of rCD4-IgG related toxicity. Seven of 41 patients had severe adverse reactions following 300 to 1000 mcg/kg IV doses over 12 weeks. Reactions included nausea, fever, abnormal liver function tests and neutropenia. [Int Conf AIDS 1992 Jul 19-24;8(2); p 1391 (abstract no. PoB 3028); Antimicrob Agents Chemother 1991 Dec;35(12); p 2580-6; J Acquir Immune Defic Syndr Hum Retrovirol 1995 Feb 1; 8(2); p 154-60] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: CD4-IgG2 is a novel fusion protein comprising human IgG2 in which the Fv portions of both heavy and light chains have been replaced by the V1 and V2 domains of human CD4. [AIDS Res Hum Retroviruses p 533-9] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Lyophilized powder. [Protocol ID: ACTG 121 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials of 5.0 mg rCD4-IgG. Reconstitute with 1.2 ml sterile water for injection. This results in a concentration of 5.0 mg/ml. [Protocol ID: ACTG 121 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous; intramuscular. [Int Conf AIDS 1992 Jul 19-24;8(2); p 1391 (abstract no. PoB 3028)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Stored refrigerated at 2-8 C. [Protocol ID: ACTG 121 ] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 REFERENCES MED/97202714. Lacoux X, Barragan V, Dewynter G, Leydet A, Roque JP, Montero JL. Synthesis and biological activity of acylated and telomerized peptides as potential HIV-fixation inhibitors. Farmaco. 1996 Dec;51(12):767-73. MED/96183910. Gaudin MC, Allaway GP, Maddon PJ, Barbas CF 3rd, Burton DR, Koup RA. Effective ex vivo neutralization of human immundeficiency virus type 1 in plasma by recombinant immunoglobulin molecules. J Virol. 1996 Apr;70(4):2586-92. AIDS/96920348. Israel R, Jurcic J, Sgouros G, Minamoto G, Straus D, Polsky B, Olson W, Allaway G, Maddon P, Larson S. A phase I Trial of (131)I-CD4-gamma2 (recombinant human CD4-IgG2 fusion protein) in HIV-1 infected patients. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:117. MED/96093887. Allaway GP, Davis-Bruno KL, Beaudry GA, Garcia EB, Wong EL, Ryder AM, Hasel KW, Gauduin MC, Koup RA, McDougal JS, et al. Expression and characterization of CD4-IgG2, a novel heterotetramer that neutralizes primary HIV type 1 isolates. AIDS Res Hum Retroviruses. 1995 May;11(5):533-9. MED/96053309. Hurez V, Kaveri SV, Mouhoub A, Dietrich G, Mani JC, Klatzmann D, Kazatchkine MD. Anti-CD4 activity of normal human immunoglobulin G for therapeutic use. (Intravenous immunoglobulin, IVIg). Ther Immunol. 1994 Oct;1(5):269-77. MED/96007276. Collier AC, Coombs RW, Katzenstein D, Holodniy M, Gibson J, Mordenti J, Izu AE, Duliege AM, Ammann AJ, Merigan T, et al. Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Oct 1;10(2):150-6. MED/95393289. Shearer WT, Duliege AM, Kline MW, Hammill H, Minoff H, Ammann AJ, Chen S, Izu A, Mordenti J. Transport of recombinant human CD4-immunoglobulin G across the human placenta: pharmacokinetics and safety in six mother-infant pairs in AIDS clinical trial group protocol 146. Clin Diagn Lab Immunol. 1995 May;2(3):281-5. MED/90247436. Meng TC, Fischl MA, Cheeseman SH, Spector SA, Resnick L, Boota A, Petrakis T, Wright B, Richman DD. Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Feb 1;8(2):152-60. MED/95015917. Chamow SM, Zhang DZ, Tan XY, Mhatre SM, Marsters SA, Peers DH, Byrn RA, Ashkenazi A, Junghans RP. A humanized, bispecific immunoadhesin-antibody that retargets CD3+ effectors to kill HIV-1-infected cells. J Immunol. 1994 Now 1;153(9):4268-80. ENTRY MONTH 199104 LAST REVISION DATE 20000801 271 UNIQUE IDENTIFIER DRG-0075 NAME OF SUBSTANCE Amoxicillin trihydrate [USPD 1998; p. 52] REGISTRY NUMBER 61336-70-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxyli- c acid, 6-((amino(4-hydroxyphenyl)acetyl)amino)-3,3-d- imethyl-7-oxo-, trihydrate (2S-(2alpha,5alpha,6beta(S*)))- [ChemIDplus. Available at:http://chem.sis.nlm.nih.gov/chemidplus/. Accessed Nov 6, 2000.] SYNONYMS (component of) Augmentin [USP DI 2000; p. 2418] SYNONYMS Amoxil [USP DI 2000; p. 2395] SYNONYMS Polymox [USP DI 2000; p. 2396] SYNONYMS Trimox [USP DI 2000; p. 2395] SYNONYMS Wymox [USP DI 2000; p. 2395] PROTOCOL ID NUMBERS Complete FDA 243A PROTOCOL ID NUMBERS No longer recruiting FDA 019A PHARMACOLOGICAL ACTION MODE OF ACTION: Amoxicillin is stable in the presence of gastric acid, is rapidly absorbed after oral administration, and diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when the meninges are inflamed. Its half-life is 61.3 minutes. Most of amoxicillin is excreted unchanged in the urine; excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approx. 20% protein bound as compared to 60% for penicillin G. Orally administered doses of 250 mg and 500 mg of amoxicillin capsules result in average peak blood levels 1 - 2 hours after administation in the range of 3.5 mcg/mL to 5.0 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL respectively. Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptides. Because it does not resist destruction by penicillinase, it is not effective against penicillinase-producing bacteria, particularly resistant staphylococci. All strains of Pseudomonas and most strains of Klebsiella and Enterobacteria are resistant. [PDR 1997; p 2631] DISEASES STUDIED/TREATED Bacterial infections. [Protocol ID: 019A ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2389] OTHER MAJOR USES Amoxicillin is indicated in the treatment of infections due to susceptible strains of gram-negative organisms, such as H. influenza, E. coli, P. mirablilis and N. gonorrhea, and gram-positive organisms such as Streptococci, D. pneumonia, and non-penicillinase producing staphylococci. [PDR 1997; p 2631] SUBSTANCE INTERACTIONS The effectiveness of estrogen containing oral contraceptives may be reduced by ampicillin or amoxicillin. In patients with hyperuricemia, concomitant allopurinal may increase the incidence of rash. Urinary excretion of this drug can be delayed by concurrent administration of probenecid. [AHFS Drug Information 1997; p 316] ADVERSE EFFECTS Hypersensitivity, especially in subjects who have previously demonstrated a penicillin hypersensitivity, and in those with a history of allergy, asthma, hay fever or urticaria, has been reported. Mild to severe pseudomembranous colitis, usually due to Clostridum difficile, has also occurred. May cause nausea, vomiting, diarrhea, erythematous maculopapular rashes and urticaria, anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranulocytosis, moderate rise in serum glutamic oxaloacetic transaminase (SGOT). [PDR 1997; p 2631] CONTRAINDICATIONS Contraindicated in patients with history of allergic reaction to any of the penicillins. Because a percentage of patients with infectious mononucleosis have developed a rash during aminopenicillin therapy, amoxicillin probably should not be used in these patients. [AHFS Drug Information 1997; p 318] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semisynthetic penicillin, an analog of ampicillin. [PDR 1997; p 2631] CHEMICAL/PHYSICAL DATA Molecular Formula: C16-H19-N3-O5-S.3H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 419.46 [USPD 1998; p. 52] CHEMICAL/PHYSICAL DATA Elemental Comp: C52.59%, H5.24%, N11.50%, O21.89%, S8.78% (base) [Merck Index 1996; p. 97] CHEMICAL/PHYSICAL DATA Solubility: (mg/ml) of trihydrate: Water 4.0; methanol 7.5; absolute ethanol 3.4 (trihydrate insoluble in hexane, benzene, ethyl acetate, and acetonitrile). [Merck Index 1996; p 97] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, practically odorless, crystalline powder (trihydrate). [AHFS Drug Information 1997; p 318] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules, suspension, chewable tablets, or pediatric drops. [PDR 1997; p 2032] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral (Trihydrate). [PDR 1997; p 2631-2] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store in tightly closed container, preferably under refrigeration. Unused portions of reconstituted suspensions must be discarded after 14 days. Store capsules and unreconstituted powders between 15-30 C. [USP DI 1997; p 2270; PDR 1997; p 2632] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 REFERENCES MED/96098371. Salvemini JN, Baldwin HE. Botryomycosis in a patient with acquired immunodeficiency syndrome. Cutis. 1995 Sep;56(3):158-60. MED/95303854. Duval X, Paty MC, Longuet P, Lacassin F, Perronne C, Leport C, Vilde JL. [Pneumopathies caused by Streptococcus pneumoniae in 27 HIV infected patients]. Presse Med. 1995 Apr 15-22;247(15):715-8. MED/95023711. Torri O, Mariel C, Veyssier P, Cevallos R, Bouchaud O, Carbon C, Jarousse B, Masson H, Patey O, Fantin B. [Streptococcus pneumoniae bacteremia and HIV infection. Retrospective study of 41 episodes in 30 patients]. Presse Med. 1994 Jun 4;23(21):972-5. ICA10/94371149. Ciaffi L, Franzetti F, Gervasoni C, Romaniello A, Maillard M, Moro M, Ruggieri A, Cernuschi M, Lazzarin A. Azithromycin versus amoxicillin/clavulanate in community acquired pneumonias of HIV-patients. Int Conf AIDS. 1994 Aug 7-12;10(2):135 (abstract no. PB0554). ICA9/93335101. Rolfs R, Gold M, Hackett K, Augenbraun M, Brady W, Larsen S. Treatment of early syphilis in HIV-infected and HIV-uninfected patients--preliminary report of the syphilis & HIV study group. Int Conf AIDs. 1993 Jun 6-11;9(1):391 (abstract no. PO-B11-1534). MED/94133949. Prabhakaran K, Harris EB, Randhawa B, Adams LB, Williams DL, Hastings RC. Use of beta-lactam/beta-lactamase-inhibitor combinations as antimycobacterial agents. Microbios. 1993;76(309):251-61. MED/93160304. Maini M, French P, Prince M, Bingham JS. Urethritis due to Neisseria meningitidis in a London genitourinary medicine clinic population. Int J STD AIDS. 1992 Nov-Dec;3(6):423-5. MED/92235429. Drancourt M, Bonnet E, Gallais H, Peloux Y, Raoult D. Rhodococcus equi infection in patients with AIDS. J Infect. 1992 Mar;24(2):123-31. MED/91351782. Principi N, Marchisio P, Tornaghi R, Onorato J, Massironi E, Picco P. Acute otitis media in human immunodeficiency virus-infected children. Pediatrics. 1991 Sep;88(3):566-71. ICA5/00178689. Phillip H, Harris JR, Goldmeier D. Retreatment of syphilis in HIV positive patients. Int Conf AIDS. 1989 Jun 4-9;5:361 (abstract no. W.B.P.58). ENTRY MONTH 199104 LAST REVISION DATE 20001106 272 UNIQUE IDENTIFIER DRG-0074 NAME OF SUBSTANCE Ampicillin sodium [USPD 1998; p. 53] REGISTRY NUMBER 69-52-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.; (parent drug)p 51] STANDARD CHEMICAL NAME 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxyli- c acid, 6-((aminophenylacetyl)amino)-3,3-dimethyl-7-o- xo-, monosodium salt, (2S-(2alpha,5alpha,6beta(S*)))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS (component of) Unasyn [USP DI 2000; p. 2419] SYNONYMS Omnipen-N [USP DI 2000; p. 2397] SYNONYMS Polycillin-N [USP DI 2000; p. 2397] SYNONYMS Totacillin-N [USP DI 2000; p. 2397] PROTOCOL ID NUMBERS No longer recruiting FDA 019A PHARMACOLOGICAL ACTION MODE OF ACTION: Ampicillin inhibits mucopeptide synthesis in the bacterial cell wall. Ampicillin, like other aminopenicillins, binds to several enzymes in the bacterial cytoplasmic membrane that are involved in cell wall synthesis and cell division causing lysis and cell death. Ampicillin appears to produce abnormally elongated or filamentous morphologic effects in susceptible bacterial cell walls in contrast to amoxicillin which appears to cause rapid formation of spheroplasts and lysis. It is possible that variations in morphological response result in variations in antibacterial spectra. Ampicillin has a similar spectrum of activity to amoxicillin; however, ampicillin is less active in vitro on a weight basis against enterococci and Salmonella but more active than amoxicillin against Shigella and Enterobacter. In general, ampicillin and other aminopenicillins, are active in vitro against most gram positive and gram negative aerobic cocci, except penicillinase producing strains, some gram positive aerobic and anaerobic bacilli, and some spirochetes. Ampicillin is inactive against Mycoplasma, Rickettsia, fungi, and viruses. Between 30-55% of an oral dose is absorbed from the GI tract in a fasting adult. Maximum serum concentration is usually attained in about 2 hours. Two hours after oral doses of 250 mg in fasting individuals average peak serum levels of 1.8-2.9 mcg/ml are attained. A 500 mg oral dose results in average peak serum levels of 3-6 mcg/ml. Absorption is decreased by food in the gastrointestinal tract. Following IM doses of ampicillin sodium peak serum concentrations are generally reached more rapidly and are higher than those following equivalent oral doses. Following IV doses, single 2 g dose over twenty minutes in healthy adults, serum levels averaged 47.6 mcg/ml within 30 minutes and 3.7 mcg/ml after 4 hours. Serum levels and half-life are prolonged in patients with impaired renal function. Biliary levels of ampicillin in patients with normal biliary function may be 1-30 times greater than simultaneous serum levels following a single oral dose. [AHFS Drug Information 1995; p 227, 276, 298; AHFS Drug Information 1997; p 327] DISEASES STUDIED/TREATED Treatment of bacterial infections. [Protocol ID: 019A ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2389] OTHER MAJOR USES Ampicillin is indicated in genitourinary tract infections, including gonorrhea; respiratory tract infections; gastrointestinal tract infections caused by Shigella, S. typhosa and other Salmonella, E. coli, P. mirabilis and enterococci and in N. meningitidis infections. [PDR 1997; p 2872-3] SUBSTANCE INTERACTIONS Oral probinecid decreases the renal tubular excretion of ampicillin resulting in increased blood levels and/or increased toxicity. Estrogen-containing oral contraceptives may be less effective and increased breakthrough bleeding may occur. Allopurinol may increase the possibility of skin rash, especially in hyperuricemic patients. [AHFS Drug Information 1997; p 316-7] ADVERSE EFFECTS Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Although these reactions are more frequent following parenteral therapy, they have occured with oral therapy. These reactions are more likely to occur in patients with a history of sensitivity to multiple allergens (e.g., cephalosporins). Ampicillin adverse effects are similar to those of other aminopenicillins, however, diarrhea and rash have been reported more frequently with ampicillin. The following additional reactions have been reported with ampicillin: gastrointestinal effects such as glossitis, stomatitis, nausea and vomiting, and pseudomembranous colitis; hepatotoxicity, hematologic reactions, e.g., anemia, thrombocytopenic, leukopenia and agranulocytosis. [AHFS Drug Information 1997; p 315, 327; PDR 1997; p 2873] CONTRAINDICATIONS Contraindicated if there is a history of previous hypersensitivity to any of the penicillins. Contraindicated in infections caused by penicillinase-producing organisms. [PDR 1997; p 2873] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Ampicillin is an aminopenicillin. It differs structurally from penicillin G only in the presence of an amino group in the alpha position on the benzene ring at R of the penicillin nucleus. [AHFS Drug Information 1997; p 326] CHEMICAL/PHYSICAL DATA Molecular Formula: C16-H18-N3-O4-S.Na [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 371.39 [USPD 1998; p. 53] CHEMICAL/PHYSICAL DATA Elemental Comp: C55.00%, H5.48%, N12.03%, O18.32%, S9.18% (base) [Merck Index 1996; p. 99] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water (anhydrous and trihydrate). [AHFS Drug Information 1997; p 326] CHEMICAL/PHYSICAL DATA Stability: The stability of reconstituted parenteral solutions is dependent on the diluent used, the concentration of the solution and the storage temperature. Oral suspensions are stable for 7 days at room temperature and 14 days in the refrigerator. [AHFS Drug Information 1997; p 326] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, practically odorless crystalline powder (anhydrous and trihydrate). [AHFS Drug Information 1997; p 326] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules, oral suspension, and vials for injection containing 125 mg - 10 g of base. [AHFS Drug Information 1997; p 329] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, intramuscular or intravenous injection. [AHFS Drug Information 1997; p 329] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature (approx. 25 C (77 F)). When suspension is stored in the refrigerator, discard unused portions after 14 days; when stored at room temperature, discard after 7 days. [PDR 1997; p 2874] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Professional Information (800)438-1985 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Unspecified (800)438-1985 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)934-5556 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Audrey Ashby (610)971-5823 REFERENCES MED/97148115. Lorder B. Listeriosis. Clin Infect Dis. 1997 Jan;24(1):1-9. MED/97190678. Sherrard J, Barlow D. Gonorrhoea in men: clinical and diagnostic aspects. Genitourin Med. 1996 Dec;72(6):422-6. MED/95196791. Hagelskjaer LH. A fatal case of systemic strongyloidiasis and review of the literature. Eur J Clin Microbiol Infect Dis. 1994 Dec;13(12):1069-74. MED/94304908. Zenati M, Milano A, Livi U, Cattelan A, Casarotto D. Successful treatment of disseminated infection with Listeria monocytogenes in a heart transplant recipient [letter]. J Heart Lung Transplant. 1994 Mar-Apr;13(2):345-6. ICA9/93335461. Sanchez M, May LP, Moy J. Toxic epidermal necrolysis (TEN) in patients with the acquired immunodeficiency syndrome (AIDS). Int Conf AIDS. 1993 Jun 6-11;9(1):447 (abstract no. PO-B20-1874). MED/94133949. Prabhakaran K, Harris EB, Randhawa B, Adams LB, Williams DL, Hasting RC. Use of beta-lactam/beta-lactamase-inhibitor combinations as antimycobacterial agents. Microbios. 1993;76(309):251-61. MED/93152634. Bygdeman SM, Ruden AK, Jonsson A, Lidbrink P, Olofsson MB, Backman M, Gastrin B, Kallings I, Ramberg M, Rylander M, et al. Antibiotic susceptibility, serovars and auxotypes of gonococcal isolates in Stockholm. Relation to geographical origin of the infection. Int J STD AIDS. 1993 Jan-Feb;4(1):33-40. MED/93163839. De Simone C, Trinchieri V, Tzantzoglou S, Famularo G, Moretti S, Delia S. AIDS patients with bacterial lower respiratory tract infections: treatment with ofloxacin versus sulbactam-ampicillin. J Chemother. 1992 Dec;4(6):376-80. MED/94098174. da Silva LJ, Resende MR, de Abreu WB, Aoki FH, Bocatto RB, Branchinni ML, Goncales Junior FL, de Lima JN, von Nowakonski A, Papaiordanou PM, et al. Listeriosis and AIDS: case report and literature review. Rev Inst Med Trop Sao Paulo. 1992 Sep-Oct;34(5):475-8. MED/92164984. Garcia-Tsao G, Panzini L, Yoselevitz M, West AB. Bacillary peliosis hepatis as a cause of acute anemia in a patient with the acquired immunodeficiency syndrome. Gastroenterology. 1992 Mar;102(3):1065-70. ICA7/1106891. Martin A, Castillo R, Dupla M, Pintado V, Valencia E, Lavilla P, Gil A. Nontyphoid salmonellosis in HIV-infection. A report of 17 patients in Madrid. Int Conf AIDS. 1991 Jun 16-21;7(2):260 (abstract no. W.B.2313). MED/91327062. Decker CF, Simon GL, DiGioia RA, Tuazon CU. Listeria monocytogenes infections in patients with AIDS: report of five cases and review. Rev Infect Dis. 1991 May-Jun;13(3):413-7. ENTRY MONTH 199104 LAST REVISION DATE 20001107 273 UNIQUE IDENTIFIER DRG-0073 NAME OF SUBSTANCE Ketoconazole [USPD 1998; p. 404] REGISTRY NUMBER 65277-42-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Piperazine, 1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1H-- imidazol-1-ylmethyl)-1, 3-dioxolan-4-yl)methoxy)phenyl)-, cis- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Nizoral [USP DI 2000; p. 326] PROTOCOL ID NUMBERS No longer recruiting FDA 012B PHARMACOLOGICAL ACTION MODE OF ACTION: Ketoconazole is usually fungistatic in action, but may be fungicidal at high concentrations after prolonged incubation or against very susceptible organisms. Like other imidazole derivatives, ketoconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased membrane permeability,secondary metabolic effects, and growth inhibition. Although the exact mechanism of action of ketoconazole has not been fully determined,it has been suggested that the fungistatic activity of the drug may result from interference with ergosterol synthesis, probably via inhibition of C-14 demethylation of sterol intermediates (e.g., lanosterol). Like some other imidazole derivatives (e.g., miconazole), the fungicidal activity of ketoconazole at high concentrations may result from a direct physiochemical effect of the drug on the fungal cell membrane, but the direct effect of ketoconzazole on cell membranes appears to be substantially less than that of miconazole. Ketoconazole directly inhibits synthesis of adrenal steroids and testosterone in vitro and in vivo. Ketoconazole appears to inhibit steroid synthesis principally by blocking several P-450 enzyme stystems (e.g., 11beta-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme). Ketoconazole is rapidly absorbed from the gastrointestinal tract. Following oral administration, ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach. The bioavailability of oral ketoconazole depends on the pH of the gastric contents in the stomach; an increase in the pH results in decreased absorption of the drug. In healthy, fasting adults, peak plasma concentrations of approximately 4.2, 5, or 6.2 ug/ml occurred 1-2 hours following oral administration of a single 200mg dose as tablets, a suspension or a solution, respectively. Following oral administration of a single 200mg dose of ketoconazole as tablets to nonfasting adults, peak plasma concentrations of the drug were attained within 1-4 hours and ranged from 1.5-4.5 mg/ml; plasma concentrations of the drug were usually less than 0.05 mg/ml after 24 hours. Plasma concentrations of ketoconazole appear to decline in a biphasic manner with a half-life of approximately 2 hours in the initial phase and approximately 8 hours in the terminal phase. Ketoconazole is 84-99% bound to plasma proteins, primarily albumin. Ketoconazole has been detected in urine, bile, saliva, sebum, cerumen, synovial fluid, and CSF. Ketoconazole is partially metabolized in the liver to several inactive metabolites by oxidation and degradation of the imidazole and piperazine ring, by oxidative O-dealkylation, and by aromatic hydroxylation. The major route of elimination of ketoconazole and its metabolites appears to be excretion into feces via the bile. Ketoconazole does not appear to be appreciatively absorbed systemically following topical application to the skin. [AHFS Drug Information 1997; p 96, 2694] DISEASES STUDIED/TREATED Approved oral or topical antifungal drug used for the treatment of systemic or topical fungal infections including candidiasis, candiduria, blastomycosis, coccidioidomycosis, and histoplasmosis. [AmfAR Treat Dir 1997;8(3); p 73, AMFAR TX Dir 1997; 8(3)] CLASSIFICATION CODE Antiadrenal [USP DI 2000; p. 319] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 319] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 319] OTHER MAJOR USES Cream is indicated for the topical treatment of tinea corporis, tinea cruris, tinea pedis, tinea (pityriasis) versicolor, cutaneous candidiasis, and seborrheic dermatitis, caused by susceptible organisms. Shampoo is indicated for the reduction of scaling due to dandruff. Tablets are indicated for the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidiodomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis, and severe recalcitrant cutaneous dermatophyte infections not responding to topical therapy or oral grieseofulvin. [PDR 1997; p 1344-6] SUBSTANCE INTERACTIONS Ketoconazole may interact with the following drugs, drugs affecting gastric acidity: antacids, climetidine, ranitidine, antimuscarinic; hepatotoxic drugs; antituberculosis agents: rifampin, and isoniazid; antiviral agents: acyclovir, and vidarabine; quinolones: norfloxacin; coumarin anticoagulants; cyclosporine; phenytoin; theophylline; terfenadine and astemizole; loratadine; corticosteroids; and alcohol. Other drugs such as cisapride, triazolam, oral sulfonylurea antidiabetic agent, and paclitaxel may also interact with ketoconazole. [AHFS Drug Information 1997; p 99-100, 2965] ADVERSE EFFECTS Adverse effects reported with ketoconazole cream include severe irritation, pruritus, and stinging. Rare reports of contact dermatitis have been associated with ketoconazole cream or one of its ingredients in formulation, namely sodium sulfite or propylene glycol. Adverse effects reported with ketoconazole shampoo include: increase in normal hair loss, irritation, abnormal hair texture, scalp pustules, mild dryness of the skin, and itching. When used orally, ketoconazole has been associated with hepatic toxicity, including some fatalities. The most frequent adverse effects reported with ketoconazole tablets include nausea and/or vomiting, abdominal pain, and pruritus; less frequently headache, dizziness, gynecomastia, impotence, thrombocytopenia, leukopenia, hemolytic anemia, and bulging fontanelles; rarely alopecia, paresthesia, signs of increased intracranial pressure including fontanelles and papilledema, neuropsychiatric disturbances including suicidal tendencies and severe depression. In rare cases, anaphylexis has been reported after the first dose. [PDR 1997; p 1344-6] CONTRAINDICATIONS Contraindicated in patients who have shown hypersensitivity to the active or any ingredients in the formulation. Concurrent administration of terfenadine or astemizole with ketoconazole tablets is contraindicated. [PDR 1997; p 1344-6] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Imidazole derivative,struturally related to miconazole. [AHFS Drug Information 1997; p 2693] CHEMICAL/PHYSICAL DATA Molecular Formula: C26-H28-Cl2-N4-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 531.44 [USPD 1998; p. 404] CHEMICAL/PHYSICAL DATA Melting Point: 146 C [Merck Index 1996; p. 905] CHEMICAL/PHYSICAL DATA Elemental Comp: C58.76%, H5.31%, Cl13.34%, N10.54%, O12.04% [Merck Index 1996; p. 905] CHEMICAL/PHYSICAL DATA Solubility: Soluble in acids. [PDR 1997; p 1345] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to slightly beige, odorless powder. [AHFS Drug Information 1997; p 96, 2692; PDR 1997; p1345] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (200 mg), topical cream (2%) and shampoo (2%). [PDR 1997; p 1344-6] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; topical. [PDR 1997; p 1344-6] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at room temperature (59-77 F/15-25 C) and protected from moisture. Cream should be stored below 25 C (77 F). Shampoo should be stored at a temperature not above 25 C and protected from light. [PDR 1997; p 1344-6] MANUFACTURERS 0000001070: Janssen Pharmaceutica Inc 1125 Trenton-Harbourton Rd / PO Box 200 Titusville, NJ 085600200 Contact: Dr Richard Meibach (908)730-3135 MANUFACTURERS 0000001070: Janssen Pharmaceutica Inc 1125 Trenton-Harbourton Rd / PO Box 200 Titusville, NJ 085600200 Contact: Unspecified (800)526-7736 REFERENCES MED/97098246. Zeldis JB. HIV-related skin diseases [letter]. Lancet. 1996 Nov;348(9040):1151-2. ICA11/96921297. Silverman S Jr, Gallo JW, McKnight ML. Clinical characteristics and management responses in 85 HIV-infected patients with positive oral candida cultures. Int Conf AIDS. 1996 Jul 7-12;11(1):94 (abstract no.Mo.B.1233). MED/96302588. Aly R, Berger T. Common superficial fungal infections in patients with AIDS. Clin Infect Dis. 1996 May;22 suppl 2:S128-32. MED/96147524. Sirisanthana V, Sirisanthana T. Dissemination penicillium marneffei infection in human immunodeficiency virus-infected children. 1995 Nov;14(11):935-40. MED/96008522. Anonymous. Drugs for AIDS and associated infections. Med Lett Drugs Ther. 1995 Oct;37(959):87-94. MED/96051682. St-Germain G, Dion C, Espinel-Ingroff A, Ratelle J, de Repentigny L. Ketoconazole and itraconazole susceptibility of Candida albicans isolated from patients infected with HIV. J Antimicrob Chemother. 1995 Jul;36(1):109-18. MED/94349966. Hernandez-Sampelayo T. Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV-infected children. Eur J Clin Microbiol Infect Dis. 1994 Apr;13(4):340-4. MED/94168182. Parente F, Ardizzone S, Cernuschi M, Antinori S, Esposito R, Moroni M, Lazzarin A, Porro GB. Prevention of symptomatic recurrences of esophageal candidiasis in AIDS patients after the first episode: a prospective open study. Am J Gastroenterol. 1994 Mar;89(3):416-20. MED/94043874. Knupp CA, Brater DC, Relue J, Barbhaiya RH. Pharmacokinetics of didanosine and ketoconazole after coadministration to patients seropositive for the human immunodeficiency virus. J Clin Pharmacol. 1993 Oct;33(10):912-7. MED/92411496. Laine L, Dretler RH, Conteas CN, Tuazon C, Koster FM, Sattler F, Squires K, Islam MZ. Fluconazole compared with ketoconazole for the treatment of Candida esophagitis in AIDS. A randomized trial. Ann Intern Med. 1992 Oct 15;117(8):655-60. ENTRY MONTH 199104 LAST REVISION DATE 20001107 274 UNIQUE IDENTIFIER DRG-0072 NAME OF SUBSTANCE Clotrimazole [USPD 1998; p. 186] REGISTRY NUMBER 23593-75-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.; (Parent drug)] STANDARD CHEMICAL NAME 1H-Imidazole, 1-((2-chlorophenyl)diphenylmethyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Mycelex Troches [USP DI 2000; p. 951] PROTOCOL ID NUMBERS Complete NIAID ACTG 981 PROTOCOL ID NUMBERS No longer recruiting FDA 012M PHARMACOLOGICAL ACTION MODE OF ACTION: Clotrimazole is fungistatic, may be fungicidal (depending on its concentration), and has some antibacterial activity. It inhibits biosynthesis of ergosterol and other sterols, damaging the fungal cell wall membrane, altering its permeability, potentially causing loss of essential intracellular elements. It also inhibits the biosynthesis of triglycerides and phospholipids by fungi. It inhibits oxidative and peroxidative enzyme activity, causing intracellular buildup of toxic levels of hydrogen peroxide, which may contribute to deterioration of subcellular organelles and cellular necrosis. It is poorly and erratically absorbed, even when swallowed. Absorbed clotrimazole is metabolized in the liver to inactive compounds; it induces hepatic microsomal activity which accelerates its own catabolism. Duration of action is up to 3 hours. Elimination of clotrimazole is principally through the fecal route. Clotrimazole exerts its antifungal activity by altering cell membrane permeability, apprently by binding with phospholipids in the fungal cell membrane. As a result of alteration of permeability, the cell membrane is unable to function as a selective barrier, and potassium and other cellular constituents are lost. Clotrimazole inhibits or kills many fungi, including yeasts and dermatophytes. The drug is also active against some gram-positive bacteria. Following oral administration of a lozenge containing 10 mg of clotrimazole and dissolution of the lozenge in the mouth (which takes approximatly 15-30 minutes), concentrations of clotrimazole sufficient to inhibit most species of Candida are present in saliva for up to 3 hours. Administration of a 10-mg clotrimazole lozenge every 3 hours reportedly maintains salivary concentrations of clotrimazole greater than the MIC of the drug for most species of Candida. The long-term effective concentration of clotrimazole in saliva apperas to be related to slow release of the drug from the oral mucosa to which the drug is apparently bound. Only very small amounts of the drug appear to be absorbed systemically following topical application to the skin. Small amounts of the drug are absorbed systemically when the drug is administered intravaginally. About 3-10% of an intravaginal dose of the drug reaches systemic circulation, principally as metabolites. [USP DI 1995; p 798] DISEASES STUDIED/TREATED Treatment and prophylaxis of oropharyngeal candidiasis and treatment of vulvovaginal candidiasis. [USP DI 1997; p 2688] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 330, 951] OTHER MAJOR USES Used for the treatment of oropharyngeal candidiasis; for the treatment of tinea pedis, tinea cruris, and tinea corporis caused by T.rubrum, T.mentagrophytes, E.floccosum, or M.canis; for the treatment of tinea versicolor caused my Malassezia furfur (Pityrosporum orbiculare); and for the treatment of cutaneous candidiasis (moniliasis); in the treatment of vaginal trichomoniasis. [AHFS Drug Information 1997; p2689] ADVERSE EFFECTS Although clotrimazole is usually well tolerated, the following adverse effects have been reported for the indicated preparations, topical preparations: blistering, erythema, edema, prutitus, burning, stinging, peeling, urticaria, skin fissures, and general irritation of the skin; vaginal tablets: rarely skin rash, itching, vulval irritation, lower abdominal cramps, bloating, slight cramping, vaginal soreness during intercourse, dyspareunia, slingt urinary frequency, and burning or irrittation in the sexual partner; vaginal cream: vaginal burning, erythema, irritation, burning, and intecurrent cystitis; oral lozenges: abnormal liver function, elevanted serum AST (SGOT) concentrations, and nausea and vomiting. [AHFS Drug Information 1997; p2689] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to clotrimazole or any ingredient in the formulation. [AHFS Drug Information 1997; p 2689] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic chlorinated imidazole derivative closely related to miconazole. [AHFS Drug Information 1997; p 2687] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H17-Cl-N2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 344.85 [USPD 1998; p. 186] CHEMICAL/PHYSICAL DATA Melting Point: 147-149 C [Merck Index 1996; p. 410] CHEMICAL/PHYSICAL DATA Elemental Comp: C76.63%, H4.97%, Cl10.28%, N8.12% [Merck Index 1996; p. 410] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water, benzene, toluene, soluble in acetone, chloroform, ethyl acetate, and DMF. [Merck Index 1996; p 410] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Odorless, white to pale yellow crystalline powder. [AHFS Drug Information 1997; p 2687] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lozenges (10 mg), vaginal cream (1%), vaginal tablets (100 mg, 500 mg), topical cream, lotion, or solution (1%). [AHFS Drug Information 1997; p 2690] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral (lozenges), vaginal insertion (cream or tablets), lotion (topical), solution (topical). [AHFS Drug Information 1997; p 2690] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Topical cream, lotion, and solution and vaginal cream and tablets should be stored at 2-30 C. Lozenges should be stored at less than 30 C; freezing should be avoided. [AHFS Drug Information 1997; p 2687] MANUFACTURERS 0000001074: Miles Inc Pharmaceutical Division 400 Morgan Lane West Haven, CT 06516 Contact: Dr Kenneth Kashkin (203)937-2468 MANUFACTURERS 0000005230: Bayer Corporation 400 Morgan Lane West Haven, CT 065164175 Contact: Unspecified (800)288-8371 MANUFACTURERS 0000002813: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Joe Lamendola (908)298-2628 MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Dr Janice Albrecht (908)298-7985 REFERENCES MED/97308826. Sharland M; Gibb D; Tudor-Williams G; Walters S; Novelli V. Pediatric HIV infection. Arch Dis Child, 1997 Apr; 76 (4) 293-6. AIDS/96700643. Anonymous. Fungal infection overview. Treat Rev. 1995 May; No 18:10. AIDS/95700464. Cheng B. Preventing opportunistic infections. PI Perspect. 1995 May; No 16:14-5. MED/95157588. Powderly WG, Finkelstein D, Feinberg J, Frame P, He W, van der Horst C, Koletar SL, Eyster ME, Carey J, Waskin H, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infectons in patients with advanced human immunodeficiency virus infection. N Engl J Med. 1995 Mar 16;332(11):700-5. MED/95029463. Sangeorzan JA, Bradley SF, He X, Zarins LT, Ridenour GL, Tiballi RN, Kauffman CA. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconzale resistance. Am J Med. 1994 Oct;97(4):339-46. MED/95095443. Gooskens V, Ponnighaus JM, Clayton Y, Mkandawire P, Sterne JA. Treatment of superficial mycoses in the tropics: Whitfield's ointment versus clotrimazole. Int J Dermatol. 1994 Oct;33(10):738-42. MED/94358249. Greenspan D. Treatment of oropharyngeal candidiasis in HIV-positive patients. J Am Acad Dermatol. 1994 Sep;31(3 Pt 2):S51-5. MED/94076125. Pons V, Greenspan D, Debruin M. Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. J Acquir Immune Defic Syndr. 1993 Dec;6(12):1311-6. ICA9/93334327. Higgins S, Woolley PD, Chandiok S. Comparison of topical clotrimazole, oral fluconazole and oral itraconazole in acute vulvovaginal candidiasis. Int Conf AIDS. 1993 Jun 6-11;9(1):274 (abstract no. PO-A36-0840). MED/91138452. Lalor E, Rabeneck L. Esophageal candidiasis in AIDS. Successful therapy with clotrimazole vaginal tablets taken by mouth. Dig Dis Sci. 1991 Mar;36(3):279-81. ENTRY MONTH 199104 LAST REVISION DATE 20001107 275 UNIQUE IDENTIFIER DRG-0071 NAME OF SUBSTANCE Ceftriaxone sodium [USPD 1998; p. 146] REGISTRY NUMBER 73384-59-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxy- lic acid, 7-(((2-amino-4-thiazolyl)(methoxyimino)acetyl- )amino)-8-oxo-3-(((1,2, 5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triaz- in-3-yl)thio)methyl)-, (6R-(6alpha,7beta(Z)))- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Rocephin [USP DI 2000; p. 842] PROTOCOL ID NUMBERS Complete NIAID ACTG 145 PROTOCOL ID NUMBERS No longer recruiting FDA 019A PHARMACOLOGICAL ACTION MODE OF ACTION: Average plasma concentrations of ceftriaxon following a single 30-minute intravenous infusion of a 0.5, 1, or 2 g dose after 30 minutes were 82, 151, and 257 mcg/ml respectively (for intramuscular administration of a single 0.5 or 1 g dose, the concentrations were 22 and 40 mcg/ml, respectively). The drug was completely absorbed following intramuscular administration with mean maximum plasma levels occurring between 2 and 3 hours after dosing. Multiple intravenous or intramuscular doses ranging from 0.5-2 g at 12-24 hour intervals resulted in 15-36% accumulation of the drug above single dose values. High levels of the drug appear in urine, declining to low levels after 24-48 hours. A total of 33-67% of a ceftriaxone dose was excreted in urine as unchanged drug, with the remainder secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 g intravenous dose, mean levels of the drug found from 1-3 hours after dosing in the gallbladder bile, common duct bile, cystic duct bile, gallbladder wall, and concurrent plasma were 581, 788, 898, 78.2, and 62.1 mcg/ml, respectively. Over a 0.15-3 g dose range in healthy adult subjects, drug elimination half-life ranged from 5.8-8.7 hours; apparent volume of distribution from 5.78-13.5L; plasma clearance from 0.58-1.45L/hour; and renal clearance from 0.32-0.73 l/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from 95% bound at plasma levels of less than 25 mcg/ml to 85% bound at 300 mcg/ml. After 3-4 hours following a 50 mg/kg intravenous dose, the mean peak plasma level (mcg/ml), elimination half-life (hours), plasma clearance (ml/hour/kg), volume of distribution (ml/kg), and cerebrospinal fluid level (mcg/ml) in pediatric patients with bacterial meningitis were 216, 4.6, 49, 338, and 5.6, respectively (following a 75 mg/kg intravenous dose, the respective values were 275, 4.3, 60, 373, and 6.4). Relative to healthy adults, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction. Ceftriaxone was not significantly removed from the plasma by hemodialysis. Plasma elimination rates may be markedly reduced in some patients, requiring monitoring for any necessary dosage adjustments. [PDR 1997; p 2305] DISEASES STUDIED/TREATED An antibiotic under investigation as an alternative to penicillin for the treatment of neurosyphilis. Single dose chancroid therapy may be less effective in HIV patients and other anti-infectives should be used. [AmfAR Treat Dir 1995;7(4); p 62; AHFS Drug Information 1997; p 166] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 820] OTHER MAJOR USES Used in the treatment of the following infections when caused by susceptible organisms: lower respiratory tract infections, skin and skin structure infections, urinary tract infections, uncompleted gonorrhea, pelvic inflammatory disease, bacterial septicemia, bone and joint infections, intra-abdominal infections, meningitis, and surgical prophylaxis. [PDR 1997; p2306] SUBSTANCE INTERACTIONS Probenecid has been shown to increase blood levels of ceftriaxone. [AmfAR Treat Dir 1997;8(3); p68] ADVERSE EFFECTS Ceftriaxone sodium is generally well tolerated. Adverse reactions include the following, local reactions: pain, induration, tenderness, and phlebitis; hypersensitivity reactions: rash, pruritus, fever or chills: hematologic effects: eosinophilia, thrombocytosis, leukopenia, anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia, and prolongation of the prothrombin time; gastrointestinal effects: diarrhea, nausea or vomiting, dysgeusia, and onset of pseudomembranous colitis; hepatic effects: elevations of SGOT, SGPT, alkaline phosphatase, or bilirubin; renal effects: elevations of BUN, creatinine, or presence of casts in urine; central nervous sytem: headache, or dizziness; genitourinary effects: moniliasis, or vaginitis; miscellaneous reactions: diaphoresis, and flushing. Other rarely observed adverse effects include leukocytosis, lymphocytosis,monocytosis, basophilia, a decrease in the prothrombin time, jaundice, gallbladder sludge, glycosuria, hematuria, anaphylaxis, bronchospasm, serum sickness, abdominal pain, colitis, flatulence, dyspepsia, palpitations, and epistaxis. [PDR 1997; p2306] CONTRAINDICATIONS Contraindicated for patients with known allergy to the cephalosporin class of antibiotics. [PDR 1997; p 2306] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Semisynthetic 3rd generation cephalosporin derivative. [PDR 1997; p 2305] CHEMICAL/PHYSICAL DATA Molecular Formula: C18-H16-N8-Na2-O7-S3.(3&1/2)H2-O [USPD 1998; p. 146] CHEMICAL/PHYSICAL DATA Molecular Weight: 661.61 [USPD 1998; p. 146] CHEMICAL/PHYSICAL DATA Melting Point: >155 C [Merck Index 1996; p. 324] CHEMICAL/PHYSICAL DATA Elemental Comp: C38.98%, H3.27%, N20.20%, O20.19%, S17.35% (base) [Merck Index 1996; p. 324] CHEMICAL/PHYSICAL DATA Solubility: Readily soluble in water, approximately 40 g/100 ml; sparingly soluble in methanol; very slightly soluble in ethanol at 25 C. [PDR 1997; 2305] CHEMICAL/PHYSICAL DATA Stability: The commercial product, Rocephin, should not be physically mixed with or piggy backed into solutions containing other antimicrobial drugs or into diluent solutions, other than those recommended by the manufacturer. Do not freeze thawed solutions. [PDR 1997; p 2307] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to yellowish-orange crystalline powder. [PDR 1997; p 2305] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials of powder containing 250 mg, 500 mg, 1 g, 2 g, and 10 g of drug. Parenteral injection in dextrose solution containig 20, and 40 mg/ml of drug. [AHFS Drug Information 1997; p 173] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous or intramuscular injection. [PDR 1997; p 2305-7] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Sterile powder should be stored at room temperature or below and protected from light. Injection solutions should be stored frozen at a temperature not greater than -20 C. [AHFS Drug Information 1997; p162] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES ICA11/96920991. de Clerck M, Crabbe F, Vuylsteke B, Laga M. Cost-effectiveness of management stategies of acute urethritis. Int Conf AIDS. 1996 Jul 7-12;11(1):37 (abstract no.Mo.C.342). MED/96357952. Borgna-Pignatti C, Bezzi TM, Reverberi R. Fatal ceftriaxone-induced hemolysis in a child with immunodeficiency syndrome. Pediatr Infect Dis J. 1995 Dec;14(12):1116-7. MED/96178190. Friedland LR, Kulick RM, Biro FM, Patterson A. Cost-effectiveness decision analysis of intramuscular ceftriaxon versus oral cefixime in adolescents with gonococcal cervicitis. Ann Emerg Med. 1996 Mar;27(3):299-304. MED/95260944. Sands M, Markus A. Lues maligna, or ulceronodular syphilis, in a man infected with human immunodeficiency virus: case report and review. Clin Infect Dis. 1995 Feb;20(2):387-90. MED/94266284. Merianos A, Gilles M, Chuah J. Ceftriaxone in the treatment of chronic donovanosis in central Australia. Genitourin Med. 1994 Apr;70(2):84-9. ICA10/94371840. Adjei O. Surveillance of Neisseria gonorrhoea in Kumasi, 1989-1992. Int Conf AIDS. 1994 Aug 7-12;10(2):292 (abstract no. PC0553). MED/95067571. Schutze GE, Landers S. Management of infants born to women with sexually transmitted diseases. Am Fam Physician. 1994 Nov 15;50(7):1479-86. MED/93132404. Tyndall M, Malisa M, Plummer FA, Ombetti J, Ndinya-Achola JO, Ronald AR. Ceftriaxone no longer predictably cures chancroid in Kenya. J Infect Dis. 1993 Feb; 167(2):469-71. MED/93072012. Dowell ME, Ross PG, Musher DM, Cate TR, Baughn RE. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Am J Med. 1992 Nov;93(5):481-8. MED/90297613. Bryan JP, Hira SK, Brady W, Luo N, Mwale C, Mpoko G, Krieg R, Siwiwaliondo E, Reichart C, Waters C, et al. Oral ciprofloxacin versus ceftriaxone for the treatment of urethritis from resistant Neisseria gonorrhoeae in Zambia. Antimicrob Agents Chemother. 1990 May;34(5):819-22. ENTRY MONTH 199104 LAST REVISION DATE 20010104 276 UNIQUE IDENTIFIER DRG-0070 NAME OF SUBSTANCE Keyhole-Limpet Hemocyanin [Merck Index 1996; p. 794] PROTOCOL ID NUMBERS No longer recruiting CC 87 I-114 PROTOCOL ID NUMBERS Recruiting FDA 259H PHARMACOLOGICAL ACTION MODE OF ACTION: It was hypothesized that localized deposition of antigen into the human lung would induce local inflammatory and immnune responses in antigen-exposed sites. To test this, segmental instillation of a highly immunogenic, soluble antigen, keyhole limpet hemocyanin (KHL) was performed in 10 healthy, nonsmoking volunteers. Ten to fifteen days after instillation bronchoalveolar lavage (BAL) was performed in immunized segments and contralateral control segments (CS). Greater albumin concentrations and cell recoveries were found in immunized segments than in CS BAL, suggesting local inflammation. [Am J Respir Cell Mol Biol 1994 Nov; 11(5)] DISEASES STUDIED/TREATED Used as control agent in immune response studies of AIDS patients. [Protocol ID: 87 I-114 ] CLASSIFICATION CODE Immunomodulator [MeSH ] OTHER MAJOR USES Immunological control agent; baseline immune response in clinical research. [Protocol ID: 87 I-114 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Non-heme, oxygen-carrying copper protein found in arthropods and mollusca. [Merck Index 1996; p 794] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Oxygenated form (oxyhemocyanin) is blue, while the deoxygenated form (deoxyhemocyanin) is colorless. [Merck Index 1996; p 794] MANUFACTURERS 0000005174: Calbiochem-Novabiochem Corporation 10394 Pacific Center Court San Diego, CA 92121 REFERENCES MED/97062475. Alkan SS, Akdis SS, Feuerlein D, Gruninger M. Direct measurement of cytokines (IFN-gamma, IL-4, -5, and -6) from organs after antigenic challenge. Ann N Y Acad Sci. 1996 Oct 31;796:82-90. MED/96138045. Jurincic-Winkler C, Metz KA, Beuth J, Engelmann U, Klippel KF. Immunohistological findings in patients with superficial bladder carcinoma after intravesical instillation of keyhole limpet haemocyanin. Br J Urol. 1995 Dec;76(6):702-7. MED/95033273. Weissman DN, Bice DE, Crowell RE, Schuyler MR. Intrapulmonary antigen deposition in the human lung: local responses. Am J Respir Cell Mol Biol. 1994 Nov;11(5):607-14. ICA9/93335758. Goldstein AL, Sarin PS, Markham R, Kahn J, Heseltine P, Gazzard B, Youle M. Cytotoxic and humoral immune responses to HIV-1 p17 synthetic peptide HGP-30 in human volunteers. Int Conf AIDS. 1993 Jun 6-11;9(1):492 (abstract no. PO-B27-2139). MED/93314078. Whittle H, Egboga A, Todd J, Morgan G, Rolfe M, Sabally S, Wilkins A, Corrah T. Inmmunological responses of Gambians in relation to clinical stage of HIV-2 disease. Clin Exp Immunol. 1993 Jul;93(1):45-50. ICA9/93334185. Sarin PS, Traviss C, Pettit-Barrett D, Goldstein AL. Immune response of HIV-1 p17 synthetic peptide HGP-30/KLH in different adjuvants. Int Conf AIDS. 1993 Jun 6-11;9(1):252 (abstract no. PO-A29-0705). MED/93103799. Kahn JO, Stites DP, Scillian J, Murcar N, Stryker R, Volberding PA, Naylor PH, Goldstein AL, Sarin PS, Simmon VF, et al. A phase I study of HGP-30, a 30 amino acid subunit of the human immunodeficiency virus (HIV) p17 synthetic peptide analogue sub-unit vaccine in seronegative subjects. AIDS Res Hum Retroviruses. 1992 Aug;8(8): 1321-5. ICA8/92400741. Okuda K, Inami S, Kaneko T. Strong synergistic effects of polyvalent vaccine for human immunodeficiency virus (HIV-1) infection. Int Conf AIDS. 1992 Jul 19-24;8(2):A73 (abstract no. PoA 2425). MED/92387824. Naylor PH, Sztein MB, Wada S, Maurer S, Holterman D, Kirkley JE, Naylor CW, Zook BC, Hitzelberg RA, Gibbs CJ Jr, et al. Preclinical and clinical studies on immunogenicity and safety of the HIV-1 p17-based synthetic peptide AIDS vaccine--HGP-30-KLH. Int J Immunopharmacol. 1991;13 Suppl 1:117-27. ICA6/40105490. Stambuk D, Vallerich M, Youle M, Rios A, Naylor P, Sarin P, Goldstein A, Gazzard B. Phase I study of HGP-30, an HIV p17 synthetic peptide analogue sub-unit vaccine in humans. Int Conf AIDS. 1990 Jun 20-23;6(2):327 (abstract no. 1054). ICA5/00149889. Samson J, Charest J, Paquet C, Lapointe N. HIV activation by cofactors: P-24 antigenemia after injections of soluble antigens in children with AIDS. Int Conf AIDS. 1989 Jun 4-9;5:312 (abstract no. T.B.P.151). ENTRY MONTH 199104 LAST REVISION DATE 20000801 277 UNIQUE IDENTIFIER DRG-0069 NAME OF SUBSTANCE Ibuprofen [USPD 1998; p. 367] REGISTRY NUMBER 15687-27-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Alpha-Methyl-4-(2-methylpropyl)benzeneacetic acid [Merck Index 1996; p 839] SYNONYMS Advil [USP DI 2000; p. 424] SYNONYMS Haltran [USP DI 2000; p. 424] SYNONYMS Ibuprin [USP DI 2000; p. 424] SYNONYMS Medipren [USP DI 2000; p. 424] SYNONYMS Motrin [USP DI 2000; p. 424] SYNONYMS Nuprin [USP DI 2000; p. 424] SYNONYMS Rufen [USP DI 2000; p. 424] SYNONYMS Trendar [USP DI 2000; p. 424] PROTOCOL ID NUMBERS No longer recruiting FDA 044A PHARMACOLOGICAL ACTION MODE OF ACTION: Nonsteroidal anti-inflammatory analgesics (NSAIAs) such as ibuprofen inhibit the activity of the enzyme cyclo-oxygenase, resulting in decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. While the resultant decrease in prostaglandin synthesis/activity in various tissues may cause many of the therapeutic (and adverse) effects of NSAIAs other actions may also contribute significantly to the therapeutic effects of these medications. These actions include antirheumatic; analgesic; anti-inflammatory; antipyretic; antidysmenorrheal; and vascular headache prophylaxis. NSAIAs also reversibly inhibit platelet aggregation, with possible recovery of platelet function within 1 day after drug discontinuation. Onset of action using ibuprofen for treatment of pain is 0.5 hours, with duration of action being 4-6 hours. Some 80% of oral ibuprofen is absorbed from intestinal tract. In adults bioavailablility of the drug is similar with conventional tablets (120 min.), chewable tablets (62 min) or suspensions (47 min.). Peak plasma concentrations of a single 200mg. dose were 15, 19 or 20 microgram/mL respectively. Plasma half-life has been reported to be 2-4 hours. About 50-60% of an oral dose is excreted as a metabolite in urine, less than 10% in urine unchanged, and the remained is eliminated in the feces. [USP DI 1997; p 381; AHFS Drug Information 1997; p 1499-1501] DISEASES STUDIED/TREATED Inflammation and pain. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); p 99 (abstract no. PuB 7304)] CLASSIFICATION CODE Analgesic [USP DI 2000; p. 403] CLASSIFICATION CODE Antipyretic [USP DI 2000; p. 403] CLASSIFICATION CODE Antirheumatic [USP DI 2000; p. 403] CLASSIFICATION CODE Nonsteroidal anti-inflammatory [USP DI 2000; p. 403] OTHER MAJOR USES Treatment of rheumatoid arthritis, osteoarthritis, mild to moderate pain, dysmenorrhea, nonrheumatic inflammation, acute headache, and reduction of fever. [PDR 1997; p 1563-4] SUBSTANCE INTERACTIONS Should be used with caution when used concomitantly with anticoagulants (e.g., warfarin) or thrombolytic agents (e.g., streptokinase). Decreased blood concentrations of ibuprofen may result when it is taken with aspirin. May potentiate the adverse GI effects of other nonsteroidal anti-inflammatory agents. May increase plasma concentration and lower renal clearance of lithium. May reduce the blood pressure response to angiotensin-converting enzyme inhibitors (e.g., captorpril, enalapril). [AHFS Drug Information 1997; p 1502-3] ADVERSE EFFECTS The most frequent adverse effects involve the GI tract; they may include dyspepsia, heartburn, nausea, vomiting, diarrhea and abdominal pain. Reported adverse CNS effects include dizziness, headache, and nervousness. Optic and ocular effects such as tinnitus, amblyopia have been reported. Severe hepatic reactions have occurred rarely with ibuprofen. Dermatologic effects such as uricaria, vesiculobullous and erythematous macular rashes have been reported. Adverse hematologic effects and renal effects also have been associated with ibuprofen therapy. [AHFS Drug Information 1997; p 1500-1] CONTRAINDICATIONS Contraindicated in patients having a history of sensitivity to ibuprofen or other NSAIAs. Risk-benefit should be considered for patients having the following medical problems: anemia, asthma, compromised cardiac function, hypertension, congestive heart failure, diabetes, pre-existing edema, extracellular volume depletion, sepsis, hemophilia or other bleeding problems (coagulation, platelet dysfunction), hepatic dysfunction, peptic ulcer, ulcerative colitis, upper gastrointestinal tract disease, renal impairment, stomatitis, adverse symptoms produced by aspirin or other NSAIAs, or systemic lupus erythematosus. [USP DI 1997; p 390] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Arylpropionic acid derivative. [USP DI 1995; p 1997] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H18-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 206.29 [USPD 1998; p. 367] CHEMICAL/PHYSICAL DATA Melting Point: 75-77 C [Merck Index 1996; p. 839] CHEMICAL/PHYSICAL DATA Elemental Comp: C75.69%, H8.80%, O15.51% [Merck Index 1996; p. 839] CHEMICAL/PHYSICAL DATA Solubility: Relatively insoluble in water; very soluble in alcohol, and most organic solvents. [Merck Index 1996; p 839776] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder, having a slight, characteristic odor. [AHFS Drug Information 1997; p 1499] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, 200, 300, 400, 600 and 800 mg; pediatric suspension, 100mg/5ml. [USP DI 1997; p 399; AHFS Drug Information 1997; p 1503-4] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1565] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15-30 C (59-86 F); store suspension in a well-closed container. [USP DI 1997; p 399] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001226: Whitehall Laboratories Inc 5 Giralda Farms Madison, NJ 079400871 Contact: Dr Steven Stravinski (201)660-5509 MANUFACTURERS 0000001226: Whitehall Laboratories Inc 5 Giralda Farms Madison, NJ 079400871 Contact: Unspecified (800)322-3129 MANUFACTURERS 0000005221: Roberts Pharmaceutical Corporation 4 Industrial Way West Eatontown, NJ 077242274 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000005225: Thompson Medical 777 South Flagler West Palm Beach, FL 33401 Contact: Dr Steven Stravinski (201)660-5509 MANUFACTURERS 0000005220: McNeil Consumer Healthcare 7050 Camp Hill Road Ft Washington, PA 19034 Contact: Unspecified (800)322-3129 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)992-9306 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)521-7857 MANUFACTURERS 0000005218: Knoll Pharmaceutical Co 3000 Continental Drive North Mount Olive, NJ 078281234 Contact: Unspecified (800)469-5268 MANUFACTURERS 0000001226: Whitehall Laboratories Inc 5 Giralda Farms Madison, NJ 079400871 Contact: Dr Donald M Demke (616)833-8586 REFERENCES MED/97050872. Mansilla-Rosello A, Ferron-Orihuela JA, Ruiz-Cabello F, Garrote-Lara D, Delgado-Carrasco S, Tamayo-Pozo F. Interleukin-1beta and ibuprofen effects on CD4/CD8 cells after endotoxic challenge. J Surg Res. 1996 Sep;65(1):82-6. MED/96379336. Klaus BD. Peripheral neuropathey [news]. Nurse Pract. 1996 Jun;21(6):130-1. MED/96161267. Scott EM, Tariq VN, McCrory RM. Demonstration of synergy with fluconazole and either ibuprofen, sodium salicylate, or propylparaben against Candida albicans in vitro. Antimicrob Agents Chemother. 1995 Dec;39(12):2610-4. MED/95191088. Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial. JAMA. 1995 Mar 22-29;273(12):929-33. MED/94215284. Schachtel BP, Cleves GS, Konerman JP, Brown AT, Markham AO. A placebo-controlled model to assay the onset of action of nonprescription-strength analgesic drugs. Clin Pharmacol Ther. 1994 Apr;55(4):464-70. MED/94335460. Nephrotoxicity of non-steroidal anti-inflammatory drugs [clinical conference]. Lancet. 1994 Aug 20;344(8921):515-8. MED/93373784. Chetty KG, Ramirez MM, Mahutte CK. Drug-induced pulmonary edema in a patient infected with human immunodeficiency virus. Chest. 1993 Sep;104(3):967-9. MED/93295700. Cooper SA, Quinn PD, MacAfee K, Hersh EV, Sullivan D, Lamp C. Ibuprofen controlled-release formulation. A clinical trial in dental impaction pain. Oral Surg Oral Med Oral Pathol. 1993 Jun;75(6):677-83. ICA8/92404589. Lefkowitz M, Lebovits A, Smith G, Maignan M. The prevalence and management of pain in patients with AIDS: a second look three years later. Int Conf AIDS. 1992 Jul 19-24;8(3):99 (abstract no. PuB 7304). ICA8/92403474. Perlman DM. Ibuprofen-induced aseptic meningitis in individuals with HIV. Int Conf AIDS. 1992 Jul 19-24;8(3):119 (abstract no. PuB 7425). ENTRY MONTH 199104 LAST REVISION DATE 20000801 278 UNIQUE IDENTIFIER DRG-0068 NAME OF SUBSTANCE Disulfiram [USPD 1998; p. 248] REGISTRY NUMBER 97-77-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Thioperoxydicarbonic diamide (((H2N)C(S))2S2), tetraethyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Antabuse [USP DI 2000; p. 1301] PROTOCOL ID NUMBERS Complete FDA 024A PHARMACOLOGICAL ACTION MODE OF ACTION: Produces irreversible inhibition of the enzyme responsible for oxidation of the ethanol metabolite, acetaldehyde, resulting in accumulation of acetaldehyde which may be responsible for most of the signs and symptoms occurring after ethanol ingestion in disulfiram-treated patients. During alcohol metabolism following disulfiram intake, the level of acetaldehyde occurring in the blood may be 5-10 times higher than that found during metabolism of the same amount of alcohol alone. Disulfiram does not seem to influence the rate of alcohol elimination from the body. The observed hypotensive response may be due to inhibition of norepinephrine synthesis by the major disulfiram metabolite, diethyldithiocarbamate. Disulfiram is absorbed slowly and incompletely from the gastrointestinal tract and is eliminated slowly from the body. Its biotransformation occurs in the liver. Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more sensitive the patient becomes to alcohol. Initial onset of action may be delayed for up to 12 hours since disulfiram is initially localized in body fat. Reaction from alcohol ingestion during disulfiram maintenance usually occurs within 5-10 minutes. The duration of disulfiram action is up to 14 days following the last dose. Disulfiram elimination is primarily renal, as metabolites, although about 5-20% of a dose is eliminated unchanged in the feces and some of the medication is exhaled as carbon disulfide; up to 20% of a dose may remain in the body for 1 week or longer. [PDR 1997; p 2802; USP DI 1997; p 1240] DISEASES STUDIED/TREATED Primary HIV infection. [Int Conf AIDS 1989 Jun 4-9;5; 403 (abstract no. W.B.P. 307)] CLASSIFICATION CODE Alcohol-abuse deterrent [USP DI 2000; p. 1299] OTHER MAJOR USES Used to help maintain sobriety in treating chronic alcoholism. Used as an adjunct to supportive and psychotherapeutic measures. [PDR 1997; p 2802] SUBSTANCE INTERACTIONS May decrease plasma clearance and prolong duration of action of alfentanil. May increase anticoagulant effect of anticoagulants due to inhibition of enzymatic metabolism of the anticoagulant; disulfiram also may act directly in the liver to increase the hypoprothrombinemia-inducing activity of coumarin derivatives; anticoagulant dosage adjustments based on prothrombin time may be necessary. May increase serum levels of hydantoins, especially phenytoin, possibly leading to hydantoin toxicity. Concurrent use of disulfiram with tricyclic antidepressants (especially amitriptyline) may cause transient delirium. Ascorbic acid may interfere with the disulfiram-alcohol reaction, especially with chronic use or high doses of ascorbic acid. Concurrent use of disulfiram and the following drugs may enhance or potentiate toxic effects: metronidazole, midizolam, paraldehyde, neurotoxic medications, hepatic enzyme inhibitors, central nervous system (CNS) depression-producing medications, and isoniazid. [PDR 1997; p 2802] ADVERSE EFFECTS May cause eye pain, optic neuritis, cholestatic and fulminant hepatitis, psychotic reactions, peripheral neuritis and polyneuritis in hands or feet, drowsiness, headache, skin eruptions, impotence, dermatitis, metallic/garlic-like aftertaste. [PDR 1997; p 2803] CONTRAINDICATIONS Contraindicated in patients receiving or having recently received metronidazole, paraldehyde, alcohol, or alcohol-containing preparations, e.g., cough syrups, tonics. Disulfiram medications should never be administered to patients who are in a state of alcohol intoxication or without knowledge on the part of the patient. Patients intolerant of other thiuram derivatives may be intolerant of disulfiram as well. Contraindicated in patients with severe myocardial disease or coronary occlusion, psychoses, and hypersensitivity to disulfram or other thiuram derivatives used in pesticides and rubber vulcanization. [PDR 1997; p 2802] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Alkyl thiocarbamoyl derivative. [PDR 1997; p 2802] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H20-N2-S4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 296.55 [USPD 1998; p. 248] CHEMICAL/PHYSICAL DATA Melting Point: 70 C [Merck Index 1996; p. 570] CHEMICAL/PHYSICAL DATA Elemental Comp: C40.50%, H6.80%, N9.45%, S43.25% [Merck Index 1996; p. 570] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water (0.02 g/100 ml); soluble in alcohol (3.82 g/100 ml) and ether (7.14 g/100 ml); also soluble in acetone, benzene, chloroform, carbon disulfide. [Merck Index 1996; p 570] CHEMICAL/PHYSICAL DATA Stability: Aqueous suspensions prepared from disulfiram powder or tablets are stable up to 295 days when stored at room temperature and protected from light. [Facts and Comparisons 1995; p 736] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white, odorless, almost tasteless crystalline powder. [PDR 1997; p 2802] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (250 mg or 500 mg). [PDR 1997; p 2803] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2803] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store below 40 C (104 F) preferably between 15-30 C (59-86 F) in tight, light-resistant container. [USP DI 1997; p 1243] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Unspecified (800)934-5556 REFERENCES MED/97126224. Hathout Y, Fabris D, Han MS, Sowder RC 2nd, Henderson LE, Fenselua C. Characterization of intermediates in the oxidation of zinc fingers in human immunodeficiency virus type 1 nucleocapsid protein P7. Drug Metab Dispos. 1996 Dec;24(12):1395-400. MED/94252206. Wodak A. Managing illicit drug use. A practical guide. Drugs. 1994 Mar;47(3):446-57. TOXBIB/95/197816. Forns X, Caballeria J, Bruguera M, Salmeron JM, Vilella A, Mas A, Pares A, Rodes J. Disulfiram-induced hepatitis. Report of four cases and review of the literature. J Hepatol. 1994 Nov;21(5):853-7. CAT/9303772. Gessner PK, Gessner T. Disulfiram and its metabolite diethyldithiocarbamate: pharmacology and status in the treatment of alcoholism, HIV infections, AIDS and heavy metal toxicity. London; New York: Chapman & Hall, 1992 xix, 452 p.: ill. MED/92095476. Gallant DM, Head-Dunham R. Antabuse (disulfiram) and AIDS. Alcohol Clin Exp Res. 1991 Oct;15(5):900-1. MED/90229140. Hording M, Gotzsche PC, Bygbjerg IC, Christensen LD, Faber V. Lack of immunomodulating effect of disulfiram on HIV positive patients. Int J Immunopharmacol. 1990;12(2):145-7. MED/90319858. Kahn S, Farnum JB, Thomas E. Disulfiram-induced hepatitis. South Med J. 1990 Jul;83(7):833-6. ICA5/00349189. Bihari B, Fleischer T, Devine J, Seaman JD. Disulfiram as an immunomodulating agent - follow up. Int Conf AIDS. 1989 Jun 4-9;5:661 (abstract no. C.619). ICA5/00203389. Davis I, Leibel J, Paroski P, Morgan A, Norris B. Case report of disulfiram as first line therapy in seropositive patients attending a community clinic. Int Conf AIDS. 1989 Jun 4-9;5:403 (abstract no. W.B.P.307). ENTRY MONTH 199104 LAST REVISION DATE 20001107 279 UNIQUE IDENTIFIER DRG-0067 NAME OF SUBSTANCE Clofazimine [USPD 1998; p. 180] REGISTRY NUMBER 2030-63-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N,5-Bis(4-chlorophenyl)-3,5-dihydro-3- ((1-methylethyl)imino)-2-phenazinamine [Merck Index 1996; p 401] SYNONYMS Lamprene [USPD 1998; p. 180] PROTOCOL ID NUMBERS Complete NIAID ACTG 135 PROTOCOL ID NUMBERS Complete NIAID ACTG 238 PROTOCOL ID NUMBERS No longer recruiting FDA 027A PROTOCOL ID NUMBERS No longer recruiting FDA 214A PROTOCOL ID NUMBERS No longer recruiting CC 92 I-165 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 027 PHARMACOLOGICAL ACTION MODE OF ACTION: This drug exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) by inhibiting mycobacterial growth via binding preferentially to mycobacterial DNA. It also exerts anti-inflammatory properties in controlling erythema nodosum leprosum reactions. Its precise mechanisms of action are unknown. Its absorption in leprosy patients ranges from 45-62% after oral administration. Average serum concentrations in leprosy patients treated with 100 mg and 300 mg daily were 0.7 and 1.0 micrograms/ml, respectively. Clofazimine exhibits a prolonged body retention, with a half-life following repeated oral doses estimated to be at least 70 days. Following ingestion of a single 300 mg dose, elimination of unchanged clofazimine and its metabolites in a 24-hour urine collection was negligible. Part of the ingested drug recovered from the feces may represent excretion via the bile; a small amount also is eliminated in the sputum, sebum, and sweat. The drug is highly lipophilic and tends to be deposited predominantly in fatty tissue and in reticuloendothelial system cells; it is taken up by macrophages throughout the body. Autopsies performed on leprosy patients revealed clofazimine crystals predominantly in the mesenteric lymph nodes, adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin. [PDR 1997; p 846] DISEASES STUDIED/TREATED Clofazamine has been used in combination with other antimycobacterial drugs in immunocompromised patients with Mycobacterium avium complex infections. Results have been ineffective, bacteriologic cures are unusual and prognosis is poor. [AHFS Drug Information 1997; p 641-2] CLASSIFICATION CODE Antibacterial, antimycobacterial [USP DI 1998; p. 853] OTHER MAJOR USES Used in treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. [PDR 1997; p 846] SUBSTANCE INTERACTIONS Concomitant administration of clofazimine and isoniazid may result in increased plasma and urinary concentrations of clofazimine and decreased concentrations of the drug in skin. Despite the result of various studies, there is no evidence to date that clofazimine and dapsone interfere with the antimycobacterial activity of each other. Drug interactions reported in concomitant administration of clofazimine and rifampin alone or in conjunction with dapsone need to be confirmed. [AHFS Drug Information 1997; p 643] ADVERSE EFFECTS Generally, clofazimine is well tolerated when doses not exceeding 100 mg/day are used. Clofazimine may cause skin pigmentation (pink to brownish-black) in 75-100% of the patients within a few weeks of treatment. Other adverse reactions may include ichthyosis and dryness, rash and pruritus, abdominal and epigastric pain, diarrhea, nausea, vomiting, gastrointestinal intolerance, conjunctival and corneal pigmentation (due to clofazimine crystal deposits), ocular dryness, burning, itching and irritation, discoloration of urine, feces, sputum, and sweat, elevated blood sugar, and elevated erythrocyte sedimentation rate (ESR). Rare adverse reactions (occurring in less than 1% of patients) may include: effects on the skin (phototoxicity, erythroderma, acneiform eruptions, monilial cheilosis); gastrointestinal system (bowel obstruction, gastrointestinal bleeding, anorexia, constipation, weight loss, hepatitis, jaundice, eosinophilic enteritis, enlarged liver); eyes (diminished vision); nervous system (dizziness, drowsiness, fatigue, headache, giddiness, neuralgia, taste disorder); psychiatric (depression secondary to skin discoloration); and clinical values (elevated albumin, serum bilirubin, and AST (SGOT); eosinophilia; hypokalemia); other effects (splenic infarction, thromboembolism, anemia, cystitis, bone pain, edema, fever, lymphadenopathy, vascular pain). [PDR 1997; p 847] CONTRAINDICATIONS No known contraindications, however, clofazimine should be used with caution in patients who have gastrointestinal problems such as abdominal pain and diarrhea. [PDR 1997; p 847] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Iminophenazine derivative. [PDR 1997; p 846] CHEMICAL/PHYSICAL DATA Molecular Formula: C27-H22-Cl2-N4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 473.41 [USPD 1998; p. 180] CHEMICAL/PHYSICAL DATA Melting Point: 210-212 C [Merck Index 1996; p. 401] CHEMICAL/PHYSICAL DATA Elemental Comp: C68.50%, H4.68%, Cl14.98%, N11.83% [Merck Index 1996; p. 401] CHEMICAL/PHYSICAL DATA Solubility: Readily soluble in benzene, soluble in chloroform, poorly soluble in acetone and in ethyl acetate, sparingly soluble in methanol and ethanel, and virtually insoluble in water. [PDR 1997; p 846] CHEMICAL/PHYSICAL DATA Stability: The commercially available capsules have an expiration date of 5 years following the date of manufacture. [AHFS Drug Information 1997; p 640] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Reddish-brown powder. [PDR 1997; p 846] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (50 mg). [PDR 1997; p 847] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 846] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store bleow 30 C (86 F). Protect from moisture. Dispense in tight container. [PDR 1997; p 847] MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (888)669-6682 REFERENCES AIDS/96701170. Cheng B. Advances in prevention and treatment of MAC. PI Perspect. 1995 Dec;(no. 17):11. ICA11/96922552. Singer J, Thorne A, Raboud JM, Fanning M, Toma E, Turgeon F, Duperval R, Schlech WF, Cameron DW, Smail FM, Lemieux C, Senay H, Mackie ID, Mcfadden DK, Williams KE, Thompson GW, Walmsley SL, Shafran S. The canadian randomized open-label trial of combination therapy for MAC bacteremia: quality of life outcomes. Int Conf AIDS. 1996 Jul 7-12;11(1):325 (abstract no.Tu.B.2350). AIDS/96920606. Benson CA. MAC: pathogenesis and treatment. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;166. AIDS/96920603. Chaisson RE, Keiser P, Pierce M, Fessel WJ, Ruskin J, Lahart C, Meek K. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;164. AIDS/96920206. Dube M, Sattler F, Torriani F, See D, Havlir D, Kemper C, Dezfuli M, Bozzette S, Bartok A, Leedom J, Tilles J, McCutchan J. Prevention of relapse of MAC bacteremia in AIDS: a randomized study of clarithromycin plus clofazimine, with or without ethambutol. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;91. AIDS/96700801. Ferreira T. Disseminated MAC: current treatment strategies. STEP Perspect. 1995 Summer;7(2):15-6. AIDS/95920146. Maggio C, Irizarry A, Padilla M, Dickinson G. Limited survival of patients with AIDS-associated disseminated Mycobacterium avium complex (DMAC) treated with 3 drug regimen. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan29-Feb 2;75. AIDS/95920145. Wynne B, Sullam P, Olliaro P, Morelli P, Pirotta N, Schoenfelder J, Sassella D. Worldwide studies suggest that rifabutin regimens are safe and effective for the treatment of Mycobacterium avium complex (MAC) in AIDS. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;75. AIDS/95920040. Parent D, Ellner J, Hafner R, Williams M, Jacobs P, Hojczyk P. A phase I/II trial of Rifampin (RIF), Ciprofloxach (CIPRO), Clofazimine (CLOF), Ethambutol (ETH), +/Amikacin (AK) in the treatment (RX) of Disseminated Mycobacterium avium (MA) infection in HIV-infection individuals (PTS). Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;56. MED/95268881. Kissinger P, Clark R, Morse A, Brandon W. Comparison of multiple drug therapy regimens for HIV-related disseminated Mycobacterium avium complex disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Jun; 9(2):133-7. ENTRY MONTH 199104 LAST REVISION DATE 20000801 280 UNIQUE IDENTIFIER DRG-0066 NAME OF SUBSTANCE Ditiocarb sodium [USPD 1998; p. 249] REGISTRY NUMBER 148-18-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Diethylcarbamodithioic acid sodium salt [Merck Index 1996; p 572] PROTOCOL ID NUMBERS Complete NIAID ACTG 166 PROTOCOL ID NUMBERS No longer recruiting FDA 010A PHARMACOLOGICAL ACTION MODE OF ACTION: Ditiocarb sodium (DTC) induces hepatosin production by the liver. DTC induces T-lymphocyte differentiation and enhances T-lymphocyte mediated immune functions. DTC has increased the following: T-cell numbers, the T4 number, the T4/T8 ratio and natural killer cell response. The drug is well absorbed, about 50% of an oral dose is detectable in the plasma within 20 minutes. Elimination is rapid, 60% of a dose is excreted within 3 hours. Following an IV dose the elimination half-life is about 20 minutes. [USP DI 1995; p 2974] DISEASES STUDIED/TREATED Enhancement of immune function in HIV infection in patients with ARC or AIDS. Latest findings show no beneficial immunomodulatory effects when patients are treated with ditiocarb sodium. [AmfAR Treat Dir 1993;6(3); p 24-5] CLASSIFICATION CODE Chelator [Merck Index 1996; p. 572] CLASSIFICATION CODE Immunomodulator [Merck Index 1996; p. 572] OTHER MAJOR USES Treatment of Wilson's Disease and antidote for nickel and cadmium poisoning. [Merck Index 1996; p 572] ADVERSE EFFECTS Slow intravenous infusion is well tolerated. Rapid intravenous infusion is associated with malaise, cyanosis, and dyspnea. Side effects reported include a metallic taste that subsides within a day, abdominal discomfort, fatigue, nausea, and reduced mental acuity. DTC produces an Antabuse-like reaction (nausea, vomiting and fever) when alcohol is ingested. [AmfAR Treat Dir 1993;6(3); p 24-5] CONTRAINDICATIONS Do not ingest alcohol during therapy. [USP DI 1995; p 2974] CHEMICAL/PHYSICAL DATA Molecular Formula: C5-H10-N-Na-S2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 171.26 [USPD 1998; p. 249] CHEMICAL/PHYSICAL DATA Elemental Comp: C35.07%, H5.89%, N8.18%, Na13.42%, S37.45% [Merck Index 1996; p. 572] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water; sol in ethanol, methanol, acetone. Insol in ether, benzene (trihydrate). [Merck Index 1996; p 572] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White hydrophilic powder. [USP DI 1995; p 2974] SUBSTANCE DELIVERY DATA DOSAGE FORM: Enterocoated capsules 125 mg each, IV. [AmfAR Treat Dir 1993;6(3); p 24-5; Lancet 1988 September 24; p 702-6] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous injection; oral. [AmfAR Treat Dir 1993;6(3); p 533; Lancet 1988 September 24; p 702-6] MANUFACTURERS 0000003865: Pasteur Merieux Connaught / Connaught Laboratories Route 611 / Box 187 / 1 Discovery Drive Swiftwater, PA 183700187 Contact: Bill Laps, Regulatory Affairs (570)839-6176 MANUFACTURERS 0000005240: Aventis Pasteur 1 Discovery Drive Swiftwater, PA 183700187 Contact: Dr John Zahradnik (570)839-4647 REFERENCES MED/96398111. Liu J, Shigenaga MK, Yan LJ, Mori A, Ames BN. Antioxidant activity of diethyldithiocarbamate. Free Radic Res. 1996 Jun;24(6):461-72. MED/95070030. Shenep JL, Hughes WT, Flynn PM, Roberson PK, Behm FG, Fullen GH, Kovnar SG, Guito KP, Brodkey TO. Decreased counts of blood neutrophils, monocytes, and platelets in human immunodeficiency virus-infected children and young adults treated with diethyldithiocarbamate. Antimicrob Agents Chemother. 1994 Jul;38(7):1644-6. MED/93283063. Vanham GL, Kestens L, Van Hoof J, Penne G, Colebunders R, Goilav C, Vandenbruaene M, el Habib R, Gigase P. Immunological parameters during treatment with ditiocarb (Imuthiol). AIDS. 1993 Apr;7(4):525-30. MED/93152291. Multicenter, randomized, placebo-controlled study of ditiocarb (Imuthiol) in human immunodeficiency virus infected asymptomatic and minimally symptomatic patients. AIDS Res Hum Retroviruses. 1993 Jan;9(1):83-9. ICA8/92403400. Mentzer D, Linde R, Beeg T, Funk M, Gungor T, Straube M, Ehrenforth S, Klarmann D, Kreuz W. Experience with Dithiocarb in HIV infected child. Int Conf AIDS. 1992 Jul 19-24;8(3):108 (abstract no. PuB 7358). ICA7/3216391. Pameix P, Salmi LR, Dabis F, Hessel L. Effectiveness of ditiocarb sodium in HIV-infected patients: a long term comparative study. Int Conf AIDS. 1991 Jun 16-21;7(2):222 (abstract no. W.B.2163). MED/91189640. Sunderman FW Sr. Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS. Ann Clin Lab Sci. 1991 Jan-Feb;21(1):70-81. MED/91155198. Hersh EM, Brewton G, Abrams D, Bartlett J, Galpin J, Gill P, Gorter R, Gottlieb M, Jonikas JJ, Landesman S, et al. Ditiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. A randomized, double-blind, placebo-controlled, multicenter study [see comments]. JAMA. 1991 Mar 27;265(12):1538-44. MED/90190134. Reisinger EC, Kern P, Ernst M, Bock P, Flad HD, Dietrich M. Inhibition of HIV progression by dithiocarb. Lancet. 1990 Mar 24;335(8691):679-82. ICA6/40207390. Kirstetter M, Mathis C, Felten A, Boutitie F. Multicenter double blind placebo controlled dose response study of diethyldithiocarbamate (DTC, Imuthiol) associated with zidovudine in patients with HIV infection. Int Conf AIDS. 1990 Jun 20-23;6(2);372 (abstract no. 2073). ENTRY MONTH 199104 LAST REVISION DATE 20000801 281 UNIQUE IDENTIFIER DRG-0065 NAME OF SUBSTANCE Thymopentin [USPD 1998; p. 730] REGISTRY NUMBER 69558-55-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N-(N-(N-(N2-L-Arginyl-L-lysyl)-L-alpha- aspartyl) -L-valyl)-L-tyrosine [Merck Index 1996; p 1605] PROTOCOL ID NUMBERS Complete FDA 015I PROTOCOL ID NUMBERS No longer recruiting FDA 015A PROTOCOL ID NUMBERS No longer recruiting FDA 015B PROTOCOL ID NUMBERS No longer recruiting FDA 015C PROTOCOL ID NUMBERS No longer recruiting FDA 015D PROTOCOL ID NUMBERS No longer recruiting FDA 015E PROTOCOL ID NUMBERS No longer recruiting FDA 015H PHARMACOLOGICAL ACTION MODE OF ACTION: In vitro, TP-5 regulates the function of peripheral T cells, acting via a cyclic GMP-linked cell surface receptor and enhances T-cell functions by increasing lymphokine production. The mechanism of action in HIV disease is unclear. It has been reported that thymopentin had no effect on HIV replication in vitro. Thymopentin is a thymic hormone analog corresponding to residues 32-36 of thymopoietin, which exhibits the full biological activity of the natural hormone. These activities include selective induction of T-cell maturation from prothymocytes and inhibition of B-cell differentiation. The hormone is a factor causing impaired neuromuscular transmission in myasthenia gravis. [AmfAR Treat Dir 1997;8(3); p 66; Merck Index 1996; p 1605] DISEASES STUDIED/TREATED Stimulation of immune function in HIV patients. [AmfAR Treat Dir 1997;8(3); p 66] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Treatment of rheumatoid arthritis. [Ann N Y Acad Sci 1992 May 4;651; p 564-9; Arzneimittelforschung 1994;44(10); p 1145-9] ADVERSE EFFECTS Adverse effects include respiratory congestion. [AmfAR Treat Dir 1997;8(3); p 66; Meyler's Side Effects of Drugs 1989 11th ed; p 796] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Thymopentin (TP-5) is a biologically active synthetic pentapeptide that corresponds to the active site of the thymic hormone, thymopoietin. [AmfAR Treat Dir 1997;8(3); p 66] CHEMICAL/PHYSICAL DATA Molecular Formula: C30-H49-N9-O9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 679.78 [USPD 1998; p. 730] CHEMICAL/PHYSICAL DATA Elemental Comp: C53.01%, H7.27%, N18.54%, O21.18% [Merck Index 1996; p. 1605] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: 015A-E ] MANUFACTURERS 0000001145: Immunobiology Research Institute Route 22 East / PO Box 999 Annandale, NJ 088010999 Contact: Linda Meyerson (908)730-1750 REFERENCES MED/96435817. Merigan TC, Hirsch RL, Fisher AC, Meyerson LA, Goldstein G, Winters MA. The prognostic significance of serum viral load, codon 215 reverse transcriptase mutation and CD4+ T cells on progression of HIV disease in a double-blind study of thymopentin. AIDS. 1996 Feb;10(2):159-65. MED/95162795. Goldstein G, Conant MA, Beall G, Grossman HA, Galpin JE, Blick G, Calabrese LH, Hirsch RL, Fisher A, Stampone P, et al. Safety and efficacy of thymopentin in zidovudine (AZT)-treated asymptomatic HIV-infected subjects with 200-500 CD4 cells/mm3: a double-blind placebo-controlled trial. J Acquir Immne Defic Syndr Hum Retrovirol. 1995 Mar 1;8(3):279-88. AIDS/95920544. Goldstein G, Hirsch RL, Meyerson L, Beall G, Blick G, Calabrese L, Conant MA, Galpin J, Grossman H, Fisher A. Open label thymopentin treatment reduces disease progression in asymptomatic HIV subjects previously on double-blind placebo. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:150. MED/95255685. Biselli R, Fagiolo U, Nisini R, Paganelli R, D'Offizi G, Ferrara R, Bertollo L, D'Amelio R. Humoral response to influenza hemagglutinin: oligoclonal spectrotype and failure of the thymopentin as immunoadjuvant. Gerontology. 1995;41(1):3-10. AIDS/95920757. Goldstein G, Fisher A, Hirsch R, Hwang CC, Meyerson L. Thymopentin treatment reduces disease progression in asymptomatic HIV infected subjects. Program Abst Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:62. ICA9/93335762. Goldstein G, Conant MA, Beall G, Grossman H, Galpin J, Hirsch RL. Thymopentin with zidovudine (AZT) reduces disease progression in asymptomatic HIV infected patients. Int Conf AIDS. 1993 Jun 6-11;9(1):492 (abstract no. PO-B28-2144). MED/93112308. Conant MA, Calabrese LH, Thompson SE, Poiesz BJ, Rasheed S, Hirsch RL, Meyerson LA, Kremer AB, Wang CC, Goldstein G. Maintenance of CD4+ cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebo-controlled study. AIDS. 1992 Nov;6(11):1335-9. ICA7/3213091. Barbarini G, Poma G, Zanaboni D, Capelli D, Comolli G, Campisi D, Chiesa A. Therapy of HIV infection with thymostimulin and zidovudine. Int Conf AIDS. 1991 Jun 16-21;7(2):214 (abstract no. W.B.2130). MED/92116115. Cognazzo A, Seliak D, Fruttero A. Effect of thymopentin on peripheral blood T-lymphocytes subsets and on the clinical course of the disease in patients affected by multiple sclerosis. Riv Neurol. 1991 May-Jun;61(3):110-5. ICA6/30048590. Conant M, Goldstein G, Hirsch RL, Meyerson LA, Kremer AB. Twenty-four week double-blind evaluation of thymopentin treatment on disease progression in HIV infected patients. Int Conf AIDS. 1990 Jun 20-23;6(2):207 (abstract no. S.B.485). ENTRY MONTH 199104 LAST REVISION DATE 20000801 282 UNIQUE IDENTIFIER DRG-0064 NAME OF SUBSTANCE Nystatin [USPD 1998; p. 523] REGISTRY NUMBER 1400-61-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Nystatin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Mycostatin [USP DI 2000; p. 2288] SYNONYMS Nilstat [USP DI 2000; p. 2286] SYNONYMS Nyotran [Protocol ID: 103A-C ] SYNONYMS Nystex [Facts and Comparisons p. 1615] PROTOCOL ID NUMBERS Complete FDA 103A PROTOCOL ID NUMBERS No longer recruiting FDA 012Q PROTOCOL ID NUMBERS No longer recruiting FDA 026A PROTOCOL ID NUMBERS No longer recruiting FDA 026B PROTOCOL ID NUMBERS No longer recruiting FDA 103B PROTOCOL ID NUMBERS No longer recruiting FDA 103C PHARMACOLOGICAL ACTION MODE OF ACTION: Nystatin is both fungistatic and fungicidal in vitro against a wide variety of yeast and yeast-like fungi. Candida albicans exhibits no significant resistance to nystatin in vitro on repeated subculture in increasing levels of nystatin; other candida species become quite resistant. Nystatin acts by binding to sterols in cell membranes of susceptible fungi with resultant changes in cell membrane permeability allowing leakage of intracellular components. Nystatin exhibits no activity against bacteria, protozoa, trichomonads or viruses. Gastrointestinal absorption of nystatin is insignificant. Most orally administered nystatin is passed unchanged in the stool. Mean nystatin concentrations in excess of those required in vitro to inhibit growth of clinically significant candida persisted in saliva for 2 hours after oral dissolution of 2 nystatin pastilles (400,000 units). [PDR 1997; p 713] DISEASES STUDIED/TREATED Treatment of HIV-related candidiasis. [AmfAR Treat Dir 1997;8(3); p 75] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 2285] OTHER MAJOR USES Nystatin is used topically for the treatment of cutaneous, mucocutaneous, and oropharyngeal infections caused by C. albicans (monilia), such as oral thrush, perleche, intertriginous candidiasis, paronychia, vulvovaginal candidiasis, and diaper rash. Nystatin creams and ointments are commercially available in combination with a corticosteroid (i.e., trimcinolone acetonide) for the treatment of cutaneous candidiasis. [AHFS Drug Information 1997; p 2700] ADVERSE EFFECTS Adverse reactions to topically applied nystatin are very infrequent, even during prolonged use. Irritation has occurred rarely. Hypersensitivity reactions to nystatin have been reported only rarely; however, preservatives (e.g., ethylenediamine, parabens, thimerosal) in some of the formulations are associated with a high incidence of contact dermatitis. Adverse effects also occur infrequently with oral nystatin therapy. Mild and transitory nausea, vomiting, gastrointestinal distress, and diarrhea have occured; high oral doses (e.g., greater than 5 million units daily) are most likely to produce these adverse gastrointestinal effects. Hypersensitivity reactions have been reported very rarely. [AHFS Drug Information 1997; p 2700, 104] CONTRAINDICATIONS Contraindicated in patients showing hypersensitivity to this drug or any ingredient in the respective formulation. [AHFS Drug Information 1997; p 2701] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Nystatin is an amphoteric polyene macrolide, antifungal antibiotic complex containing 3 biologically active components, A1, A2, and A3. Nystatin is produced by Streptomyces noursei, S. aureus and other Streptomyces species. [Merck Index 1996; p 1158] CHEMICAL/PHYSICAL DATA Molecular Formula: C47-H75-N-O17 (Nystatin A1) [Merck Index 1996; p. 1158] CHEMICAL/PHYSICAL DATA Solubility: Solubility (mg/ml at about 28 C): Water, 4.0; methanol, 11.2; ethanol, 1.2; carbon tetrachloride, 1.23; chloroform, 0.48; benzene, 0.28; ethylene glycol, 8.75. [Merck Index 1996; p 1158] CHEMICAL/PHYSICAL DATA Stability: Solutions and aqueous suspensions begin to lose activity soon after preparation; aqueous suspensions are stable for 10 minutes on heating to 100 C at pH 7.0; also stable in moderately alkaline media, but labile at pH 9 and pH 2; heat, light, and oxygen accelerate decomposition. [Merck Index 1996; p 1158] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Hygroscopic, yellow to light tan powder with a cereal-like odor. [AHFS Drug Information 1997; p 2699] SUBSTANCE DELIVERY DATA DOSAGE FORM: Topical cream, ointment, or powder (100,000 units/g); vaginal tablet (100,000 units); oral suspension (100,000 units/ml); oral tablet (500,000 units); oral lozenge (200,000 units); oral solutions for suspension (50, 150, 500 million units; and 1, 2, 5 billion units). [AHFS Drug Information 1997; p 2701-2] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: May be applied topically as cream, ointment, powder; vaginal tablet; or oral lozenge, suspension, or tablets. [AHFS Drug Information 1997; p 2701-2] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Topical cream and ointment should be stored at 15-30 C and protected from freezing; vaginal tablets should be stored at 2-15 C; lozenge and powder should be stored at 2-8 C in tight, light-resistant containers; oral suspensions should be stored at room temperature in tight, light-resistant containers, and protected from freezing. [AHFS Drug Information 1997; p 2699] MANUFACTURERS 0000001042: Argus Pharmaceuticals Inc 8707 Technology Forest Place The Woodlands, TX 773811191 Contact: Dr Rafael Correa Coronas (713)367-1666 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000001183: Paddock Laboratories Inc 3940 Quebec Avenue North Minneapolis, MN 55427 Contact: Martin Erikson (612)546-4676 MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Dr Amy Baim (914)732-2147 MANUFACTURERS 0000001042: Argus Pharmaceuticals Inc 8707 Technology Forest Place The Woodlands, TX 773811191 Contact: Dr John Riefler (914)732-2035 MANUFACTURERS 0000005222: Savage Laboratories 60 Baylis Road Melville, NY 11747 Contact: Unspecified (800)934-5556 REFERENCES MED/96335108. MacPhail LA, Hilton JF, Dodd Cl, Greenspan D. Prophylaxis with nystatin pastilles for HIV-associated oral candidiasis. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Aug;12(5):470-6. MED/96008522. Anonymous. Drugs for AIDS and associated infections. Med Lett Drug Ther. 1995 Oct;37(959):87-94. MED/95363615. Flynn PM, Cunningham CK, Kerkering T, San Jorge AR, Peters VB, Pitel PA, Harris J, Gilbert G, Castagnaro L, Robinson P. Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. The Multicenter Fluconazole Study Group. J Pediatr. 1995 Aug;127(2):322-8. MED/96045019. Zakrzewska JM, Aly Z, Speight PM. Oral hairy leukoplakia in a HIV-negative asthmatic patient on systemic steroids. J Oral Pathol Med. 1995 Jul;24(6):282-4. ICA10/94371192. Lloveras S, Macias JR, Masini R, Franchi M, Rodriguez Rios E, Navarro L. Vaginal candidiasis in females HIV+/AIDS, local therapy with nystatin. Int Conf AIDS. 1994 Aug 7-12;10(2):144 (abstract no. PB0590). MED/94358249. Greenspan D. Treatment of oropharyngeal candidiasis in HIV-positive patients. J Am Acad Dermatol. 1994 Sep;31(3 Pt 2):S51-5. MED/94227316. Grasela TH, Goodwin SD, Pasko MT, Walawander CA, Raebel MA. Use of antifungal therapy in hospitalized patients. I. Results prior to the marketing of fluconazole. Ann Pharmacother. 1994 Feb;28(2):252-60. ICA9/93335697. Rios A, Brewton G, Crofoot G, Quesada J, Lenk R, Lopez-Berenstein G. A phase I-II clinical study of Nystatin-LF IV in patients with HIV infections. Int Conf AIDS. 1993 Jun 6-11;9(1):483 (abstract no. PO-B26-2089). ICA9/93335386. Heinic GS, Greenspan D, MacPhail LA, Dodd CL, Beck C, Greenspan JS. Fluconazole-resistant Candida in eight HIV-seropositive patients. Int Conf AIDS. 1993 Jun 6-11;9(1):436 (abstract no. PO-B18-1808). MED/93294379. Rios A, Rosenblum M, Crofoot G, Lenk RP, Lopez-Berenstein G. Pharmacokinetics of liposomal nystatin in patients with human immunodeficiency virus infection [letter]. J Infect Dis. 1993 Jul;168(1):253-4. ENTRY MONTH 199104 LAST REVISION DATE 20001107 283 UNIQUE IDENTIFIER DRG-0063 NAME OF SUBSTANCE Megestrol acetate [USPD 1998; p. 447] REGISTRY NUMBER 595-33-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dion- e acetate [Merck Index 1996; p 989] SYNONYMS Megace [USP DI 2000; p. 2576] PROTOCOL ID NUMBERS Complete NIAID ACTG 313 PROTOCOL ID NUMBERS No longer recruiting FDA 025A PROTOCOL ID NUMBERS No longer recruiting FDA 025B PROTOCOL ID NUMBERS No longer recruiting FDA 025C PROTOCOL ID NUMBERS No longer recruiting FDA 266A PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 004 PHARMACOLOGICAL ACTION MODE OF ACTION: Megestrol acetate shares the actions of the progestins: induction of secretory changes in the endometrium, increase in basal body temperature, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen. In animals, the drug suppresses ovulation and produces antigonadotrophic, antiuterotrophic and antiandrogenic/antimyotrophic effects. It has slight glucocorticoid activity but no estrogenic, androgenic or anabolic activities. The exact mechanism of its antineoplastic action has not been determined. It has been suggested that such action may result from suppression of luteinizing hormone by inhibition of pituitary function. The mechanism for megestrol-induced weight gain has not been clearly established, but the activity may be related to the drug's appetite stimulant or metabolic effects rather than its glucocorticoid-like effects or the production of edema. It has been suggested that megestrol and/or its metabolites may, either directly or indirectly, stimulate appetite resulting in weight gain or may alter metabolic pathways via interference with the production or action of mediators such as cachetin (a hormone that inhibits adipocyte lipogenic enzymes). The drug is well absorbed from the GI tract; peak plasma concentrations of the drug and its metabolite were obtained in 1-5 hours. Following daily, single 800mg doses of megestrol acetate to cachetic AIDS patients, steady-state peak plasma concentrations on day 21 occurred 5 hours after administration and averaged 753 ng/ml. The drug is completely metabolized in the liver to free steroids and glucuronides of steroidal metabolites. The major route of elimination appears to be urinary excretion. [AHFS Drug Information 1997; p 820] DISEASES STUDIED/TREATED FDA approved 9/10/93 for treatment of anorexia, cachexia, and unexplained substantial weight loss in patients with AIDS. Designated an orphan drug by the FDA for this use. [AHFS Drug Information 1997; p 820] CLASSIFICATION CODE Antianorectic [USP DI 2000; p. 2566] CLASSIFICATION CODE Anticachectic [USP DI 2000; p. 2566] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 2566] OTHER MAJOR USES Palliative management of endometrial or breast carcinoma. Megestrol acetate has been used alone or in combination with estrogens for ovulation control, in the prevention of conception, and in the treatment of prostatic hypertrophy, endometriosis and endometrial hyperplasia (not currently in FDA-approved labeling). [AHFS Drug Information 1997; p 820-1] SUBSTANCE INTERACTIONS Possible interactions of megestrol acetate with concomitant medications have not been investigated. [PDR 1997; p 709] ADVERSE EFFECTS Megestrol acetate is usually well tolerated. Adverse reactions include the following, gastrointestinal: diarrhea, flatulence, nausea, vomiting, constipation, dyspepsia, dry mouth, increased salivation, and oral candidiasis; genitourinary: impotence, decreased libido, urinary frequency, urinary incontinence, urinary tract infection, vaginal bleeding and discharge (including breakthrough bleeding); cardiovascular: hypertension or mild elevation in blood pressure in patients receiving high dose (480-1600 mg daily) megestrol therapy, cardiomyopathy, palpitation, chest pain, chest pressure, edema, peripheral edema, and congestive heart failure; respiratory: pneumonia, dyspnea, cough, pharyngitis, lung disorder, and hyperpnea; nervous system: insomnia, headache, asthenia, paresthesia, confusion, seizures, depression, neuropathy, hypesthesia, and abnormal thinking. Other adverse effects include fever, anemia, leukopenia, hepatomegaly, pain (including abdominal pain), infections, candidiasis, herpes, pruritus, vesiculobullous rash, sweating, skin disorders, amblyopia, increase in LDH, sarcoma, Carpal tunnel syndrome, thromboembolic phenomena (e.g., deep-vein thrombophlebitis, pulmonary embolism), gynecomastia, tumor flare (with or without hypercalcemia), hyperglycemia, rash, feeling of coldness, alopecia, and diabetes mellitus in at least one patient. [AHFS Drug Information 1997; p 821] CONTRAINDICATIONS Contraindicated as a diagnostic test for pregnancy. Should not be used during pregnancy. [PDR 1997; p 709-10] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic derivative of the naturally occurring steroid hormone progesterone. [PDR 1997; p 708] CHEMICAL/PHYSICAL DATA Molecular Formula: C24-H32-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 384.52 [USPD 1998; p. 447] CHEMICAL/PHYSICAL DATA Melting Point: 214-216 C [Merck Index 1996; p. 990] CHEMICAL/PHYSICAL DATA Elemental Comp: C74.97%, H8.39%, O16.64% [Merck Index 1996; p. 989] CHEMICAL/PHYSICAL DATA Solubility: (37 C) water, 2 mcg/ml; plasma, 24 mcg/ml. [Merck Index 1996; p 990] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline solid. [PDR 1997; p 708] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral suspension (lemon-lime flavored, 40 mg/ml, micronized megestrol acetate); tables (20, and 40 mg). [PDR 1997; p 710-1] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 708] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Oral suspension should be stored at or below 25 C, protected from light, and dispensed in a tight container. Tablets should be stored at room temperature, and protected from temperature above 40 C (104 F). [PDR 1997; p 710-1] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/97048282. Gonzalez Del Valle L, Herrero Ambrosio A, Martinez Hernandez P, Garcia Diaz B, Jimenez Caballero E. Hyperglycemia induced by megestrol acetate in a patient with AIDS. Ann Pharmaother. 1996 Oct;30(10):1113-4. ICA11/96923186. Clark RA, Bessinger R, Kissinger P, Thomas C. Experience with megestrol-acetate for treatment of HIV-related cachexia in women. Int Conf AIDS. 1996 Jul 7-12;11(2):21 (abstract no.We.B.184). ICA11/96922451. Johnston S, Clotet B, Gatell JM, Podzamczer D, Gimenez-Arnau JM, Bestit I, Gel S, Diaz B, Virgili N, Giro M. Int Conf AIDS. 1996 Jul 7-12;11(1):308 (abstract no.Tu.B.2247). AIDS/96920386. Timpone JG, Wright D, Li N, Egorin MJ, Enama ME, Mayers J, Galetto G. The safety and pharmacokinetics of single agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV-wasting syndrome. 3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;125. MED/96185937. Pimentel G, Santos E, Arastu M, Cowan JA. Hyperglycemia in an AIDS patient taking megestrol. Hosp Prat (Off Ed). 1996 Apr 15;31(4):27-8. MED/95259939. Leinung MC, Liporace R, Miller CH. Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med. 1995 Jun 1;122(11):843-5. MED/95060581. Von Roenn JH. Randomized trials of megestrol acetate for AIDS-associated anorexia and cachexia. Oncology. 1994 Oct;51 Suppl 1:19-24. MED/94330644. Oster MH, Enders SR, Samuels SJ, Cone LA, Hooton TM, Browder HP, Flynn NM. Megestrol acetate in patients with AIDS and cachexia. Ann Intern Med. 1994 Sep 15;121(6):400-8. MED/95061100. Brady MT, Koranyi KI, Hunkler JA. Megestrol acetate for treatment of anorexia associated with human immunodeficiency virus infection in children. Pediatr Infect Dis J. 1994 Aug;13(8):754-6. TOXBIB/92/074711. Henry K, Rathgaber S, Sullivan C, McCabe K. Diabetes mellitus induced by megestrol acetate in a patient with AIDS and cachexia[see comments]. Ann Intern Med; VOL 116, ISS 1, 1992, P53-4. ENTRY MONTH 199104 LAST REVISION DATE 20000801 284 UNIQUE IDENTIFIER DRG-0062 NAME OF SUBSTANCE Epoetin alfa [USPD 1998; p. 277] REGISTRY NUMBER 113427-24-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-165-Erythropoietin (human clone lambda HEPOFL13 protein moiety), glycoform alpha [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Epogen [USP DI 2000; p. 1412] SYNONYMS Procrit [USP DI 2000; p. 1412] PROTOCOL ID NUMBERS No longer recruiting FDA 004A PROTOCOL ID NUMBERS No longer recruiting FDA 004B PROTOCOL ID NUMBERS No longer recruiting FDA 004C PROTOCOL ID NUMBERS No longer recruiting FDA 004D PROTOCOL ID NUMBERS No longer recruiting FDA 004E PROTOCOL ID NUMBERS No longer recruiting FDA 004F PROTOCOL ID NUMBERS No longer recruiting FDA 004G PROTOCOL ID NUMBERS No longer recruiting FDA 061A PROTOCOL ID NUMBERS No longer recruiting FDA 077A PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-01 PHARMACOLOGICAL ACTION MODE OF ACTION: Endogenous human erythropoietin, a growth factor, is a glycosylated protein hormone that appears to be secreted principally by renal peritubular interstitial cells. Secretion of the hormone occurs principally in response to reduction in arterial or venous oxygen tension and tissue oxygenation in the kidneys. Erythropoietin induces the production of erthrocytes principally by stimulating the proliferation and differentiation of committed erythroid precursors (i.e., burst-forming units-erythroid and colony-forming units-erythroid). In patients with chronic renal failure (CRF), production of erythropoietin is impaired and this deficiency is the primary cause of their anemia. Recombinant human erythropoietin has been shown to stimulate erythropoiesis in anemic patients with CRF. Because of the length of time required for erythropoiesis-several days for erythroid progenitors to mature and be released into circulation-a clinically significant increase in hematocrit is usually not observed in less than 2 weeks. Responsiveness to erythropoietin in HIV-infected patients (receiving zidovudine) is dependent upon the endogenous serum erythropoietin level prior to treatment. Patients with levels of less than or equal to 500 mU/mL (with zidovudine of less than or equal to 4,200 mg/week) may respond to erythropoietin therapy; patients with higher levels do not seem to respond. [AHFS Drug Information 1997; p 1125; PDR 1997; p 1896] DISEASES STUDIED/TREATED Approved for the treatment of anemia in both AZT-treated HIV-infected subjects and chronic renal-failure patients. It is only indicated in patients with endogenous erythropoietin levels less than 500 mU/ml. [AmfAR Treat Dir 1996;8(2); p 77] CLASSIFICATION CODE Antianemic [USP DI 2000; p. 1408] OTHER MAJOR USES Treatment of anemia of chronic renal failure patients, including patients on dialysis (end stage renal disease) and patients not on dialysis. Indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. [PDR 1997; p 1896] SUBSTANCE INTERACTIONS Systematic drug interaction studies have not been performed. However, erythropoietin clinical trials with other drugs or biologicals have shown no evidence of clinically important interactions. Androgens have been used as adjuncts to erythropoietin therapy in a few patients to decrease the total amount of erythropoietin needed for ameliorate anemia. However, controlled studies are needed to establish potential benefits and risks of such combination therapies. Probenecid has been shown to inhibit the renal tubular secretion of endogenous erythropoietin in animals. While relevance of such an interaction to humans is not known, it should be considered when these two substances are given concomitantly. [AHFS Drug Information 1997; p 1134] ADVERSE EFFECTS Erythropoietin is generally well tolerated. Adverse events reported in clinical trials with erythropoietin in zidovudine-treated HIV-infected patients were consistent with progression of the HIV infection. Such events were not very different from those in placebo-treated patients. [PDR 1997; p 1898-9] CONTRAINDICATIONS Erythropoietin is contraindicated in patients with uncontrolled hypertension. The manufacturers state that the drug is also contraindicated in patients with known sensitivity to mammalian cell-derived products and known hypersensitivity to human albumin. To prevent potential exacerbation of thrombocytosis, some clinicians suggest that erythropoietin therapy be used with caution in patients with high baseline platelet count (e.g., exceeding 500,000/cubic mm). Erythropoietin therapy should be initiated cautiously in patients with documented unstable angina or a history of recent myocardial infarction. Safety and efficacy of erythropoietin have not been established in patients with preexisting seizure disorders. Since erythropoietin is a growth factor, it should be used with caution in patients with a known neoplasm or leukemic disease. However, in vitro tests indicate that the risks of tumor growth enhancement in patients may be minimal for nonmyeloid cell neoplasms. Erythropoietin should be used with caution in patients with a history of porphyria. [AHFS Drug Information 1997; p 1132-3] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Erythropoietin is a glycoprotein produced in the kidney that stimulates red blood cell production and the division and differentiation of committed erythroid progenitors of the bone marrow. Epoetin alfa is the proper name for recombinant human erythropoietin, a 165 amino acid glycoprotein that has the same effect as natural erythropoietin. It is produced by Chinese hamster ovary into which the human erythropoietin gene has been inserted by recombinant DNA technology. Urinary human erythropoietin occurs as a mixture of two forms, alpha and beta. Each form has the same functional polypeptide portion and produces the same in vivo response. The distinguishing characteristic between the two forms is the overall carbohydrate composition; the alpha form appears to have the greater percentage of N-acetylneuraminic acid in its carbohydrate portion. [AHFS Drug Information 1997; p 1124] CHEMICAL/PHYSICAL DATA Molecular Formula: C809-H1301-N229-O240-S5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: approx. 18,200 [USPD 1998; p. 277] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Sterile, coloress liquid. [PDR 1997; p 1896] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 1 ml, single-dose, preservative-free solutions (2,000, 3,000, 4,000, and 10,000 units/ml), or 2 ml, multidose, preserved solutions (10,000 units/ml). [PDR 1997; p 1900] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous injection; subcutaneous injection. [PDR 1997; p 1896] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2 to 8 C (36 to 46 F). Do not freeze or shake. [PDR 1997; p 1900] MANUFACTURERS 0000001008: Ortho Pharmaceutical Corp Route 202 / PO Box 300 Raritan, NJ 088690602 Contact: Mrs Dorothy Thompson (908)704-5150 MANUFACTURERS 0000003330: Amgen Inc 1840 Dehavilland Dr Thousand Oaks, CA 913201799 Contact: Professional Services (800)772-6436 MANUFACTURERS 0000001008: Ortho Pharmaceutical Corp Route 202 / PO Box 300 Raritan, NJ 088690602 Contact: Unspecified (800)772-6436 REFERENCES MED/96426463. Caselli D, Maccarbruni A, Zuccotti GV, Riva E, Fundaro C, Portelli V, Galli L, Zizzadoro P, Gabiano C, Forni GL. Recombinant erythropoietin for treatment of anaemia in HIV-infected children [letter]. AIDS. 1996 Jul;10(8):929-31. MED/96432046. Perrella O, Finelli E, Perrella A, Tartaglia G, Scognamiglio P, Scalera G. Combined therapy with zidovudine, recombinant granulocyte colony stimulating factors and erythropoietin in asymptomatic HIV patients. J Chemother. 1996 Feb;8(1):63-6. MED/96371978. Hermans P. Haematopoietic growth factors as supportive therapy in HIV-infected patients. AIDS. 1995 Dec; 9 suppl 2:S9-S14. MED/95289405. Shrivastava D, Rao TK, Sinert R, Khurana E, Lundin AP, Friedman EA. The efficacy of erythropoietin in human immunodeficiency virus-infected end-stage renal disease patients treated by maintenance hemodialysis. Am J Kidney Dis. 1995 Jun;25(6):904-9. MED/95371946. Krantz SB. Erythropoietin and the anaemia of chronic disease. Nephrol Dial Transplant. 1995;10 suppl 2:10-7. MED/96131197. Kuehl AK, Noormohamed SE. Recombinant erythropoietin for zidovudine-induced anemia in AIDS. Ann Pharmacother. 1995 Jul-Aug;29(7-8):778-9. ICDB/94601587. Bukowski R, Glaspy J, Steinberg D, Taylor CW, Vadhan-Raj S, Sarokhan B, Lonczak L. Phase IV clinical evaluation of recombinant human erythropoietin (r-HuEPO) in anemic cancer patients receiving chemotherapy (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol. 1994;13:A1594. ICA10/94369786. Caselli D, Maccabruni A, Fundaro C, Portelli E, De Santis U, Gabiano C, Forni GL. Human recombinant erythropoietin (r-Hu EPO) for treatment of anemia in HIV-infected children. Int Conf AIDS. 1994 Aug 7-12;10(1):224 (abstract no. PBO324). MED/94180309. Bozzette SA, Parker R, Hay J. A cost analysis of approved antiretroviral strategies in persons with advanced human immunodeficiency virus disease and zidovudine intolerance [published erratum appears in J Acquir Immune Defic Syndr 1994 Nov;7(11):1212]. J Acquir Immune Defic Syndr. 1994 Apr;7(4):355-62. MED/94082388. Goodnough LT, Anderson KC, Kurtz S, Lane TA, Pisciotto PT, Sayers MH, Silberstein LE. Indications and guidelines for the use of hematopoietic growth factors. Transfusion. 1993 Nov-Dec;33(11):944-59. ENTRY MONTH 199104 LAST REVISION DATE 20001107 285 UNIQUE IDENTIFIER DRG-0061 NAME OF SUBSTANCE Spiramycin [USPD 1998; p. 681] REGISTRY NUMBER 8025-81-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Leucomycin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS Complete NIAID ACTG 113 PROTOCOL ID NUMBERS No longer recruiting FDA 011A PHARMACOLOGICAL ACTION MODE OF ACTION: Spiramycin is a macrolide antibiotic with an antibacterial spectrum similar to that of erythromycin and clindamycin. It is bacteriostatic at serum concentrations but may be bactericidal at achievable tissue concentrations. Its mechanism of action is not clear, but it is known to act on the 50s subunit of bacterial ribosomes and to interfere with translocation. Absorption from the GI tract is irregular; approximately 20-50% of an oral dose is absorbed. Peak plasma levels are achieved within 2-4 hours of an oral dose. Peak plasma concentrations after 1 g oral dose or 1.5 million unit IV infusion are ca. 1 mcg/ml and 1.5-3.0 mcg/ml. It is widely distributed in the body and has a short distribution half-life (10.2+/-3.72 minutes) when administered orally. The drug is excreted primarily in the bile. [USP DI 1995; p 2997] DISEASES STUDIED/TREATED Treatment of chronic diarrhea due to cryptosporidium in patients with HIV infection. Per 4/2/93 communication - spiramycin is not helpful or available for treatment of HIV cryptosporidiosis. [MMWR 1984 March 9; 9;33(9):117-9; Rhone-Poulenc Rorer Pharmaceuticals ] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2819] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2819] OTHER MAJOR USES Treatment of bacterial infections. Alternative drug for treatment of toxoplasmosis. Often given in combination with pyrimethamine-sulfamethoxazole. Spiramycin appears to be useful in treating acute Toxoplasma gondii infections during pregnancy as congenital infections (IND use in US). [Current Medical Diagnosis and Treatment 1986; p 925; Conn's Current Therapy 1995; p 131] SUBSTANCE INTERACTIONS May increase serum theophylline concentration and occasionally cause symptoms of toxicity. Cross resistance between microorganism resistant to erythromycin and carbomycin. Can increase the effects of oral anticoagulant and of digoxin. Spiramycin and metronidazole in combination can be efficacious in the treatment of those patients with AIDS and diarrhea in which cryptosporidium is identified. [Meyler's Side Effects of Drugs 1989 11th ed; p 294, 557-60] ADVERSE EFFECTS Serious side effects from spiramycin are rare. Nausea, vomiting, diarrhea and indigestion are common side effects from oral administration. Less frequent side effects (oral administration) are fatigue, epistaxis, sweating, heaviness in the chest, and a cool sensation in the mouth or pharynx. Acute colitis is experienced by 1% of the patients. IV administration is associated with paresthesias in the extremities, irritation at injection site, dyesthesia, giddiness, pain, stiffness, burning sensation and hot flashes. Long-term use of spiramycin may result in superinfection. [USP DI 1995; p 2997-8] CONTRAINDICATIONS Contraindicated with the concomitant use of ergotamine. [Meyler's Side Effects of Drugs 1989 11th ed; p 294, 557-60] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A macrolide antibiotic of the erythromycin/carbomycin type produced by Streptomyces ambofaciens from soil of Northern France. [AmfAR Treat Dir 1993;6(3); p 52] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water; soluble in most organic solvents. [Merck Index 1996; p 1496] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White or slightly yellow amorphous powder. [USP DI 1995; p 2997] SUBSTANCE DELIVERY DATA DOSAGE FORM: Available as 500 mg capsules (equivalent to 1.5 million International Units [MIU]) or injections containing 1.5 MIU per vial. [USP DI 1995; p 2998] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous, subcutaneous, oral. [Protocol ID: ACTG 113 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Vials should be stored at room temperature. [Protocol ID: ACTG 113 ] MANUFACTURERS 0000001190: Rhone - Poulenc Rorer 500 Arcola Road Collegeville, PA 19426 Contact: David Lester (610)454-5399 REFERENCES MED/96163978. Halme M, Jokipil L, Jokipil AM, Ristola M, Lahdevirta J. Toxoplasma pneumonia in a patient with AIDS [letter]. J Infect. 1995 Nov;31(3):252-3. MED/95060360. Knowles JB, Gilmore N. Discontinuation of total parenteral nutrition in a patient with acquired immunodeficiency syndrome: a Canadian perspective. Nutr Rev. 1994 Aug;52(8 Pt 1):271-4. MED/95207817. Wu KZ, Chew SK, Oh HM, Lin RV, Allen DM, Monteiro EH. Acquired immunodeficiency syndrome and Cryptosporidium infection. Singapore Med J. 1994 Aug;35(4):418-9. ICA9/93335434. Sanchez-Mejorada G, Ponce-de-Leon S, Santiago Y, Carranza D. Efficacy of combined spiramycin and metronidazole in diarrheas due to Cryptosporidium or with unidentified cause in patients with AIDS. Int Conf AIDS. 1993 Jun 6-11;9(1):443 (abstract no. PO-B19-1847). TOXBIB/93/319275. Dylewski J, Clecner B, Dubois J, St-Pierre C, Murray G, Bouchard C, Phillips R. Comparison of spiramycin and doxycycline for treatment of Chlamydia trachomatis genital infections. Antimicrob Agents Chemother. 1993 Jun;37(6):1373-4. MED/92291970. Weikel C, Lazenby A, Belitsos P, McDewitt M, Fleming HE Jr, Barbacci M. Intestinal injury associated with spiramycin therapy of Cryptosporidium infection in AIDS. J Protozool. 1991 Nov-Dec;38(6):147S. MED/91284926. Ruf B, Pohle HD. Role of clindamycin in the treatment of acute toxoplasmosis of the central nervous system. Eur J Clin Microbiol Infect Dis. 1991 Mar;10(3):183-6. MED/91254430. Garrido Davila JI, Ramirez Ronda CH. Updates on AIDS cryptosporidiosis: a review. Bol Asoc Ned P R. 1991 Feb;83(2):65-8. MED/93029764. Brites CB, Moreira Junior ED, Bina JC, Johnson Junior WD, Badaro R. Multiple drug regimen for severe diarrhea associated with Cryptosporidium in AIDS patients. Rev Soc Bras Med Trop. 1991 Apr-Jun;24(2):117. ENTRY MONTH 199104 LAST REVISION DATE 20001107 286 UNIQUE IDENTIFIER DRG-0060 NAME OF SUBSTANCE Imipramine hydrochloride [USPD 1998; p. 374] REGISTRY NUMBER 113-52-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 5H-Dibenz(b,f)azepine-5-propanamine, 10,11-dihydro-N,N-dimethyl-, monohydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Tipramine [USP DI 2000; p. 297] SYNONYMS Tofranil [USP DI 2000; p. 297] PROTOCOL ID NUMBERS Complete NIMH 87-DEP PHARMACOLOGICAL ACTION MODE OF ACTION: The mechanism of action of the tricyclic antidepressants remains undefined despite the large body of knowledge that has accumulated. Initially the tricyclic antidepressants usually block the reuptake of norepinephrine and serotonin into their respective nerve terminals within the central nervous system. They also block serotonergic, noradrenergic (alpha 1), histaminergic (H1 more than H2), and muscarenic receptors to varying degrees. These combined effects on reuptake and receptor occupation reduce the synthesis and turnover of norepinephrine and serotonin and reduce the discharge rates of the neurons of these two transmitters. Correlation of specific neurochemical actions of the tricyclic compounds with their therapeutic effects must take into consideration the one to three weeks that elapse before such effects are apparent. After prolonged administration, blockade of the neuronal reuptake of norepinephrine and serotonin continues and turnover and discharge rates gradually return to normal. A decrease in beta- and alpha2- adrenergic receptor sensitivity and in the number of 5HT2 receptors occurs in animals following long term administration of most of the antidepressants and electroconvulsive therapy. Probably no change or a slight increase occurs in alpha1-adrenergic receptor sensitivity and in the number of muscarinic receptors. All tricyclic compounds are well absorbed orally, extensively metabolized, highly protein bound in plasma and tissue, and eliminated slowly. Mean half-life for imipramine is 7.6 (4 to 17.6) hours. In studies with radiolabeled imipramine, the drug was completely absorbed from GI track. Peak plasma concentrations occurred within 1-2 hours after oral administration, and 30 minutes after IM administration. Plasma half-life ranges from 8-16 hours. Imipramine is metabolized via the same pathway as are other tricyclic antidepressants; desipramine, its N-monodemethylated metabolite, is pharmacologically active. Approx. 40% of a dose of imipramine is excreted in urine as inactive metabolites within 24 hours, and 70% within 72 hours. Small amounts are excreted in feces. Imipramine and its active metabolite, desipramine, are distributed into milk concentrations similar to those present in maternal plasma. [Drug Evaluations Annual 1992; p 273-6; PDR 1997; p 873; AHFS Drug Information 1997; p 1683] DISEASES STUDIED/TREATED Treatment of depression. [PDR 1997; p 873] CLASSIFICATION CODE Antidepressant [USP DI 2000; p. 288] CLASSIFICATION CODE Antineuralgic [USP DI 2000; p. 288] CLASSIFICATION CODE Antipanic agent [USP DI 2000; p. 288] OTHER MAJOR USES For relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. May be useful as temporary adjunctive therapy in reducing enuresis in children aged 6 and older. [PDR 1997; p 873; AHFS Drug Information 1997; p 1684] SUBSTANCE INTERACTIONS The biomedical activity of the drug metabolizing isozyme cytochrome P450 2D6 is reduced in a subset of the Caucasian population (7%-10%) making them poor metablizers. Reliable estimate of tis effect among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations to the tricyclic antidepressants. This increase may be as high as 8-fold. Certain drugs (e.g., quinidine, cimetidine) inhibit the activity of the isozyme make normal metabolizers resemble poor metabolizers. Caution should be used when imipramine is given to patients on thyroid medications or receiving methylphenidate hydrochloride. Imipramine may increase CNS depressant effects of alcohol. Concurrent administration of imipramine and electroshock therapy may increase the hazards. In patients receiving anticholinergic drugs (including antiparkinsonism agents), the atropine-like effects may become more pronounced (e.g., paralytic ileus). Avoid the concomitant use of decongestants and local anesthetics containing sympathomimetic amines (e.g., epinephrine, norepinephrine). Use caution when using imipramine with agents that lower blood pressure. Plasma concentration of imipramine may increase when given with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetin). It may decrease when given with hepatic enzyme inducers (e.g., barbiturates, phenytoin). Excessive exposure to sunlight should be avoided since there have been reports of photosensitization. [PDR 1997; p 874] ADVERSE EFFECTS May cause orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, electrocardiographic changes, precipitation of congestive heart failure, stroke, hallucinations, disorientation, anxiety, restlessness, agitation, insomnia, hypomania, numbness, tingling, paresthesias of extremities, incoordination, ataxia, tremors, seizures, tinnitus, dry mouth, blurred vision, eye pain, fainting, change in regular heartbeat, nervousness, shakiness, difficult/fast breathing, convulsions, severe drowsiness, fever, vomiting, nausea, diarrhea, trouble in sleeping, vivid dreams, sexual impairment, constipation, abdominal cramps, agranulocytosis, eosinophilia, purpura, thrombocytopenia, skin rash, breast enlargement, jaundice, and altered liver function. [PDR 1997; p 874] CONTRAINDICATIONS Contraindicated with the concomitant use of monoamine oxidase inhibiting compounds which may result in hyperpyretic crises or severe convulsive seizures, which can be serious or even fatal. Imipramine hydrochloride is also contraindicated during the acute recovery period after a myocardial infarction and in patients having a known hypersensitivity to the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind. Imipramine should be used with caution in patients who perform potentially hazardous tasks (e.g., driving or operating machinery). [PDR 1997; p 873; AHFS Drug Information 1997; p 1684] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Dibenzazepine derivative (tertiary amine) tricyclic antidepressant. Commercially available as hydrochloride or pamoate. [USP DI 1989; p 316] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H24-N2.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 316.88 [USPD 1998; p. 374] CHEMICAL/PHYSICAL DATA Melting Point: 174-175 C [Merck Index 1996; p. 845] CHEMICAL/PHYSICAL DATA Elemental Comp: C81.38%, H8.63%, N9.99% (base) [Merck Index 1996; p. 845] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water and in alcohol; soluble in acetone; slightly soluble in ether. [Merck Index 1996; p 845] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white, odorless or practically odorless crystalline powder. [AHFS Drug Information 1997; p 1683] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets, capsules, or solution for intramuscular administration. [PDR 1997; p 873, 875] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral or intramuscular administration. [PDR 1997; p 873, 875] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F) unless otherwise specified by the manufacturer; store in a tight container. [PDR 1997; p 873, 875] MANUFACTURERS 0000002862: Major Pharmaceuticals Inc 31778 Enterprise Drive Livonia, MI 48150 Contact: Dr John Miligeni (201)503-6687 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (800)642-1232 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Unspecified (888)669-6682 REFERENCES MED/97086935. Wagner GJ, Rabkin JG, Rabkin R. A comparative analysis of standard and alternative antidepressants in the treatment of human immunodeficiency virus patients. Comp Psychiatry. 1996 Nov-Dec;37(6):402-8. MED/94197253. Rabkin JG, Rabkin R, Harrison W, Wagner G. Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry. 1994 Apr;151(4):516-23. MED/94103145. Wagner GJ, Rabkin JG, Rabkin R. Sexual activity among HIV-seropositive gay men seeking treatment for depression. J Clin Psychiatry. 1993 Dec;54(12):470-5. MED/93255966. Nielsen BM, Behnke K, Arup P, Christiansen PE, et al. A comparison of fluoxetine and imipramine in the treatment of outpatients with major depressive disorder. Acta Psychiatr Scand. 1993;87(4):269-72. MED/92239495. Dening TR, Klimes I, Catalan J, Rizza CR, Peto T. HIV infection, the brain and behaviour: major psychiatric disorder without cognitive impairment before or after the episode. Int J STD AIDS. 1992 Mar-Apr;3(2):132-3. MED/91206620. Nunes EV, Quitkin FM, Brady R, Stewart JW. Imipramine treatment of methadone maintenance patients with affective disorder and illicit drug use. Am J Psychiatry. 1991 May;148(5):667-9. MED/91079125. Hintz S, Kuck J, Peterkin JJ, Volk DM, Zisook S. Depression in the context of human immunodeficiency virus infection: implications for treatment. J Clin Psychiatry. 1990 Dec;51(12):497-501. ICA6/10003290. Manning D, Jacobsberg L, Erhart S, Perry S, Frances A. The efficacy of imipramine in the treatment of HIV-related depression. Int Conf AIDS. 1990 Jun 20-23;6(1):141 (abstract no. Th.B.32). ICA6/30038990. Peterkin J, Hintz S, Kuck J, Zisook S. Depression in the context of human immunodeficiency virus infection: implications for treatment. Int Conf AIDS. 1990 Jun 20-23;6(3):183 (abstract no. S.B.389). MED/90196384. Rabkin JG, Harrison WM. Effect of imipramine on depression and immune status in a sample of men with HIV infection [see comments]. Am J Psychiatry. 1990 Apr;147(4):495-7. ENTRY MONTH 199104 LAST REVISION DATE 20001107 287 UNIQUE IDENTIFIER DRG-0059 NAME OF SUBSTANCE HIVAC-1e [J Clin Immunol 1992 Nov;12(6); p 429-39] PROTOCOL ID NUMBERS Complete FDA 063A PROTOCOL ID NUMBERS Complete NIAID AVEG 002 PROTOCOL ID NUMBERS Complete NIAID AVEG 002A PROTOCOL ID NUMBERS Complete NIAID AVEG 002B PROTOCOL ID NUMBERS Complete NIAID AVEG 008 PROTOCOL ID NUMBERS Complete NIAID AVEG 010 PHARMACOLOGICAL ACTION MODE OF ACTION: Priming with a live recombinant vector followed vy subunit boosting is a promising strategy for human immunodeficiency virus (HIV) immunization. HIVAC-1e has been shown to induce antibodies to gp160 more frequently in vaccinia-naive persons than has been reported for vaccine positive persons. HIV-1 specific Ab and LP responses appear to be more persistent in HIVAC-1e immunized persons than in persons immunized with rgp160 alone. HIVAC-1e provides a significant benefit in the magnitude of HIV-specific antibody response, but offers no enhancement in functional antibody activity. Cellular immunity is stimulated with an additional boost with soluble recombinant gp160 (VaxSyn, MicroGeneSys). HIVAC-le-primed vaccines were more likely to have antibody to V3- and CD4-binding regions of gp120 and less likely to have antibody to constant regions 2 and 3 than vaccines immunized with rgp160 alone. [Int Conf AIDS 1996 Jul 7-12;11(1); Mo9 (abstract no. MoB 0027); Int Conf AIDS 1991 Jun 16-21;7(2); (abstract no. FA 1); J Infect Dis 1994 Oct;170(4); p 782-6] DISEASES STUDIED/TREATED Prevention of AIDS. [J Clin Immunol 1992 Nov;12(6); p 429-39] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 008 ] ADVERSE EFFECTS (Human data unavailable.) None of the animals tested (mice, monkeys, and chimpanzees) developed any untoward effects due to immunization. All recombinant viruses produced localized cutaneous lesions typical of vaccinia virus. Risks are those of vaccinations: risk of accidental spread of vaccine virus infection to other parts of the body of a vaccinated person or to his or her contacts. Less common but more serious complications include abnormal skin eruptions, disorders affecting the nervous system, and other rare or less severe reactions. [Protocol ID: AVEG 002 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: HIVAC-1e vaccine is a sterile suspension of a live vaccinia v-env5NY virus in phosphate buffered saline. The v-env5NY virus is produced in human diploid cells MRC-5 at a concentration of 2 (+ or - 1) x 10-9 plaque-forming units (PFU)/ml. It was created to contain the entire coding sequence of the envelope glycoproteins of HIV-1. The vaccinia viral vector used is a derivative of the New York Board of Health strain obtained by plaque purification from a commercial preparation of smallpox vaccine using three successive plaque purifications in tissue culture cells. [Protocol ID: AVEG 002 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile, frozen suspension in capped, labeled vials containing 2 + or - 1 x 10-9 plaque-forming units (pfu)/ml. [Protocol ID: AVEG 002 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Vaccination (scarification). [Protocol ID: AVEG 002 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at < -10 C. [Protocol ID: AVEG 002 ] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 REFERENCES MED/97096294. Zhou J, Montefiori DC. Complement-activating antibodies in sera from infected individuals and vaccinated volunteers that target human immunodeficiency virus type 1 to complement receptor type 1 (CR1, CD35). Virology. 1996 Dec 1;226(1):13-21. MED/95376334. Perales MA, Schwartz DH, Fabry JA, Lieberman J. A vaccinia-gp160-based vaccine but not a gp160 protein vaccine elicits anti-gp160 cytotoxic T lymphocytes in some HIV-1 seronegative vaccines. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Sep 1;10(1):27-35. MED/94210368. Schwartz DH, Cosentino LM, Shirai A, Conover J, Daniel S, Klinman DM. Lack of correlation between the number of circulating B cells and the concentration of serum antibodies reactive with the HIV-1 envelope glycoprotein. J Acquir Immune Defic Syndr. 1994 May;7(5):447-53. MED/95016023. Graham BS, Gorse GJ, Schwartz DH, Keefer MC, McElrath MJ, Matthews TJ, Wright PF, Belshe RB, Clements ML, Dolin R, et al. Determinants of antibody response after recombinant gp160 boosting in vaccinia-naive volunteers primed with gp160-recombinant vaccinia virus. J Infect Dis. 1994 Oct;170(4):782-6. MED/93366323. McDonnell WM. Gene transfer as a new mode of vaccination: implications for HCV. Hepatology. 1993 Sep;18(3):696-8. MED/93352832. Montefiori DC, Graham BS, Zhou J, Bucco RA, Schwartz DH, Cavacini LA, Posner MR. V3-specific neutralizing antibodies in sera from HIV-1 gp160-immunized volunteers block virus fusion and act synergistically with human monoclonal antibody to the conformation-dependent CD4 binding site of gp120. NIH-NIAID AIDS Vaccine Clinical Trials Network [see comments in: J Clin Invest 1993 Aug;92(2):535]. J Clin Invest. 1993 Aug;92(2):840-7. MED/93179773. Graham BS, Matthews TJ, Belshe RB, Clements ML, Dolin R, Wright PF, Gorse GJ, Schwartz DH, Keefer MC, Bolognesi DP, et al. Augmentation of human immunodeficiency virus type 1 neutralizing antibody by priming with gp160 recombinant vaccinia and boosting with rgp160 in vaccinia-naive adults. The NIAID AIDS Vaccine Clinical Trials Network. J Infect Dis. 1993 Mar;167(3):533-7. MED/93103800. Graham BS. Clinical trials of AIDS vaccines in seronegative volunteers: vectors and combinations. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1327-8. MED/92340929. Graham BS, Belshe RB, Clements ML, Dolin R, Corey L, Wright PF, Gorse GJ, Midthun K, Keefer MC, Roberts NJ Jr, et al. Vaccination of vaccinia-naive adults with human immunodeficiency virus type 1 gp160 recombinant vaccinia virus in a blinded, controlled, randomized clinical trial. The AIDS Vaccine Clinical Trials Network. J Infect Dis. 1992 Aug;166(2):244-52. ENTRY MONTH 199104 LAST REVISION DATE 20000801 288 UNIQUE IDENTIFIER DRG-0058 NAME OF SUBSTANCE Vidarabine [USPD 1998; p. 778] REGISTRY NUMBER 24356-66-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 9H-Purin-6-amine, 9-beta-D-arabinofuranosyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Vira-A [USP DI 2000; p. 3131] PROTOCOL ID NUMBERS Complete NIAID ACTG 095 PHARMACOLOGICAL ACTION MODE OF ACTION: Following intravenous injection, vidarabine is rapidly deaminated into arabinosylhypoxanthine, its principal metabolite, which is rapidly distributed into the tissues (mean half-life of the metabolite is 3.3 hours). The metabolite penetrates into the cerebrospinal fluid (CSF) to give a CSF: plasma ratio of approximately 1:3; however, in patients with impaired renal function, the metabolite may accumulate in the plasma and reach levels severalfold higher than typical values. After slow infusion of 10 mg/kg of the drug into adults, peak plasma levels of the drug and its metabolite ranged from 0.2-0.4 and 3-6 mcg/ml, respectively; these levels reflect the rate of infusion and show no accumulation across time. The drug is principally excreted via the kidneys, with urinary excretion constant over 24 hours; a total of 41-53% of the daily dose is recovered in the urine as the metabolite, with 1-3% appearing as the parent compound; there is no evidence of fecal excretion of the drug or its metabolites. Studies of the mode of action of the drug have shown that it possesses in vitro and in vivo antiviral activity against Herpes simplex virus types 1 and 2. While the antiviral mechanism of action of this drug has not yet been established, it is known that it is converted into nucleosides which inhibit viral DNA polymerase. Exact mechanism of vidarabine's antiviral activity has not be elucidated; it appears to involve inhibition of viral replication by inhibiting viral DNA polymerase. Vidarabine is only minimally incorporated into viral DNA. It is not immunosuppressive. In the body, vidarabine is rapidly deaminated into ara-HX (arabinosylhypoxanthine) which also possesses antiviral activity but substantially less than vidarabine. Following topical application of vidarabine to the eye in patients with epithelial defect in the cornea, trace amounts of the drug and its major matabolite, ara-HX, can be detected in aqueous humor. [AHFS Drug Information 1997; p 2116; USP DI 1997; p 2968] DISEASES STUDIED/TREATED IV or topical antiviral drug active against herpes simplex and varicella-zoster (VZV) viruses. Used to treat HSV (herpes simplex virus) encephalitis; neonatal encephalitis, infections of the skin, eyes, mouth, disseminated HSV and VZV infections with visceral involvement, and herpes zoster (shingles) due to reactivated VZV infections in immunosuppressed patients. [AmfAR Treat Dir 1997;8(3); p 79] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 3130] OTHER MAJOR USES Vidarabine is used topically in the treatment of keratitis and keratoconjunctivitis caused by herpes simplex virus types 1 and 2. In a limited number of patients, topical vidarabine has been used successfully in the treatment of vaccinia keratitis. [AHFS Drug Information 1997; p 2116-7] ADVERSE EFFECTS Like other ophthalmic ointments, vidarabine may produce a temporary visual haze. Burning, itching, and mild irritation of the affected eye are the most common adverse effects of topical vidarabine therapy; however, lacrimation, foreign body sensation, conjunctival injection, superficial punctate keratitis, pain, photophobia, punctal occlusion, and sensitivity may also occur. [AHFS Drug Information 1997; p 2117] CONTRAINDICATIONS Concurrent topical application of vidarabine and a corticosteroid is contraindicated in superficial herpes simplex keratitis; although concomitant application may be of benefit in severe infections. Contraindicated in patients with a known or suspected hypersensitivity to the drug. Both topically and parenterally administered vidarabine has been reported to be teratogenic in animals. Additionally, ocular penetration of vidarabine (ophthalmic preparation) is low. The drug should be used in pregnancy only when potential benefits justify possible risk to the fetus. It is unlikely that vidarabine is distributed into milk following ophthalmic use. However, the drug has shown to be tumorigenic (in animals) and a decision should be made whether to discontinue nursing or use the drug. [AHFS Drug Information 1997; p 2117; USP DI 1997; p 2968-9] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Purine nucleoside derivative obtained from fermentation cultures of Streptomyces antibioticus. [AHFS Drug Information 1997; p 2116] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H13-N5-O4.H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 285.26 [USPD 1998; p. 778] CHEMICAL/PHYSICAL DATA Melting Point: 257-257.5 C [Merck Index 1996; p. 1702] CHEMICAL/PHYSICAL DATA Elemental Comp: C42.11%, H5.30%, N24.55%, O28.04% [Merck Index 1996; p. 1701] CHEMICAL/PHYSICAL DATA Solubility: 0.45 mg/ml (25 C) (Monohydrate). [AHFS Drug Information 1997; p 2116] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [AHFS Drug Information 1997; p 2116] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial containing sterile suspension of 1 g of the drug in 5 ml (for dilution with intravenous infusion solution); 3% ophthalmic ointment. [PDR 1993; p 1821-3; AHFS Drug Information 1997; p 2117] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion; topical. [PDR 1993; p 1821-3; AHFS Drug Information 1997; p 2116] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Dilute just prior to administration and use the diluted solution within 24 hours; do not refrigerate the dilution solution. Vidarabine opthalmic ointment should be stored at a temperature less than 40 C, preferably between 15 - 30 C; freezing should be avoided. [PDR 1993; p 1821-3; AHFS Drug Information 1997; p 2116] MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 Contact: Unspecified (800)223-0432 MANUFACTURERS 0000005234: Parke-Davis 201 Tabor Road Morris Plains, NJ 07950 REFERENCES MED/97030930. Whitley RJ. The past as prelude to the future: history, status, and future of antiviral drugs. Ann Pharmacother 1996 Sep;30(9):967-71. [COMMENT: Ann Pharmacother 1996 Sep;30(9)964-61]. MED/94149559. Balfour HH Jr, Benson C, Braun J, Cassens B, Erice A, Friedman-Kien A, Klein T, Polsky B, Safrin S. Management of acyclovir-resistant herpes simplex and varicella-zoster virus infections. J Acquir Immune Defic Syndr. 1994 Mar;7(3):254-60. MED/95089941. McGrath BJ, Newman CL. Genital herpes simplex infections in patients with the acquired immunodeficiency syndrome. Pharmacotherapy. 1994 Sep-Oct;14(5):529-42. MED/94041096. Washio M, Hamada T, Goda H, Yoshimitsu T, Kajioka T, Koga H, Shogakuchi Y, Fujishima M, Okayama M. Acyclovir-resistant herpes zoster encephalitis successfully treated with vidarabine: a case report. Fukuoka Igaku Zasshi. 1993 Oct;84(10):436-9. MED/93169809. Sasadeusz JJ, Sacks SL. Systemic antivirals in herpesvirus infections. Dermatol Clin. 1993 Jan;11(1):171-85. MED/92166423. Whitley RJ, Gnann JW Jr, Hinthorn D, Liu C, Pollard RB, Hayden F, Mertz GJ, Oxman M, Soong SJ. Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. J Infect Dis. 1992 Mar;165(3):450-5. MED/92376688. Teich SA, Cheung TW, Friedman AH. Systemic antiviral drugs used in ophthalmology. Surv Ophthalmol. 1992 Jul-Aug;37(1):19-53. MED/91312406. Safrin S, Crumpacker C, Chatis P, Davis R, Hafner R, Rush J, Kessler HA, Landry B, Mills J. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. N Engl J Med. 1991 Aug 22;325(8):551-5. MED/90258626. Shepp DH, Farber BF. Ineffectiveness of vidarabine in mucocutaneous herpes simplex virus infection [letter]. Lancet 1990 Jun 2;335(8701):1344. MED/90119687. Gizzi M, Rudolph S, Perakis A. Ocular flutter in vidarabine toxicity. Am J Ophthalmol. 1990 Jan 15;109(1):105. ENTRY MONTH 199104 LAST REVISION DATE 20001107 289 UNIQUE IDENTIFIER DRG-0057 NAME OF SUBSTANCE Oxazepam [USPD 1998; p. 536] REGISTRY NUMBER 604-75-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2H-1,4-Benzodiazepin-2-one, 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Serax [USP DI 2000; p. 588] PROTOCOL ID NUMBERS Complete NIAID ACTG 124 PHARMACOLOGICAL ACTION MODE OF ACTION: In general, benzodiazepines act as CNS depressants. The precise site and mechanism of action have not been completely established. It is believed that benzodiazepines enhance or facilitate the neurotransmitter action of gamma-amino butyric acid (GABA). Benzodiazepines act as agonists at the benzodiazepine receptors which have been shown to form a supramolecular unit - the benzodiazepine-GABA receptor chloride ionophore complex. Activation of the GABA receptor results in the opening of the chloride channel, allowing the flow of chlorides through the neuronal membrane. Usually this results in hyperpolarization of the post-synaptic neuron which inhibits firing of that neuron. THis translates into decreased neuronal excitability. Oxazepam shows significant separation of doses required to relieve anxiety and doses producing sedation or ataxia. Capsule, tablet and suspension of oxazepam (single 30 mg dose) were equivalent in extent of absorption and produced plasma levels of 450 ng/ml 3 hours after dosing. The mean elimination half-life was approx. 8.2 hours. The single major inactive metabolite in man, a glucuronide, was excreted in the urine. The acute oral LD50 in mice was 5000 mg/kg. [PDR 1997; p 2916-7; USP DI 1997; p 533] DISEASES STUDIED/TREATED AIDS-related depression. [Protocol ID: ACTG 124 ] CLASSIFICATION CODE Antianxiety agent [USP DI 2000; p. 568] CLASSIFICATION CODE Sedative-hypnotic [USP DI 2000; p. 568] OTHER MAJOR USES Indicated for adjunctive management of anxiety associated with mental depression and relief of acute alcohol withdrawal symptoms. [PDR 1997; p 2917] SUBSTANCE INTERACTIONS Additive CNS depression may occur when benzodiazepines are given with other CNS depressants, including other antidepressants and alcohol. Concurrent administration of benzodiazepines with disulfiram may result in some inhibition of metabolism of the former. Benzodiazepines should be given with caution to patients on levodopa. There have reports of impaired motor functions in patients on benzodiazepines and tricyclic antidepressants. Antacids such as calcium or magnesium hydroxides may decrease the rate of GI absorption of some benzodiazepines. Limited evidence suggests that some benzodiazepines may reduce renal excretion of digoxin resulting in increased plasma half-life and possible toxicity of the digoxin. [AHFS Drug Information 1997; p 1804-5] ADVERSE EFFECTS The necessity for discontinuation of therapy due to undesirable effects has been rare. Transient mild drowsiness is commonly seen in the first few days of therapy. If it persists, the dosage should be reduced. In few instances, dizziness, vertigo, headache, and rarely syncope have occurred either alone or together with drowsiness. Mild paradoxical reactions, i.e., excitement, stimulation of affect, have been reported in psychiatric patients; these reactions may be secondary to relief of anxiety and usually appear in the first 2 weeks of therapy. Rare reactions include skin rashes, nausea, lethargy, edema, slurred speech, tremors, altered libido, leukopenia, hepatic dysfunction including jaundice, and ataxia. [PDR 1997; p 2917] CONTRAINDICATIONS Contraindicated in patients with history of previous hypersensitivity reaction to oxazepam or in patients with psychoses. As with other central nervous system (CNS) acting drugs, patients should be cautioned against driving automobiles or operating dangerous machinery until it is known that they do not become drowsy or dizzy on oxazepam therapy. Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of oxazepam, possibly requiring adjustment of dosage or elimination of such agents. Not advised in pregnant women. An increased risk of congenital malformations associated with the use of minor tranquilizers during the first trimester of pregnancy has been suggested. [PDR 1997; p 2917] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: The first of a new series of chemical compounds called the 3-hydroxybenzodiazepinones. [PDR 1997; p 2916] CHEMICAL/PHYSICAL DATA Molecular Formula: C15-H11-Cl-N2-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 286.72 [USPD 1998; p. 536] CHEMICAL/PHYSICAL DATA Melting Point: 205 - 206 C [Merck Index 1996; p. 1189] CHEMICAL/PHYSICAL DATA Elemental Comp: C62.84%, H3.87%, Cl12.37%, N9.77%, O11.16% [Merck Index 1996; p. 1188] CHEMICAL/PHYSICAL DATA Solubility: In alcohol, chloroform, dioxane. Practically insoluble in water. [Merck Index 1996; p 1189] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Creamy white or pale yellow powder. [AHFS Drug Information 1997; p 1821] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules and tablets. Controlled substance in the U.S. Usual adult dose for antianxiety is 10 to 15 mg 3 or 4 times a day; as a sedative-hypnotic and for alcohol withdrawal the dose is 15 or 30 mg 3 or 4 times a day. Strengths available are 10 mg, 15 mg, and 30 mg. [AHFS Drug Information 1997; p 1821; PDR 1997; p 2917] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral administration of capsules or tablets. [PDR 1997; p 2917] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), in a well-closed container. [AHFS Drug Information 1997; p 1821] MANUFACTURERS 0000000999: Wyeth - Ayerst Pharmaceuticals PO Box 8299 Philadelphia, PA 191011245 Contact: Audrey Ashby (610)971-5823 MANUFACTURERS 0000002865: Wyeth - Ayerst Research PO Box 8299 Philadelphia, PA 19101 Contact: General Information (610)688-4400 REFERENCES MED/95071801. Storm G. Oosterhuis B, Sollie FA, Visscher HW, Sommer W, Beitinger H, Jonkman JH. Lack of pharmacokinetic interaction between vinpocetine and oxazepam. Br J Clin Pharmacol 1994 Aug;38(2):143-6. MED/93108250. Mole L, Israelski D, Bubp J, O'Hanley P, Merigan T, Blaschke T. Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient. J Acquir Immune Defic Syndr. 1993 Jan;6(1):56-60. MED/95166965. Landon JF, Sher KJ, Shah JH. Effects of oxazepam on anxiety: implications for Fowles' psychophysiological interpretation of Gray's model. Psychopharmacology (Berl). 1993;113(1);137-43. MED/92398693. Stuppaeck CH, Pycha R, Miller C, Whitworth AB, Oberbauer H, Fleischhacker WW. Carbamazepine versus oxazepam in the treatment of alcohol withdrawal: a double-blind study. Alcohol Alcohol. 1992 Mar;27(2):153-8. MED/92387666. Herz LR, Volicer L, Ross V, Rheaume Y. A single-case-study method for treating resistiveness in patients with Alzheimer's disease. Hosp Community Psychiatry. 1992 Jul;43(7):720-4. MED/93072522. Herz LR, Volicer L, Ross V, Rheaume Y. Pharmacotherapy of agitation in dementia [letter; comment]. Am J Psychiatry. 1992 Dec;149(12):1757-8. MED/92288822. Sheikh JI. Anxiety disorders and their treatment. Clin Geriatr Med. 1992 May;8(2):411-26. MED/91367880. Rimon R, Kultalahti ER, Kalli A, Koskinen T, Lepola U, Naarala M, Tick E. Alprazolam and oxazepam in the treatment of anxious out-patients with depressive symptoms: a double-blind multicenter study. Pharmacopsychiatry. 1991 May;24(3):81-4. MED/92187061. Ansseau M, Papart P, Gerard MA, von Frenckell R, Franck G. Controlled comparison of buspirone and oxazepam in generalized anxiety. Neuropsychobiology. 1990-91;24(2):74-8. MED/91009052. Strand M, Hetta J, Rosen A, Sorensen S, Malmstrom R, Fabian C, Marits K, Vetterskog K, Liljestrand AG, Hegen C. A double-blind, controlled trial in primary care patients with generalized anxiety: a comparison between buspirone and oxazepam. J Clin Psychiatry. 1990 Sep;51 Suppl:40-5. ENTRY MONTH 199104 LAST REVISION DATE 20001107 290 UNIQUE IDENTIFIER DRG-0056 NAME OF SUBSTANCE Allopurinol [USPD 1998; p. 34] REGISTRY NUMBER 315-30-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4H-Pyrazolo(3,4-d)pyrimidin-4-one, 1,5-dihydro- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Lopurin [USP DI 2000; p. 56] SYNONYMS Zyloprim [USP DI 2000; p. 56] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PHARMACOLOGICAL ACTION MODE OF ACTION: Acts on purine catabolism, without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. Inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. Allopurinol is metabolized to the corresponding xanthine analog oxipurinol (alloxanthine), which also is an inhibitor of xanthine oxidase. Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is enhanced when their oxidations are inhibited by allopurinol and oxipurinol. This reutilization does not disrupt normal nucleic acid anabolism. Allopurinol is approximately 90% absorbed from the gastrointestinal tract. Peak plasma levels generally occur at 1.5 hours and, and after a single oral dose of 300 mg, maximum plasma levels of about 3 mcg/ml of allopurinol and 6.5 mcg/ml of oxipurinol are produced. Approximately 20% of ingested drug is excreted in the feces. Plasma half-life is about 1-2 hours. Oxypurinol, however, has a plasma half-life of about 15.0 hours. Allopurinol is cleared essentially by glomerular filtration, but oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid. [PDR 1997; p 1194] DISEASES STUDIED/TREATED Especially useful in preventing hyperuricemia and uric acid nephropathy resulting from tissue breakdown after cancer chemotherapy or radiation therapy. [AHFS Drug Information 1997; p 2843] CLASSIFICATION CODE Antihyperuricemic [USP DI 2000; p. 52] OTHER MAJOR USES Allopurinol is indicated in the management of patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis and/or nephropathy); the managment of patients with leukemia, lymphoma, and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels; the management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceends 800 mg/day in male patients and 750 mg/day in female patients. [PDR 1997; p 1194] SUBSTANCE INTERACTIONS In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300-600 mg allopurinol per day requires a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of these two drugs should be made on the basis of therapeutic response and the appearance of toxic effects. Concomitant administration of uricosuric agents and allopurinol has been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared with that observed with allopurinol alone. Renal function should be monitored in patients receiving thiazide diuretics and allopurinol even in the absence of renal failure. The half-life of the anticoagulant dicumarol has been reported to be prolonged by allopurinol. An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of allopurinol. However, in a well-controlled study of patients with lymphoma on combination therapy, allopurinol did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine. Chlorpropamide's plasma half-life may be prolonged by allopurinol, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if these two drugs are given concomitantly in the presence of renal insufficiency. [PDR 1997; p 1195] ADVERSE EFFECTS The most frequent event following initiation of allopurinol treatment was an increase in acute attacks of gout, originally 6%, now < 1%. The most frequent adverse reaction to allopurinol is skin rash, which can be severe and sometimes fatal. Some patients with the most severe reaction also had fever, chills, arthralgias, cholestatic jaundice, eosinophilia, and mild leukocytosis or leukopenia. The most common reactions, probably causally related are diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase, acute attacks of gout, rash, maculopapular rash. Other reactions, with an incidence < 1%, probably causally related, are ecchymosis, fever, headache, necrotizing angiitis, vasculitis, hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, dyspepsia, thrombocytopenia, eosinophilia, leukocytosis leukopenia, myopathy, arthralgias, peripheral neuropathy, neuritis, paresthesia, somnolence, epistaxis, erythema multiforme exudativum (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), hypersensitivity vasculitis, purpura, vesicular bullous dermatitis, exfoliative dermatitis, eczematoid dermatitis, pruritus, urticaria, alopecia, onycholysis, lichen planus, taste loss/perversion, renal failure, uremia. Reactions with an incidence < 1%, causal relationship unknown, include malaise, pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation, infertility (male), hypercalcemia, gynecomastia (male), hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, anorexia, aplastic anemia, agranulocytosis eosinophilic fibrohistiocytic lesion of the bone marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis, myalgia, optic neuritis, confusion, dizziness, vertigo, foot drop, decreases in libido, depression, amnesia, tinnitus, asthenia, insomnia, bronchospasm, asthma, pharyngitis, rhinitis, furunculosis, facial edema, sweating, skin edema, cataracts, macular retinitis, iritis, conjunctivitis, amblyopia, nephritis, impotence, primary hematuria, albuminuria. [PDR 1997; p 1195-6] CONTRAINDICATIONS Patients who have developed a severe reaction to allopurinol should not be restarted on the drug. Treatment should be discontinued at the first sign of a skin rash which may indicate an allergic reaction. In patients with pre-existing liver disease, periodic liver function tests are recommended during early stages of treatment. Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal functions. Experience with the drug during human pregnancy is limited, but because of adverse effects in some animal studies, allopurinol should be used during pregnancy only if clearly needed. Since the effects of allopurinol on the nursing infant are unknown, caution should be used when the drug is administered to nursing women. [PDR 1997; p 1194-5] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Structural isomer of hypoxanthine. [AHFS Drug Information 1997; p 2842] CHEMICAL/PHYSICAL DATA Molecular Formula: C5-H4-N4-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 136.11 [USPD 1998; p. 34] CHEMICAL/PHYSICAL DATA Melting Point: > 350 C [Merck Index 1996; p. 52] CHEMICAL/PHYSICAL DATA Elemental Comp: C44.12%, H2.96%, N41.16%, O11.75% [Merck Index 1996; p. 52] CHEMICAL/PHYSICAL DATA Solubility: 0.48 mg/ml in water; 0.30 mg/ml in ethanol; 4.6 mg/ml in DMSO at 25 C. [Merck Index 1996; p 52] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystals. [Merck Index 1996; p 5248] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (100 and 300 mg). [PDR 1997; p 1196] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1194] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-25 C (59-77 F) in a dry place. [PDR 1997; p 1196] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000005218: Knoll Pharmaceutical Co 3000 Continental Drive North Mount Olive, NJ 078281234 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000001092: Barr Laboratories Inc 2 Quaker Rd / PO Box D-2900 Pomona, NY 10970 Contact: Jaime Hernandez (919)483-6300 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Medical & Consumer Relations (919)483-9959 REFERENCES MED/96346924. Torrus D, Boix V, Massa B, Portilla J, Perez-Mateo M. Fluconazole plus allopurinol in treatment of visceral leishmaniasis [letter]. J Antimicrob Chemother. 1996 May;37(5):1042-3. MED/96126035. Raffi F, Merrien D, Le Pape P, Reliquet V. Use of an Itraconazole/allopuninol combinations for the treatment of visceral leishmaniasis in a patient with AIDS. Clin Infect Dis. 1995 Nov;21(5):1338-9. MED/95066605. Razis E, Arlin ZA, Ahmed T, Feldman EJ, Puccio C, Cook P, Chun HG, Helson L, Mittelman A. Incidence and treatment of tumor lysis syndrome in patients with acute leukemia. Acta Haematol. 1994;91(4):171-4. MED/94375911. Laguna F, Lopez-Velez R, Soriano V, Montilla P, Alvar J, Gonzalez-Lahoz JM. Assessment of allopurinol plus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV. J Infect. 1994 May;28(3):255-9. MED/95146184. Alfandari S, Beuscart C, Delaporte E, Senneville E, Mouton Y. Toxic epidermal necrolysis in a patient suffering from acquired immune deficiency syndrome. Infection. 1994 Sep-Oct;22(5):365. ICA9/93335010. Ventura G, Federico G, Camilli G, Caldarola G, Tumbarello M, Cauda R. Visceral leishmaniasis in HIV patients. Int Conf AIDS. 1993 Jun 6-11;9(1):378 (abstract no. PO-B10-1456). ICA9/93335017. Martinez A, Boix V, Portilla J, Perez-Mateo M. Visceral leishmaniasis (VL). Influence of HIV coinfection. Int Conf AIDS. 1993 Jun 6-11;9(1):379 (abstract no. PO-B10-1464). MED/93158628. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med. 1993 Feb;94(2):133-9. MED/93152036. Medrano FJ, Hernandez-Quero J, Jimenez E, Pineda JA, Rivero A, Sanchez-Quijano A, Velez ID, Viciana P, Castillo R, Reyes MJ, et al. Visceral leishmaniasis in HIV-1-infected individuals: a common opportunistic infection in Spain? AIDS. 1992 Dec;6(12):1499-503. ICA8/92403452. Paez Pena M, Gomez Rodrigo J, Padilla B, Delgado Iribarren A, Guerra L, Jusdado J. Visceral leishmaniasis and HIV infection. Is secondary prophylaxis needed? Int Conf AIDS. 1992 Jul 19-24; 8(3):115 (abstract no. PuB 7401). ENTRY MONTH 199104 LAST REVISION DATE 20001107 291 UNIQUE IDENTIFIER DRG-0055 NAME OF SUBSTANCE Inosine pranobex [USPD 1998; p. 379] REGISTRY NUMBER 36703-88-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Inosine-2-hydroxypropyldimethylammonium 4-acetamidobenzoate (1:3) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting FDA 008A PROTOCOL ID NUMBERS No longer recruiting FDA 008B PROTOCOL ID NUMBERS No longer recruiting FDA 008C PROTOCOL ID NUMBERS No longer recruiting FDA 008D PROTOCOL ID NUMBERS No longer recruiting FDA 008E PROTOCOL ID NUMBERS No longer recruiting FDA 008F PROTOCOL ID NUMBERS No longer recruiting NIAID NS 403 PHARMACOLOGICAL ACTION MODE OF ACTION: Antiviral activity via augmentation of immunologic responsiveness. Inosine pranobex (INPX) is a synthetic immunopotentiating agent which has been shown capable of in vitro enhancement of mitogen-induced lymphocyte proliferation, macrophage activation, T-rosette formation of lymphocyte, natural killer (NK) cell activity, and production of lymphotoxin. In vitro studies have also suggested that isoprinosine may have the ability to enhance interleukin-1 (IL-1) and interleukin-2 (IL-2) production and IL-2 receptor formation. The results of human clinical trials in HIV positive patients with persistent generalized lymphadenopathy (PGL) or AIDS related complex (ARC) have shown that INPX had a profound and lasting effect on the immunologic and clinical status of these patients. Treatment with INPX at 3 g/day for 28 days resulted in significant increases in NK cell activity, total T-lymphocytes, and T-helper cells. [Drug Evaluations Annual 1992; p 1738; AmfAR Treat Dir 1989 May; p 94; Cancer Detect Prev Suppl 1 (1987); p 1:597-609] DISEASES STUDIED/TREATED Primary HIV infection: Persistent generalized lymphadenopathy and ARC. [Protocol ID: NS 403 ] CLASSIFICATION CODE Antiviral [Merck Index 1996; p. 854] CLASSIFICATION CODE Immunomodulator [Merck Index 1996; p. 854] OTHER MAJOR USES Used in Europe to treat a number of viral diseases, including herpesvirus, rhinovirus, influenza A infections, and viral hepatitis. Treatment of subacute sclerosing panencephalitis (SSPE),of immunodepressed patients after burns, cancer chemotherapy, surgery, and other clinically distinct immunodeficiencies. [Drug Evaluations Annual 1992; p 1657; Cancer Detect Prev Suppl 1 (1987); p 1:597-609; USP DI 1997; p 3108] ADVERSE EFFECTS Adverse effects include mild and transient elevation of serum and urinary uric acid due to the metabolism of INPX, and the conversion of the inosine moiety to uric acid through normal purine metabolic pathway. [Meyler's Side Effects of Drugs 1989 11th ed; 797] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic drug, chemically combining 1 part inosine with 3 parts each of p-acetamidobenzoic acid and dimethylamino-isopropanol. Naturally occurring substance found in the metabolic pathway of purines and in small amounts in cells and tissue fluids. [Merck Index 1989; p 788] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H12-N4-O5.C14-H22-N2-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 550.57 [USPD 1998; p. 379] CHEMICAL/PHYSICAL DATA Solubility: Neutral water soluble solid. [Merck Index 1996; p 854] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [AmfAR Treat Dir 1989 May; p 94] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (500 mg). [Protocol ID: NS 403 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: NS 403 ] MANUFACTURERS 0000003729: Newport Pharmaceuticals 897 West Sixteenth St Newport Beach, CA 92663 REFERENCES MED/97104918. Riva C, Barra Y. Effects of isoprinosine on 3'-Azido-3'-deoxythymidine uptake and phosphorylation in human peripheral blood mononuclear cells. Chemotherapy. 1996 May-Jun;42(3):192-8. MED/96187111. Carstens J, Teglbjaerg LS, Black FT. Neopterin and beta 2-microglobulin as serum markers in a placebo-controlled anti-HIV therapy trial. Eur J Clin Chem Clin Biochem. 1995 Sep;33(9):559-62. MED/94345841. Thorsen S, Pedersen C, Sandstrom E, Petersen CS, Norkrans G, Gerstoft J, Karlsson A, Christensen KC, Hakansson C, Pehrson PO, et al. [Controlled, clinical trial of isoprinosine administration to HIV-infected patients. Results of Danish/Swedish multicenter study. The Scandinavian Isoprinosine Study Group]. Ugeskr Laeger. 1994 May 30;156(22):3314-8. MED/94188296. al-Habet SM, Nosbisch C, Williamson T, Tsai CC, Unadkat JD. Interaction of zidovudine (azidothymidine) with isoprinosine and probenecid in Macaca fascicularis. Pharm Res. 1994 Jan;11(1):181-3. MED/94096550. Gohchi K, Matsuda J. [Immunotherapy for HIV carrier]. Nippon Rinsho. 1993 Sep;51 Suppl:338-42. MED/93319249. Kovacs JA, Powell F, Voeller D, Allegra CJ. Inhibition of Pneumocystis carinii dihydropteroate synthetase by para-acetamidobenzoic acid: possible mechanism of action of isoprinosine in human immunodeficiency virus infection. Antimicrob Agents Chemother. 1993 Jun;37(6):1227-31. ICA9/93334855. Shavdia N, Sharvadze L, Tsertsvadze T, Medulashvili G, Aladashvili M, Chubinishvili O. The comparative efficacy of acyclovir, isoprinosine and their combination in patients with herpes simplex. Int Conf AIDS. 1993 Jun 6-11;9(1):354 (abstract no. PO-B08-1313). MED/93028055. De Simone C, Famularo g, Giacomelli R, Tzantzoglou S. Inosine pranobex in the combination therapy of HIV infection. Pharmacol Res. 1992 Sep;26 Suppl 2:60-1. MED/92317863. Thorsen S, Pedersen C, Sandstrom E, Petersen CS, Norkrans G, Gerstoft J, Karlsson A, Christensen KC, Hakansson C, Pehrson PO, et al. One-year follow-up on the safety and efficacy of isoprinosine for human immunodeficiency virus infection. J Intern Med. 1992 Jun;231(6):607-15. MED/92215479. Teglbjaerg LL, Kroon S, Sandstrom E, Moestrup T, Hansson BG, Vestergaard BF. Effect of isoprinosine on HIV antigenaemia. AIDS. 1992 Feb;6(2):199-201. ENTRY MONTH 199104 LAST REVISION DATE 20001107 292 UNIQUE IDENTIFIER DRG-0054 NAME OF SUBSTANCE Interferon beta-1b [USPD 2000 p. 374] REGISTRY NUMBER 145155-23-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2-166-Interferon beta1 (human fibroblast reduced), 17-L-serine- [USPD 1998; p. 381] SYNONYMS Betaseron [USP DI 2000; p. 1807] PROTOCOL ID NUMBERS Complete NIAID ACTG 057 PROTOCOL ID NUMBERS No longer recruiting FDA 002A PROTOCOL ID NUMBERS No longer recruiting FDA 017A PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism by which interferon beta induces cellular resistance to viral infection is incompletely understood whether the interferon is endogenously produced or exogenously administered. A prevalent view of interferon action is that, following binding, there is synthesis of new cellular RNA's and proteins, which mediate the antiviral effect. Interferon beta-1b receptor binding is 5 to 10 times that of the alpha interferons. Chromosome 21 is required to develop the antiviral state in humans no matter which species of IFN (alpha, beta, or gamma) is employed. At least three of the newly synthesized proteins in interferon-treated cells appear to be associated with the development of the antiviral state: (1) a 2',5' oligoadenylate (2-5A) synthetase, (2) a protein kinase, and (3) an endonuclease. The antiviral state is not fully expressed until these primed cells are infected with virus. Double stranded RNA, which is produced during the replication of many viruses, activates 2-5A synthetase and protein kinase. The activated synthetase catalyzes the polymerization of ATP into 2'-5' oligonucleotides that in turn activate endogenous cellular endoribonuclease, which degrades viral RNA. The activated protein kinase phosphorylates the alpha subunit of eukaryotic initiation factor 2 resulting in inhibition of viral protein synthesis. The combined effects of protein kinase and endonuclease are thought to result in inhibtion of virus protein synthesis and virus replication. Interferon, in retroviruses, appears not to act by inhibiting virus-specific RNA or protein synthesis in all virus systems. Interferon appears to inhibit the final maturation of retroviruses in infected cells so that they are not released into the medium but instead accumulate on the cell surface. [Drug Evaluations Annual 1992; p 1649-51; Drug Evaluations Annual 1995; p 2204] DISEASES STUDIED/TREATED Kaposi's sarcoma; primary HIV infection; cytomegalovirus (CMV) retinitis. Received licensure July 23, 1993. [Int Conf AIDS 1992 Jul 19-24;8(2); B108 (abstract no. PoB 3126)] CLASSIFICATION CODE Multiple sclerosis therapy [USP DI 2000; p. 1805] OTHER MAJOR USES Interferon beta-1b is being investigated in hairy cell leukemia, renal cell carcinoma, recurrent glioma and other malignant brain tumors. It is approved for use in multiple sclerosis therapy. [Drug Evaluations Annual 1995; p 442, 2204] SUBSTANCE INTERACTIONS Interferon beta has been shown to be synergistic with zidovudine (AZT) in suppressing HIV expression in human peripheral blood lymphocytes in vitro. [Int Conf AIDS 1988 Jun 12-16;4; p 174 (abstract no. 3633)] ADVERSE EFFECTS The most common side effects are injection site reactions which occur in 85% of the patients and flu-like symptoms which occur in 75% of the patients. Possible adverse effects from parenteral administration may include fever, headache, chills, rigors, arthralgias, myalgias, dizziness, paresthesias, diaphoresis, nausea, fatigue, proteinuria, leukopenia, thrombocytopenia, pain at injection site, anorexia, diarrhea, emesis, elevation of serum liver enzyme levels, transient visual disturbances, seizures, confusion, and formation of antibodies to interferon. [Drug Evaluations Annual 1992; p 1649-51; Int Conf AIDS 1988 Jun 12-16;4; p 174 (abstract no. 3633); Drug Evaluations Annual 1995; p 442] CONTRAINDICATIONS Should not be used by pregnant or lactating women or by patients with evidence of clinically significant cardiac dysfunction. [Protocol ID: ACTG 057 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Interferon beta is a cytokine that is one of three classes of interferons identified. The native molecule can be readily induced in cultured human foreskin fibroblasts by synthetic double-stranded RNA. Recombinant interferon beta is produced in Escherichia coli and has specific activity comparable to that of the native molecule. [Proc Annu Meet Am Assoc Cancer Res 1987; 28(460):1824] CHEMICAL/PHYSICAL DATA Molecular Formula: C903-H1399-N245-O252-S5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 19,879.60 [USPD 2000 p. 374] CHEMICAL/PHYSICAL DATA Stability: Generally stable at pH 2 [Merck Index 1983; p 725] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial (5 ml) containing 0.3 mg (54 million units (MU)) as a sterile lyophilized powder, reconstituted in 1.2 ml sterile water to obtain a solution of 0.25 mg/ml (45 MU) of Interferon beta. [Protocol ID: ACTG 057 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection as a bolus. [Protocol ID: ACTG 057 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refrigerate vials containing lyophilized powder at 2-8 C (stability up to 36 months); reconstituted interferon beta solution should be used immediately or held at 2-8 C for no more than 3 hours to ensure stability. [Protocol ID: ACTG 057 ] MANUFACTURERS 0000001214: Berlex Laboratories 300 Fairfield Rd Wayne, NJ 074707358 Contact: Unspecified (888)237-5394 MANUFACTURERS 0000001214: Berlex Laboratories 300 Fairfield Rd Wayne, NJ 074707358 REFERENCES MED/96287924. Nakayama J, Takeuchi M, Mayumi H, Nagae S, Matsuda K, Yasui H, Takahashi S, Hori Y. Two cases of metastatic malignant melanoma of the lower limb treated with hyperthermic isolated limb perfusion and concomitant infusion of either carboplatin or beta-interferon. J Dermatol. 1996 Jan;23(1):6-15. MED/96130176. Agy MB, Acker RL, Sherbert CH, Katze MG. Interferon treatment inhibits virus replication in HIV-1-and SIV-infected CD4+ T-cell lines by distinct mechanisms: evidence for decreased stability and aberrant processing of HIV-1 proteins. Virology. 1995 Dec 20;214(2):379-86. MED/96126175. Vieillard V, Lauret E, Maguer V, Jacomet C, Rozenbaum W, Gazzolo L, De Maeyer E. Autocrine interferon-beta synthesis for gene therapy of HIV infection: increased resistance to HIV-1 in lymphocytes from healthy and HIV-infected individuals. AIDS. 1995 Nov;9(11):1221-8. MED/96172466. Ebbesen P, Hager H, Norskov-Lauritsen N, Aboagye-Mathiesen G, Zdravkovic M, Villadsen J, Liu X, Petersen PM, Bambra C, Nyongo A, et al. Concurrence of high levels of interferons alpha and beta in cord and maternal blood and simultaneous presence of interferon in trophoblast in an African population. J Interferon Cytokine Res. 1995 Feb;15(2):123-8. MED/95273791. Gessani S, Puddu P, Varano B, Borghi P, Conti L, Fantuzzi L, Papacchini M, Belardeli F. Role of interferons in the restriction of HIV replication in human monocytes/macrophages. Res Immunol. 1994 Oct-Dec;145(8-9):659-62;discussion 662-3. MED/94339220. Olmos L, Vilata J, Rodriguez Pichardo A, Lloret A, Ojeda A, Calderon MD. Double-blind, randomized clinical trial on the effect of interferon-beta in the treatment of condylomata acuminata. Int J STD AIDS. 1994 May-Jun;5(3):182-5. MED/94252455. Semprini AD, Stillo A, Marcozzi S, Castagna C, Fiore S, Radaelli U. Treatment with interferon for genital HPV in HIV-positive and HIV-negative women. Eur J Obstet Gynecol Reprod Biol. 1994 Feb;53(2):135-7. MED/94229320. Frega A, di Renzi F, Stentella P, Pachi A. Management of human papilloma virus vulvo-perineal infection with systemic beta-interferon and thymostimulin in HIV-positve patients. Int J Gynaecol Obstet. 1994 Mar;44(3):255-8. ICA9/93333672. Izzo CM, Buonocore S, De Sena R, Manzillo E, Maio G, Manzillo G. Treatment of chronic hepatitis by HCV with association of beta-interferon and zidovudine in patients (pts) HIV positive. Int Conf AIDS. 1993 Jun 6-11;9(1):174 (abstract no. PO-A13-0238). ICA9/93335587. Brockmeyer NH, Keller A, Seemann U, Mock M, Martins L, Goos M. Two year double blind randomized trial of zidovudine alone or in combination with low dose interferon alpha or interferon beta. Int Conf AIDS. 1993 Jun 6-11;9(1):466 (abstract no. PO-B26-1987). ENTRY MONTH 199104 LAST REVISION DATE 20000801 293 UNIQUE IDENTIFIER DRG-0053 NAME OF SUBSTANCE Probenecid [USPD 1998; p. 603] REGISTRY NUMBER 57-66-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzoic acid, 4-((dipropylamino)sulfonyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Benemid [USP DI 2000; p. 2550] SYNONYMS Probalan [USP DI 2000; p. 2550] PROTOCOL ID NUMBERS Complete NIAID ACTG 027 PROTOCOL ID NUMBERS Complete NIAID ACTG 107 PROTOCOL ID NUMBERS Complete NIAID ACTG 281 PROTOCOL ID NUMBERS Complete NIAID ACTG 350 PROTOCOL ID NUMBERS No longer recruiting FDA 216A PROTOCOL ID NUMBERS No longer recruiting FDA 216B PROTOCOL ID NUMBERS No longer recruiting NCI 97 C-27 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 363 PROTOCOL ID NUMBERS Recruiting CC 97 C-0024 PROTOCOL ID NUMBERS Terminated NIAID ACTG 352 PHARMACOLOGICAL ACTION MODE OF ACTION: Probenecid is a renal tubular blocking agent. The drug competitively inhibits active reabsorption of uric acid at the proximal convoluted tubule, thus promoting urinary excretion of uric acid and reducing serum urate concentrations. Probenecid may reduce plasma protein binding of urate and, in subtherapeutic doses, may inhibit renal secretion of uric acid. At the proximal and distal tubules, probenecid competitively inhibits the secretion of many weak organic acids including penicillins, most cephalosporins, and some other beta-lactam antibiotics. Therefore, probenecid substantially increases plasma concentrations of acidic drugs eliminated principally by renal secretion, but increases plasma concentrations only slightly if the drug is eliminated mainly by filtration. The cellular mechanism(s) responsible for the inhibition of renal tubular transport by probenecid is not known. The drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules. Probenecid is rapidly and completely absorbed from the gastrointestinal tract. Plasma probenecid concentrations of 25 ug/ml are reached 30 minutes after a single 1-g oral dose; plasma concentrations peak in 2-4 hours and remain above 30 ug/ml for 8 hours. Probenecid usually produces maximal renal clearance of uric acid 30 minutes after administration and exerts its effect on plasma penicillin concentrations after about 2 hours. At a plasma concentration of 14 ug/ml, about 75% of the drug is bound to proteins.Following oral administration of 2-g of probenecid, plasma half-life of the drug ranges from 4-17 hours; the half-life decreases as the dose decreases from 2-g to 500mg. Probenecid is slowly metabolized by the liver to probencid monoacyl glucuronide, two monohydroxylated compounds, a carboxylated metabolite, and an N-depropylated compound. These metabolites may possess some uricosuric activity. Small amounts of probenecid are filtered at the glomeruli, but most of the drug is actively secreted at the proximal tubule. Renal tubular reabsorption of the drug is nearly complete in acidic urine; however, probenecid metabolites are not reabsorbed as extensively as the parent compound. After 2 days, 5-11% of a single 2-g oral dose is excreted in urine as unchanged drug, 16-33% as its monoacyl glucuronide, and the remainder as approximately equal amounts of the 4 other metabolites. [PDR 1997; p 1651; AHFS Drug Information 1997; p 2065-6] DISEASES STUDIED/TREATED Possible use in reducing the glucuronidation of zidovudine (azidothymidine (AZT)), thereby reducing the amount of AZT needed. [USP DI 1996; p 1355] CLASSIFICATION CODE Antibiotic adjunct [USP DI 2000; p. 2546] CLASSIFICATION CODE Antihyperuricemic [USP DI 2000; p. 2546] OTHER MAJOR USES Used for the treatment of hyperuricemia associated with gout and gouty arthritis; used as an adjuvant to therapy with penicillin or with ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin, for elevation and prolongation of plasma levels by whatever route the antibiotic is given. [PDR 1997; p 1652] SUBSTANCE INTERACTIONS Probenecid inhibits renal tubular secretion of many weak organic acids including penicillins, most cephalosporins, some beta-lactam antibiotics, nitrofurantoin, methotrexate, chlorpropamide and other oral sulfonylurea antidiabetic agents, heparin, aminosalicylic acid, and dapsone. Concomitant administration of probenecid and the above mentioned weak organic acid drug may increase plasma concentrations of the acid drug, resulting in an increased incidence of adverse reactions associated with these weak organic acid drugs. The uricosuric actions of probenecid and salicylates are mutually antagonistic. Salicylate-induced uricosuria is inhibited by usual doses of probenecid. However, probenecid-induced uricosuria appears to be inhibited principally when the serum salicylate concentration exceeds 50 ug/ml. Concomitant administration of probenecid and indomethacin increases plasma concentration, plasma half-life, and therapeutic effects of indomethacin. Concomitant administration of probenecid and some nonsteroidal anti-inflammatory agents (e.g., ketoprofen, meclofenamate, naproxen, sulindac) increases the plasma elimination half-lives and plasma concentrations of these agents. Probenecid has also been reported to affect renal excretion of the following drugs:Sulfinpyrazone and its active metabolite, the active metabolite of allopurinol, acetaminophen, lorazepam, furosemide, ethacrynic acid, thiopental sodium. Probenecid increases excretion of calcium, magnesium, and citrate in patients taking thiazide diuretics, but does not antagonize thiazide-induced naturesis. [AHFS Drug Information 1997; p 2067] ADVERSE EFFECTS Reported adverse reactions include the following (listed in order of decreasing severity within each category), central nervous system: headache, dizziness; metabolic: precipitation of acute gouty arthritis; gastrointestinal: hepatic necrosis, vomiting, nausea, anorexia, sore gums; genitourinary: nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency; hypersensitivity: anaphylaxis, fever, urticaria, pruritis; hematologic: aplastic anemia, leukopenia, hemolytic anemia which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells, anemia; integumentary: dermatitis, alopecia, and flushing. [PDR 1997; p 1653] CONTRAINDICATIONS Should not be given to people with a known hypersensitivity to probenecid or to children under 2 years of age. Probenecid is not recommended for patients with known blood dyscrasias, uric acid kidney stones, or during an acute attack of gout. [PDR 1997; p 1652] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A sulfonamide derivative uricosuric drug. [AHFS Drug Information 1997; p 2065] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H19-N-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 285.37 [USPD 1998; p. 603] CHEMICAL/PHYSICAL DATA Melting Point: 194-196 C [Merck Index 1996; p. 1331] CHEMICAL/PHYSICAL DATA Elemental Comp: C54.72%, H6.71%, N4.91%, O22.43%, S11.24% [Merck Index 1996; p. 1331] CHEMICAL/PHYSICAL DATA Solubility: Soluble in dilute alkali, in alcohol, in chloroform, and in acetone; it is practically insoluble in water and in dilute acids. [PDR 1997; p 1651] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White or practically white, practically odorless, fine, crystalline powder. [AHFS Drug Information 1997; p 2065] SUBSTANCE DELIVERY DATA DOSAGE FORM: Yellow capsule-shaped, film-coated tablets (0.5 g). [PDR 1997; p 1653] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AHFS Drug Information 1997; p 2067] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store between 15 C and 30 C in a well-closed container. [AHFS Drug Information 1997; p 2065] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)325-9994 MANUFACTURERS 0000001241: Lannett Co Inc 9000 State Rd Philadelphia, PA 19136 Contact: Vlad Mikijanic (215)333-9000 REFERENCES MED/97226442. Chavez-de la Paz E, Arevalo JF, Kirsch LS, Munguia D, Rahhal FM, De Clercq E, Freeman WR. Anterior nongranulomatous uveitis after intravitreal HPMPC (cidoforvir) for the treatment of cytomegalovirus retinitis. Analysis and prevention. Opthalmology. 1997 Mar;104(3):539-44. MED/97172876. Lalezari JP, Stagg RJ, Kupperman BD, Holland GN, Kramer F, Ives DV, Youle M, Robinson MR, Drew WL, Jaffe HS. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med. 1997 Feb;126(4):257-63. MED/96439409. Lea AP, Bryson HM. Cidofovir. Drugs. 1996 Aug;52(2):225-230 (discussion in 231). MED/96012180. Cundy KC, Petty BG, Flaherty J, Fisher PE, Polis MA, Wachsman M, Lietman PS, Lalezari JP, Hitchcock MJ, Jaffe HS. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1995 Jun;39(6):1247-52. MED/95221982. Lalezari JP, Drew WL, Glutzer E, James C, Miner D, Flaherty J, Fisher PE, Cundy K, Hannigan J, Martin JC, et al. (S)-1-[3-hydroxy-2(phosphonylmethoxy)propyl]c- ytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis. 1995 Apr;171(4):788-96. ICA10/94370878. Gaines K, Wong R, Jung D, Cimoch P, Lavelle J, Pollard R. Pharmacokinetic interactions with oral ganciclovir: zidovudine, didanosine, probenecid. Int Conf AIDS. 1994 Aug 7-12;10(1):7 (abstract no. 004B). ICA9/93335101. Rolfs R, Gold M, Hackett K, Augenbraun M, Brady W, Larsen S. Treatment of early syphilis in HIV-infected and HIV-uninfected patients--preliminary report of the syphilis & HIV study group. Int Conf AIDS. 1993 Jun 6-11;9(1):391 (abstract no. PO-B11-1534). ICA7/3104891. Berrebi A, Dumas JC, Giroux M, Teixeira MG, Clottes A, Houin G, Grandjean H. AZT materno-fetal and feto-maternal transfer: an ex-vivo study. Int Conf AIDS. 1991 Jun 16-21;7(2):104 (abstract no. W.A.1048). MED/90301666. Hedaya MA, Elmquist WF, Sawchuk RJ. Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers. Pharm Res. 1990 Apr;7(4):411-7. ICDB/90665058. Hedaya MA. Zidovudine Pharmacokinetics and Interaction Studies with Probencid. Diss Abstr Int [B]. 1990;50(8):3422. ENTRY MONTH 199104 LAST REVISION DATE 20001107 294 UNIQUE IDENTIFIER DRG-0052 NAME OF SUBSTANCE Quinine sulfate [USPD 1998; p. 623] REGISTRY NUMBER 6119-70-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Cinchonan-9-ol, 6'-methoxy-, (8alpha,9R)-, sulfate (2:1) (salt), dihydrate [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Quinamm [Merck Index 1996; p. 1387] PROTOCOL ID NUMBERS Complete NIAID ACTG 027 PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of antimalarial activity of quinine has not been determined but it appears to interfere with the function of plasmodial DNA. Quinine has several effects on skeletal muscle. Quinine increases the tension response to a single maximum stimulus to muscle which is either received directly or through a nerve; however, the drug increases the refractory period of the muscle by a direct action on the muscle fiber so that the responses to tetanic stimulation is diminished. Quinine has a curarelike effect and decreases the excitability of the motor endplate so that responses to repetitive nerve stimulation or acetylcholine are reduced. The drug also appears to affect the distribution of calcium within muscle fiber. Quinine has a local anesthetic action similar to those of quinidine. Quinine is a blood schizonticidal agent and is active against the asexual erythrocytic forms of plasmodium falciparum, P. malariae,P. Ovale, and P. vivax. The drug is not active against sporozoites or preerythrocytic or exoerythrocytic forms of plasmodia. Quinine is also gametocyticidal for P. malariae and P. vivax, but has no direct activity against the gametocytes of P. falciparum. Quinine sulfate is almost completely absorbed from the GI tract. Absorption of quinine occurs mainly from the upper small intestine. Following administration of a single oral dose, peak serum concentrations of quinine generally occur within 1-3 hours. Plasma concentrations of quinine are higher and the plasma half-life of the drug may be longer in patients with malaria than in healthy individuals or patients convalescing from malaria, apparently because malaria can cause impaired hepatic function which results in a decrease in total body clearance of quinine and a decrease in the volume of distribution of the drug. Quinine is widely distributed in body tissues. Concentrations of quinine in CSF are reported to be 2-7% of concurrent plasma concentrations of the drug. Quinine readily crosses the placenta and is distributed into milk. Quinine is approximately 70% bound to plasma proteins in healthy adults. The plasma elimination half-life of quinine reportedly averages 11-12 hours in those with malaria and 6 hours in those convalescing from the disease. Quinine sulfate is extensively metabolized, mainly in the liver. Following oral administration of a single dose of quinine sulfate, metabolites of the drug are excreted in urine and less than 5% of the dose is excreted in urine as unchanged drug. Because quinine is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline. Quinine is removed by hemodialysis or charcoal hemoperfusion, but the drug is not effectively removed by peritoneal dialysis. [AHFS Drug Information 1997; p 571] DISEASES STUDIED/TREATED Possible use in reducing the amount of AZT needed for treating patients with symptomatic HIV infection (AIDS or symptomatic AIDS-related complex (ARC)), via impairment of renal AZT elimination. The combination of quinine sulfate and clindamycin may be useful in the treatment of cryptosporidiosis. [Int Conf AIDS 1986 (2nd); DeMiranda P, et al. (Abstracts) Paris, France; AHFS Drug Information 1997; p 572] CLASSIFICATION CODE Antimyotonic [USP DI 2000; p. 2618] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2618] OTHER MAJOR USES Treatment of malaria, nocturnal recumbent leg muscle cramps and Babesia microti infections. [AHFS Drug Information 1997; p 571-2] SUBSTANCE INTERACTIONS Quinine interacts with mefloquine, cardiac glycosides (e.g. digoxin, digitoxin),astemizole, terfenadine, antacids containing aluminum, cimetidine, neuromuscular blocking agents (particularly pancuronium, succinylcholine, and tubocurarine), cinchona alkaloids (including quinine), heparin, agents that increase the urinary pH(e.g., sodium bicarbonate, acetazolamide). [AHFS Drug Information 1997; p 573] ADVERSE EFFECTS Adverse effects include the following, hypersensitivity reactions: cutaneous flushing, pruritus, rash (urticarial, papular, scarlatinal), fever, facial edema, GI distress, dyspnea, tinnitus, and impairment of vision, and rarely hemoglobinuria and asthma; nervous system effects: cinchonism, visual disturbances, deafness, vertigo, headache, sweating, restlessness, confusion, syncope, apprehension, and fever, gastrointestinal system effects: nausea, vomiting, epigastric pain, hematologic effects: thrombocytopenia, leukopenia, pancytopenia, coagulopathy, disseminated intravascular coagulation, thrombocytopenic purpura, hypoprothrombinemia, and rarely agranulocytosis; hepatic effects: rarely granulomatous hepatitis and hepatocellular cholestatic hepatotoxicity; cardiovascular effects: conduction disturbances, ventricular tachycardia, and anginal symptoms. Other adverse effects include hypoglycemia, and renal failure. [AHFS Drug Information 1997; p 572; USP DI 1997; p 2496] CONTRAINDICATIONS May cause fetal harm and congenital malformations when administered to pregnant women, and is contraindicated in women who are or may become pregnant. It is also contraindicated in patients with known quinine hypersensitivity, and in patients with glucose-6-phosphate dehydrogenase deficiency, history of thrombocytopenic purpura, tinnitus or optic neuritis, or history of blackwater fever, cardiac arrhythmias, hypoglycemia or myastheniagravis. [AHFS Drug Information 1997; p 572; USP DI 1997; p 2496] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Alkaloid obtained from the bark of the cinchona tree. [AHFS Drug Information 1997; p 571] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H24-N2-O2.1/2H2-O4-S.2H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 782.96 [USPD 1998; p. 623] CHEMICAL/PHYSICAL DATA Melting Point: 177 C (some decomposition) [Merck Index 1996; p. 1386] CHEMICAL/PHYSICAL DATA Elemental Comp: C74.05%, H7.46%, N8.63%, O9.86% (base) [Merck Index 1996; p. 1386] CHEMICAL/PHYSICAL DATA Solubility: 1 g dissolves in 810 ml water, 32 ml boiling water, 120 ml alcohol. Slightly soluble in chloroform, either, but freely soluble in a mixture of 2 vols chloroform and 1 vol absolute alcohol. [Merck Index 1996; p 1387] CHEMICAL/PHYSICAL DATA Stability: Quinine sulfate darkens on exposure to light. [AHFS Drug Information 1997; p 571] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Quinine sulfate occurs as fine, needle-like, white crystals that usually are lusterless and make a light and readily compressible mass, it has a persistant, very bitter taste. [AHFS Drug Information 1997; p 571] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (260, 325 mg). [AHFS Drug Information 1997; p 574] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral (sulfate). Intravenously (dihydrochloride). [AHFS Drug Information 1997; p 571] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored in well-closed containers at a temperature less than 40 C, preferably between 15-30 C. [AHFS Drug Information 1997; p 571] MANUFACTURERS 0000001167: Merrell Dow Pharmaceuticals (nka Aventis Pharmaceuticals) PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Clinical Research (513)948-7796 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Medical Information (800)633-1610 MANUFACTURERS 0000002728: Hoechst Marion Roussel Inc PO Box 9627 / 10236 Marion Park Dr Kansas City, MO 641340627 Contact: Unspecified (888)242-9321 REFERENCES MED/97285146. Dankwa E. Aids to smoking cessation [letter]. N Z Med J, 1997 Apr 11, 110:1041, 131-2. MED/96309048. Falagas ME, Klempner MS. Babesiosis in patients with AIDS: a chronic infection presenting as fever of unknown origin. Clin Infect Dis. 1996 May;22(5):809-12. MED/94295478. Niyongabo T, Deloron P, Aubry P, Ndarugirire F, Manirakiza F, Muhirwa G, Ndayiragije A, Brelivet JC. Prognostic indicators in adult cerebral malaria: a study in Burundi, an area of high prevalence of HIV infection. Acta Trop. 1994 Apr;56(4):299-305. ICA7/3129191. Dayachi F, Kabongo L, Ngoie K. Decreased mortality from malaria in children with symptomatic HIV infection. Int Conf AIDS. 1991 Jun 16-21;7(2):164 (abstract no. W.A.1291). MED/91037077. Colebunders R, Bahwe Y, Nekwei W, Ryder R, Perriens J, Nsimba K, Turner A, Francis H, Lebughe I, Van der Stuyft P, et al. Incidence of malaria and efficacy of oral quinine in patients recently infected with human immunodeficiency virus in Kinshasa, Zaire. J Infect. 1990 Sep;21(2):167-73. MED/89363690. Kornhauser DM, Petty BG, Hendrix CW, Woods AS, Nerhood LJ, Bartlett JG, Lietman PS. Probenecid and zidovudine metabolism [see comments]. Lancet. 1989 Aug 26;2(8661):473-5. MED/84141731. Update: treatment of cryptosporidiosis in patients with acquired immunodeficiency syndrome (AIDS). MMWR Morb Mortal Wkly Rep. 1984 Mar 9;33(9):117-9. MED/84278951. Ruocco V, Sacerdoti G, Astarita C. Does quinine facilitate AIDS? Antibiot Chemother. 1983;32:159-60. ENTRY MONTH 199104 LAST REVISION DATE 20000801 295 UNIQUE IDENTIFIER DRG-0051 NAME OF SUBSTANCE Uravadine [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] REGISTRY NUMBER 84472-85-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3'-Azido-2',3'-dideoxyuridine [MeSH ] PROTOCOL ID NUMBERS No longer recruiting CC 89 CC-62 PHARMACOLOGICAL ACTION MODE OF ACTION: (Human data unavailable.) Inhibits HIV replication by inhibiting reverse transcriptase. In peripheral blood mononuclear cells, the major metabolite of 3'-azido-2',3'-dideoxyuridine (AzdU) is AzdU-5' monophosphate. It is believed that this monophosphate becomes di- and triphosphorylated by cellular enzymes. Triphosphorylated AzdU interferes with the RNA-dependent DNA polymerase (reverse transcriptase) of several retroviruses, including HIV, and thus inhibits HIV replication preventing cDNA synthesis. Like zidovudine (azidothymidine (AZT)), it inhibits cellular DNA polymerase alpha; however, concentrations of AzdU that inhibit cellular DNA polymerase are 3000- to 5000-fold greater than those required to inhibit HIV reverse transcriptase. In various cell-virus systems, the activity of AzdU varied from system to system: the anti-viral activity of AzdU in peripheral blood mononuclear (PBM) and MT-4 cell cultures was 100 times less than that of AZT, regardless of the type of retrovirus used; in HeLa-T4 cell cultures, AZT was only 3.5 times more active than AzdU; in ATH8 cells, AzdU and AZT inhibited HIV-induced CPE equally well; in human monocytes and macrophages, AzdU was 10-20 times more active than in PBM cell cultures. [AmfAR Treat Dir 1988 Dec; p 57; Protocol ID: 89 CC-62 ] DISEASES STUDIED/TREATED Primary HIV infection. [Protocol ID: 89 CC-62 ] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS According to one in vitro study, 3'-azido-2',3'-dideoxyuridine (AzdU) is 30 times less toxic to human bone marrow derived granulocyte-macrophage and erythroid precursor cells than zidovudine. No overt toxicity was observed in animal studies using rats and dogs (given, respectively, 2500 and 1000 mg/kg, orally for 28 days). In human studies, maximum tolerated dose has not yet been reached. Azdu has been well tolerated with mild headache being the only major subjective side effect to date. No patient has developed anemia, but one patient in a phase I trial developed grade 3 neutropenia which resolved with a 50% dose decrease. [Int Conf AIDS 1990 Jun 20-23;6(3); 206 (abstract no. S.B. 482); AmfAR Treat Dir 1988 Dec; p 57; Protocol ID: 89 CC-62 ] CONTRAINDICATIONS Contraindicated in pregnant or breastfeeding women, or in patients with previous systemic allergic reaction to the study drug. [Protocol ID: 89 CC-62 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic pyrimidine nucleoside analog of zidovudine. [AmfAR Treat Dir 1988 Dec; p 57] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H11-N5-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 253.22 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Stability: Approximately 7 mg/ml in water at 20 C. [Protocol ID: 89 CC-62 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White powder. [Protocol ID: 89 CC-62 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Drug supplied for injection is unpreserved, sterile, isotonic solution at concentration of 6.67 mg/ml, supplied in glass bottles of 200 mg of drug in 30 ml of ready-to-use injectable solution. For oral use, drug is supplied in white, capsule-shaped tablets in 10 and 100 mg strengths. [Protocol ID: 89 CC-62 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous injection; oral. [Protocol ID: 89 CC-62 ] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/96206497. Hong CI, Nechaev A, Kirisits AJ, Vig R, West CR, Manouilov KK, Chu CK. Nucleoside conjugates. 15. Synthesis and biological activity of anti-HIV nucleoside conjugates of ether and thioether phospholipids. J Med Chem. 1996 Apr 26;39(9):1771-7. ICA10/94371446. Chu CK, Manouilov KK, White CA, Federov I, Boudinot FD. Disposition of AZT and AZdU in lymph nodes of mice. Int Conf AIDS. 1994 Aug 7-12;10(2):202 (abstract no. PB0822). MED/94062551. Cretton EM, Sommadossi JP. Reduction of 3'-azido-2',3'-dideoxynucleosides to their 3'-amino metabolite is mediated by cytochrome P-450 and NADPH-cytochrome P-450 reductase in rat liver microsomes. Drug Metab Dipos. 1993 Sep-Oct;21(5):946-50. MED/91315592. Resetar A, Minick D, Spector T. Glucuronidation of 3'-azido-3'deoxythmidine catalyzed by human liver UDP-glucuronosyltransferase. Significance of nucleoside hydrophobicity and inhibition by xenobiotics. Biochem Pharmacol. 1991 Jul 15;42(3):559-68. MED/91219338. Gallo JM, Etse JT, Doshi KJ, Boudinot FD, Chu CK. Hybrid pharmacokinetic models to describe anti-HIV nucleoside brain disposition following parent and prodrug administration in mice. Pharm Res. 1991 Feb;8(2):247-53. MED/90325212. Chu CK, Bhadti VS, Doshi KJ, Etse JT, Gallo JM, Boudinot FD, Schinazi RF. Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine. J Med Chem. 1990 Aug;33(8):2188-92. ICA6/30048390. Polis M, Davey R, Lee D, Falloon J, Kovacs J, Metcalf J, Amantea M, Zurlo J, Zunich K, Rosenthal Y, et al. A dose escalation study to evaluate the safety, anti-viral and immunological effects of 3'-azido-2',3'-dideoxyuridine (AZDU) in patients with HIV-1 infection. Int Conf AIDS. 1990 Jun 20-23;6(3):206 (abstract no. S.B.483). ICA6/30048290. Mitsuyasu RT, Miles SA, Wallenberg J, Williams G, Marcus S. Phase I trial of 3'-azido-2',3'-dideoxyuride (AZDU) in patients with symptomatic HIV infection. Int Conf AIDS. 1990 Jun 20-23;6(3):206 (abstract no. S.B.482). MED/91047526. Myers MW. New antiretroviral agents in the clinic. Rev Infect Dis. 1990 Sep-Oct;12(5):944-50. ICA6/10026190. Tsai CC, Follis KE, Yarnall M, Deaver LE, Benveniste RE, Sager PR. Screening for the antiretroviral agents against SIV in vitro. Int Conf AIDS. 1990 Jun 20-23;6(1):185 (abstract no. Th.A.261). ENTRY MONTH 199104 LAST REVISION DATE 20000801 296 UNIQUE IDENTIFIER DRG-0050 NAME OF SUBSTANCE Methylprednisolone [USPD 1998; p. 465] REGISTRY NUMBER 83-43-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6alpha,11beta)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Depo-Medrol (acetate) [USP DI 2000; p. 1056] SYNONYMS Medrol [USP DI 2000; p. 1055] SYNONYMS Solu-Medrol (sodium succinate) [USP DI 2000; p. 1056] PROTOCOL ID NUMBERS Terminated NIAID ACTG 030 PROTOCOL ID NUMBERS Terminated NIAID ACTG 170 PHARMACOLOGICAL ACTION MODE OF ACTION: May cause profound and varied metabolic effects, modifying the body's immune responses to diverse stimuli. Increases salt, calcium, and water retention and decreases potassium excretion. Anti-inflammatory actions include inhibition of accumulation of inflammatory cells (including macrophages and leukocytes) at inflammation sites, and inhibition of phagocytosis, lysosomal enzyme release, and synthesis and/or release of several chemical mediators; immunosuppressant actions may involve prevention/suppression of cell-mediated (delayed hypersensitivity) immune reactions and more specific actions affecting immune response; immunosuppressant actions may also contribute significantly to the anti-inflammatory effect. Oral dose is rapidly and almost completely absorbed from gastrointestinal tract (intramuscular dose of acetate form is slowly but completely absorbed); biotransformation is primarily hepatic; elimination is primarily by renal excretion of inactive metabolites. Oral dose of methylprednisolone has a peak effect of 1-2 hours and a duration of action of 1.25-1.5 days; intramuscular injection of the acetate form has an onset of action of 6-48 hours, a peak effect of 4-8 days, and a duration of action of 1-4 weeks. Intravenous doses (sodium succinate) have a rapid onset of action. [PDR 1995; p 2561; USP DI 1997; p 958-966, 971] DISEASES STUDIED/TREATED Used in conjunction with TMP/SMX (trimethoprim-sulfamethoxazole) or alternative regimens at the beginning of treatment of an acute episode of moderate to servere Pneumocystis carinii pneumonia. [AmfAR Treat Dir 1997;8(3); p 111] CLASSIFICATION CODE Anti-inflammatory [USP DI 2000; p. 1037] CLASSIFICATION CODE Corticosteroid [USP DI 2000; p. 1037] CLASSIFICATION CODE Immunosuppressant [USP DI 2000; p. 1037] OTHER MAJOR USES Used for treating adrenocortical function abnormalities; various disorders (allergic; collagen; dermatologic; gastrointestinal; hematologic; ophthalmic; oral; respiratory; rheumatic); hepatic disease; carcoidosis; nonrheumatic inflammation; neoplastic disease; nephrotic syndrome; neurologic disease. [PDR 1995; p 2561] SUBSTANCE INTERACTIONS May cause neurological complications and lack of antibody response if smallpox vaccine or other immunization vaccines are used while being treated with this drug. Troleandomycin may decrease metabolism of methylprednisolone; may exhibit interactions with a variety of drugs similar to those reported for other adrenocorticoids having systemic glucocorticoid effects. Concurrent use of cyclosporine can result in inhibition of the metabolism of both drugs. Convulsions have also been reported with concurrent cyclosporine use. Hepatic enzyme inducers may increase the clearance of methylprednisolone and may require an increased dose of the steroid. Aspirin clearance may be increased, decreasing salicylate levels. The activity of oral anticoagulants has been both decreased and increased by concomitant methylprednisolone. [PDR 1995; p 2562] ADVERSE EFFECTS May cause fluid and electrolyte disturbances and a wide variety of adverse musculoskeletal, gastrointestinal, neurological, endocrine, opthalmic, or metabolic effects. The 24 mg tablet contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions, including bronchial asthma, in certain individuals, frequently in patients who also have aspirin hypersensitivity. [USP DI 1997; p 964] CONTRAINDICATIONS Contraindicated for patients with systemic fungal infections. [PDR 1995; p 2561] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Glucocorticoid; adrenocorticoid. [PDR 1995; p 2561] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H30-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 374.48 [USPD 1998; p. 465] CHEMICAL/PHYSICAL DATA Melting Point: 228-237 C [Merck Index 1996; p. 1043] CHEMICAL/PHYSICAL DATA Elemental Comp: C70.56%, H8.07%, O21.36% [Merck Index 1996; p. 1042] CHEMICAL/PHYSICAL DATA Solubility: Sparingly soluble in alcohol, dioxane, and methanol; slightly soluble in acetone and chloroform; very slightly soluble in ether; practically insoluble in water. [PDR 1995; p 2561] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Practically white, odorless, crystalline powder. [AHFS Drug Information 1996; p 2235] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets containing 2, 4, 8, 16, 24, or 32 mg of drug; sterile methylprednisolone acetate suspensions, 20 mg, 40 mg or 80 mg/ml and rectal enema, 40 mg. Intravenous and intramuscular sodium succinate injections, 40 mg, 125 mg, 500 mg, 1g, and 2 g vials. [PDR 1995; p 2541-3, 2561, 2583; USP DI 1997; p 971-2] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Methylprednisolone is administered orally. The acetate or the sodium succinate may be administered by IM, intra-articular, intralesional, or soft tissue injection. [AHFS Drug Information 1996; p 2235-6; USP DI 1997; p 972] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature of 15-30 C (59-86 F). Use reconstituted methylprednisolone sodium succinate within 48 hours. Do not use if the solution is cloudy or contains a precipitate. [USP DI 1997; p 971-2] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 REFERENCES MED/96085718. Martos A, Podzamczer D, Martinez-Lacasa J, Rufi G, Santin M, Gudiol F. Steroids do not enhance the risk of developing tuberculosis or other AIDS-related diseases in HIV-infected patients treated for Pneumocystis carinii pneumonia. AIDS. 1995 Sep;9(9):1037-41. MED/95187915. Bozzette SA, Morton SC. Reconsidering the use of adjunctive corticosteroids in Pneumocystis pneumonia? [editorial;comment]. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Apr 1;8(4):345-7. MED/95187916. Walmsley S, Levinton C, Brunton J, Muradali D, Rappaport D, Bast M, Spence D, Salit I. A multicenter randomized double-blind placebo-controlled trial of adjunctive corticosteroids in the treatment of Pneumocystis carinii pneumonia complicating the acquired immune deficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Apr 1;8(4):348-57. MED/94204810. Bernstein B, Flomenberg P, Letzer D. Disseminated cryptococcal disease complicating steroid therapy for Pneumocystis carinii pneumonia in a patient with AIDS. South Med J. 1994 Apr;87(4):537-8. MED/94312804. Galli E, Chini L, Moschese V, Paone F, Menichelli A, Fraioli G, Rossi P. Methylprednisolone bolus: a novel therapy for severe atopic dermatitis. Acta Paediatr. 1994 Mar;83(3):315-7. MED/94079095. Bentsen KD, Nielsen TL, Eaftinck Schattenkerk JK, Jensen BN, Lundgren JD. Serum type III procollagen peptide in patients with Pneumocystis carinii infection. Am Rev Respir Dis. 1993 Dec;148(6 Pt 1):1558-62. MED/93127239. Elli A, Rivolta R, Di Palo FQ, Parenti M, Vergallo G, Palazzi P, Zafiropulu S, Abelli P, Zanussi C. A randomized trial of deflazacort versus 6-methylprednisolone in renal transplantation--immunosuppressive activity and side effects. Transplantation. 1993 Jan;55(1):209-12. MED/92386980. LaRocco A Jr, Amundson DE, Wallace MR, Malone JL, Oldfield EC 3d. Corticosteroids for Pneumocystis carinii pneumonia with acute respiratory failure. Experience with rescue therapy. Chest. 1992 Sep;102(3):892-5. MED/93043729. Sistek CJ, Wordell CJ, Hauptman SP. Adjuvant corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS patients. Ann Pharmacother. 1992 Sep;26(9):1127-33. MED/91042861. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A double-blind, placebo-controlled trial. N Engl J Med. 1990 Nov 22;323(21):1444-50. ENTRY MONTH 199104 LAST REVISION DATE 20001107 297 UNIQUE IDENTIFIER DRG-0049 NAME OF SUBSTANCE Flucytosine [USPD 1998; p. 314] REGISTRY NUMBER 2022-85-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Ancobon [PDR 2000; p. 1391] PROTOCOL ID NUMBERS Complete NIAID ACTG 059 PROTOCOL ID NUMBERS Complete NIAID ACTG 159 PROTOCOL ID NUMBERS Complete NIAID ACTG 202 PROTOCOL ID NUMBERS No longer recruiting FDA 012F PROTOCOL ID NUMBERS No longer recruiting FDA 012G PROTOCOL ID NUMBERS No longer recruiting FDA 213A PROTOCOL ID NUMBERS No longer recruiting FDA B013 PHARMACOLOGICAL ACTION MODE OF ACTION: Flucytosine has in vitro and in vivo activity against Candida and Cryptococcus. It has been proposed that it acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, it is metabolized to 5-flurouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Flucytosine is rapidly and well absorbed (75-90%) from the gastrointestinal tract. In patients with normal renal function, peak serum concentrations of 30-45 ug/ml are reached within 6 hours following a 2-g oral dose. After 4 days or more of flucytosine therapy, peak serum concentrations occur within 2 hours after a dose is given. Peak serum concentrations are higher, more prolonged, and reach more slowly in patients with impaired renal function; in anephric patients, peak serum concentrations maybe 50% higher than those in patients with normal renal function. Flucytosine is widely distributed into body tissues and fluids including liver, kidney, spleen, heart, aqueous humor, and bronchial secretions. It appears that CSF concentrations may range from 60-100% of serum concentrations of the drug. The apparent volume of distribution is about 0.68% L/kg in healthy adults and has ranged from 0.4-0.7 L/kg in patients with renal failure. At a concentration of 2-55 ug/ml, flucytosine is approximately 2-4% bound to serum proteins. The elimination half-life of flucytosine has been variously reported to be 2.5-6 hours in patients with normal renal functions. Only minimal amounts of flucytosine are metabolized in humans. About 75-90% of an oral dose of flucytosine is excreted unchanged in urine. Urinary concentrations of flucytosine are generally 10-100 times greater than serum concentrations, although urinary drug concentrations are much lower in patients with impaired renal function. Unabsorbed flucytosine is excreted unchanged in the feces. Flucytosine is readily removed by peritoneal dialysis or hemodialysis. [PDR 1997; p 2254; AHFS Drug Information 1997; p 88] DISEASES STUDIED/TREATED Used with amphotericin B for treating acute cryptococcal meningitis. [AmfAR Treat Dir 1996;8(2); p 78, 101] CLASSIFICATION CODE Antifungal [USP DI 1998; p. 1444] OTHER MAJOR USES Flucytosine is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. [PDR 1997; p 2254] SUBSTANCE INTERACTIONS Synergistic relationship has been demonstrated between flucytosine and amphotericin B in the inhibtion of strains of Cryptococcus neoformans, Candida albicans, and Candida the inhibition of strains of Cryptococcus neoformans, Candida albicans, and Candida tropicals. Concomitant administration of amphotericin B and flucytosine may increase the toxicity of flucytosine. Norfloxacin may enhance the antifungal activity of flucytosine. Cytarabine reportedly antagonizes the antifungal activity of flucytosine. Drugs which impair glomerular filtration may prolong the biological half-life of flucytosine. [AHFS Drug Information 1997; p 89] ADVERSE EFFECTS Adverse reactions include the following, cardiovascular: cardiac arrest, respiratory: respiratory arrest, chest pain, dyspnea; dermatologic: rash, pruritus, urticaria, photosensitivity; gastrointestinal: nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, hepatic dysfunction, jaundice, ulcerative colitis, bilirubin elevation; genitourinary: azotemia, creatinine and BUN elevation, crystalluria, renal failure; hematologic: anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia; neurologic: ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation; psychiatric: confusion, hallucinations, psychosis. Other miscellaneous adverse effects include fatigue, hypoglycemia, hypokalemia, weakness. [PDR 1997; p 2255] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to the drug. Should be considered with extreme caution for patients with impaired renal funtion and patients with bone marrow depression. Since the drug has shown experimental teratogenic effects, its potential benefits and hazards should be considered before administering to pregnant or lactating women or women of child-bearing age. [PDR 1997; p 2254-5] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fluorinated pyrimidine chemically related to fluorouracil and floxuridine. [AHFS Drug Information 1997; p 88] CHEMICAL/PHYSICAL DATA Molecular Formula: C4-H4-F-N3-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 129.09 [USPD 1998; p. 314] CHEMICAL/PHYSICAL DATA Melting Point: 295-297 C [Merck Index 1996; p. 698] CHEMICAL/PHYSICAL DATA Elemental Comp: C37.22%, H3.12%, F14.72%, N32.55%, O12.39% [Merck Index 1996; p. 698] CHEMICAL/PHYSICAL DATA Solubility: 1.5 g/100 ml (25 C, in water) [Merck Index 1996; p 698] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder which may be odorless or have a slight odor. [AHFS Drug Information 1997; p 88] SUBSTANCE DELIVERY DATA DOSAGE FORM: 250 mg and 500 mg gelatin capsules. [PDR 1997; p 2254] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 2254] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at controlled room temperature of 15-30 C (59-86 F) in a tight, light-resistant container. [AHFS Drug Information 1997; p 88] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES MED/97046181. Aberg JA, Powderly WG. Cryptococcosis. Adv Pharmacol. 1997;37:215-51. MED/97143058. Barbaro G, Barbarini G, Di Lorenzo G. Fluconazole vs itraconazole-flucytosine association in the treatment of esophageal candidiasis in AIDS patients. A double-blind, multicenter placebo-controlled study. The Candida Esophagitis Multicenter Italian Study (CEMIS)Group. Chest. 1996 Dec;110(6):1507-14. AIDS/97702139. D'Amico R. ICAAC update on opportunistic infections. Posit Aware. 1996 Nov/Dec;7(6):16-8. MED/97068983. Gyaurgieva OH, Bogomolova TS, Gorshkova GI. Meningitis caused by Rhodotorula rubra in an HIV-infected patient. J Med Vet Mycol. 1996 Sep-Oct;34(5):357-9. MED/97032328. Gonzalez CE, Shetty D, Lewis LL, Mueller BU, Pizzo PA, Walsh TJ. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1996 Sep;15(9):796-800. MED/96437752. Zeind CS, Cleveland KO, Menon M, Brown JR, Solomon DK. Cryptococcal meningitis in patients with acquired immunodeficiency syndrome. Pharmacotherapy. 1996 Jul-Aug;16(4):547-61. MED/97008503. Riantawan P, Ponglertnapakorn P. Clinical Efficacy of itraconazole with initial flucytosine in AIDS-related cryptococcal meningitis: a preliminary study. J Med Assoc Thai. 1996 Jul;79(7):429-33. MED/96435304. Witt MD, Lewis RJ, Larsen RA, Milefchik EN, Leal MA, Haubrich RH, Richie JA, Edwards JE Jr, Ghannoum MA. Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: the role of antifungal susceptibility testing [see comments]. Clin Infect Dis. 1996 Feb;22(2):322-8. [Comment in Clin Infect Dis. 1996 Feb;22(2):329-30.] MED/96358229. Benard G, Gryschek RC, Duarte AJ, Shikanai-Yasuda MA. Cryptococcosis as an opportunistic infection in immunodeficiency secondary to paracoccidioidomycosis. Mycopathologia. 1996;133(2):65-9. MED/96008522. Drugs for AIDS and associated infections. Med Lett Drugs Ther. 1995 Oct;37(959):87-94. ENTRY MONTH 199104 LAST REVISION DATE 20000801 298 UNIQUE IDENTIFIER DRG-0048 NAME OF SUBSTANCE Cyclophosphamide [USPD 1998; p. 202] REGISTRY NUMBER 6055-19-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N,N-Bis (2-chloroethyl)tetrahydro- 2H- 1,3,2- oxazaphosphorin- 2- amine 2-oxide monohydrate [Merck Index 1996; p 463] SYNONYMS Cytoxan [USP DI 2000; p. 1161] SYNONYMS Neosar [USP DI 2000; p. 1161] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-207 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 380 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PROTOCOL ID NUMBERS Terminated NIAID ACTG 252 PHARMACOLOGICAL ACTION MODE OF ACTION: Following conversion to active metabolites in the liver, cyclophosphamide functions as an alkylating agent, interfering with DNA replication and transcription of RNA, and ultimately resulting in the disruption of nucleic acid function. The drug exibits phsophorylating properties that also enhance its cytotoxicity. The drug also possesses potent immunosuppressive activity. Cyclophosphamide appears to be well absorbed following oral administration with a reported bioavailablitiy greater than 75%. Maximum plasma concentrations of the drug occur at about 1 hour. Concentrations of cyclophosphamide metabolites reportedly reach maximum levels 2-3 hours after an intravenous dose of the drug. Cyclophosphamide and its metabolites appear to be distributed throughout the body, including the brain and CSF, but probably not in concentrations sufficient to treat meningeal leukemia. It is assumed that cyclophosphamide crosses the placenta, and is distributed into milk. The seurm half-life after intravenous administration of cyclophosphamide has been reported to range from 3-12 hours; however, the drug and/or its metabolites can be detected in the serum up to 72 hours after administration. Cyclophosphamide is metabolized in the liver by enzymatic mixed-function oxidase system of liver microsomes to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide, the cyclic tautomer. 4-Hydroxycyclophosphamide may be enzymatically metabolized to 4-ketocyclophosphamide, and aldophosphamide may be enzymatically metabolized to carboxyphosphamide, phosphoramide mustard, and acrolein. Cyclophoshamide and its metabolites are excreted principally in urine, with about 36-99% of a dose being eliminated within 48 hours; of the amount excreted, about 5-30% is unchanged drug. [AHFS Drug Information 1997; p 719] DISEASES STUDIED/TREATED Approved for anti-cancer therapy, under investigation for lymphoma. [AmfAR Treat Dir 1997;8(3); p 70] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1155] CLASSIFICATION CODE Immunosuppressant [USP DI 2000; p. 1155] OTHER MAJOR USES Cyclophosphamide has been used for the treatment of the following malignant diseases: malignant lymphomas (stages III and IV of the Ann Arbor staging system), Hodgkin's disease, lymphocytic lymphoma, mixed cell type lymphoma, histiocystic lymphoma, Burkitt's lymphoma; multiple myeloma; chronic lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children; mycosis fungoides (advanced disease); neuroblastoma (disseminated disease);adenocarcinoma of the ovary; retinoblastoma; carcinoma of the breast. [PDR 1997; p 700] SUBSTANCE INTERACTIONS Mesna (sodium 2-mercaptoethanesulphonate, a synthetic sulfhydryl compound) can chemically interact with urotoxic metabolites (and/or their precusros) of cyclophosphamide (e.g., acrolein, 4-hydroxycyclophosphamide) and other oxazaphophorine derivatives (e.g., ifosfamide) to decrease the incidence and severity of, or prevent, bladder toxicity (e.g., hemorrhagic cysitis) induced by these drugs. Concomitant administration of cyclophosphamide and other cardiotoxic drugs such as doxorubicin may potentiate the cardiotoxic effects of these drugs. Barbiturates and other drugs which induce liver microsomal enzymes may cause an increased pharmacologic effect and increased toxicity of cyclophosphamide because of increased conversion of the drug to active metabolites. Other drugs which may inhibit microsomal enzyme activity in the liver and therefore interfere with the metabolism of cyclophophamide include allopurinol, chloramphenicol, chloroquine, imipramine, phenothiazines, potassium iodide, and vitamin A. Cyclophosphamide reportedly reduced serum pseudocholinesterase concentrations and may prolong the neuromuscular blocking activity of succinylcholine, especially in very ill patients who are receiving large IV doses of the drug. The rate of metabolism and the leukopenic activity of the drug reportedly are increased by chronic administration of high doses of phenobarbital. [AHFS Drug Information 1997; p 722] ADVERSE EFFECTS Adverse reactions include the following, reproductive system: fetal harm, sterility in both sexes, amenorrhea, ovarian fibrosis, oligospermia or azoospermia; digestive system: nausea and vomiting, anorexia, and abdominal discomfort or pain and diarrhea, hemorrhagic colitis, oral mucosal ulceration and jaundice; skin: alopecia, skin rash, pigmentation changes in skin and nails; hematopoietic system: leukopenia, fever, thrombocytopenia or anemia; urinary system: hemorrhagic cystitis, urinary bladder fibrosis, hemorrhagic ureteritis, renal tubular necrosis; infections: suppression of immune responses; carcinogenesis: development of second malignancies with or without a latency of several years; respiratory system: interstitial pulmonary fibrosis. Rare instances of anaphylactic reaction including one death have also been reported. [PDR 1997; p 700-1] CONTRAINDICATIONS Contraindicated in patients who have demonstrated a previous hypersensitivity to it. Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Should not be used by pregnant or lactating women or by persons with heart conditions (cardiotoxicity). [PDR 1997; p 700-1] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Cyclophosphamide is a nitrogen mustard derivative which is a polyfunctional alkylating agent. [AHFS Drug Information 1997; p 718] CHEMICAL/PHYSICAL DATA Molecular Formula: C7-H15-Cl2-N2-O2-P.H2-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 279.10 [USPD 1998; p. 202] CHEMICAL/PHYSICAL DATA Melting Point: 41-45 C [Merck Index 1996; p. 463] CHEMICAL/PHYSICAL DATA Elemental Comp: C30.12%, H6.14%, Cl25.40%, N10.04%, O17.20%, P11.10% [Merck Index 1996; p. 463] CHEMICAL/PHYSICAL DATA Solubility: 40 g/l in water; slightly soluble in alcohol, benzene, ethylene glycol, carbon tetrachloride, dioxane; sparingly soluble in ether and acetone. [Merck Index 1996; p 429] CHEMICAL/PHYSICAL DATA Stability: Reconstituted solutions for injection are stable for 24 hours at room temperature or 6 days when stored at 2 to 8 C; however, manufacturers recommend usage within 6 hours due to lack of preservatives. Properly prepared extemporaneous oral liquid are stable for 14 days when stored at 2 to 8 C. [AHFS Drug Information 1997; p 719] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [AHFS Drug Information 1997; p 718] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lyophilized powders for injection available in 100, 200, and 500 mg single dose vials and 1, and 2 g multidose vials; tablets (25 and 50 mg). [PDR 1997; p 701] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous, intramuscular, intraperitoneal, or intrapleural injection. [PDR 1997; p 701] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powders and tablets should be stored at or below 25 C (77 F), product will withstand brief exposure to temperature up to 30 C (86 F) but should be protected from temperature above 30 C. Extemporaneous liquid preparations for oral administration should be stored under refrigeration in glass containers and used within 14 days. [PDR 1997; p 701] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 REFERENCES MED/97076184. Sparano JA, Wiernik PH, Hu X, Sarta C, Schwartz EL, Soeiro R, Henry DH, Mason B, Ratech H, Dutcher JP. Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma. J Clin Oncol. 1996 Nov;14(11):3026-35. MED/96320583. Levine AM, Tulpule A, Espina B, Boswell W, Buckley J, Rasheed S, Stain S, Parker J, Nathwani B, Gill PS. Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincrisitine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency virus and serum interleukin-6 levels over time. Cancer. 1996 Aug;78(3):517-26. MED/96141068. Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation. Blood. 1996 Jan 15;87(2):491-4. MED/95271261. Timmerman JM, Northfelt DW, Small EJ. Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy. J Clin Oncol. 1995 Jun;13(6):1391-7. MED/95399331. Jost LM, Jacky E, Dommann-Scherrer C, Honegger HP, Maurer R, Sauter C, Stahel RA. Short-term weekly chemotherapy followed by high-dose therapy with autologous bone marrow transplantation for lymphoblastic and Burkitt's lymphomas in adult patients. Ann Oncol. 1995 May;6(5):445-51. MED/95218170. Kaplan LD, Shiramizu B, Herndier B, Hahn J, Meeker TC, Ng V, Volberding PA, McGrath MS. Influence of molecular characteristics on clinical outcome in human immunodeficiency virus-associated non-Hodgkin's lymphoma: identification of a subgroup with favorable clinical outcome. Blood. 1995 Apr 1;85(7):1727-35. MED/95220734. Fishman DA, Viscarello R, Cass I, Schwartz PE. Effect of combination chemotherapy with cisplatin and cyclophosphamide on human immunodeficiency virus type-1 surrogate markers in a patient with advanced epithelial ovarian cancer. Gynecol Oncol. 1995 Apr;57(1):105-8. MED/95212522. Schurmann D, Grunewald T, Weiss R, Jautzke G, Pohle HD, Ruf B. Intensive treatment of AIDS-related non-Hodgkin's lymphomas with the MACOP-B protocol. Eur J Haematol. 1995 Feb;54(2):73-7. MED/94293029. Misra AK, Mishra SK, Eigen AC, Tourtellotte WW. Successful immunosuppressive therapy for HTLV-I associated myelopathy. J Neurol Sci. 1994 Apr;122(2):155-6. MED/93195673. Walsh C, Wernz JC, Levine A, Rarick M, et al. Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. J Acquir Immune Defic Syndr. 1993 Mar;6(3):265-71. ENTRY MONTH 199104 LAST REVISION DATE 20000801 299 UNIQUE IDENTIFIER DRG-0047 NAME OF SUBSTANCE Doxorubicin hydrochloride [USPD 1998; p. 256] REGISTRY NUMBER 25316-40-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexo- pyranosyl)oxy)-7,8,9,10 -tetrahydro-6,8,11-trihydroxy-8-(hydroxyacety- l)-1-methoxy-, hydrochloride, (8S-cis)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Adriamycin PFS [USP DI 2000; p. 1359] SYNONYMS Adriamycin RDF [USP DI 2000; p. 1359] SYNONYMS Doxil (liposomal) (see separate record) [USP DI 2000; p. 1364] SYNONYMS Rubex [USP DI 2000; p. 1359] PROTOCOL ID NUMBERS Complete NIAID ACTG 006 PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 075 PROTOCOL ID NUMBERS Complete NIAID ACTG 094 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 149 PROTOCOL ID NUMBERS Complete NIAID ACTG 163 PROTOCOL ID NUMBERS No longer recruiting FDA 121A PROTOCOL ID NUMBERS No longer recruiting FDA 134A PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PROTOCOL ID NUMBERS Terminated NIAID ACTG 252 PHARMACOLOGICAL ACTION MODE OF ACTION: The precise mechanism(s) of the drug is not fully understood. It appears that the cytotoxic effect of the drug results from a complex system of mulitple models of action related to free radical formation secondary to metabolic activation of the drug by electron reduction, intercalation of the drug into DNA, induction of DNA breaks and chromosomal abberations, and alterations in cell membranes induced by the drug. These and other mechanisms (chelation of metal ions to produce drug-metal complexes) also may contribute to the cardiotoxic effects of the drug. Doxorubicin undergoes enzymatic 1- and 2-electron reduction to the corresponding semi- and dihydro-quinone. Semiquinone reacts with oxygen to produce the hydroxyl radical in a cascade of reactions; this radical may lead to cell death by reacting with DNA, RNA, cell membranes, and proteins. In the presence of oxygen, dihydroquinone reacts to form hydrogen peroxide, and in its absence, loses its sugar and gives rise to the quinone methide, a monofunctional alkylating agent with low affinity for DNA. Experimental evidence indicates that doxorubicin forms a complex with DNA by intercalation between base pairs, causing inhibition of DNA synthesis and DNA-dependent RNA synthesis by the resulting template disordering and steric obstruction. Doxorubicin is widely distributed in plasma and in tissues. As early as 30 seconds after intravenous administration, doxorubicin is present in the liver, lungs, heart, and kidneys; it is absorbed by cells and binds to cellular plasma proteins. Doxorubicin is metabolized by NADPH-dependent aldoketoreductases to the hydrophilic 1,3-hydroxyl metabolite doxorubicinol, which exhibits antineoplastic activity and is the major metabolite; the reductases are present in most if not all cells, but particularly in erythrocytes, liver, and kidney. Doxorubicin and its metabolites are excreted predominantly in bile; about 10-20% of a single dose is excreted in feces in 24 hours, and 40-50% of a dose is excreted in bile or feces within 7 days. About 4-5% of the administered dose is excreted in urine after 5 days, principally as unchanged drug, and very little urinary excretion occurs afterwards. Although only small urinary concentrations of the drug usually are achieved, doxorubicin often imparts a red color to the urine for the first hours to days after administration. Plasma concentrations of doxorubicin and its metabolites decline in a biphasic or triphasic manner. Plasma clearance of the drug ranges from 400-583 ml/min per m2. [AHFS Drug Information 1997; p 739] DISEASES STUDIED/TREATED Treatment of Kaposi's sarcoma. [AmfAR Treat Dir 1997;8(3); p 70] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1355] OTHER MAJOR USES The drug has been used successfully to produce regression in disseminated neoplastic conditions such as acute lypmphoblastic leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcoma, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types. [PDR 1997; p 2057] SUBSTANCE INTERACTIONS Doxorubicin may potentiate the toxicity of other antineoplastic therapies and vice versa; it reportedly may enhance cyclophosphamide-induced hemorrhagic cystitis and mercaptopurine-induced hepatotoxicity; concomitant or previous administration with cyclophosphamide, irradiation of the cardiac region, daunorubicin, idarubicin, or mitoxantrone may potentiate the cardiotoxic effects of doxorubicin; concomitant administration with calcium-channel blocking agents may potentiate doxorubicin-induced cardiotoxicity; concomitant administration with cyclosporine may induce seizures and/or coma; phenobarbital may increase the elimination of doxorubicin; doxorubicin may decrease serum levels of phenytoin; streptozocin may inhibit hepatic metabolism of doxorubicin; concomitant administration with live vaccines to immunosuppressed patients, including those undergoing cytotoxic chemotherapy, may be hazardous. Doxorubicin should not be mixed with heparin or fluorouracil since failure to do so may result in precipatation. [AHFS Drug Information 1997; p 744-5] ADVERSE EFFECTS Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity. Reported adverse effects include the following, cardiotoxicity: myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure; cutaneous: reversible complete alopecia in most cases, hyperpigmentation of nailbeds and dermal crease primarily in children, and onycholysis; gastrointestinal: acute nausea and vomiting frequently and may be severe, mucositis (stomatitis and esophagitis) may be severe leading to ulceration and represents a site of origin for severe infections, anorexia, and diarrhea; vascular: phlebosclerosis when small veins or a single vein is used for repeated administration, facial flushing may occur if the injection is given too rapidly; local: severe cellulitis, vesication and tissue necrosis will occur if extravasation of doxorubicin occurs during administration, erythematous streaking along the vein proximal to the site of injection; hematologic: secondary acute myeloid leukemia with or without preleukemic phase with a short latency of 1 to 3 years; hypersensivity: fever, chills, urticaria, and anaphylaxis; the drug impart a red coloration to the urine for 1 to 2 days after administration. Other rare adverse reactions include conjunctivitis and lacrimation. [PDR 1997; p 2058] CONTRAINDICATIONS Contraindicated in patients who have marked myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy. Doxorubicin is not recommended for use by patients with cardiac problems; it is contraindicated in patients who received previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenes. Should not be used during pregnancy unless the benefits to the patient outweigh the risks of potential toxicity to the fetus. [PDR 1997; p 2057] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius consisting of a naphthacenequinone nucleus linked through a glycosidic bond at position 7 to the amino sugar, daunosamine. [PDR 1997; p 2057] CHEMICAL/PHYSICAL DATA Molecular Formula: C27-H29-N-O11.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 579.99 [USPD 1998; p. 256] CHEMICAL/PHYSICAL DATA Melting Point: 204-205 C [Merck Index 1996; p. 582] CHEMICAL/PHYSICAL DATA Elemental Comp: C59.67%, H5.38%, N2.58%, O32.38% (base) [Merck Index 1996; p. 581] CHEMICAL/PHYSICAL DATA Solubility: Hydrochloride salt is soluble in water, methanol, aqueous alcohols; practically insoluble in acetone, benzene, chloroform, ethyl ether, and petroleum ether. [Merck Index 1996; p 582] CHEMICAL/PHYSICAL DATA Stability: Doxorubicin hydrochloride is unstable in solutions with a pH less than 3 or greater then 7. It is chemically imcompatible with heparin sodium injection and fluorouracil, and precipitation may form if the solutions are mixed. All preparations should be stored protected from light. [AHFS Drug Information 1997; p 739] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Orange-red colored thin needles (hydrochloride salt). [Merck Index 1996; p 582] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lyophilized powders available in 10, 20, and 50 mg single dose vials and a 150 mg multidose vial. Solutions for parenteral infusion available in 10 mg (5 ml), 20 mg (10 ml), 50 mg (25 ml), and 75 mg (37.5 ml) single dose vials and a 200 mg (100 ml) multidose vial. [PDR 1997; p 2057] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Injection; intravenous. [PDR 1997; p 2057] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powders should be stored at controlled room temperature, 15 to 30 C (59 to 86 F), and protected from light; reconstituted solutions should be stored according to manufacturer's instructions. Parenteral solutions should be stored under refrigeration, 2 to 8 C (36 to 46 F), and protected from light. [PDR 1997; p 1433] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000005209: ALZA Corporation 1900 Charleston Road / PO Box 7210 Mountain View, CA 940397210 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)227-9953 REFERENCES MED/97201005. Sparano JA, Hu X, Wiernik PH, Sarta C, Reddy DM, Hanau L, Henry DH. opportunistic infection and immunologic function in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma treated with chemotherapy. J Natl Cancer Inst. 1997 Feb;89(4):301-7. MED/97178757. Northfelt DW, Dezube BJ, Thommes JA, Levine R, Von Roenn JH, Dosik GM, Rios A, Krown SE, DuMond C, Mamelok RD. Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy. J Clin Oncol. 1997 Feb;15(2):653-9. ASHM8/97153607. Newell M, Milliken S, Chipman M, Cebon J, Lewis C, Goldstein D, Cooper DA. DOX-SL (stealth liposomal doxorubicin HCL) maintenance therapy after response in AIDS-related Kaposi's sarcoma. Annu Conf Australas Soc HIV Med. 1996 Nov 14-17;8:48 (abstract no.27). MED/97076184. Sparano JA, Wiernik PH, Hu X, Sarta C, Schwartz EL, Soeiro R, Henry DH, Mason B, Ratech H, Dutcher JP. Pilot trial of infusional cyclophoshamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma. J Clin Oncol. 1996 Nov;14(11):3026-35. MED/96326437. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, et al. Randomized phase III trial of liposomal daunorubicin versus dxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. MED/96320583. Levine AM, Tupule A, Espina B, Boswell W, Buckley J, Rasheed S, Stain S, Parker J, Nathwani B, Gill PS. Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma. Effect on human immunodeficiency virus and serum interleukin-6 levels over time. Cancer. 1996 Aug;78(3):517-26. MED/96424783. Subach RA, Ruble J, Misprint of dosage interval for liposomal doxorubicin hydorchloride [letter]. Am J Health Syst Pharm. 1996 Jul;53(14):1727. MED/96206031. Tavio M, Vaccher E, Antinori A, Ammassari A, Cusini M, Fasan M, Accurso V, Garavelli LP, Repetto L, Tirelli U. Combination chemotherapy with doxorubicin, bleomycin, and vindesine for AIDS-related Kaposi's sarcoma. Cancer. 1996 May;77(10):2117-22. MED/96265821. Porche DJ. Liposomal doxorubicin (Doxil). J Assoc Nurses AIDS Care. 1996 Mar-Apr;7(2):55-9. MED/95325896. Tirelli U, Errante Dolcetti R, Gloghini A, Serraino D, Vaccher E, Franceschi S, Boiocchi M, Carbone A. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol. 1995 Jul:13(7):1758-67. ENTRY MONTH 199104 LAST REVISION DATE 20001107 300 UNIQUE IDENTIFIER DRG-0046 NAME OF SUBSTANCE Vincristine sulfate [USPD 1998; p. 779] REGISTRY NUMBER 2068-78-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 22-Oxovincaleukoblastine [Merck Index 1996; p 1704] SYNONYMS Oncovin [USP DI 2000; p. 3138] SYNONYMS Vincasar [USP DI 2000; p. 3138] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 075 PROTOCOL ID NUMBERS Complete NIAID ACTG 094 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 163 PROTOCOL ID NUMBERS Complete NIAID ACTG 286 PROTOCOL ID NUMBERS No longer recruiting FDA 121A PROTOCOL ID NUMBERS No longer recruiting FDA 134A PROTOCOL ID NUMBERS No longer recruiting FDA 134B PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS Recruiting CC 97 C-0040 PROTOCOL ID NUMBERS Terminated NIAID ACTG 252 PHARMACOLOGICAL ACTION MODE OF ACTION: Although the mechanism of action has been fully elucidated, vincristine and other vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of the microtubles that form the mitotic spindle. The formation of vincristine-tublin complexes prevent the polymerization of the tubulin subunits into microtublues and induces depolymerization of microtubules resulting in inhibition of microtubule assembly and cellular metaphase arrest. In high concentrations, the drug also exerts complex effects on nucleic acid and protein synthesis. Vincristine exerts some immunosuppressive activity. Vincristine sulfate is unpredictably absorbed from the GI tract. Following rapid IV injection of a 2-mg dose in patients with normal renal and hepatic function, peak serum drug concentrations of approximately 0.19-0.89 uM occur immediately and the drug is rapidly cleared from serum. The drug is rapidly and apparently widely distributed following IV administration. Drug that is distributed into tissues is tightly but reversibly bound. Vincritine and its metabolites (and/or decomposition products) are rapidly and extensively distributed into bile, with peak biliary concentrations occurring within 2-4 hours after rapid IV injection of the drug. Vincristine and its metabolites (and/or decomposition products) cross the blood-brain barrier poorly following rapid IV injection and generally do not appear in the CSF in cytotoxic concentrations. Following rapid IV infection of vincristine, serum concentrations of the vincristine has ranged form 10.5-155 hours. The metabolic fate of vincristine has not been clearly determined; the drug appears to be extensively metabolized, probably in the liver by the cytochrome P-450 microsomal enzyme system, including CYP3A, but the extent of metabolism is not clear since the drug also apparently undergoes decomposition in vivo. Vincristine and its metabolites (and/or decomposition products) are excreted principally in feces via biliary elimination. Following rapid IV injection in adults with normal renal and hepatic function, about 30% of a dose is excreted in feces with 24 hours and 70% with 72 hours; about 10% of a dose is excreted in urine within 24 hours, with very little urinary excretion occuring thereafter. In patients with hepatic impairment, metabolism of vincristine may be decreased. [AHFS Drug Information 1997; p 878] DISEASES STUDIED/TREATED Under investigation for the treatment of Kaposi's sarcoma and lymphoma. [AmfAR Treat Dir 1997;8(3); p 79] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 3135] OTHER MAJOR USES Indicated in acute leukemia and in combination with other oncolytic agents for treating Hodgkin's disease, non-Hodgkin's lymphoma, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. [PDR 1997; p 1521] SUBSTANCE INTERACTIONS Combinations of phenytoin and antineoplastic agents, including vincristine, have reduced phenytoin blood levels and increased seizure activity. Concomitant administration of itraconazole, a potent inhibitor of the cytochrome P450 isoenzyme CYP3A, and vincristine has been associated with earlier and/or increased severity of neuromuscular adverse effects, probably related to inhibition of vincristine metabolism. Since varying degrees of permanent or temporary hearing imnpairment associated with eighth cranial nerve damage have been reported in patients receiving vinca alkaloids, vincristine should be used concomitantly with other potentially ototoxic drugs such as platinum-containing antineoplastic agents with extreme caution. [PDR 1997; p 1522] ADVERSE EFFECTS In general, adverse reactions to vincristine are dose related and reversible. The most common adverse reactions is hair loss; the most troublesome adverse reactions are neuromuscular in origin. Adverse effects include the following: nervous system effects (neurotoxicity manifested as peripheral neuropathy, autonomic and CNS toxicity); dermatologic effects (alopecia, and occasionally rash); sensitivity reactions (allergic reactions including anaphylaxcis, rash, and edema); hematologic effects (occasionally mild leukopenia, mild anemia, and thrombocytopenia); local effects (phlegitis and necrosis); cardiovascular effects (hypertension, hypotension, coronary artery disease and myocardial infarction); otic effects (eight cranial nerve damage). Other adverse effects include nausea, vomiting, diarrhea, abdominal distention, stomatitis, oral ulceration, intestinal necrosis and/or perforation, fever, weight loss, syndrome of inappropriate antidiuretic hormone secretion, hyperuricemia. [AHFS Drug Information 1997; p 879-80; PDR 1997; p 1522] CONTRAINDICATIONS Should not be given to patients with demyelinating form of Charcot-Marie-Tooth syndrome. Caution should be exercised when administering vincristine to patients with preexisting neuromuscular disease and when other drugs with neurotoxic potential are being used. Vincristine can cause fetal harm, pregnant women receiving this drug should be apprised of the potential hazard to the fetus. In breast-feeding women, a decision should be made to discontinue breast-feeding or the drug since it is not known whether it is excreted in breast milk. [PDR 1997; p 1521-2] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Alkaloid obtained from the periwinkle plant, Vinca rosea. [PDR 1997; p 1521] CHEMICAL/PHYSICAL DATA Molecular Formula: C46-H56-N4-O10.H2-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 923.06 [USPD 1998; p. 779] CHEMICAL/PHYSICAL DATA Elemental Comp: C66.97%, H6.84%, N6.79%, O19.39% (base) [Merck Index 1996; p. 1704] CHEMICAL/PHYSICAL DATA Solubility: Soluble in methanol, freely soluble in water, only slightly soluble in 95% ethanol. [PDR 1997; p 1521] CHEMICAL/PHYSICAL DATA Stability: Vincrisine sulfate solution is light-sensitive and must be protected from light. [AHFS Drug Information 1997; p 878] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white or slightly yellow, hygroscopic, amorphous or crystalline powder. [AHFS Drug Information 1997; p 878] SUBSTANCE DELIVERY DATA DOSAGE FORM: 1 ml, 2 ml and 5 ml multiple dose vials containing 1 mg/ml. Disposable syringes, 1 ml and 2 ml, containing 1 mg/ml. [PDR 1997; p 1523] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Fatal if given intrathecally. Intravenous injection/infusion. [PDR 1997; p 1521-2] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be refrigerated between 2-8 C (36-46 F) and protected from light. [AHFS Drug Information 1997; p 878] MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 REFERENCES MED/96326437. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-26. MED/96320583. Levine AM, Tulpule A, Espina B, Boswell W, Buckley J, Rasheed S, Stain S, Parker J, Nathwani B, Gill PS. Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma. Effect on human immunodeficiency virus and serum interleukin-6 levels over time. Cancer. 1996 Aug;78(3):517-26. MED/95271261. Timmeran JM, Northfelt DW, Small EJ. Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy. J Clin Oncol. 1996 Jun;13(6):1391-7. MED/97150982. Torresin A, Cassola G, Penco G, Crisalli MP, Piersantelli N. Vinca alkaloids and marcrolides in human immunodeficiency virus-related malignancies: a safe association [letter]. Cancer Chemother Pharmacol. 1996;39(1-2):176-7. MED/96259804. Denton AS, Simpson JK, Hallam M, Spittle MF, Miller RF. Effects on pulmonary function of two regimens of chemotherapy for AIDS-related Kaposi's sarcoma. Clin Oncol (R Coll Radiol). 1996;8(1):48-50. MED/96122066. Stein ME, Lachter J, Spencer D, Bezwoda WR. Chemotherapy for AIDS-related and endemic African Kaposi's sarcoma in southern Africa. Int J Dermatol. 1995 Oct;34(10):729-32. MED/95176677. Lingenfelser T, Daiss W, Overkamp D, Weber P. Successful monochemotherapy of extensive gastrointestinal Kaposi's sarcoma with bowel obstruction in acquired immunodeficiency syndrome. Z Gastroenterol. 1994 Dec;32(12):688-90. MED/95064624. Cadranel JL, Kammoun S, Chevret S, Parrot A, Denis M, Winter C, Carette MF, Rozenbaum W, Akoun GM, Mayaud CM. Results of chemotherapy in 30 AIDS patients with symptomatic pulmonary Kaposi's sarcoma. Thorax. 1994 Oct;49(10):958-60. MED/94089092. Stein ME, Spencer D, Ruff P, Lakier R, MacPhail P, Bezwoda WR. Endemic African Kaposi's sarcoma: clinical and therapeutic implications. 10-year experience in the Johannesburg Hospital (1980-1990). Oncology. 1994 Jan-Feb;51(1):63-9. MED/94103498. Nagatani T, Miyazawa M, Matsuzaki T, Iemoto G, Kim S, Baba N, Miyakawa K, Miyamoto H, Nakajima H, Hirai Y. Successful treatment of adult T-cell leukemia/lymphoma with MACOP-B, M-FEPA and VEPP-B combination chemotherapy. J Dermatol. 1993 Oct;20(10):623-9. ENTRY MONTH 199104 LAST REVISION DATE 20000801 301 UNIQUE IDENTIFIER DRG-0045 NAME OF SUBSTANCE Bleomycin sulfate [USPD 1998; p. 102] REGISTRY NUMBER 9041-93-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.; (Bleomycin)] SYNONYMS Blenoxane [USP DI 2000; p. 646] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 075 PROTOCOL ID NUMBERS Complete NIAID ACTG 094 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 149 PROTOCOL ID NUMBERS Complete NIAID ACTG 163 PROTOCOL ID NUMBERS Complete NIAID ACTG 286 PROTOCOL ID NUMBERS No longer recruiting FDA 121A PROTOCOL ID NUMBERS No longer recruiting FDA 134A PROTOCOL ID NUMBERS No longer recruiting FDA 134B PHARMACOLOGICAL ACTION MODE OF ACTION: The precise mechanism(s) of action of bleomycin is not fully known. Several studies in E. Coli and HeLa cells suggest that the drug inhibits the incorporation of thymidine into DNA. In these in vitro studies, DNA synthesis was inhibited to a greater extent than was RNA or protein synthesis. Bleomycin also appears to labilize the DNA structure, resulting in scission of both single- and double-stranded DNA. Bleomycin sulfate is not significantly absorbed from the GI tract and the drug must be administered parenterally. Bleomycin is absorbed systemically following intrapleural or intraperitoneal administration. Systemic absorption of 45% has been reported following intrapleural administration. In patients with normal renal function, the serum or plasma terminal half-life of bleomycin is about 2 hours. In patients with moderately severe renal impairment (creatine clearance of less than 35 ml/min), the terminal half-life of the drug is inversely related to creatinine clearance. The metabolic fate of bleomycin has not been deteremined. In patients with normal renal function, 60-70% of a parenterally administered dose is excreted in the urine as active drug. In patients with creatine clearance of less than 35 ml/min, less than 20% of a parenterally administered dose is excreted in urine as active drug, indicating that accumulation of the drug may occur in patients with severe renal impairment. [AHFS Drug Information 1997; p 685] DISEASES STUDIED/TREATED Used alone or in combination chemotherapy for the palliative treatment of AIDS-related Kaposi's sarcoma. [AHFS Drug Information 1997; p 686] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 643] OTHER MAJOR USES Blenoxane has been used in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents: squamous cell carcinomas (head, neck, penis, cervix, and vulva); lymphomas (Hodgkin's disease, and non-Hodgkin's lymphoma); testicular carcinoma (embryonal cell, choriocarcinoma, and teratocarcinoma). Bleonxane has also been shown to be useful in the management of malignant pleural effusion and prevention of recurrent pleural effusions. [PDR 1997; p 697] SUBSTANCE INTERACTIONS Interactions of bleomycin have been reported with general anesthetics, other antineoplastics, cisplatin, vincristine, and with radiation therapy. [USP DI 1997; p 610] ADVERSE EFFECTS Pulmonary fibrosis is the most severe toxicity associated with Blenoxane. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total doses, but pulmonary toxicity has been observed in young patients and those treated with low doses. Severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills and wheezing has been reported in approximately 1% of lymphoma patients treated with Blenoxane. The most frequent side effects, being reported in approximately 50% of treated patients, include erythema, rash, striae, vesiculation, hyperpigmentatin, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. Other frequently reported side effects include fever, chills, vomiting, anorexia, and weight loss; infrequently pain in tumor site, phlebitis, and other local reactions. [PDR 1997; p 697-8] CONTRAINDICATIONS Should not be used by patients who have demonstrated a hypersensitive or idiosyncratic reaction to bleomycin. Safe use of blenoxane in pregnant women has not been established. [PDR 1997; p 697-8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Bleomycin sulfate is a mixture of basic cytotoxic glycopeptide antibiotics produced by Streptomyces verticillus. Bleomycin A2 and B2 are the major components in this mixture. [AHFS Drug Information 1997; p 685] CHEMICAL/PHYSICAL DATA Molecular Formula: H2-O4-S.x-W99 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Very soluble in water and methanol, slightly soluble in ethanol, insoluble in acetone, ethyl acetate, butyl acetate, or ether. [Merck Index 1996; p 217] CHEMICAL/PHYSICAL DATA Stability: Inactivated in vitro by agents containing sulfhydryl groups, hydrogen peroxide, and ascorbic acid. [AHFS Drug Information 1997; p 685] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: A cream-colored amorphous powder. [AHFS Drug Information 1997; p 685] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial containing 15, or 30 units as sterile bleomycin sulfate for parenteral adminstration. [AHFS Drug Information 1997; p 688] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous, intramuscular, subcutaneous, and intrapleural (intracavitary). [AHFS Drug Information 1997; p 688] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Sterile powder should be stored under refrigeration at 2-8 C (36-46 F). Reconstituted solution in 0.9% sodium chloride is stable for 24 hours at room temperature. [PDR 1997; p 698] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/96326437. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, Rarick MU, Myers AM, Shephard F, Sawka C, Pike MC, Ross ME. Randomized phase III trial of limposomal daunorubicin versus doxorubincin, bleomycin, and vincrisitine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. MED/96320583. Levine AM, Tulpule A, Espina B, Boswell W, Buckley J, Rasheed S, Stain S, Parker J, Nathwani B, Gill PS. Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma. Effect on human immunodeficiency virus and serum interleukin-6 levels over time. Cancer 1996 Aug;78(3):517-26. MED/95271261. Timmerman JM, Northfelt DW, Small EJ. Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy. J Clin Oncol. 1996 Jun;13(6):1391-7. MED/96303582. Patarca R, Freidlander A, Harrington WJ, Cabral L, Byrnes JJ, Fletcher MA. Peripheral blood T cell subsets as prognostic indicators of chemotherapy outcome in AIDS patients with large cell lymphoma. AIDS Res Hum Retroviruses. 1996 May;12(8):645-9. MED/96206031. Tavio M, Vaccher E, Antinori A, Ammassari A, Cusini M, Fasan M, Accurso V, Garavelli LP, Reptto L, Tirelli U. Combination chemotherapy with doxorubicin, bleomycin, and vindesine for AIDS-related Kaposi's sarcoma. Cancer 1996 May;77(10):2117-22. MED/96259804. Denton AS, Simpson JK, Hallam M, Spittle MF, Miller RF. Effects on pulmonary function of two regimens of chemotherapy for AIDS related Kaposi's sarcoma. Clin Oncol (R Coll Radiol). 1996;8(1):48-50. MED/96397201. Caceres W. Non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome. Bol Asoc Med P R. 1995 Oct-Dec;87(10-12):158-61. MED/96122066. Stein ME, Lachter J, Spencer D, Bezwoda WR. Chemotherapy for AIDS-related and endemic African Kaposi's sarcoma in southern Africa. Int J Dermatol. 1995 Oct;34(10):729-32. MED/95212522. Schurmann D, Grunewald T, Weiss R, Jautzke G, Pohle HD, Ruf B. Intensive treatment of AIDS-related non-Hodgkin's lymphomas with the MACOP-B protocol. Eur J Haematol. 1995 Feb;54(2):73-7. MED/95194616. Gill PS, Miles SA, Mitsyasu RT, Montgomery T, McCarthy S, Espina BM, Feldstein M, Levine AM. Phase I AIDS Clinical Trials Group (075) study of adriamycin, bleomycin and vincristine chemotherapy with zidovudine in the treatment of AIDS-related Kaposi's sarcoma. AIDS. 1994 Dec;8(12):1695-9. ENTRY MONTH 199104 LAST REVISION DATE 20000801 302 UNIQUE IDENTIFIER DRG-0044 NAME OF SUBSTANCE Itraconazole [USPD 1998; p. 401] REGISTRY NUMBER 84625-61-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-(4-(4-(4-((2-(2,4-Dichlorophenyl)-2-(1H-1,2- ,4-triazol- 1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl) -1-piperazinyl)phenyl)-2,4-dihydro-2- (1-methylpropyl)-3H -1,2,4-triazol-3-one [Merck Index 1996; p 894] SYNONYMS Sporanox [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 084 PROTOCOL ID NUMBERS Complete NIAID ACTG 120 PROTOCOL ID NUMBERS Complete NIAID ACTG 159 PROTOCOL ID NUMBERS No longer recruiting FDA 235B PROTOCOL ID NUMBERS No longer recruiting FDA 236A PROTOCOL ID NUMBERS No longer recruiting FDA 236B PROTOCOL ID NUMBERS No longer recruiting FDA 236C PROTOCOL ID NUMBERS No longer recruiting FDA 254A PROTOCOL ID NUMBERS No longer recruiting FDA 254B PROTOCOL ID NUMBERS No longer recruiting FDA B013 PHARMACOLOGICAL ACTION MODE OF ACTION: Interferes with cytochrome P-450 synthesis of ergosterol, a necessary component of fungal cell membranes. Total plasma clearance averaged 381 ml/min and apparent volume of distribution averaged 796 liters following intravenous doses. Absolute oral bioavailability was 55%. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. Renal insufficiency did not affect plasma levels. Plasma protein binding is 99.8%. [PDR 1997; p 1352-3] DISEASES STUDIED/TREATED Treatment of fungal infections: blastomycosis, pulmonary and extrapulmonary; histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or refractory to amphotericin B therapy; onychomycosis due to dermatophytes of the toenail. [PDR 1997; p 1353] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 319] OTHER MAJOR USES Itaconazole is indicated for the treatment of the following fungal infections: blastomycosis, pulmonary and extrapulmonary; histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy; onychomycosis due to dermatophytes (tinea unguium) of the toenail with or without fingernail involvement. [PDR 1997; p 1353] SUBSTANCE INTERACTIONS Both intraconzole and its major metabolite, hydroxyitraconazole, are inhibitors of the cytochrome p450 3A4 enzyme system. Coadministration of itraconazole and drugs primarily metabolized by the cytochrome p450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects. Coadministration of itraconazole with the following drugs has led to elevated plasma concentrations of drugs: terfenadine, astemizole, cisapride, midazolam (oral), triazolam, cyclosporine, tacrolimus, digoxin. Coadministration of itraconzole with the following drugs has led to reduced plasma concentrations of itraconazole: phenytoin, rifampin H2 antagonists, or isoniazid. Itraconazole has been reported to enhance the anticoagulant effect of coumarin-like drugs. Therefore, prothrombin time should be carefully monitored in patients receiving itraconazole and coumarin-like drugs simultaneously. Severe hypoglycemia has been reported in patients receiving concomitant administration of itraconazole and oral hypoglycemic agents. Tinnitus and decreased hearing have been reported in patients concomitantly receiving itraconazole and quinidine. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers. [PDR 1997; p 1353-4] ADVERSE EFFECTS The most frequent adverse effects involve the GI tract. The frequency of adverse effects may be increased during prolonged therapy. Adverse effects include the following: gastrointestinal effects (nausea, vomiting, diarrhea, abdominal pain, or anorexia); dermatologic and sensitivity reactions (rash, pruritus, urticaria, angioedema, and toxic epidermal necrosis; rarely anaphylaxis, and Steven-Johnson syndrome); nervous system (headache and dizziness, somnolence and decreased libido, insomnia, tinnitus, and depression; rarely neuropathy); cardiovascular effects (hypertension, ventricular fibrillation secondary to intraconazole-induced hypokalemia; rarely death, tachycardia, and atypical ventricular tachycardia); hepatic effects (hepatic function abnormalities manifested principally as mild transient increase in serum liver enzyme concentrations; rarely reversible idiosyncratic hepatitis); electrolyte and metabolic effects (hypokalemia, edema, adrenal insufficiency, gynecomastia, and male breast pain); genitourinary effects (albuminuria and impotence). Other adverse effects include fatigue and fever. [AHFS Drug Information 1997; p 94] CONTRAINDICATIONS Coadministration of terfenadine, astemizole, or cisapride with itraconazole is contraindicated. Concomitant administration of itraconazole with oral triazolam or with oral midazolam is contraindicated. Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Intraconazole is contraindicated in patients who have shown hypersensitivity to the drug or its excipients. Although there is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents, caution should be used in prescribing itraconazole to patients with hypersensitivity to other azoles. [PDR 1997; p 1353] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic triazole antifungal drug. [PDR 1997; p 1352] CHEMICAL/PHYSICAL DATA Molecular Formula: C35-H38-Cl2-N8-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 705.65 [USPD 1998; p. 401] CHEMICAL/PHYSICAL DATA Melting Point: 166.2 C [Merck Index 1996; p. 895] CHEMICAL/PHYSICAL DATA Elemental Comp: C59.57%, H5.43%, Cl10.05%, N15.88%, O9.07% [Merck Index 1996; p. 894] CHEMICAL/PHYSICAL DATA Solubility: Insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. [PDR 1997; p 1352] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to slightly yellowish powder. [PDR 1997; p 1352] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (100 mg). [PDR 1997; p 1354] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1354] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at room temperature, 15 C to 30 C, protect from light and moisture. [PDR 1997; 1354] MANUFACTURERS 0000001070: Janssen Pharmaceutica Inc 1125 Trenton-Harbourton Rd / PO Box 200 Titusville, NJ 085600200 Contact: Dr Richard Meibach (908)730-3135 MANUFACTURERS 0000001070: Janssen Pharmaceutica Inc 1125 Trenton-Harbourton Rd / PO Box 200 Titusville, NJ 085600200 Contact: Unspecified (800)526-7736 REFERENCES AIDS/97702139. D'Amico R. ICAAC update on opportunistic infections. Posit Aware. 1996 Nov/Dec;7(6):16-8. MED/97054332. Barbaro G, Barbarini G, Calderon W, Grisorio B, Alcini P, Di Lorenzo G. Fluconazole versus itraconazole for candida esophagitis in acquired immunodeficiency syndrome, Candida Esophaditis. Gastroenterology. 1996 Nov;111(5):1169-77. ASHM8/97153640. Saag M. The treatment of cryptococcal disease in AIDS patients. Annu Conf Australas Soc HIV Med. 1996 Nov 14-17;8:69 (abstract no.60). AIDS/97702007. Powderly WG. Candidiasis. J Int Assoc Physicians AIDS Care. 1996 Oct;2(10):36-9. MED/97057727. Phillips P, Zemcov J, Mahmood W, Montaner JS, Craib K, Clarke AM. Itraconazole cyclodextrin solution for fluconazole-refractory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptibility. AIDS. 1996 Oct;10(12):1369-76. MED/97028965. de Repentigny L, Ratelle J. Comparison of itraconazole and ketoconazole in HIV-positive patients with oropharyngeal or esophageal candidiasis. Human Immunodeficiency Virsu Itraconazole Ketoconazole Project Group. Chemotherapy. 1996 Sep-Oct;42(5):374-83. MED/97034131. Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis. 1996 Sep;23(3):608-15. MED/96412895. Duong TA. Infection due to Penicillium marneffei, an emerging pathogen: review of 155 reported cases. Clin Infect Dis. 1996 Jul;23(1):125-30. MED/97008503. Riantawan P, Ponglertnapakorn P. Clinical efficacy of itraconazole with initial flucytosine in AIDS-related cryptococcal meningitis: a preliminary study. J Med Assoc Thai. 1996 Jul;79(7):429-33. MED/96302584. Bradsher RW. Hisptoplasmosis and blastomycosis. Clin Infect Dis. 1996 May;22(suppl 2):S102-11. ENTRY MONTH 199104 LAST REVISION DATE 20000801 303 UNIQUE IDENTIFIER DRG-0043 NAME OF SUBSTANCE Stavudine [USPD 1998; p. 685] REGISTRY NUMBER 3056-17-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Thymidine, 2',3'-didehydro-3'-deoxy- [USPD 1998; p 685] SYNONYMS Zerit [USP DI 2000; p. 2824] PROTOCOL ID NUMBERS Complete NIAID ACTG 089 PROTOCOL ID NUMBERS Complete NIAID ACTG 240 PROTOCOL ID NUMBERS Complete NIAID ACTG 246/946 PROTOCOL ID NUMBERS Complete NIAID ACTG 290 PROTOCOL ID NUMBERS Complete NIAID ACTG 298 PROTOCOL ID NUMBERS Complete NIAID ACTG 302 PROTOCOL ID NUMBERS Complete NIAID ACTG 306 PROTOCOL ID NUMBERS Complete NIAID ACTG 320 PROTOCOL ID NUMBERS Complete NIAID ACTG 327 PROTOCOL ID NUMBERS Complete NIAID ACTG 330 PROTOCOL ID NUMBERS Complete NIAID ACTG 343 PROTOCOL ID NUMBERS Complete NIAID ACTG 373 PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS Complete NIAID ACTG A5039 PROTOCOL ID NUMBERS No longer recruiting FDA 015H PROTOCOL ID NUMBERS No longer recruiting FDA 039D PROTOCOL ID NUMBERS No longer recruiting FDA 039E PROTOCOL ID NUMBERS No longer recruiting FDA 039G PROTOCOL ID NUMBERS No longer recruiting FDA 116A PROTOCOL ID NUMBERS No longer recruiting FDA 116B PROTOCOL ID NUMBERS No longer recruiting FDA 200F PROTOCOL ID NUMBERS No longer recruiting FDA 225C PROTOCOL ID NUMBERS No longer recruiting FDA 228E PROTOCOL ID NUMBERS No longer recruiting FDA 229D PROTOCOL ID NUMBERS No longer recruiting FDA 229G PROTOCOL ID NUMBERS No longer recruiting FDA 229H PROTOCOL ID NUMBERS No longer recruiting FDA 229P PROTOCOL ID NUMBERS No longer recruiting FDA 232D PROTOCOL ID NUMBERS No longer recruiting FDA 232E PROTOCOL ID NUMBERS No longer recruiting FDA 244A PROTOCOL ID NUMBERS No longer recruiting FDA 244B PROTOCOL ID NUMBERS No longer recruiting FDA 244C PROTOCOL ID NUMBERS No longer recruiting FDA 244D PROTOCOL ID NUMBERS No longer recruiting FDA 244E PROTOCOL ID NUMBERS No longer recruiting FDA 244F PROTOCOL ID NUMBERS No longer recruiting FDA 246D PROTOCOL ID NUMBERS No longer recruiting FDA 246F PROTOCOL ID NUMBERS No longer recruiting FDA 246J PROTOCOL ID NUMBERS No longer recruiting FDA 246M PROTOCOL ID NUMBERS No longer recruiting FDA 246R PROTOCOL ID NUMBERS No longer recruiting FDA 260A PROTOCOL ID NUMBERS No longer recruiting FDA 260B PROTOCOL ID NUMBERS No longer recruiting FDA 264N PROTOCOL ID NUMBERS No longer recruiting FDA 264P PROTOCOL ID NUMBERS No longer recruiting FDA 281C PROTOCOL ID NUMBERS No longer recruiting FDA 281D PROTOCOL ID NUMBERS No longer recruiting FDA 283E PROTOCOL ID NUMBERS No longer recruiting FDA 285A PROTOCOL ID NUMBERS No longer recruiting FDA 285C PROTOCOL ID NUMBERS No longer recruiting FDA 292C PROTOCOL ID NUMBERS No longer recruiting FDA 296A PROTOCOL ID NUMBERS No longer recruiting FDA 304A PROTOCOL ID NUMBERS No longer recruiting FDA 312A PROTOCOL ID NUMBERS No longer recruiting CC 95 C-0192 PROTOCOL ID NUMBERS No longer recruiting CC 95 CC-102 PROTOCOL ID NUMBERS No longer recruiting CC 97 C-0119 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 328 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 332 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 338 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 370 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 377 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 380 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 395 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 403 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5014 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5051 PROTOCOL ID NUMBERS No longer recruiting FDA ATLANTIC STUDY PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-03-005 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 039F PROTOCOL ID NUMBERS Recruiting FDA 246T PROTOCOL ID NUMBERS Recruiting FDA 246U PROTOCOL ID NUMBERS Recruiting FDA 259H PROTOCOL ID NUMBERS Recruiting FDA 298C PROTOCOL ID NUMBERS Recruiting FDA 298D PROTOCOL ID NUMBERS Recruiting FDA 302A PROTOCOL ID NUMBERS Recruiting CC 98 C-0041 PROTOCOL ID NUMBERS Recruiting CC 99 C-0118 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 356 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5015 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5116 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-05-003 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-08-002 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Suspended FDA 298B PROTOCOL ID NUMBERS Suspended FDA 300B PROTOCOL ID NUMBERS Terminated FDA 292D PROTOCOL ID NUMBERS Terminated FDA 292E PROTOCOL ID NUMBERS Terminated NIAID ACTG 111 PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PROTOCOL ID NUMBERS Terminated NIAID AIEDRP AI-03-001 PHARMACOLOGICAL ACTION MODE OF ACTION: Stavudine is phosphorylated by cellular kinases to stavudine triphosphate which exerts antiviral activity. Stavudine triphosphate inhibits HIV replication by two known mechanisms: (1) it inhibits HIV reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate (K1 = 0.0083 to 0.032microM); and (2) it inhibits viral DNA synthesis by causing DNA chain termination because stavudine lacks the 3'-hydroxyl group necessary for DNA elongation. In addition to the inhibitory effect on HIV reverse transcriptase, stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA. Following oral administration to HIV-infected patients, stavudine is rapidly absorbed with a mean bioavailability of 86.4+18.2%. Peak plasma concentrations increase in a dose-related manner for doses ranging from 0.03 to 4 mg/kg within 1 hour after dosing. Area under the plasma concentration-time curve (AUC) increases in proportion to dose after both single and multiple doses. There is no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours. Stavudine has an intracellular half-life of 3.5 hours. Stavudine distributes into extracellular spaces. Mean apparent volume of distribution following administration of single oral doses ranging from 0.03 to 4 mg/kg was 66+22 L. Volume of distribution was independent of dose and did not correlate with body weight. Plasma clearance and terminal elimination half-life were independent of dose over an intravenous dosing range of 0.0625 to 1 mg/kg and an oral dosing range of 0.03 to 4 mg/kg. After single oral doses, the mean terminal elimination half-life was 1.44+0.30 hours. Following single-dose oral administration, mean apparent oral clearance was independent of dose, at about 8.0 ml/min/kg. Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. Mean cumulative urinary excretion of unchanged drug over 6 to 24 hours after administration of an oral dose was 39+23% of the dose. Strains of HIV-1 with reduced susceptibility to stavudine have been produced in the laboratory. Such strains have also emerged during therapy with the drug. Some of these HIV-1 strains were also resistant to zidovudine and didanosine. [PDR 1999; p 812-5; AHFS Drug Information 1999; p 622] DISEASES STUDIED/TREATED Stavudine was approved by the FDA on 6/27/94 for the treatment of adults with HIV infection. The drug is now also approved for use in children. Stavudine is most effective when used in combination with other antiretroviral drugs such as ddI, 3TC and protease inhibitors. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 49] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 2822] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 658] SUBSTANCE INTERACTIONS Caution should be used in coadministration of stavudine with other drugs that may cause peripheral neuropathy, such as chloramphenicol, cisplatin, dapsone, didanosine, ethambutol, ethionamide, hydralazine, isoniazid, lithium, nitrofurantoin, phenytoin, vincristine, and zalcitabine. In vitro studies had detected an antagonistic antiviral effect between stavudine and zidovudine (molar ration of 20:1). [USP DI 1999; p 2627] ADVERSE EFFECTS The major clinical toxicity of stavudine is peripheral neuropathy. Patients should be monitored for the development of neuropathy that is usually characterized by numbness, tingling, or pain in the feet or hands. Neuropathy may resolve if therapy is withdrawn promptly. Patients with a history of peripheral neuropathy are at increased risk for the development of neuropathy. Selected adverse effects include headache, chills/fever, diarrhea, rash, nausea and vomiting, peripheral neurologic symptoms, abdominal pain, myalgia, insomnia, anorexia, peripheral neuropathy, allergic reaction, and pancreatitis. The manufacturer warns that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combinations including stavudine. A majority of these cases have been in women. [PDR 1999; p 813-4] CONTRAINDICATIONS Stavudine is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation. It should be used during pregnancy only if clearly needed. The CDC recommends that mothers with HIV not breast-feed their infants because HIV in the breast milk can infect the infant. [PDR 1999; p 813-4] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Stavudine, a synthetic antiretroviral agent, is a dideoxynucleoside reverse transcriptase inhibitor. It is an analogue of thymidine, a naturally occurring pyrimidine nucleoside. It differs from thymidine in the 2'-3'double bond on the deoxyribose moiety and the replacement of the 3'-hydroxyl group with hydrogen. The absence of free 3'-hydroxyl group results in the inability of stavudine to form phosphodiester linkages at this position. [AHFS Drug Information 1999; p 622] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H12-N2-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 224.22 [USPD 1998; p. 685] CHEMICAL/PHYSICAL DATA Melting Point: 165-166 C [Merck Index 1996; p. 1502] CHEMICAL/PHYSICAL DATA Elemental Comp: C53.57%, H5.39%, N12.49%, O28.54% [Merck Index 1996; p. 1502] CHEMICAL/PHYSICAL DATA Solubility: Solubility in water is about 83 mg/ml and 30 mg/ml in propylene glycol at 23 C. [PDR 1999; p 812] CHEMICAL/PHYSICAL DATA Stability: Stavudine solids are stable to heat, light, high moisture, and are hygroscopic; d4T is stable in acidic solution, and thus does not require enteric coating. [Protocol ID: ACTG 089 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline solid. [PDR 1997; p 732] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (15, 20, 30, and 40 mg). [PDR 1999; p 814] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 814] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store capsules in a tightly closed container at 15C to 30C (59F to 86F). [PDR 1999; p 815] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/99426952. Saboulard D, Naesens L, Cahard D, Salgado A, Pathirana R, Velazquez S, McGuigan C, De Clercq E, Balzarini J. Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Mol Pharmacol 1999 Oct;56(4):693-704. MED/99326732. Molina JM, Chene G, Ferchal F, Journot V, Pellegrin I, Sombardier MN, Rancinan C, Cotte L, Madelaine I, Debord T, Decazes JM. The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus. J Infect Dis 1999 Aug;180(2):351-8. MED/99240968. Kline MW, Van Dyke RB, Lindsey JC, Gwynne M, Culnane M, Diaz C, Yogev R, McKinney RE Jr, Abrams EJ, Mofenson LM. Combination therapy with stavudine (d4T) plus didanosine (ddI) in children with human immunodeficiency virus infection. The Pediatric AIDS Clinical Trials Group 327 Team. Pediatrics 1999 May;103(5):e62. MED/99323692. Kuritzkes DR, Marschner I, Johnson VA, Bassett R, Eron JJ, Fischl MA, Murphy RL, Fife K, Maenza J, Rosandich ME, Bell D, Wood K, Sommadossi JP, Pettinelli C. Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators. AIDS 1999 Apr 16;13(6):685-94. MED/99169769. Piscitelli SC, Kelly G, Walker RE, Kovacs J, Falloon J, Davey RT Jr, Raje S, Masur H, Polis MA. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1999 Mar;43(3):647-50. MED/99254899. von Giesen HJ, Hefter H, Jablonowski H, Arendt G. Stavudine and the peripheral nerve in HIV-1 infected patients. J Neurol 1999 Mar;246(3):211-7. MED/99217478. Gallant JE, Chaisson RE, Keruly JC, Moore RD. Stavudine in zidovudine (ZDV)-experienced compared with ZDV-naive patients. AIDS 1999 Feb 4;13(2):225-9. MED/99143287. Siddiqui AQ, Ballatore C, McGuigan C, De Clercq E, Balzarini J. The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship. J Med Chem 1999 Feb 11;42(3):393-9. MED/99102127. Kaul S, Dandekar KA, Schilling BE, Barbhaiya RH. Toxicokinetics of 2',3'-didehydro-3'-deoxythymidine, stavudine (D4T). Drug Metab Dispos 1999 Jan;27(1):1-12. MED/99030033. Raffi F, Reliquet V, Auger S, Besnier JM, Chennebault JM, Billaud E, Michelet C, Perre P, Lafeuillade A, May T, Billaudel S. Efficacy and safety of stavudine and didanosine combination therapy in antiretroviral-experienced patients. AIDS 1998 Oct 22;12(15):1999-2005. ENTRY MONTH 199104 LAST REVISION DATE 20000801 304 UNIQUE IDENTIFIER DRG-0042 NAME OF SUBSTANCE Butyldeoxynojirimycin [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 100 PROTOCOL ID NUMBERS No longer recruiting FDA 057A PROTOCOL ID NUMBERS No longer recruiting FDA 057B PHARMACOLOGICAL ACTION MODE OF ACTION: This drug may be effective in vivo at breaking the cycle of HIV infection by progressive elimination of HIV. In vitro studies in certain lymphocyte-derived cell lines have shown that a minimum drug concentration of between 0.5-20 mcg/ml markedly inhibits HIV-induced syncytial formation and reduces p24 core antigen production. The antiviral effect in vitro of aminosugar derivatives such as castanospermine, deoxynojirimycin (DNJ) and SC-48334 (n-butyl-DNJ), is attributed to alteration of N-linked oligosaccharide biosynthesis through inhibition of glucosidase activity. In animal studies (Rhesus primates), a dose of 165 mg/kg/day achieved a minumum plasma level of 10.9 mcg/ml; the drug was not substantially metabolized and was excreted unchanged in the urine; oral bioavailability was 72%, with a plasma half-life of about 2 hours. Preclinical studies showed inhibition of cytopathic effect and 4-log reduction in tissue culture infectious dose (TCID) in HIV-infected T-45 cells by a 10 mcg/ml concentration of the drug. At 50 and 100 mcg/ml, the drug showed a 5-log reduction in TCID. Similar results were seen against HIV-2 and reported for a section T-cell line, MOLT-4. Similar results were seen in another HIV-1 infected cell line, H-9. The drug was also shown to markedly inhibit p24 antigen production in acutely infected HIV-1 H9 cells. Related derivatives (N-methyl- and N-ethyldeoxynojirimycin) produced inhibition of glucosidase. [Int Conf AIDS 1993 Jun 6-11;9(1); 27 (abstract no. WS-A11-2); Protocol ID: ACTG 100 ] DISEASES STUDIED/TREATED Primary HIV infection. Trials in AIDS/ARC patients indicated that the drug had no significant effect on p24 antigen levels or CD4 cell counts. [AmfAR Treat Dir 1995;7(4); p 56-7] CLASSIFICATION CODE Enzyme inhibitor [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.; p 56-7] SUBSTANCE INTERACTIONS Animal studies (mice) showed that the drug did not inhibit the development of an antibody response to 2,4,6-trinitrophenyl keyhole limpet hemocyanin (a T-cell dependent antigen). [Protocol ID: ACTG 100 ] ADVERSE EFFECTS Inhibition of intestinal disaccharides in vivo can lead to carbohydrate malabsorbtion and diarrhea. Based on animal toxicology studies, adverse effects that might be experienced are gastrointestinal disturbances (diarrhea, gastric irritation, nausea, emesis), decreased platelet counts, elevated transaminases, and hepatic changes (vacuolization, hepatomegaly, changes in liver enzymes); with escalating doses (Rhesus primates), clinical symptoms increased in severity. In vitro studies have indicated the drug to be non-toxic to the target lymphocyte. [Int Conf AIDS 1993 Jun 6-11;9(1); p 27 (abstract no. WS-A11-2); Protocol ID: ACTG 100 ] CONTRAINDICATIONS Contraindicated in the presence of pregnancy or known hypersensitivity to this drug. [Protocol ID: ACTG 100 ] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H21-N-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Powder. [Protocol ID: ACTG 100 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Opaque white gelatin capsules of 100 mg and 500 mg. [Protocol ID: ACTG 100 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 100 ] MANUFACTURERS 0000001201: G D Searle & Co 5200 Old Orchard Road Skokie, IL 60077 Contact: Dr Richard Aspinall (708)982-8651 REFERENCES MED/96142217. Tierney M, Pottage J, Kessler H, Fischl M, Richman D, Merigan T, Powderly W, Smith S, Karim A, Sherman J, et al. The tolerability and pharmacokinetics of N-butyl-deoxynojirimycin in patients with advanced HIV disease (ACTG 100). The AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Dec 15;10(5):549-53. MED/95363994. Fischer PB, Collin M, Karlsson GB, James W, Butters TD, Davis SJ, Gordon S, Dwek RA, Platt FM. The alpha-glucosidase inhibitor N-butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding. J Virol 1995 Sep;69(9):5791-7. MED/96021491. Cook CS, Karabatsos PJ, Schoenhard GL, Karim A. Species dependent esterase activites for hydrolysis of an anti-HIV prodrug glycovir and bioavailabilty of active SC-48334. Pharm Res. 1995 Aug;12(8):1158-64. MED/95088414. Rusconi S, Merrill DP, Hirsch MS. Inhibition of human immunodeficiency virus type 1 replication in cytokine-stimulated monocytes/macrophages by combination therapy. J Infect Dis. 1994 Dec;170(6):1361-6. MED/94133083. Fischl MA, Resnick L, Coombs R, Kremer AB, Pottage JC Jr, Fass RJ, Fife KH, Powderly WG, Collier AC, Aspinall RL, et al. The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3. J Acquir Immune Defic Syndr. 1994 Feb;7(2):139-47. AIDS/95921589. Yangco B, Resnick L, Barbero D, Keiser P, Wallemark C, Smith S, Sobol J. Pilot safety and efficacy of combination SC-48334 (N-Butyl-deoxynojirimycin[NB-DNJ]) and Zidovudine (ZDV) in symptomatic HIV-1 infected patients with greater than or equal to 200- less than or equal to 500 CD4 cells/mm3. Natl Conf Hum Regroviruses Relat Infect (1st). 1993 Dec 12-16;:160. AIDS/95921597. Smith S, Piergies A, Smith M, Wallemark C, Karim A, Sherman J. Multiple oral dose safety and pharmokinetics of SC-49483 (N-butyl deoxynojirimycin [NB-DNJ] Prodrug). Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:160. ICA9/93334689. Bryant M, Mueller R, Smidt M, Tiemeier D, Jacobs G, Platt F, Butters T, Karlsson N, Houseman K, Marr J. Anti-HIV properties of alpha-glucosidase inhibitor SC-48334, the active component of prodrug SC-49483. Int Conf AIDS. 1993 Jun 6-11;9(1):33 (abstract no. WS-A17-6). ICA9/93335648. Fischl M, Resnick L, Coombs R, Pottage J, Smith S, Wallemark C. The preliminary efficacy and safety of N-butyl-deoxynojirimycin (SC-48334), an alpha-glucosidase I inhibitor, in combination with zidovudine (ZDV). Int Conf AIDS. 1993 Jun 6-11;9(1):475 (abstract no. PO-B26-2039). MED/93290922. Ratner L, Vander Heyden N. Mechanism of action of N-butyl deoxynojirimycin in inhibiting HIV-1 infection and activity in combination with nucleoside analogs. AIDS Res Hum Retroviruses. 1993 Apr;9(4):291-7. ENTRY MONTH 199104 LAST REVISION DATE 20000801 305 UNIQUE IDENTIFIER DRG-0041 NAME OF SUBSTANCE gp160 Vaccine (MicroGeneSys) [AmfAR Treat Dir 1993;6(3); p 27-8] PROTOCOL ID NUMBERS Complete FDA 063A PROTOCOL ID NUMBERS Complete NIAID ACTG 137 PROTOCOL ID NUMBERS Complete NIAID ACTG 148 PROTOCOL ID NUMBERS Complete NIAID ACTG 218 PROTOCOL ID NUMBERS Complete NIAID ACTG 221 PROTOCOL ID NUMBERS Complete NIAID ACTG 234 PROTOCOL ID NUMBERS Complete NIAID AVEG 002 PROTOCOL ID NUMBERS Complete NIAID AVEG 002A PROTOCOL ID NUMBERS Complete NIAID AVEG 002B PROTOCOL ID NUMBERS Complete NIAID AVEG 003 PROTOCOL ID NUMBERS Complete NIAID AVEG 003A PROTOCOL ID NUMBERS Complete NIAID AVEG 003B PROTOCOL ID NUMBERS Complete NIAID AVEG 008 PROTOCOL ID NUMBERS No longer recruiting CC 87 I-114 PROTOCOL ID NUMBERS No longer recruiting CC 90 I-5 DISEASES STUDIED/TREATED Primary HIV infection. [AmfAR Treat Dir 1997;8(3); p 60] CLASSIFICATION CODE Vaccine [Protocol ID: AVEG 008 ] ADVERSE EFFECTS Intramuscular dosage forms are well tolerated, local reactions are common, including tenderness and indurations at the injection site. Mild fever, myalgia or fatigue may occur. Intradermal injections produced subcutaneous nodules, prolonged skin discoloration and resulted in occasional purulent drainage and local pruritis. Nausea and headache were also reported. [AmfAR Treat Dir 1997;8(3); p 60] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Molecularly-cloned, denatured envelope glycoprotein derived from the LAV strain of HIV-1. VaxSyn is propagated in insect cells and adsorbed to an alum adjuvant. The preparation is expressed in baculovirus. [AmfAR Treat Dir 1997;8(3); p 60] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Formulated powder. [Protocol ID: AVEG 008 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: 1-ml vials containing 320 mcg/ml HIV-1 gp160 adsorbed onto 0.5 mg aluminum phosphate. [Protocol ID: AVEG 008 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [AmfAR Treat Dir 1997;8(3); p 60] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 2-8 C. Use within 24 hours after opening sealed vials. Do not freeze. [Protocol ID: AVEG 008 ] MANUFACTURERS 0000001169: MicroGeneSys Inc 1000 Research Parkway Meriden, CT 06450 Contact: Unspecified ENTRY MONTH 199104 LAST REVISION DATE 20000801 306 UNIQUE IDENTIFIER DRG-0040 NAME OF SUBSTANCE Peptide T [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 106362-33-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N-(N-(N(2)-(N-(N-(N-(N-D-alanyl-L-seryl)- L-threonyl)-L-threonyl)-L-threonyl)-L-asparag- inyl)- L-tyrosyl)-L-threonine [CHEMLINE ] PROTOCOL ID NUMBERS No longer recruiting FDA 115A PROTOCOL ID NUMBERS No longer recruiting NIMH 89 MH-28 PROTOCOL ID NUMBERS No longer recruiting NIMH 89 MH-SF PROTOCOL ID NUMBERS No longer recruiting NIMH 90 OD-0013 PHARMACOLOGICAL ACTION MODE OF ACTION: Blocks receptor for HIV in the brain. Blocks viral entry by competing for receptor sites on the CD4 molecule; HIV attachment to human CD4+ lymphocytes and brain cells appears to occur through this polypeptide sequence. Peptide T and two closely related analogs were found to exhibit the ability to block HIV infection of human T cells. It was reported that Peptide T and vasoactive intestinal peptide, a natural hormone which normally interacts with CD4 receptors, can prevent gp120-induced neuronal cell death in vitro. In a clinical trial with 6 AIDS patients with neuropsychiatric disorders and 5 control subjects, serum half-life of Peptide T was extended 4-4.5 hours and its concentration in cerebrospinal fluid was 1/8 of achieved plasma levels; all AIDS patients reported an increase in energy, arithmetic concentration, logical memory, and visuospatial processing. Increases in health related quality of life due to fatique suppression has been reported in studies of peptide T. [Int Conf AIDS 1992 Jul 19-24;8(3); 1992 Jul 19-24;8(3); p 73 (abstract no. PuB 7149); Protocol ID: 89 MH-SF ; Protocol ID: 89 MH-28 ] DISEASES STUDIED/TREATED Primary HIV infection; studied as a treatment for HIV associated neuropathy and neuropsychiatric impairment. [AmfAR Treat Dir 1995;7(4); p 69, 107] CLASSIFICATION CODE Immunomodulator [Protocol ID: 89 MH-28 ] CLASSIFICATION CODE Investigational - Antiviral [Drug Evaluations Annual 1995; p 1838] ADVERSE EFFECTS May cause rash and itching after several weeks of treatment; no mucosal toxicity was observed in AIDS patients during intranasal administration of Peptide T. [AmfAR Treat Dir 1988 Dec; p 82] CONTRAINDICATIONS Should not be used by pregnant women or by patients having a long previous history of psychiatric illness. [Protocol ID: 89 MH-28 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic hydrophilic octapeptide (ASTTTNYT); Octapeptide sequence of HIV envelope gp120; named peptide T because of high threonine content. [Merck Index 1996; p 1230] CHEMICAL/PHYSICAL DATA Molecular Formula: C35-H55-N9-O16 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 857.57 [Merck Index 1996; p. 1230] CHEMICAL/PHYSICAL DATA Elemental Comp: C49.00%, H6.46%, N14.69%, O29.84% [Merck Index 1996; p. 1230] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Powder. [Protocol ID: 89 MH-SF ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile solution. [Protocol ID: 89 MH-28 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous administration; intranasal administration. [AmfAR Treat Dir 1993;6(3); p 52] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Stable in lyophilized state at room temperature for greater than one week. [Protocol ID: 89 MH-SF ; Protocol ID: 89 MH-28 ] MANUFACTURERS 0000001178: Natl Institute of Mental Health 5600 Fishers Lane / Room 15-105 Rockville, MD 20857 Contact: Joan Abell (301)443-4513 MANUFACTURERS 0000002226: Advanced Peptides 201 Grant St / Box 93 Sewickley, PA 15143 Contact: Gerald Tarantino (412)741-0983 REFERENCES MED/97065958. Simpson DM, Dorfman D, Olney RK, McKinley G, Dobkin J, So Y, Berger J, Ferdon MB, Friedman B. Peptide T in the treatment of painful distal neuropathy associated with AIDS: results of a placebo-controlled trial. The Peptide T Neuropathy Study Group. Neurology. 1996 Nov;47(5):1254-9. MED/96268149. Vilemagne VL, Phillips RL, Liu X, Gilson SF, Dannals RF, Wong DF, Harris PJ, Ruff M, Pert C, Bridge P, London ED. Peptide T and glucose metabolism in AIDS dementia complex. J Nucl Med. 1996 Jul; 37(7):1177-80. ICA9/93335784. MacFadden DK, Phipps DJ, Doob PR. Peptide T immunomodulation: patient data. Int Conf AIDS. 1993 Jun 6-11;9(1):496 (abstract no. PO-B28-2164). MED/94152177. Johansson O, Hilliges M, Talme T, Marcusson JA, Wetterberg L. Speculations around the mechanism behind the action of peptide T in the healing of psoriasis: a minireview. Acta Derm Venereol. 1993 Dec;73(6):401-3. ICA8/92401494. Bridge P, Linde R, Ollo C, Easton E, Parker E, Mayer K, Heseltine P, Ruff M, Pert C. Peptide T HIV-1 cognitive effects. Int Conf AIDS. 1992 Jul 19-24;8(2):B218 (abstract no. PoB 3765). ICA7/4009091. Bridge P, Linde R, Ollo C, Mayer K. Neuropsychologic results of control HIV-1 trial of peptide T. Int Conf AIDS. 1991 Jun 16-21;7(2):79 (abstract no. TH.B.90). MED/92131963. Bridge TP, Heseltine PN, Parker ES, Eaton EM, Ingraham LJ, McGrail ML, Goodwin FK. Results of extended peptide T administration in AIDS and ARC patients. Psychopharmacol Bull. 1991;27(3):237-45. ICA7/1200691. Heseltine P, Eaton E, Buchsbaum M, Parker E, McGrail M, Leedom J, Bridge P. Effect of peptide T on AIDS dementia complex (ADC): correlation of PET scans and cognitive domains. Int Conf AIDS. 1991 Jun 16-21;7(1):183 (abstract no. M.B.2006). MED/92108228. Ruff MR, Smith C, Kingan T, Jaffe H, Heseltine P, Gill MA, Mayer K, Pert CB, Bridge TP. Pharmacokinetics of peptide T in patients with acquired immunodeficiency syndrome (AIDS). Prog Neuropsychopharmacol Biol Psychiatry. 1991;15(6):791-801. ENTRY MONTH 199104 LAST REVISION DATE 20000801 307 UNIQUE IDENTIFIER DRG-0039 NAME OF SUBSTANCE Dideoxyadenosine [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] REGISTRY NUMBER 4097-22-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Adenosine, 2',3'-dideoxy- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS No longer recruiting NCI 87 C-158D PHARMACOLOGICAL ACTION Dideoxyadenosine is rapidly deaminated to didanosine in plasma and various tissues. The use of dideoxyadenosine in clinical trials has been discontinued in favor of didanosine because the latter exhibits superior characteristics. (See Didanosine.) Didanosine is further metabolized to dideoxyadenosine triphosphate (ddA-TP), which is the pharmacologically active metabolite. [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.; AHFS Drug Information 2000; p 601] DISEASES STUDIED/TREATED Dideoxyadenosine produces antiviral effects by acting as a reverse transcriptase inhibitor. [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CLASSIFICATION CODE Investigational - Nucleoside analogue [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS Oral administration of dideoxyadenosine has caused severe nephrotoxicity in animals. The degree of nephrotoxicity appears to be greater than that of its related compound, didanosine. (See Didanosine.) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Dideoxyadenosine is a synthetic analogue of adenosine, a naturally occurring purine nucleoside. Dideoxyadenosine is a dideoxynucleoside in which the 3'-hydroxy group on the ribose moiety is replaced by a hydrogen atom. This modification results in the inability of dideoxyadenosine to form phosphodiester linkages that are needed for the completion of nucleic acid chains. [Merck Index 1996; p 525; ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H13-N5-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 235.25 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Melting Point: 184-186 C [Merck Index 1996; p. 525] CHEMICAL/PHYSICAL DATA Elemental Comp: C51.06%, H5.57%, N29.77%, O13.60% [Merck Index 1996; p. 525] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystals from ethanol [Merck Index 1996; p 525] MANUFACTURERS 0000002734: Natl Cancer Institute 9000 Rockville Pike / Clinical Ctr Bethesda, MD 20892 Contact: Dr Robert Yarchoan (301)496-0328 REFERENCES MED/97057096. Thumann-Schweitzer C, Gosselin G, Perigaud C, Benzaria S, Girardet JL, Lefebvre I, Imbach JL, Kirn A, Aubertin AM. Anti-human immunodeficiency virus type 1 activities of dideoxynucleoside phosphotriester derivatives in primary monocytes/macrophages. Res Virol. 1996 Mar-Jun;147(2-3):155-63. MED/96156480. Marongiu ME, Pani A, Tinti E, Grifanini M, Franchetti P, Cristalli G, La Colla P. Enhancement of the anti-HIV-1 activity of ddAdo by coformycin, EHNA and deaza-EHNA derivatives. New Microbiol. 1995 Oct;18(4):359-70. MED/96012182. Hawkins ME, Mitsuya H, McCully CM, Godwin KS, Murakami K, Poplack DG, Balis FM. Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys. Antimicrob Agents Chemother. 1995 Jun;39(6):1259-64. MED/95058950. Ahluwalia GS, Cooney DA, Shirasaka T, Mitsuya H, Driscoll JS, Johns DG. Enhancement by 2'-deoxycoformycin of the 5'-phosphorylation and anti-human immunodeficiency virus activity of 2',3'-dideoxyadenosine and 2'-beta-fluoro-2',3'-dideoxyadenosine. Mol Pharmacol. 1994 Nov;46(5):1002-8. MED/90349972. McGowan JJ, Tomaszewski JE, Cradock J, Hoth D, Grieshaber CK, Broder S, Mitsuya H. Overview of the preclinical development of an antiretroviral drug, 2',3'-dideoxyinosine. Rev Infect Dis. 1990 Jul-Aug;12 Suppl 5:S513-20; discussion S520-1. Review. MED/90263356. Hartman NR, Yarchoan R, Pluda JM, Thomas RV, Marczyk KS, Broder S, Johns DG. Pharmacokinetics of 2',3'-dideoxyadenosine in patients with severe human immunodeficiency virus infection. Clin Pharmacol Ther. 1990 May;47(5):647-54. MED/89246584. Russell JW, Klunk LJ. Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. Biochem Pharmacol. 1989 May 1;38(9):1385-8. ENTRY MONTH 199104 LAST REVISION DATE 20000801 308 UNIQUE IDENTIFIER DRG-0038 NAME OF SUBSTANCE Cytarabine [USPD 1998; p. 205] REGISTRY NUMBER 147-94-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Amino-1-beta-D-arabinofuranosyl-2(1H)-pyrim- idinone [Merck Index 1996; p 471] SYNONYMS Cytosar-U [USP DI 2000; p. 1173] SYNONYMS Depocyt (liposomal) [USP DI 2000; p. 3198] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 243 PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-207 PROTOCOL ID NUMBERS Terminated NIAID ACTG 252 PHARMACOLOGICAL ACTION MODE OF ACTION: Cytarabine is metabolized intracellularly by deoxycytidine kinase and other nucleotide kinases to cytarabine triphosphate, the active metabolite of the drug. Although the exact mechanism of action has not been fully elucidated, cytarabine triphosphate appears to inhibit DNA polymerase by competing with the physiologic substrate, deoxycytidine triphosphate, resulting in the inhibition of DNA synthesis. Although limited, incorporation of cytarabine triphosphate into DNA and RNA may also contribute to the cytotoxic effects of the drug. Continuous IV infusions of cytarabine produce relatively constant plasma concentrations of the drug in 8-24 hours. Cytarabine is rapidly and widely distributed into tissues and fluids, including liver, plasma, and peripheral granulocytes. Following rapid IV injection, about 13% of the drug was bound to plasma proteins. Cytarabine crosses the blood-brain barrier to a limited extent. During a continuous IV or subcutaneous infusion, cytarabine concentrations in the CSF are higher than those attained after rapid IV injection and are about 40-60% of the plasma concentrations. Most of the intrathecal dose of cytarabine diffuses into the systemic circulation but is rapidly metabolized and usually only low plasma concentrations of unchanged drug occur. The drug apparently crosses the placenta. After rapid IV injection of cytarabine, plasma drug concentrations appear to decline in a biphasic manner with a half-life of about 10 minutes in the initial phase and about 1-3 hours in the terminal phase. After intrathecal injection, cytarabine concentrations in the CSF reportedly decline with a half-life of about 2 hours. Cytarabine is rapidly and extensively metabolized mainly in liver but also in kidneys, GI mucosa, granulocytes, and to a lesser extent in other tissues by the enzyme cytidine deaminase, producing the inactive metabolite 1-B-d-arabinofuranosyluracil (ara-U, uracil arabinoside). After the initial distribution phase, more than 80% of the drug in plasma is present as ara-U. In CSF, only minimal amounts of cytarabine are converted to ara-U because of low CSF concentrations of cytidine deaminase. Cytarabine triphosphate is inactivated by a pyrimidine nucleoside deaminase, which produces the uracil derivative. Cytarabine and ara-U are excreted in urine. About 70-80% of the drug is excreted in urine within 24 hours. About 90% of the urinary drug excretion occurs as ara-U and about 10% as an unchanged drug. [AHFS Drug Information 1997; p 724] DISEASES STUDIED/TREATED Used primarily in combination with other drugs for the treatment of acute myelocytic leukemia. Under investigation for treatment of Progressive Multifocal Leukoencephalopathy (PML). [AmfAR Treat Dir 1997;8(3); p 68] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 1170] OTHER MAJOR USES In combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia of adults and children. Also useful in the treatment of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration is indicated in the prophylaxis and treatment of meningeal leukemia. [PDR 1997; p 2077] SUBSTANCE INTERACTIONS Digoxin absorption may be decreased by concomitant cytarabine. Gentamicin and fluorocytosine activity may also be inhibited by cytarabine. [PDR 1997; p 2078] ADVERSE EFFECTS Its main toxic effect is bone marrow suppression with anemia, leukopenia, and thrombocytopenia (since it is a potent bone marrow suppressant, it should be started cautiously in patients with pre-existing drug-induced bone marrow suppression). Other adverse effects may include megaloblastosis, reduced reticulocytes, fever, myalgia, bone pain, occasional chest pain, maculopapular rash, conjunctivitis, malaise, hepatic dysfunction, thrombophlebitis, bleeding, anorexia, nausea, vomiting, diarrhea, or oral/anal inflammation and ulceration. There is no antidote for overdose; overdose can result in irreversible central nervous system toxicity and death. Should only be used by physicians experienced in cancer chemotherapy. [PDR 1997; p 2078] CONTRAINDICATIONS Contraindicated in those patients who are hypersensitive to the drug. Since the drug has shown to be potentially teratogenic, it should be used with women who are pregnant or who may become pregnant only after due consideration of its benefits and hazards. [PDR 1997; p 2077-8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic pyrimidine nucleoside. [AHFS Drug Information 1997; p 723] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H13-N3-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 243.22 [USPD 1998; p. 205] CHEMICAL/PHYSICAL DATA Melting Point: 212-213 C [Merck Index 1996; p. 471] CHEMICAL/PHYSICAL DATA Elemental Comp: C44.45%, H5.39%, N17.28%, O32.89% [Merck Index 1996; p. 471] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water; slightly soluble in alcohol and in chloroform. [PDR 1997; p 2077] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Odorless, white to off-white, crystalline powder. [PDR 1997; p 2077] SUBSTANCE DELIVERY DATA DOSAGE FORM: 100mg, 500mg, 1g and 2g vials. [PDR 1997; p 2079] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous; intrathecal; or subcutaneous injection. [PDR 1997; p 2077] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store powders at 15 - 30 C (59-86 F). Solutions reconstituted with bacteriostatic water for injection with benzyl alcohol may be stored at 15C to 30C for 48 hours. Solutions reconstituted with water for injection should be used immediately. [PDR 1997; p 2079] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 REFERENCES MED/97081561. Moreno S, Miralles P, Diaz MD, Berenguer J, Bernaldo de Quiros JC, Blazquez R, Cosin J, Bouza E. Cytarabine therapy for progressive multifocal leukoencephalopathy in patients with AIDS. Clin Infect Dis. 1996 Nov;23(5):1066-8. MED/96035253. Guarino M, D'Alessandro R, Rinaldi R, Stracciari A, Pazzaglia P, Costiglila P, Marinacci G, Chiodo F, Di Giandominico G, Cancellieri C. Progressive multifocal leukoencephalopathy in AIDS: treatment with cytosine arabinoside [letter][see comments]. AIDS. 1995 Jul;9(7):819-20. [Comment in AIDS. 1996 Feb;10(2):237.] MED/96023835. Major EO, Ault GS. Progressive multifocal leukoencephalopathy: clinical and laboratory observations on a viral induced demyelinating disease in the immunodeficient patient. Curr Opin Neurol. 1995 Jun;8(3):184-90. MED/95345302. Fong IW, Toma E. The natural history of progressive multifocal leukoencephalopathy in patients with AIDS. Canadian PML Study Group. Clin Infect Dis. 1995 May;20(5):1305-10. AIDS/95920337. Fong IW, Toma E. Prognostic factors in AIDS patients with progressive multifocal leukoencephalopathy. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:111. ICA10/94369687. Ravaux I, Quinson AM, North MO, Gallais H. Treatment of AIDS and progressive multifocal leukoencephalopathy (PML) with cytarabine when the brain biopsy is unsuccessful or impossible. Int Conf AIDS. 1994 Aug 7-12;10(1):201 (abstract no. PB0231). MED/94332776. Greenberg AL, Droller DG. Successful treatment of a patient with seropositive human immunodeficiency virus with high risk Burkitt's leukemia. Cancer. 1994 Aug 15;74(4):1261-4. MED/94339280. Hervas Laguna MJ, Nieto Rodriguez JA, Geijo Martinez MP, Ruiz Ribo MD, Borregon S. [Progressive multifocal leukoencephalopathy and AIDS. Response to cytarabine]. An Med Interna. 1994 May;11(5):241-3. MED/94015218. Chamberlain MC, Dirr L. Involved-field radiotherapy and intra-Ommaya methotrexate/cytarabine in patients with AIDS-related lymphomatous meningitis. J Clin Oncol. 1993 Oct;11(10):1978-84. ENTRY MONTH 199104 LAST REVISION DATE 20000801 309 UNIQUE IDENTIFIER DRG-0037 NAME OF SUBSTANCE Piritrexim isethionate [USPD 1998; p. 583] REGISTRY NUMBER 79483-69-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Pyrido(2,3-d)pyrimidine-2,4-diamine, 6-((2,5-dimethoxyphenyl)methyl)-5-methyl-, mono(2-hydroxyethanesulfonate) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] PROTOCOL ID NUMBERS No longer recruiting CC 89 CC-59 PHARMACOLOGICAL ACTION MODE OF ACTION: A lipid-soluble dihydrofolate reductase (DHFR) inhibitor with the same mechanism of action as Trimethoprim against Pneumocystis carinii. Inhibits the activity of Pneumocystis carinii DHFR enzyme in vitro at levels from 140-2000 fold less than that required by Trimethoprim and Pyrimethamine for similar inhibition. The basis for the anti-folate activity of Piritrexim is its inhibition of DHFR, an essential folate conversion enzyme for protozoan and mammalian cells. Its lipid-soluble nature enables it to diffuse across the protozoan membrane without the use of a transport mechanism (the resultant myelosuppressive effect following passive diffusion in mammalian cells can be counteracted by use of Leucovorin (folinic acid)). Similar to Trimetrexate in terms of activity, pharmacokinetics, and safety in cancer patients. Following oral dosing in cancer patients, Piritrexim peak serum levels were obtained in 1.6 hours, with a half-life of 4-5 hours. In patients receiving Piritrexim orally once daily for 5 consecutive days, the principal pharmacokinetic parameters indicated a plasma half-life of 3-4 hours, a time to maximum serum concentration of 2.0 - 2.5 hours, and a maximum concentration of approximately 5 micrograms/ml for doses of approximately 480 mg/m2. Oral bioavailability of Piritrexim is about 65%, and it is 92-95% bound to plasma protein. [Antimicrob Agents Chemother 1988; p 32:430-3; Protocol ID: 89 CC-59 ] DISEASES STUDIED/TREATED Pneumocystis carinii pneumonia (PCP). [USP DI 1995; p 2991] CLASSIFICATION CODE Antineoplastic [Merck Index 1996; p. 1291] CLASSIFICATION CODE Antiproliferative [USPD 2000 p. 573] OTHER MAJOR USES Use as an anti-cancer agent. [USP DI 1995; p 2991] SUBSTANCE INTERACTIONS Administer with leucovorin to prevent piritrexim myelosuppression. [USP DI 1995; p 2991] ADVERSE EFFECTS Leukopenia, anemia, thrombocytopenia, nausea and vomiting, mucositis and myelosuppression are the main adverse reactions. [USP DI 1995; p 2991] CONTRAINDICATIONS Should not be used by patients who have had a history of adverse reaction to Trimetrexate requiring discontinuation of treatment, or by pregnant or lactating women, or by women or men not practicing birth control. [Protocol ID: 89 CC-59 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Methotrexate analog. [USP DI 1995; p 2991] CHEMICAL/PHYSICAL DATA Molecular Formula: C17-H19-N5-O2.C2-H6-O4-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 451.51 [USPD 1998; p. 583] CHEMICAL/PHYSICAL DATA Elemental Comp: C62.76%, H5.89%, N21.52%, O9.83% (base) [Merck Index 1996; p. 1291] CHEMICAL/PHYSICAL DATA Solubility: Lipid soluble. [USP DI 1995; p 2991] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Off-white, odorless powder. [Protocol ID: 89 CC-59 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (25 mg). [Protocol ID: 89 CC-59 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, intravenous. [USP DI 1995] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-30 C (59-86 F). [Protocol ID: 89 CC-59 ] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 REFERENCES MED/96300559. Viora M, De Luca A, D'Ambrosio A, Antinori A, Ortona E. In vitro and in vivo immunodulatory effects of anti-Pneumocystis carinii drugs. Antimicrob Agents Chemother 1996 May;40(5):1294-7. MED/96251031. Piper JR, Johnson CA, Krauth CA, Carter RL, Hosmer CA, Queener SF, Borotz SE, Pfefferkorn ER. Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vivo evaluations. J Med Chem 1996 Mar 15;39(6):1271-80. MED/95182426. Rosowsky A, Mota CE, Queener SF, Waltham M, Ercikan-Abali E, Bertino JR. 2,4-Diamino-5-sustituted-quinazolines as inhibitors of a human diydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii. J Med Chem 1995 Mar 3;38(5):745-52. MED/95171109. Champness JN, Achari A, Ballantine SP, Bryant PK, Delves CJ, Stammers DK. The structure of Pneumocystis carinii dihydorfolate reductase to 1.9 A resolution. Structure. 1994 Oct 15;2(10):915-24. TOXBIB/94/072405. Perkins W, Williams RE, Vestey JP, Tidman MJ, Layton AM, Cunliffe WJ, Saihan EM, Klaber MR, Manna VK, Baker H, et al. A multicentre 12-week open study of a lipid-soluble folate antagonist, piritrexim in severe psoriasis. Br J Dermatol. 1993 Nov;129(5):584-9. MED/94046940. Rosowsky A, Mota CE, Wright JE, Freisheim JH, Heusner JJ, McCormack JJ, Queener SF. 2,4-Diaminothieno[2,3-d]pyrimidine analogues of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J Med Chem. 1993 Oct 15;36(21):3103-12. MED/93198840. de Wit R, Verweij J, Slingerland R, Stoter G. Piritrexim-induced pulmonary toxicity. Am J Clin Oncol. 1993 Apr;16(2):146-8. MED/92136902. Sattler FR, Feinberg J. New developments in the treatment of Pneumocystis carinii pneumonia. Chest. 1992 Feb;101(2):451-7. MED/92119605. Adamson PC, Balis FM, Miser J, Arndt C, Wells RJ, Gillespie A, Aronson L, Penta JS, Clendeninn NJ, Poplack DG. Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a low-dose, intermittent schedule. Cancer Res. 1992 Feb 1;52(3):521-4. MED/91241725. Hughes WT. Prevention and treatment of Pneumocystis carinii pneumonia. Annu Rev Med. 1991;42:287-95. ENTRY MONTH 199104 LAST REVISION DATE 20001107 310 UNIQUE IDENTIFIER DRG-0036 NAME OF SUBSTANCE Dapsone [USPD 1998; p. 210] REGISTRY NUMBER 80-08-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4,4'-Sulfonylbisbenzenamine [Merck Index 1996; p 478] PROTOCOL ID NUMBERS Complete CC 88 CC-85 PROTOCOL ID NUMBERS Complete CC 89 CC-02 PROTOCOL ID NUMBERS Complete CC 89 CC-17 PROTOCOL ID NUMBERS Complete NIAID ACTG 081 PROTOCOL ID NUMBERS Complete NIAID ACTG 108 PROTOCOL ID NUMBERS Complete NIAID ACTG 179 PROTOCOL ID NUMBERS No longer recruiting FDA 007A PROTOCOL ID NUMBERS No longer recruiting FDA 007B PROTOCOL ID NUMBERS No longer recruiting FDA 224A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 277 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 283 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 013 PHARMACOLOGICAL ACTION MODE OF ACTION: Dapsone is usually bacteriostatic in action, it probably has a mechanism of action similar to that of sulfonamides which involves inhibition of folic acid synthesis in susceptible organisms. Some studies indicate that dapsone may inhibit the alternate pathway of complement activation and interfere with the myeloperoxidase-H2O2-halide-mediated cytotoxic system within neutrophils. The drug also appears to inhibit spontaneous and induced synthesis of prostaglandin E2 by polymorphonuclear leukocytes obtained from healthy individuals or patients with leprosy. The mechanism of action of dapsone in the treatment of dermatitis herpetiformis is unknown; however, dapsone only suppresses the disease, and cutaneous IgA and complement deposition are not affected by the drug. It has been suggested that dapsone may act as an immunomodulator when used in the treatment of dermatitis herpetiformis and other dermatologic diseases. Dapsone is active in vivo against Mycobacterium leprae, M. tuberculosis and several other species of mycobacteria. Dapsone also has some activity against Pneumocystis carinii and Plasmaodium. Following oral administration, dapsone is almost completely absorbed from the GI tract and peak serum concentrations of the drug are generally attained within 2-8 hours. Trace amounts of dapsone may be found in serum for 8-12 days after a single 200 mg oral-dose or for as long as 35 days after discontinuance of repeated doses of the drug. Dapsone is distributed into most body tissues, and is reportedly retained in the skin, muscle, kidneys, and liver; trace concentrations of the drug may be present in these tissues up to 3 weeks after discontinuance of dapsone therapy. Dapsone is also distributed in sweat, saliva, sputum, bile, and tears. Dapsone crosses the placenta, it is also distributed into milk. Dapsone is 50-90% bound to plasma proteins. Dapsone is acetylated in the liver to monacetyl and diacetyl derivatives. The major metabolite of dapsone, monoacetyldapsone (MADDS), is almost completely bound to plasma proteins. Dapsone and its monoacetyl metabolite appear to undergo enterohepatic circulation. The plasma half-life of dapsone may range from 10-83 hours and averages 20-30 hours. The drug is also hydroxylated in the liver to hydroxylamine dapsone (NOH-DDS). NOH-DDS appears to be responsible for methemoglobinemia and hemolysis induced by the drug. Approximately 20% of each dose of dapsone is excreted in urine as unchanged drug, 70-85% is excreted in urine as water-soluble metabolites, and a small amount is excreted in feces. [AHFS Drug Information 1997; p 626-7] DISEASES STUDIED/TREATED Dapsone has been used in conjunction with trimethoprim for the treatment of initial episodes of Pneumocystis carinii pneumonia; prophylactic therapy for the primary and secondary prevention of Pneumocystis carinii pneumonia. [AHFS Drug Information 1997; p 627] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 1196] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 1196] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 1196] CLASSIFICATION CODE Dermatitis herpetiformis suppressant [USP DI 2000; p. 1196] OTHER MAJOR USES Used for treatment of Dermatitis herpetiformis and as an antibacterial drug for susceptible cases of leprosy. [PDR 1997; p 1332] SUBSTANCE INTERACTIONS The buffer system present in didanosine preparation may inhibit the gastrointestinal absorption of dapsone, which requires acidity for dissolution. Concurrent use of a folic acid antagonist (e.g., pyrimethamine) and dapsone may result in an increased risk of hematologic adverse effects, such as agranulocytosis. Because effects may be additive, dapsone should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency receiving or exposed to other drugs or agents which are capable of inducing hemolysis in these individuals (e.g., nitrite, aniline, phenylhydrazine, naphthalene, niridazole, nitrofurantoin, primaquine). Rifampin reportedly decreases serum dapsone concentrations by inducing liver enzymes responsible for inactivation of the sulfone and increases urinary excretion of the sulfone. Trimethoprim may increase plasma dapsone concentrations during concomitant therapy and potentially may increase the risk of adverse effects. [AHFS Drug Information 1997; p 629] ADVERSE EFFECTS Hematologic Effects: Dose-related hemolysis is the most common adverse effect and is seen in patients with or without glucose-6-phosphatase deficiency. Almost all patients show a related decrease of hemoglobin (1-2g), an increase in reticulocytes (2-12%), shortened red cell life span, and increased methemoglobin. May also cause agranulocytosis, aplastic anemia, and other blood dyscrasias resulting in fatalities. Nervous System Effects: Peripheral neuropathy with motor loss is a definite but unusual complication seen in non-leprosy patients. Dapsone should be withdrawn if muscle weakness appears. Recovery on withdrawal is usually complete. Some patients have tolerated retreatment at reduced dose. Body As Whole: Additional adverse reactions include: nausea, vomiting, abdominal pains, pancreatitis, vertigo, blurred vision, tinnitus, insomnia, fever, headache, psychosis, phototoxicity, pulmonary eosinophilia, tachycardia, albuminuria, nephrotic syndrome, hypoalbuminemia without proteinuria, renal papillary necrosis, male infertility, drug-induced Lupus erythematosus, and an infectious mononucleosis-like syndrome. In general these side effects regress off drug. Serious cutaneous reactions may occur including exfoliative dermatitis, toxic erythema, erythema multiforme, toxic epidermal necrolysis, morbilliform and scarlatiniforme reactions, and erythema nodosum. [PDR 1997; p 1332] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to dapsone and/or its derivatives. Should not be used by lactating mothers since dapsone is excreted in substantial amounts in breast milk; hemolytic reactions can occur in neonates. [PDR 1997; p 1332] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Aromatic amine sulfone derivative. [PDR 1996; p 1331] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H12-N2-O2-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 248.31 [USPD 1998; p. 210] CHEMICAL/PHYSICAL DATA Melting Point: 175-176 C [Merck Index 1996; p. 478] CHEMICAL/PHYSICAL DATA Elemental Comp: C58.05%, H4.87%, N11.28%, O12.89%, S12.91% [Merck Index 1996; p. 478] CHEMICAL/PHYSICAL DATA Solubility: Soluble in alcohol, methanol, acetone, dilute HCl; practically insoluble in water. [Merck Index 1996; p 478] CHEMICAL/PHYSICAL DATA Stability: Dapsone may discolor following exposure to light. [AHFS Drug Information 1997; p 626] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White odorless crystalline powder. [PDR 1997; p 1331] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (25 mg and 100 mg). [PDR 1997; p 1332] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1332] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store in light-resistant containers at controlled room temperature (59 - 86 F), and protect from light. [PDR 1997; p 1332] MANUFACTURERS 0000001019: Jacobus Pharmaceutical Co 37 Cleveland Lane / PO Box 5290 Princeton, NJ 08540 Contact: Dr David Jacobus (609)921-7447 REFERENCES MED/96185167. Korraa H, Saadeh C. Options in the management of pneumonia caused by Pneumocystis carinii in patients with acquired immune deficiency syndrome and intolerance to trimethoprim/sulfamethoxazole. South Med J. 1996 Mar;89(3):272-7. MED/96135999. Ioannidis JP, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med. 1996 Jan 22;156(2):177-88. MED/97103604. Warnock AC, Rimland D. Comparison of trimethoprim-sulfamethoxazole, dapsone, and pentamidine in the prophylaxis of Pneumocytis carinii pneumonia. Pharmaoctherapy. 1996 Nov-Dec;16(6):1030-8. MED/97006450. Antinori A, Murri R, Ammassari A. Low-dose dapsone, co-trimoxazole, and survival in Pneumocystis carinii primary prophylaxis [letter]. AIDS. 1996 Aug; 10(9):1046-7. MED/96335109. Sin DD, Shafran SD. Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Aug;12(5):477-81. MED/96300543. Lee BL, Safrin S, Makrides V, Gambertoglio JG. Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1996 May;40(5):1231-6. MED/96188893. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primarquine. ACTG 108 Study Group. Ann Intern Med. 1996 May;124(9):792-802. MED/96419545. Gatti G, Fioredda F, Lorusso C, Cruciani M, Bassetti D. Alternative dapsone dosage regimen for prophylaxis of Pneumocystis carinii pneumonia [letter]. Pediatr Infect Dis J. 1996 Feb;15(2):183-4. MED/96262026. Weinberg GA. Iron overload as a mechanism for the lowered survival in AIDS patients receiving dapsone-iron protoxalate for secondary prophylaxis of Pneumocystis carinii pneumonia [letter;comment]. J Infect Dis. 1995 Sep;174(1):241-2. [Comment in J Infect Dis. 1995 Sep;172(3):656-64.] MED/96131195. Behbahani R, Moshfeghi M, Baxter JD. Therapeutic approaches for AIDS-related toxoplasmosis [see comments]. Ann Pharmacother. 1995 Jul-Aug;29(7-8):760-8. [Comment in Ann Phamaochter. 1995 Dec;29(12):1303-4.] ENTRY MONTH 199104 LAST REVISION DATE 20000801 311 UNIQUE IDENTIFIER DRG-0035 NAME OF SUBSTANCE Interferon alfa-2b [USPD 2000 p. 373] REGISTRY NUMBER 99210-65-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Interferon alfa-2b (human leukocyte clone Hif-SN206 protein moiety reduced) [USPD 2000; p 373] SYNONYMS Intron A [USP DI 2000; p 1814] SYNONYMS PEG-Intron (Peginterferon alfa-2b) [Schering Plough. Press Release. Available at: http://www.sgp.com/news/research/2000/1-5-00.- html. Accessed 08/21/00.] PROTOCOL ID NUMBERS Complete CC 88 I-170 PROTOCOL ID NUMBERS Complete CC 88 I-181 PROTOCOL ID NUMBERS Complete NIAID ACTG 090 PROTOCOL ID NUMBERS Complete NIAID ACTG 203P PROTOCOL ID NUMBERS No longer recruiting FDA 074A PROTOCOL ID NUMBERS No longer recruiting CC 88 I-172 PROTOCOL ID NUMBERS No longer recruiting CC 90 CC-110 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 206 PROTOCOL ID NUMBERS Terminated CC 90 I-114 PHARMACOLOGICAL ACTION The mechanism of action of the antitumor and antiviral activities of interferon alfa-2b is unknown. These effects appear to be related to a direct antiproliferative action against tumor cells, inhibition of virus replication, and modulation of the host immune response. Interferon alfa must be administered parenterally to avoid degradation by gastrointestinal proteolytic enzymes. Following intramuscular or subcutaneous injection, mean serum concentrations are comparable, and the time to peak concentration is 3 to 12 hours. For both routes, the degree of absorption is greater than 80% and the elimination half-life is 2 to 3 hours. Accumulation may occur with multiple intramuscular doses. Interferon alfa-2b is metabolized principally in the kidney. It is completely filtered through the glomeruli and undergoes rapid proteolytic degradation during renal tubular reabsorption. Metabolites are almost completely reabsorbed and only negligible amounts of unchanged alfa interferon reappear in the systemic circulation. [PDR 2000; p 2808-9; AHFS Drug Information 2000; p 958; PDR 2000; p 2809; USP DI 2000; p 1811] DISEASES STUDIED/TREATED Interferon alfa-2b is FDA-approved for treatment of AIDS-related Kaposi's sarcoma in selected patients 18 years of age or older. It is used as initial therapy in patients whose disease is otherwise asymptomatic and who do not have severe immune dysfunction. Response rates are decreased in patients with prior opportunistic infections, constitutional (B) symptoms, or reduced helper/inducer T-cell counts. Interferon alfa-2b also is approved for the treatment of chronic hepatitis B and C. In addition, interferon alfa-2b is included in a number of HIV clinical trials due to its antiproliferative and antiviral effects. [USP DI 2000; p 1810; AHFS Drug Information 2000; p 961-2; USP DI 2000; p 1810; Protocol ID: ACTG 206 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1810] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 1810] OTHER MAJOR USES Interferon alfa-2b is indicated for the treatment of chronic hepatitis C, diagnosed by HCV antibody and/or a history of exposure to hepatitis C, in patients 18 years of age or older with compensated liver disease. It is also indicated for the treatment of chronic hepatitis B in select patients 1 year of age or older with compensated liver disease. Other approved uses include the treatment of hairy cell leukemia, malignant melanoma, follicular lymphoma, and condylomata acuminata. [PDR 2000; p 2810-1; USP DI 2000; p 1810] SUBSTANCE INTERACTIONS There are no reported food interactions with interferon alfa-2b. Interferon alfa-2b has been reported to reduce the clearance of theophylline. Also, alfa interferons may inhibit the activity of hepatic cytochrome P450 isoenzymes. Although the clinical relevance of this effect is unknown, the potential for interactions between interferon alfa-2b and other similarly metabolized drugs should be considered. The concomitant use of interferon alfa with interleukin-2 (aldesleukin) may increase the risk of renal failure; exacerbation of autoimmune and inflammatory disorders also has occurred. The combination of interferon alfa with zidovudine or acyclovir, while causing synergistic antiviral effects, also can increase the risk of hematologic and hepatic toxicity. Interferon alfa-2b should be used with caution in patients receiving other potentially myelosuppressive drugs. [PDR 2000; p 2809; AHFS Drug Information 2000; p 980; AHFS Drug Information 2000; p 980; PDR 2000; p 2815] ADVERSE EFFECTS Almost all patients experience adverse effects at some time during the course of interferon alfa therapy. The incidence and severity of side effects appear to be highest in patients with AIDS-related Kaposi's sarcoma. The underlying disease and the higher doses required are likely contributing factors. The most common adverse effect is a flu-like syndrome (fever, fatigue, myalgia/arthralgia, and headache). This has been reported in up to 79% of patients receiving the drug. Gastrointestinal side effects are common. Diarrhea, anorexia, and nausea have been reported in up to 45, 41, and 21% of patients, respectively. The incidence of reported depression and suicidal behavior is 15% or higher. If delerium or severe depression occurs, dosage reduction or cessation may be warranted. Other CNS reactions to interferon alfa-2b include dizziness, paresthesia, impaired concentration, amnesia, and confusion. Side effects such as dyspnea, coughing, pharyngitis, and sinusitus are frequently reported. Hair loss and skin rash also occur. Leukopenia, anemia, and thrombocytopenia have been reported frequently. Increases in hepatic enzymes are generally mild to moderate and transient; substantial increases are generally reversible following dosage reduction or discontinuation of the drug. [AHFS Drug Information 2000; p 972; PDR 2000; p 2814-5; USP DI 2000; p 1816; AHFS Drug Information 2000; p 974] CONTRAINDICATIONS Interferon alfa-2b is contraindicated in patients allergic to alfa interferon or any component of the product. [PDR 2000; p 2812] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Interferon alfa-2b is a synthetic interferon manufactured by recombinant DNA technology using a genetically engineered Escherichia coli bacterium. [Schering Plough. Rebetron. Available at: http://www.hep-help.com/pro/pi.htm. Accessed 08/21/00.] CHEMICAL/PHYSICAL DATA Molecular Formula: C860-H1353-N229-O255-S9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 19,268.93 [USPD 2000; p 373] CHEMICAL/PHYSICAL DATA Stability: Multidose vials prepared with enclosed diluent must be discarded 30 days after reconstitution. [USP DI 2000; p 1815] SUBSTANCE DELIVERY DATA DOSAGE FORM: Powder for injection (3 MIU, 5 MIU, 10 MIU, 18 MIU, 25 MIU, or 50 MIU per vial) supplied with diluent (bacteriostatic water for injection); solution in vials for injection (3 MIU, 5 MIU, or 10 MIU per single-dose vial, and 18 MIU or 25 MIU per multidose vial); solution in multidose pens for injection (18 MIU, 30 MIU, or 60 MIU per multidose pen) [PDR 2000; p 2809] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous, intramuscular, or intralesional injection; intravenous infusion [USP DI 2000; p 1814] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: All forms of injectable solution should be stored at 2 to 8 C (36 to 46 F). Powder for injection should be stored, both before and after reconstitution, at 2 to 8 C (36 to 46 F). [PDR 2000; p 2816] MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Dr Janice Albrecht (908)298-7985 MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Unspecified (800)526-4099 MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Dr Janice Albrecht (908)298-7985 REFERENCES MED/20079345. Goebel FD, Jablonowski H. Therapy of special HIV-associated diseases: HCV-HIV-co-infection and AIDS-related Kaposi's sarcoma - official satellite to the 7th European Conference on Clinical Aspects and Treatment of HIV-infection, October 23, 1999 in Lisbon, Portugal. Eur J Med Res. 1999 Dec 16;4(12):507-13. MED/99279313. Dieterich DT, Purow JM, Rajapaksa R. Activity of combination therapy with interferon alfa-2b plus ribavirin in chronic hepatitis C patients co-infected with HIV. Semin Liver Dis. 1999;19 Suppl 1:87-94. Review. MED/99174790. Krown SE, Aeppli D, Balfour HH Jr. Phase II, randomized, open-label, community-based trial to compare the safety and activity of combination therapy with recombinant interferon-alpha2b and zidovudine versus zidovudine alone in patients with asymptomatic to mildly symptomatic HIV infection. HIV Protocol C91-253 Study Team. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Mar 1;20(3):245-54. MED/99053866. Del Pozo MA, Arias JR, Pinilla J, Labarga P, Alcoba M, Martinez de la Cruz FJ, Anton F, Carro JA, Perez MR, Echevarria S, Garrote E, Moreno-Otero R. Interferon alpha treatment of chronic hepatitis C in HIV-infected patients receiving zidovudine: efficacy, tolerance and response related factors. Hepatogastroenterology. 1998 Sep-Oct;45(23):1695-701. MED/98041066. Rivero J, Fraga M, Cancio I, Cuervo J, Lopez-Saura P. Long-term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy. 1997;10(2):107-13. MED/96183619. Kovacs JA, Bechtel C, Davey RT Jr, Falloon J, Polis MA, Walker RE, Metcalf JA, Davey V, Piscitelli SC, Baseler M, Dewar R, Salzman NP, Masur H, Lane HC. Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial. J Infect Dis. 1996 Apr;173(4):840-8. MED/96142199. Northfelt DW, Charlebois ED, Mirda MI, Child C, Kaplan LD, Abrams DI. Continuous low-dose interferon-alpha therapy for HIV-related immune thrombocytopenic purpura. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Jan 1;8(1):45-50. MED/94223103. Schnittman SM, Vogel S, Baseler M, Lane HC, Davey RT Jr. A phase I study of interferon-alpha 2b in combination with interleukin-2 in patients with human immunodeficiency virus infection. J Infect Dis 1994 May;169(5):981-9. MED/93195492. Podzamczer D, Bolao F, Clotet B, Garcia P, Casanova A, Pagerols X, Gudiol F. Low-dose interferon alpha combined with zidovudine in patients with AIDS-associated Kaposi's sarcoma. J Intern Med. 1993 Mar;233(3):247-53. MED/90262042. Lane HC, Davey V, Kovacs JA, Feinberg J, Metcalf JA, Herpin B, Walker R, Deyton L, Davey RT Jr, Falloon J, et al. Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med. 1990 Jun 1;112(11):805-11. ENTRY MONTH 199104 LAST REVISION DATE 20001009 312 UNIQUE IDENTIFIER DRG-0034 NAME OF SUBSTANCE Interferon alfa-2a [USPD 2000; p 373] REGISTRY NUMBER 76543-88-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Interferon alfaA (human leukocyte protein moiety reduced) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS PEGASYS (Peginterferon alfa-2a) [USP DI 2000; p 3318] SYNONYMS Roferon-A [USP DI 2000; p 1813] PROTOCOL ID NUMBERS Complete NIAID ACTG 013 PROTOCOL ID NUMBERS Complete NIAID ACTG 014 PROTOCOL ID NUMBERS Complete NIAID ACTG 068 PROTOCOL ID NUMBERS Complete NIAID ACTG 096 PROTOCOL ID NUMBERS Complete NIAID ACTG 153 PROTOCOL ID NUMBERS Complete NIAID ACTG 197 PROTOCOL ID NUMBERS Complete NIAID ACTG 216 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5071 PROTOCOL ID NUMBERS Terminated CC 95 C-144 PHARMACOLOGICAL ACTION Interferon alfa-2a exhibits antitumor and antiviral activities; however, the mechanism of action is not clearly understood. These effects appear to be related to a direct antiproliferative action against tumor cells, inhibition of virus replication, and modulation of the host immune response. For systemic effects, interferon alfa must be administered parenterally to avoid degradation by gastrointestinal proteolytic enzymes. Following intramuscular and subcutaneous injection, the time to peak concentration is 3.8 and 7.3 hours, respectively. Greater than 80% of a given dose is absorbed. The volume of distribution approximates 20 to 60% of body weight. In healthy individuals, interferon alfa-2a exhibits an elimination half-life of 3.7 to 8.5 (mean 5.1) hours. Accumulation may occur with multiple intramuscular doses. Interferon alfa-2a is metabolized principally in the kidney. It is completely filtered through the glomeruli and undergoes rapid proteolytic degradation during renal tubular reabsorption. Metabolites are almost completely reabsorbed and only negligible amounts of unchanged alfa interferon reappear in the systemic circulation. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00; AHFS Drug Information 2000; p 958; Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00; AHFS Drug Information 2000; p 958; Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00; USP DI 2000; p 1811] DISEASES STUDIED/TREATED Interferon alfa-2a is FDA-approved for treatment of AIDS-related Kaposi's sarcoma in selected patients 18 years of age or older. It is used as initial therapy in patients whose disease is otherwise asymptomatic and who do not have severe immune dysfunction. Response rates are decreased in patients with prior opportunistic infections, constitutional (B) symptoms, or reduced helper/inducer T-cell counts. Interferon alfa-2a is also approved for the treatment of chronic hepatitis C. In addition, due to its antiproliferative and antiviral effects, interferon alfa-2a is included in a number of HIV clinical trials. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/20/00; AHFS Drug Information 2000; p 961-2; USP DI 2000; p 1810; Protocol ID: ACTG 197 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1810] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 1810] OTHER MAJOR USES Interferon alfa-2a is indicated for the treatment of chronic hepatitis C, diagnosed by HCV antibody and/or a history of exposure to hepatitis C, in patients 18 years of age or older with compensated liver disease. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00; USP DI 2000; p 1810] SUBSTANCE INTERACTIONS There are no reported food interactions with interferon alfa-2a. Interferon alfa-2a has been reported to reduce the clearance of theophylline. Also, alfa interferons may inhibit the activity of hepatic cytochrome P450 isoenzymes. Although the clinical relevance of this effect is unknown, the potential for interactions between interferon alfa-2a and other similarly metabolized drugs should be considered. The concomitant use of interferon alfa with interleukin-2 (aldesleukin) may increase the risk of renal failure; exacerbation of autoimmune diseases and inflammatory disorders has also occurred. The combination of interferon alfa and zidovudine or acyclovir, while causing synergistic antiviral effects, can also increase the risk of hematologic and hepatic toxicity. Interferon alfa-2a should be used with caution in patients receiving other potentially myelosuppressive drugs. In addition, the neurotoxic, hematoxic, hepatotoxic, and cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. [AHFS Drug Information 2000; p 980; Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00] ADVERSE EFFECTS Almost all patients experience adverse effects at some time during the course of interferon alfa therapy. The incidence and severity of side effects appear to be highest in patients with AIDS-related Kaposi's sarcoma. The underlying disease and the required higher doses are likely contributing factors. The most common adverse effect is a flu-like syndrome (fever, fatigue, myalgia/arthralgia, chills, and headache). This has been reported in up to 95% of patients receiving the drug. Gastrointestinal side effects are common. Anorexia, nausea, and diarrhea have been reported in up to 65, 51, and 42% of patients, respectively. The incidence of reported depression and suicidal behavior has varied among clinical trials but has been determined to be 15% or higher. If delerium or severe depression occurs, dosage reduction or cessation may be warranted. Other CNS reactions to interferon alfa-2a include dizziness, decreased mental status, paresthesias, and visual and sleep disturbances. Most of the CNS abnormalities are mild and reversible within a few days to three weeks after stopping the drug. Leukopenia, anemia, and thrombocytopenia have been reported frequently but are rarely dose limiting. Increases in hepatic enzymes are generally mild to moderate and transient; substantial increases are generally reversible following dosage reduction or discontinuation of the drug. Infrequently, proteinuria and renal toxicity have been reported. Hyperglycemia has also been observed rarely. [AHFS Drug Information 2000; p 972; Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00; AHFS Drug Information 2000; p 974; Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00] CONTRAINDICATIONS Interferon alfa-2a is contraindicated in patients allergic to alfa interferon or any component of the product; the solutions for injection contain benzyl alcohol. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Interferon alfa-2a is a synthetic interferon manufactured by recombinant DNA technology using a genetically engineered Escherichia coli bacterium. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/20/00] CHEMICAL/PHYSICAL DATA Molecular Formula: C860-H1353-N227-O255-S9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 19,240.92 [USPD 2000; p 373] CHEMICAL/PHYSICAL DATA Stability: Multiple-dose vials must be discarded 30 days after initial use. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00] SUBSTANCE DELIVERY DATA DOSAGE FORM: Solution in vials for injection (3 MIU, 6 MIU, 9 MIU, or 36 MIU per single-dose vial, and 9 MIU or 18 MIU per multidose vial); solution in single-use prefilled syringes for subcutaneous injection (3 MIU, 6 MIU, or 9 MIU per syringe) [PDR 2000; p 2658] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous or intramuscular injection [USP DI 2000; p 1813-4] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The injectable solution and prefilled syringes should be stored at 2 to 8 C (36 to 46 F). Freezing should be avoided. [Roche U.S. Pharmaceuticals. Products: Roferon. Available at: http://www.rocheusa.com/products/roferon/pi.h- tml. Accessed 08/21/00] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Unspecified (800)526-6367 REFERENCES MED/20173440. Haas DW, Lavelle J, Nadler JP, Greenberg SB, Frame P, Mustafa N, St Clair M, McKinnis R, Dix L, Elkins M, Rooney J. A randomized trial of interferon alpha therapy for HIV type 1 infection. AIDS Res Hum Retroviruses. 2000 Feb 10;16(3):183-90. MED/99334358. Begemann F, Jablonowski H. Enhancing the response to interferon-alpha. J Clin Virol. 1999 Jun;13(1-2):1-7. MED/98227672. Krown SE. Interferon-alpha: evolving therapy for AIDS-associated Kaposi's sarcoma. J Interferon Cytokine Res. 1998 Apr;18(4):209-14. Review. MED/98063663. Fischl MA, Richman DD, Saag M, Meng TC, Squires KE, Holden-Wiltse J, Meehan PM. Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. AIDS Clinical Trials Group Study 197. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Dec 1;16(4):247-53. MED/97435118. Frissen PH, de Wolf F, Reiss P, Bakker PJ, Veenhof CH, Danner SA, Goudsmit J, Lange JM. High-dose interferon-alpha2a exerts potent activity against human immunodeficiency virus type 1 not associated with antitumor activity in subjects with Kaposi's sarcoma. J Infect Dis. 1997 Sep;176(3):811-4. MED/95070047. Bocci V. Pharmacology and side-effects of interferons. Antiviral Res. 1994 Jul;24(2-3):111-9. Review. MED/92054666. Lane HC. The role of alpha-interferon in patients with human immunodeficiency virus infection. Semin Oncol. 1991 Oct;18(5 Suppl 7):46-52. Review. MED/91098825. Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet. 1990 Nov;19(5):390-9. Review. MED/91079608. Stadler R, Bratzke B, Schaart F, Orfanos CE. Long-term combined rIFN-alpha-2a and zidovudine therapy for HIV-associated Kaposi's sarcoma: clinical consequences and side effects. J Invest Dermatol. 1990 Dec;95(6 Suppl):170S-175S. MED/90140742. Krown SE. Approaches to interferon combination therapy in the treatment of AIDS. Semin Oncol. 1990 Feb;17(1 Suppl 1):11-5; discussion 38-41. Review. ENTRY MONTH 199104 LAST REVISION DATE 20001004 313 UNIQUE IDENTIFIER DRG-0033 NAME OF SUBSTANCE Sulfadoxine/Pyrimethamine [Protocol ID: ACTG 021 ] REGISTRY NUMBER 2447-57-6 (sulfadoxine) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 58-14-0 (pyrimethamine) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzenesulfonamide, 4-amino-N-(5,6-dimethoxy-4-pyrimidinyl)- [sulfadoxine] [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.; ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Fansidar [USP DI 2000; p 2838] PROTOCOL ID NUMBERS Complete NIAID ACTG 021 PHARMACOLOGICAL ACTION MODE OF ACTION: Sulfadoxine competitively inhibits dihydrofolic acid synthesis which is necessary for the conversion of p-aminobenzoic acid to folic acid. Potentiation occurs when sulfadoxine is combined with pyrimethamine (Fansidar), by sequential blockade of two enzymes involved in the biosynthesis of folinic acid within the parasites. Fansidar is effective against certain strains of Plasmodium falciparum that are resistant to chloroquine. The drugs are absorbed orally and sulfadoxine is excreted mainly via the kidneys with an apparent half-life of elimination of 100 to 231 hours. Pyrimethamine half-life ranges from 54 to 148 hours. Following a single oral dose sulfadoxine peak plasma levels of 51 to 76 mcg/ml are reached in 2.5 to 6 hours. Pyrimethamine peak levels of 0.13 to 0.4 mcg/ml are reached in 1.5 to 8 hours. Both drugs are excreted in breast milk. [PDR 1997; p 2281; AHFS Drug Information 1997; p 566] DISEASES STUDIED/TREATED The combination of pyrimethamine and sulfadoxine Fansidar is used in the prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis and in patients who cannot tolerate co-trimoxazole prophylaxis. [AHFS Drug Information 1997; p 567] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2835] OTHER MAJOR USES Fansidar: Treatment of Plasmodium falciparum malaria in chloroquine-resistant patients. [PDR 1997; p 2281] SUBSTANCE INTERACTIONS Caution should be observed when administering sulfadoxine and pyrimethamine with bone marrow depressants, caution, hepatotoxic drugs, folic acid antagonists and antidiabetic agents. [USP DI 1995; p 2525] ADVERSE EFFECTS Although sulfadoxine and pyrimethamine is generally well tolerated, severe and sometimes fatal adverse reactions have been reported when the drug was used once weekly for prophylaxis of malaria. Prolonged therapy with pyrimethamine and the high dosages of the drug required for the treatment of toxoplasmosis are associated with a high incidence of adverse hematologic effects which result from folic acid deficiency. Adverse effects include the following: hematologic (folic acid depletion and reversible bone marrow depression resulting from high dosages of the drug; megaloblastic anemia, leukopenia, thrombocytopenia, agranulocytosis, and pancytopenia; hemolysis if sulfadoxine/pyrimethamine is administered to patients with glucose-6-phosphate dehydrogenase deficiency), gastrointestinal (anorexia, abdominal cramps, diarrhea, vomiting, headache, light-headedness, insomnia, depression, malaise, fatigue, and irritability rarely); hypersensitivity reactions (severe and sometimes fatal hypersensitivity reactions have occurred with pyrimethamine/sulfadoxine therapy, in most cases, fatality resulted from severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis; serum-sickness reactions, vasculitis, urticaria, pruritus, exfoliative dermatitis, and photosensitivity in pyrimethamine/sulfadoxine therapy; dermatitis, pulmonary eosinophilia, and photosensitivity in pyrimethamine therapy); hepatic (abnormal liver functions, jaundice, hepatomegaly, and hepatitis, which can be fatal, have been reported with the pyrimethamine/sulfadoxine therapy). Other rare adverse effects include hematuria, pigmentation, and hyperphenylalaninemia. [AHFS Drug Information 1997; p 567-8] CONTRAINDICATIONS Contraindicated in patients with severe renal insufficiency, marked liver parenchymal damage or blood dyscrasias; hypersensitivity to sulfonamides; or megaloblastic anemia due to folate deficiency. Also contraindicated in infants under 2 months of age and in pregnant women at term and during nursing because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. [PDR 1997; p 2281] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A structural analog of p-aminobenzoic acid. [AHFS Drug Information 1997; p 566] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H14-N4-O4-S [sulfadoxine] and C12-H13-Cl-N4 [pyrimethamine] [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Very slightly soluble in water, slightly soluble in alcohol and methanol. Soluble in dilute mineral acids, solutions of alkali hydroxides and carbonates. [Merck Index 1996; p 1521] SUBSTANCE DELIVERY DATA DOSAGE FORM: Fansidar: Tablets (500 mg sulfadoxine and 25mg pyrimethamine). [PDR 1997; p 2282] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Fansidar: Oral. [PDR 1997; p 2282] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 15-25 C in a tight, light-resistant container. Oral suspensions prepared from the tablets are stable at room temperature for 5-7 days. [AHFS Drug Information 1997; p 566] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES MED/95276095. Bessesen MT, Miller LA, Cohn DL, Bartlett S, Ellison RT 3rd. Administration of pyrimethamine/sulfadoxine for prevention of Pneumocystis carinii pneumonia in patients with AIDS [letter]. Clin Infect Dis. 1995 Mar;20(3):730-1. MED/95035639. Jurado R, Garcia-Herola A, Garcia-Lazara M, Kindelan JM, Villanueva JL, Torre-Cisneros J. Pyrimethamine/sulfadoxine for prevention of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus [letter]. Clin Infect Dis. 1994 Jul;19(1):218-9. MED/94280720. Oksehendler E, Charreau I, Tournerie C, Azihary M, Carbon C, Aboulker JP. Toxoplasma gondii infection in advanced HIV infection. AIDS. 1994 Apr;8(4):483-7. MED/95151347. Glassroth J, Jordan M, Wallace JM, Kvale PA, Follmann DA, Rosen MJ, Reichman LB, Mossar M, Hopewell PC. Use of preventive interventions by persons infected with type-1 human immunodeficiency virus (HIV-1). The Pulmonary Complications of HIV Study Group. Am J Prev Med. 1994 Sep-Oct;10(5):259-66. ICA10/94371244. Hernandez JE, Flores LE, Estrada y Martin RM, Mayorga R, Arathoon E. Toxoplasmic disease in AIDS patients in Guatemala. Int Conf AIDS. 1994 Aug 7-12;10(2):156 (abstract no. PBO636). MED/93358921. Ruf B, Schurmann D, Bergmann F, Schuler-Maue W, Grunewald T, Gottschalk HJ, Witt H, Pohle HD. Efficacy of pyrimethamine/sulfadoxine in the prevention of toxoplasmic encephalitis relapses and Pneumocystis carinii pneumonia in HIV-infected patients. Eur J Clin Microbiol Infect Dis. 1993 May;12(5):325-9. ICA9/93336201. Grunewald T, Bergmann F, Eljaschewitsch J, Pohle HD, Ruf B. Antiprotozoal prophylaxis in AIDS patients--results of a prospective randomized study comparing Dapson/pyrimethamine and sulfadoxine/pyrimethamine. Int Conf AIDS 1993 Jun 6-11;9(1):56 (abstract no. WS-B13-3). MED/93005386. Koppen S, Grunewald T, Jautzke G, Gottschalk J, Pohle HD, Ruf B. Prevention of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus infected patients: a clinical approach comparing aerosolized pentamidine and pyrimethamine/sulfadoxine. Clin Investig. 1992 Jun;70(6):508-12. ICA8/92400961. Partisani M, De Mautort E, Hassairi N, Divine A, Fraisse P, Lang JM. Primary prophylaxis of cerebral toxoplasmosis with pyrimethamine-sulfadoxine in human immunodeficiency virus-infected individuals seropositive to Toxoplasma. Int Conf AIDS. 1992 Jul 19-24;8(2):B125 (abstract no. PoB 3230). ICA8/92401601. Eljaschewitsch J, Bergmann F, Grunewald T, Ruf B. Monitoring of compliance in HIV-positive patients treated with fansidar for primary (PP) and secondary (SP) prophylaxis of toxoplasmic encephalitis (TE) using serum level determination. Int Conf AIDS. 1992 Jul 19-24;8(2):B236 (abstract no. PoB 3870). ENTRY MONTH 199104 LAST REVISION DATE 20001130 314 UNIQUE IDENTIFIER DRG-0032 NAME OF SUBSTANCE Tumor Necrosis Factor [Merck Index 1996; p. 1672] PROTOCOL ID NUMBERS Complete NIAID ACTG 025 PROTOCOL ID NUMBERS No longer recruiting FDA 066A PHARMACOLOGICAL ACTION MODE OF ACTION: Tumor necrosis factor induces a variety of biochemical and metabolic alterations in vivo, including decreased expression in adipocytes of genes coding for lipogenic enzymes, stimulation of immune effector cells, and secretion of IL-1 and prostaglandin E2, and increased synthesis of collagen. In vitro studies have shown that rTNF acts synergistically with interferon gamma to suppress production of HIV mRNA and p24 antigen, to cause cytotoxicity in HIV-infected cells and to reduce HIV RNA levels in chronically infected cells. Induces hemorrhagic necrosis in tumors; increases viral replication in HIV-infected ACH2 cells; may produce antitumor activity in AIDS patients with Kaposi's sarcoma; in vitro antiviral activity against various RNA and DNA viruses. Is absorbed following intravenous, intramuscular, and subcutaneous injection; is rapidly cleared from blood circulation with a half-life of 15-30 minutes. [Drug Evaluations Annual 1992; p 1955; Science 1985; Sugarman, BJ et al.; 230:943-6; Protocol ID: ACTG 025 ] DISEASES STUDIED/TREATED Primary HIV infection; limited effectiveness against Kaposi's sarcoma. [J Acquir Immune Defic Syndr 1989;2(3); p 217-23] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Treatment of tumors. [Drug Evaluations Annual 1995; p 2210] SUBSTANCE INTERACTIONS Acts synergistically with interferon gamma to suppress production of HIV mRNA and p24 antigen, to cause cytotoxicity in HIV-infected cells and to reduce HIV RNA levels in chronically infected cells. [Science 1985; Sugarman, BJ, et al.;230:943-6] ADVERSE EFFECTS Reported reactions to tumor necrosis factor include rigors, fever, nausea and vomiting, headache, inflammation at the injection site, hypotension, peripheral vasoconstriction, hypertension, rhinorrhea, and chest discomfort. [Drug Evaluations Annual 1995; p 2211] CONTRAINDICATIONS Should not be used by patients with cardiac disease, hemorrhagic diathesis, active bleeding disorders, vascular disease, or lipoprotein disorders, or by pregnant or lactating women. [Protocol ID: ACTG 025 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A glycoprotein produced by macrophages (lymphokine). [Drug Evaluations Annual 1995; p 2210] CHEMICAL/PHYSICAL DATA Stability: The reconstituted injection is subject to shear stress which can cause protein aggregation. Avoid vigorous mixing or handling of the injectable solution. [Protocol ID: ACTG 025 ] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Sterile lyophilized powder for parenteral use. [Protocol ID: ACTG 025 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile liquid solution containing 0.5 mg/ml in 2 ml vials. Smaller doses may be administered by diluting TNF with normal saline. [Protocol ID: ACTG 025 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intramuscular injection. [Protocol ID: ACTG 025 ] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Ship frozen (dry ice); unreconstituted vials should be stored under refrigeration at 2-8 C. Store reconstituted vials under refrigeration at 2-8 C and use within 24 hr. Do not freeze. [Protocol ID: ACTG 025 ] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 REFERENCES MED/97456522. Kubo M, Ohashi T, Fujii M, Oka S, Iwamoto A, Harada S, Kannagi M. Abrogation of in vitro suppression of human immunodeficiency virus type 1 (HIV-1) replication mediated by CD8+ T lymphocytes of asymptomatic HIV-1 carriers by staphylococcal enterotoxin B and phorbol esters through induction of tumor necrosis factor alpha. J Virol. 1997 Oct;71(10):7560-6. MED/97404727. Li Q, Gebhard K, Schacker T, Henry K, Haase AT. The relationship between tumor necrosis factor and human immunodeficiency virus gene expression in lymphoid tissue. J Virol. 1997 Sep;71(9):7080-2. MED/97399661. Okamoto M, Makino M, Kitajima I, Maruyama I, Baba M. HIV-1-infected myelomoncytic cells are resistant to Fas-mediated apoptosis: effect of tumor necrosis factor-alpha on their Fas expression and apoptosis. Med Microbiol Immunol (Berl). 1997 Jun;186(1):11-7. MED/97296311. Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, Probert L, Kollias G, McDevitt HO. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med. 1997 May 5;185(9):1573-84. MED/97184314. Limper AH. Tumor necrosis factor alpha-mediated host defense against Pneumocystis carinii. Am J Respir Cell Mol Biol. 1997 Feb;16(2):110-1. MED/97389981. Herbein G. Cytokines, viruses and macrophages: an interactive network. An immune dysregulation involving the members of the tumor necrosis factor (TNF) receptor superfamily could be critical in AIDS pathogenesis. Pathol Biol (Paris). 1997 Feb;45(2):115-25. MED/97149436. Lazdins JK, Grell M, Walker MR, Woods-Cook K, Scheurich P, Pfizenmaier K. Membrane tumor necrosis factor (TNF) induced cooperative signaling of TNFR60 and TNFR80 favors induction of cell death rather than virus production in HIV-infected T cells. J Exp Med. 1997 Jan 6;185(1):81-90. MED/97126568. Oppenheim J, Fujiwara H. The role of cytokines in cancer. Cytokine Growth Factor Rev. 1996 Oct;7(3):279-88. MED/96369161. Piscitelli SC, Minor JR, Saville MW, Davey RT Jr. Immune-based therapies for treatment of HIV infection. Ann Pharmacother. 1996 Jan;30(1):62-76. MED/94007901. Beutler B, Grau GE. Tumor necrosis factor in the pathogenesis of infectious diseases. Crit Care Med. 1993 Oct;21(10 Suppl):S423-35. ENTRY MONTH 199104 LAST REVISION DATE 20000801 315 UNIQUE IDENTIFIER DRG-0031 NAME OF SUBSTANCE Sulfamethoxazole [USPD 1998; p. 693] REGISTRY NUMBER 723-46-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 4-Amino-N-(5-methyl-3-isoxazolyl)benzenesulfo- namide [Merck Index 1996; p 1524] SYNONYMS component of Bactrim [USP DI 2000; p. 2862] SYNONYMS component of Septra [USP DI 2000; p. 2862] SYNONYMS Gantanol [USP DI 2000; p. 2856] PROTOCOL ID NUMBERS Complete NIAID ACTG 021 PROTOCOL ID NUMBERS Complete NIAID ACTG 029 PROTOCOL ID NUMBERS Complete NIAID ACTG 031 PROTOCOL ID NUMBERS Complete NIAID ACTG 033 PROTOCOL ID NUMBERS Complete NIAID ACTG 037 PROTOCOL ID NUMBERS Complete NIAID ACTG 040 PROTOCOL ID NUMBERS Complete NIAID ACTG 081 PROTOCOL ID NUMBERS Complete NIAID ACTG 108 PROTOCOL ID NUMBERS Complete NIAID ACTG 167 PROTOCOL ID NUMBERS Complete NIAID ACTG 268 PROTOCOL ID NUMBERS No longer recruiting FDA 007A PROTOCOL ID NUMBERS No longer recruiting FDA 056A PROTOCOL ID NUMBERS No longer recruiting FDA 224A PROTOCOL ID NUMBERS No longer recruiting CC 93 I-36 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 283 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 006 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 254 PROTOCOL ID NUMBERS Terminated NIAID ACTG 030 PHARMACOLOGICAL ACTION MODE OF ACTION: Sulfamethoxazole is used in combination drug therapy with trimethoprim as co-trimoxazole. Co-trimoxazole is a fixed combination of sulfamethoxazole and trimethoprim. Co-trimoxazole acts by sequentially inhibiting enzymes of the folic acid pathway; sulfamethoxazole inhibits the formation of dihydrofolic acid from p-aminobenzoic acid and, by inhibiting dihydrofolate reductase, trimethoprim inhibits the formation of tetrahydrofolic acid from dihydrofolic acid. By inhibiting synthesis of tetrahydrofolic acid, the metabolically active form of folic acid, co-trimoxazole inhibits bacterial thymidine synthesis. Following oral administration, peak plasma concentrations of sulfamethoxazole are reached within 3-4 hours. Sulfamethoxazole is widely distributed into most body tissues; it also crosses the placenta. In general, the total serum protein binding of sulfamethoxazole is considered to be 50-70%; the acetylated metabolite of sulfamethoxazole is protein bound to a somewhat greater extent than is the unmetabolized drug. Sulfamethoxazole has an apparent volume of distribution of 10-16 L. In individuals with normal renal function, the elimination half-life of sulfamethoxazole is 7-12 hours. Sulfamethoxazole undergoes N4-acetylation and N4-glucuronide conjugation in the tissues, mainly in the liver. The acetylated derivative of the drug (its major metabolite) is not microbiologically active, but contributes to the nephrotoxicity of the drug. Sulfamethoxazole is excreted mainly in urine. Unconjugated forms of sulfamethoxazole are excreted by tubular secretion; acetylated drug is excreted by glomerular filtration. Within 24 hours following oral administration, 25-75% of a sulfamethoxazole dose is excreted. In urine, approximately 20% of the drug present is unchanged drug, 50-70% is the acetylated derivative, and 15-20% is the glucuronide conjugate. Concentrations of sulfamethoxazole in urine are approximately 3 times concurrent drug blood concentrations. [AHFS Drug Information 1997; p 622] DISEASES STUDIED/TREATED Sulfamethoxazole is used in formulation with trimethoprim for treatment and prophylaxis of Pneumocystis carinii pneumonia (PCP) in AIDS patients. [AHFS Drug Information 1995; p 563] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 2851] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2851] OTHER MAJOR USES Sulfamethoxazole is coformulated with trimethoprim (co-trimoxazole) for the treatment and prophylaxis of Pneumocystis carinii infections; upper respiratory tract infections and bronchitis caused by H. influenzae or S. pneumoniae; nocardia infections; gonorrhea and associated infections; and pertussis. Sulfamethoxazole is used in conjunction with pyrimethamine for the treatment of toxoplasmosis. Sulfamethoxazole has been used in conjunction with quinine sulfate and pyrimethamine for the treatment of uncomplicated chloroquine-resistant Plasmodium falciparum malaria. [AHFS Drug Information 1997; p 617,646-8] SUBSTANCE INTERACTIONS Because pyrimethamine and trimethoprim also interfere with folic acid synthesis in susceptible organisms, but at different stages, these drugs act synergistically with sulfonamides against some organisms. This synergism is used to therapeutic advantage in the treatment of toxoplasmosis and malaria. Sulfonamides may potentiate the effects of methotrexate by displacing methotrexate from its protein binding sites or inhibiting renal tubular secretion of the antineoplastic agent. Because the antibacterial activity of sulfonamides involves competitive inhibition of p-aminobenzoic acid (PABA), the concomitant use of PABA or local anesthetics which are derivatives of PABA (e.g., chloroprocaine, piperocaine, procaine, propoxycaine, tetracaine) reportedly may antagonize the antibacterial activity of sulfonamides. Sulfonamides may potentiate the effects of coumarin anticoagulants by displacing the anticoagulants from their protein-binding sites. Sulfonamides may potentiate the hypoglycemic effects of tolbutamide and chlorpropamide by displacing the antidiabetic agents from their protein-binding sites. [AHFS Drug Information 1997; p 618-9] ADVERSE EFFECTS Adverse effects of the sulfonamides are numerous and may involve nearly all organ systems. Although serious, and in some cases fatal, reactions that have been reported occur infrequently. Adverse effects include the following: dermatologic (rash, pruritus, urticaria, erythema nodosum, erythema multiforme [Steven-Johnson syndrome], Behcet's syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and photosensitivity); hematologic (methemoglobinemia, sulfhemoglobinemia, granulocytopenia, leukopenia, eosinophilia, hemolytic anemia, agranulocytosis, aplastic anemia, purpura, clotting disorder, thrombocytopenia, hypofibrinogenemia, and hypoprothrombinemia, rarely resulting in death); hepatic (jaundice, focal or diffuse necrosis of the liver); renal (renal colic, nephritis, urolithiasis, toxic nephrosis with anuria and oliguria, hematuria, proteinuria, kidney stone formation, and elevation of BUN and creatinine concentrations); gastrointestinal (nausea, vomiting, abdominal pain, anorexia, glossitis, stomatitis, pancreatitis, gastroenteritis, diarrhea, GI hemorrhage, melena, flatulence, and salivary gland enlargement); nervous system (less frequently headache, dizziness, vertigo, peripheral neuritis, ataxia, mental depression, hallucinations, disorientation, confusion, seizures, intracranial hypertension, tinnitus, hearing loss, anxiety, apathy, and acute psychosis; rarely peripheral neuropathy, paresthesia, weakness, fatigue, drowsiness, lassitude, restlessness, and insomnia). Other adverse effects include goiter production, hypothyroidism, hypoglycemia, diuresis, pharyngitis, arthralgia, acidosis, and cyanosis. [PDR 1995; p 2037-8] CONTRAINDICATIONS Sulfonamides are contraindicated in patients with a history of hypersensitivity to sulfonamides or other chemically related drugs (e.g., sulfonylureas, thiazides). The drugs are also contraindicated in patients with marked renal or hepatic impairment. Sulfonamides are contraindicated in patients with porphyria, since the drugs precipitate an acute attack. Sulfonamides should be used with caution in patients with impaired hepatic function, impaired renal function, urinary obstruction, blood dyscrasia, severe allergies or asthma, or glucose-6-phosphate dehydrogenase deficiency. [AHFS Drug Information 1997; p 617, 646-8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Sulfonamide derivative [AHFS Drug Information 1997; p 622] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H11-N3-O3-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 253.28 [USPD 1998; p. 693] CHEMICAL/PHYSICAL DATA Melting Point: 167 C [Merck Index 1996; p. 1524] CHEMICAL/PHYSICAL DATA Elemental Comp: C47.42%, H4.38%, N16.59%, O18.95%, S12.66% [Merck Index 1996; p. 1524] CHEMICAL/PHYSICAL DATA Solubility: Practically insoluble in water, ether, and chloroform; freely soluble in acetone and dilute solutions of NaOH; sparingly soluble in alcohol. [USP DI 1989; p 2214] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white, practically odorless, crystalline powder [AHFS Drug Information 1997; p 622] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets containing 0.5 gm sulfamethoxazole; intravenous combination products containing 16 mg/ml trimethoprim and 80 mg/ml sulfamethoxazole; oral suspensions containing 40 mg/5 ml trimethoprim and 200 mg/5 ml sulfamethoxazole. [AHFS Drug Information 1997; p 622, 652] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous (combined with trimethoprim) [AHFS Drug Information 1997; p 622, 652] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 15-30 C and protected from light. Sulfamethoxazole and trimethoprim combination concentrate for injection should be stored at 15-30 C and never refrigerated. Suspensions and tablets of the combination drug should be stored in well-closed, light-resistant containers at 15-30 C unless otherwise specified by the manufacturers. [PDR 1995; p 813, 816, 2028, 2030, 2038] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Medical & Consumer Relations (919)483-9959 REFERENCES MED/97125611. Edge MD, Rimland D. Community-acquired bacteremia in HIV-positive patients: protective benefit of co-trimoxazole. AIDS. 1996 Dec; 10(14):1635-9. MED/97103604. Warnock AC, Rimland D. Comparison of trimethoprim-sulfamethoxazole, dapsone, and pentamidine in the prophylaxis of Pneumocystis carinii pneumonia. Pharmacotherapy. 1996 Nov-Dec; 16(6):1030-8. MED/97087839. Kalanadhabhatta V, Muppidi D, Sahni H, Robles A, Kramer M. Successful oral desensitization to trimethoprim-sulfamethoxazole in acquired immune deficiency syndrome. Ann Allergy Asthma Immunol. 1996 Nov; 77(5):394-400. MED/97034198. Perazella MA, Mahnensmith RL. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol. 1996 Sep; 46(3):187-92. MED/97034199. Chertow GM, Seifter JL, Christiansen CL, O'Donnell WJ. Trimethoprim-sulfamethoxazole and hypouricemia. Clin Nephrol. 1996 Sep; 46(3):193-8. MED/96426462. Stricker RB, Gullet JH, Williams LE, Goldberg B. Co-trimoxazole desensitization syndrome: delayed hematologic toxicity complicating prophylactic therapy in AIDS patients [letter]. AIDS. 1996 Jul; 10(8):927-9. MED/96315827. Palusci VJ, Kaul A, Lawrence RM, Haines KA, Kwittken PL. Rapid oral desensitizatioin to trimethoprim-sulfamethoxazole in infants and children. Pediatr Infect Dis J. 1996 May; 15(5):456-60. MED/96188893. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. Ann Intern Med. 1996 May; 124(9):792-802. MED/96189193. Belchi-Hernandez J, Espinosa-Parra FJ. Management of adverse reactions to prophylactic trimethoprim-sulfamethoxazole in patients with human immunodeficiency virus infection. Ann Allergy Asthma Immunol. 1996 Apr; 76(4):355-8. MED/97037031. van der Ven AJ, Riegr A, Branten A, Reiman R, Vree TB, Koopsman PP, van der Meer JW. Cutaneous reactions to trimethoprim-sulphametrole in AIDS patients treated for Pneumocystis carinii pneumonia. AIDS. 1996 Mar; 10(3):341-2. ENTRY MONTH 199104 LAST REVISION DATE 20000801 316 UNIQUE IDENTIFIER DRG-0030 NAME OF SUBSTANCE Trimethoprim [USPD 1998; p. 759] REGISTRY NUMBER 738-70-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 5-((3,4,5-Trimethoxyphenyl)methyl) -2,4-pyrimidinediamine [Merck Index 1996; p 1654] SYNONYMS component of Bactrim [USP DI 2000; p. 2862] SYNONYMS component of Septra [USP DI 2000; p. 2862] SYNONYMS Proloprim [USP DI 2000; p. 3062] SYNONYMS Trimpex [USP DI 2000; p. 3062] PROTOCOL ID NUMBERS Complete NIAID ACTG 021 PROTOCOL ID NUMBERS Complete NIAID ACTG 029 PROTOCOL ID NUMBERS Complete NIAID ACTG 031 PROTOCOL ID NUMBERS Complete NIAID ACTG 033 PROTOCOL ID NUMBERS Complete NIAID ACTG 037 PROTOCOL ID NUMBERS Complete NIAID ACTG 040 PROTOCOL ID NUMBERS Complete NIAID ACTG 081 PROTOCOL ID NUMBERS Complete NIAID ACTG 108 PROTOCOL ID NUMBERS Complete NIAID ACTG 167 PROTOCOL ID NUMBERS Complete NIAID ACTG 268 PROTOCOL ID NUMBERS No longer recruiting FDA 007A PROTOCOL ID NUMBERS No longer recruiting FDA 056A PROTOCOL ID NUMBERS No longer recruiting FDA 224A PROTOCOL ID NUMBERS No longer recruiting CC 93 I-36 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 283 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 006 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 254 PROTOCOL ID NUMBERS Terminated NIAID ACTG 030 PHARMACOLOGICAL ACTION MODE OF ACTION: Trimethoprim is slowly bactericidal. The drug acts on the folic acid pathway to inhibit the reduction of dihydrofolic acid to tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. By inhibiting synthesis of tetrahydrofolic acid, the metabolically active form of folic acid, trimethoprim inhibits bacterial thymidine synthesis. [PDR 1997; p 1141; AHFS Drug Information 1997; p 644] DISEASES STUDIED/TREATED Used in combination with sulfamethoxazole for treatment or prophylaxis of Pneumocystis carinii pneumonia. [AHFS Drug Information 1995; p 553] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 3059] OTHER MAJOR USES Trimethoprim is used in the treatment of individuals with initial episodes of uncomplicated urinary tract infections due to susceptible strains of E. coli, P. mirabilis, K. pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus. [PDR 1997; p 1141] SUBSTANCE INTERACTIONS Trimethoprim may inhibit the hepatic metabolism of phenytoin, increasing the half-life and decreasing its metabolic clearance rate by 51% and 30%, respectively. Drug interactions have been observed in concurrent use of trimethoprim with bone marrow depressants (may increase leukopenic/thrombocytopenic effects), folate antagonists (may cause megaloblastic anemia), and rifampin (may significantly increase the elimination and shorten the elimination half-life of trimethoprim). Warfarin anticoagulant activity may be potentiated. Procainamide renal clearance may be decreased and cyclosporine nephrotoxicity may be increased. [USP DI 1995; p 2721] ADVERSE EFFECTS Adverse effects associated with trimethoprim use include: dermatologic (rash, pruritus, and phototoxic skin eruption); hypersensitivity (rarely exfoliative dermatitis, erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis [Lyell syndrome], and anaphylaxis); gastrointestinal (epigastric distress, nausea, vomiting, and glossitis; cholestatic jaundice rarely); hematologic (thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia); metabolic (hyperkalemia, methmoglobinemia); and neurologic (aseptic meningitis, hyponatremia). Other adverse effects include fever and increases in BUN and serum creatinine levels. [PDR 1997; p 1142] CONTRAINDICATIONS Trimethoprim is contraindicated in individuals hypersensitive to trimethoprim and in those with documented megaloblastic anemia due to folate deficiency. Trimethoprim should be given with caution to patients with possible folate deficiency or impaired renal or hepatic function. [PDR 1997; p 1141] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Trimethoxybenzyl-substituted pyrimidine diamine; bacteriostatic lipophilic weak base structurally related to pyrimethamine. [USP DI 1989; p 2372] CHEMICAL/PHYSICAL DATA Molecular Formula: C14-H18-N4-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 290.32 [USPD 1998; p. 759] CHEMICAL/PHYSICAL DATA Melting Point: 199-203 C [Merck Index 1996; p. 1655] CHEMICAL/PHYSICAL DATA Elemental Comp: C57.92%, H6.25%, N19.30%, O16.53% [Merck Index 1996; p. 1654] CHEMICAL/PHYSICAL DATA Solubility: (g/100 ml at 25 C): DMAC, 13.86; benzyl alcohol, 7.29; propylene glycol, 2.57; chloroform, 1.82; methanol, 1.21; water, 0.04; ether, 0.003; benzene, 0.002. [Merck Index 1996; p 1655] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to cream, bitter crystalline powder. [Merck Index 1996; p 1655] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (100 and 200 mg) [PDR 1997; p 1141] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1141] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 15-25 C (59-77 F) in a dry place and protected from light. [PDR 1997; p 1142] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Unspecified (800)526-6367 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Jaime Hernandez (919)483-6300 REFERENCES MED/97111207. Caumes E, Guermonprez G, Winter C, Katlama C, Bricaire F. A life-threatening adverse reaction during trimethoprim-sulfamethoxazole desensitization in a previously hypersensitive patient infected with human immunodeficiency virus. Clin Infect Dis. 1996 Dec; 23(6):1313-4. MED/97125611. Edge MD, Rimland D. Community-acquired bacteremia in HIV-positive patients: protective benefit of co-trimoxazole. AIDS. 1996 Dec; 10(14):1635-9. MED/97103604. Warnock AC, Rimland D. Comparison of trimethoprim-sulfamethoxazole, dapsone, and pentamidine in the prophylaxis of Pneumocystis carinii pneumonia. Pharmacotherapy. 1996 Nov-Dec; 16(6):1030-8. MED/97087839. Kalanadhabhatta V, Muppidi D, Sahni H, Robles A, Kramer M. Successful oral desensitization to trimethoprim-sulfamethoxazole in acquired immune deficiency syndrome. Ann Allergy Asthma Immunol. 1996 Nov; 77(5):394-400. MED/97034198. Perazella MA, Mahnensmith RL. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol. 1996 Sep;46(3):187-92. MED/97034199. Chertow GM, Seifter JL, Christiansen CL, O'Donnell WJ. Trimethoprim-sulfamethoxazole and hypouricemia. Clin Nephrol. 1996 Sep;46(3):193-8. MED/96426462. Stricker RB, Gullet JH, Williams LE, Goldberg B. Co-trimoxazole desensitization syndrome: delayed hematologic toxicity complicating prophylactic therapy in AIDS patients [letter]. AIDS. 1996 Jul; 10(8): 927-9. MED/96300543. Lee BL, Safrin S, Makrides V, Gambertoglio JG. Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1996 May; 40(5):1231-6. MED/96315827. Palusci VJ, Kaul A, Lawrence RM, Haines KA, Kwittken PL. Rapid oral desensitization to trimethoprim-sulfamethoxazole in infants and children. Pediatr Infect Dis J. 1996 May; 15(5):456-60. MED/97037031. van der Ven AJ, Riegr A, Branten A, Reiman R, Vree TB, Koopsman PP, van der Meer JW. Cutaneous reactions to trimethoprim-sulphametrole in AIDS patients treated for Pneumocystis carinii pneumonia. AIDS 1996 Mar; 10(3):341-2. ENTRY MONTH 199104 LAST REVISION DATE 20000801 317 UNIQUE IDENTIFIER DRG-0029 NAME OF SUBSTANCE CD4 Antigens [Lancet 1990 May 12; Vol 335 No 8698; p 1128-30] PROTOCOL ID NUMBERS Complete NIAID ACTG 066 PROTOCOL ID NUMBERS Complete NIAID ACTG 101 PROTOCOL ID NUMBERS No longer recruiting FDA 064A PROTOCOL ID NUMBERS No longer recruiting FDA 064B PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-146A PROTOCOL ID NUMBERS No longer recruiting NCI 89 C-121 PROTOCOL ID NUMBERS No longer recruiting CC 89 I-139 PROTOCOL ID NUMBERS Terminated NIAID ACTG 133 PHARMACOLOGICAL ACTION MODE OF ACTION: Recombinant soluble CD4 is capable of binding to HIV envelope gp120 with affinity similar to that of native CD4 and blocks entry of HIV-1 into CD4-bearing cells. Antiviral activity of soluble CD4 has been demonstrated in vitro by measurement of decreases in both reverse transcriptase activity and HIV-induced cell fusion. However, quantitative virologic studies performed to date on blood of patients receiving recombinant soluble CD4 (sCD4) demonstrated no efficacy in vivo despite good drug levels in serum. These results led to an examination of the neutralizing activity of sCD4 against multiple primary HIV-1 isolates from infected patients. The findings demonstrated that primary isolates were significantly more resistant to sCD4 than were laboratory strains. Serum half-life of recombinant sCD4 after intravenous administration is 45 minutes. After intramuscular injection of CD4, however, peak serum levels are not reached until 4 to 6 hours. During repeated intramuscular administration serum concentrations of the drug were relatively stable and rose in a dose-related fashion to steady-state levels of 15 to 30, 20 to 80, and 50 to 300 ng/mL for the patient cohorts receiving 3, 9, and 30 mg/d, respectively. High dose IV rsCD4 was safely administered to 3 patients and produced a subjective improvement in clinical symptoms. rsCD4 exhibited linear pharmacokinetics over the dose range studied (1-10 mg/kg). However, test of blood sera in some patients showed that injection with sCD4 failed to neutralize viruses circulating in the blood. [Am J Med Apr 10;90(4A); p 22S-26S; Ann Int Med 1990 Feb 15;112(4); p 247-52, 254-61; Conf Adv AIDS Vaccine Dev 1996 Feb 11-15; p 34] DISEASES STUDIED/TREATED Primary HIV infection. [J Acquir Immune Defic Syndr 1995; 9(2); p 145-52] CLASSIFICATION CODE Immunomodulator [Protocol ID: ACTG 066 ] CLASSIFICATION CODE Investigational - Virion receptor binding antagonist [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] ADVERSE EFFECTS In a phase I study no patient developed severe or life threatening toxicities related to rsCD4 therapy. Nine patients developed local, mild, or moderate reactions at injection sites at least once during the study consisting of mild transient erythema. One patient developed a maculopapular eruption which resolved upon withdrawal of sCD4. [Ann Int Med 1990 Feb 15;112(4); p 247-52] CONTRAINDICATIONS Should not be used by pregnant women. [Protocol ID: ACTG 066 ] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A truncated version of the complete CD4 polypeptide that includes most of the extracellular domain, but with the transmembrane and C-terminal regions deleted. This molecule is produced using recombinant technology and is soluble in serum unlike the complete CD4 polypeptide. [Ann Int Med 1990 Feb 15;112(4); P 247-52] CHEMICAL/PHYSICAL DATA Solubility: In water. [Protocol ID: ACTG 066 ] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing frozen solution (containing 5 mg/ml of rsT4). [Protocol ID: ACTG 066 ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Soluble CD4 can be given intramuscularly, subcutaneously, or by IV infusion. [Lancet 1990 May 12; Vol 335 No 8698; p 1128-30] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store frozen at -20 C to -25 C (-4 F to -13 F) until thawed for use (thaw slowly by placing at room temperature). [Protocol ID: ACTG 066 ] MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 MANUFACTURERS 0000001096: Biogen Inc 14 Cambridge Ctr Cambridge, MA 02142 Contact: Unspecified (800)821-8590 REFERENCES AIDS/97920666. Nail CD, Shaw GM, Mulligan MJ. Sera of HIV-1 vaccines fail to neutralize both acute seroconverter plasma viruses and CD4-IgG sensitive field isolates. Conf Adv AIDS Vaccine Dev. 1996 Feb 11-15 (abstract no. 34). MED/95268883. Schacker T, Collier AC, Coombs R, Unadkat JD, Fox I, Alam J, Wang JP, Eggert E, Corey L. Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995 Jun 1;9(2):145-52. MED/95135993. Meng TC, Fischl MA, Cheeseman SH, Spector SA, Resnick L, Boota A, Petrakis T, Wright B. Richman DD. Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Feb 1;8(2):152-60. MED/95052836. Davey RT Jr, Boenning CM, Herpin BR, Batts DH, Metcalf JA, Wathen L, Cox SR, Polis MA, Kovacs JA, Fallon J, et al. Use of recombinant soluble CD4 Pseudomonas exotoxin, a novel immunotoxin, for treatment of persons infected with human immunodeficiency virus. J Infect Dis. 1994 Nov;170(5):1180-8. MED/94103663. Schacker T, Coombs RW, Collier AC, Zeh EJ, Fox I, Alam J, Nelson K, Eggert E, Corey L. The effects of high-dose recombinant soluble CD4 on human immunodeficiency virus type 1 viremia. J Infect Dis. 1994 Jan;169(1):37-40. ASM93/93291833. Sachs M, Fong KL, Blanchard L, Wikler M. High-dose recombinant soluble CD4 (rsCD4) in patients with HIV-1 infection. Abstr Gen Meet Am Soc Microbiol. 1993;93:437 (abstract no. T-33). MED/93019887. Husson RN, Chung Y, Mordenti J, Butler KM, Chen S, Duliege AM, Brouwers P, Jarosinski P, Mueller BU, Ammann A, et al. Phase I study of continuous-infusion soluble CD4 as a single agent and in combination with oral dideoxyinosine therapy in children with symptomatic human immunodeficiency virus infection. J Pediatr. 1992 Oct;121(4):627-33. MED/92279274. Watanabe M, Boyson HE, Lord CI, Letvin NL. Chimpanzees immunized with recombinant soluble CD4 develop anti-self CD4 antibody responses with anti-human immunodeficiency virus activity. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5103-7. ICA7/3207591. McHardy S, Leen CL, Brettle RP, Bird AG, Bell J, Eisner J. Tolerance of continuous subcutaneous infusion (CSCI) of recombinant soluble CD4 (rsCD4). Int Conf AIDS. 1991 Jun 16-21;7(2):200 (abstract no. W.B.2075). ENTRY MONTH 199104 LAST REVISION DATE 20000801 318 UNIQUE IDENTIFIER DRG-0028 NAME OF SUBSTANCE Ribavirin [USPD 1998; p. 635] REGISTRY NUMBER 36791-04-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-ca- rboxamide [Merck Index 1996; p 1409] SYNONYMS Virazole [USP DI 2000; p. 2659] SYNONYMS Rebetol [U.S. FDA. Electronic Orange Book. Available at: http://www.fda.gov/cder/ob/default.htm. Accessed 04/05/01.] PROTOCOL ID NUMBERS Complete NIAID ACTG 034 PROTOCOL ID NUMBERS Complete NIAID ACTG 035 PROTOCOL ID NUMBERS Complete NIAID ACTG 231 PROTOCOL ID NUMBERS Complete NIAID ACTG 274 PROTOCOL ID NUMBERS No longer recruiting NIAID NS 403 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5088 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5071 PROTOCOL ID NUMBERS Terminated FDA 013A PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of action of the antiviral activity of ribavirin has not been fully elucidated, but the drug appears to exert its antiviral activity by interfering with RNA and DNA synthesis and subsequently inhibiting protein synthesis and viral replication. The antiviral activity of the drug results principally in an intracellular virustatic effect in cells infected with ribavirin-sensitive RNA or DNA viruses; however, specific mechanisms of action of the drug may vary depending on the virus. The antiviral activity of ribavirin appears to depend principally on intracelluar conversion of the drug to ribavirin-5'-triphosphate and -monophosphate. Ribavirin is readily absorbed across the cellular plasma membrane, probably via a nucleoside transport mechanism. The drug is then converted via cellular enzymes to deribosylated ribavirin (the 1,2,4-triazole-3-carboxamide) and phosphorylated to ribavirin-5'-monophosphate,-diphosphate, and -triphosphate. Phosphorylation of ribavirin occurs principally in virus-infected cells, but also occurs in uninfected cells. Formulation of rivabirin-5'-monophosphate appears to be the rate-limiting step in the formation of ribavirin-5'-triphosphate. Ribavirin-5'-triphosphate is the principle intracellular form of the drug, with only approximately 4 and 12% of the phosphorylated metabolites present as ribavirin-5'-diphosphate and -monophosphate, respectively. Ribavirin is absorbed systemically from the respiratory tract following nasal and oral inhalation. Peak plasma ribavirin concentrations generally appear to occur at the end of the inhalation period when the drug is inhaled orally and nasally using SPAG, and increase with increasing duration of the inhalation period. Ribavirin is rapidly absorbed following oral administration, with peak plasma concentrations of the drug occuring within 1-2 hours after administration. Following nasal and oral inhalation, highest ribavirin concentrations are found in the respiratory tract and erythrocytes. Ribavirin appears to distribute slowly into CSF. Ribavirin is metabolized principally to 1,2,4-triazole-3-carboxamide, probably in the liver; the antiviral activity of 1, 2, 4-triazole-3-carboxamide against various RNA and DNA viruses is reported similar to ribavirin. Ribavirin is excreted principally in urine. In healthy adults with normal renal function, approximately 37, 30, and 30% of the fraction excreted in urine appears as unchanged drug, 1,2,4-triazole-3-carboxamide, and 1,2,4-triazole-3-carboxylic acid, respectively, within 1.5-2 hours, and approximately 17, 50,and 22% respectively, within 24 hours. [AHFS Drug Information 1997; p 497-9] DISEASES STUDIED/TREATED Primary HIV infection. [AHFS Drug Information 1995; p 446] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 2657] OTHER MAJOR USES Treatment of selected hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). [PDR 1997; p 1310] SUBSTANCE INTERACTIONS Potentiates antiretroviral activity of didanosine and antagonizes antiviral activity of zidovudine and zalcitabine against HIV. [AHFS Drug Information 1997; p 504] ADVERSE EFFECTS The most common adverse effects associated with inhalation of the drug appear to include respiratory and cardiovascular effects; these effects generally occur infrequently. Adverse effects include the following: respiratory (worsening of respiratory function in infants with RSV infections or in adults with chronic obstructive pulmonary disease or asthma; aggravation and worsening of respiratory function, apnea, and physical dependence on assisted respiration in infants with underlying life-threatening conditions; deterioration in pulmonary function, and dyspnea and chest soreness in adults with COPD or asthma; minor pulmonary function abnormalities, bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis, and ventilator dependence, may be fatal); cardiovascular (cardiac arrest, hypotension, bradycardia, and cardiac glycoside intoxication; bigeminy, bradycardia, and tachycardia in patients with underlying congenital heart disease); hemotologic (reversible anemia, reticulocytosis, and hemolytic anemia). Other adverse effects include rash, erythema of the eyelids, and conjunctivitis; these effects usually resolve within hours after discontinuation. Transient increases in serum bilirubin, AST (SGOT) and ALT (SGPT) concentrations have occurred during use of oral or parenteral ribavirin therapy, but not during ribavirin inhalation therapy. Seizures and asthenia also have been reported with intravenous ribavirin therapy. [AHFS Drug Information 1997; p 502] CONTRAINDICATIONS Contraindicated in patients hypersensitive to the drug or its components and in women who are or may become pregnant. [PDR 1997; p 1310] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic nucleoside, structurally related to pyrazofurin (pyrazomycin), guanosine, and xanthosine. [AHFS Drug Information 1997; p 497] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H12-N4-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 244.21 [USPD 1998; p. 635] CHEMICAL/PHYSICAL DATA Melting Point: 174-176 C [Merck Index 1996; p. 1410] CHEMICAL/PHYSICAL DATA Elemental Comp: C39.35%, H4.95%, N22.94%, O32.76% [Merck Index 1996; p. 1409] CHEMICAL/PHYSICAL DATA Solubility: 142 mg/ml in water at 25 C (77 F); slightly soluble in ethanol. [PDR 1997; p 1310] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Stable, white crystalline compound. [PDR 1997; p 1310] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 6 grams of sterile, lyophilized powder to be reconstituted in sterile water for aerosol administration. [USP DI 2000; p 2659; Protocol ID: ACTG A5088 ; USP DI 2000; p 2659] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Nasal and oral inhalation, oral administration and intravenous injection. [AHFS Drug Information 1997; p 499, 502, 504] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Vials containing lyophilized powder should be stored in a dry location at 15-25 C (59-78 F); reconstituted solutions should be stored under sterile conditions at room temperature (20-30 C; 68-86 F) for 24 hours. [USP DI 2000; p 2659; Protocol ID: ACTG A5088 ] MANUFACTURERS 0000001014: ICN Pharmaceuticals Inc 3300 Hyland Ave Costa Mesa, CA 92626 Contact: Jack Sholl (714)545-0100 MANUFACTURERS 0000001014: ICN Pharmaceuticals Inc 3300 Hyland Ave Costa Mesa, CA 92626 Contact: Unspecified (800)548-5100 MANUFACTURERS 0000001199: Schering - Plough Research 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Professional Information (800)526-4099 REFERENCES MED/97081569. Zylberberg H, Pol S. Reciprocal interactions between human immunodeficiency virus and hepatitis C virus infections. Clin Infect Dis. 1996 Nov;23(5):1117-25. MED/97054371. Japour AJ, Lertora JJ, Meehan PM, Erice A, Connor JD, Griffith BP, Clax PA, Holden-Wiltse J, Hussey Sm Walesky M, et al. A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Nov; 13(3):235-46. MED/97081806. van der Ven AJ, Swanink CM, van Crevel R, Bootsma GP, Kooopmans PP, Galama JM. Respiratory syncytial virus pneumonia in a AIDS patient. Infection. 1996 Sep-Oct; 24(5):375-7. MED/96002807. Goetz MB, Mathisen GE. Clinical course and treatment of adults with severe measles pneumonitis [letter; comment]. Clin Infect Dis. 1995 Aug; 21(2): 443. [Comment on Clin Infect Dis. 1994 Sep; 19(3):454-62]. MED/96110670. Linn WS, Gong H Jr, Anderson KR, Clark KW, Shamoo DA. Exposures of health-care workers to ribavirin aerosol: a pharmacokinetic study. Arch Environ Health 1995 Nov-Dec;50(6):445-51. MED/94288920. Morris DJ. Adverse effects and drug interactions of clinical importance with antiviral drugs. Drug Saf. 1994 Apr;10(4):281-91. MED/94000040. Arnold SD, Alonso R. Ribavirin aerosol: methods for reducing employee exposure [published erratum appears in AAOHN J 1993 Oct;41(10):511]. AAOHN J 1993 Aug;41(8):382-92. MED/93213126. Connor E, Morrison S, Lane J, Oleske J, Sonke RL, Connor J. Safety, tolerance, and pharmacokinetics of systemic ribavirin in children with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1993 Mar;37(3):532-9. MED/93108247. Multicenter clinical trial of oral ribavirin in symptomatic HIV-infected patients. The Ribavirin ARC Study Group. J Acquir Immune Defic Syndr. 1993 Jan;6(1):32-41. ICA9/93334115. Japour A, Chatis P, Kim S, Crumpacker C. HIV-1 ddI-resistance overcome with combination ddI/ribavirin. Int Conf AIDS. 1993 Jun 6-11;9(1):241 (abstract no. PO-A26-0640). ENTRY MONTH 199104 LAST REVISION DATE 20000801 319 UNIQUE IDENTIFIER DRG-0027 NAME OF SUBSTANCE Pyrimethamine [USPD 1998; p. 617] REGISTRY NUMBER 58-14-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 5-(4-Chlorophenyl)-6-ethyl-2,4-pyrimidinediam- ine [Merck Index 1996; p 1373] SYNONYMS component of Fansidar [USP DI 2000; p. 2838] SYNONYMS Daraprim [USP DI 2000; p. 2606] PROTOCOL ID NUMBERS Complete CC 89 CC-02 PROTOCOL ID NUMBERS Complete CC 89 CC-17 PROTOCOL ID NUMBERS Complete NIAID ACTG 021 PROTOCOL ID NUMBERS Complete NIAID ACTG 077 PILOT PROTOCOL ID NUMBERS Complete NIAID ACTG 102 PROTOCOL ID NUMBERS Complete NIAID ACTG 154 PROTOCOL ID NUMBERS Complete NIAID ACTG 156 PROTOCOL ID NUMBERS Complete NIAID ACTG 237 PROTOCOL ID NUMBERS Complete NIAID CPCRA 001 PROTOCOL ID NUMBERS No longer recruiting FDA 021A PROTOCOL ID NUMBERS No longer recruiting CC 90 CC-164 PHARMACOLOGICAL ACTION MODE OF ACTION: Pyrimethamine is a folic acid antagonist and has a mechanism of action similar to that of trimethoprim. By binding to and reversibly inhibiting dihydrofolate reductase, pyrimethamine inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid. Pyrimethamine usually is used in conjunction with sulfonamides for the treatment of toxoplasmosis. Pyrimethamine interferes with the synthesis of tetrahydrofolic acid in malarial parasites at a point immediately succeeding that where sulfonamides act. Pyrimethamine is a slow-acting blood schizonticidal agent that is active against the asexual erythrocytic forms of susceptible plasmodia; the drug is not usually gametocyticidal, but arrests sporogony in mosquitoes. Pyrimethamine is well absorbed from the GI tract. Following oral administration, peak serum concentrations of the drug occurs within 2-6 hours. Pyrimethamine is distributed mainly to the kidneys, lung, liver, and spleen and has an apparent volume of distribution of about 3 L/kg in adults. Pyrimethamine is approximately 80-87% bound to plasma proteins, it has an average plasma half-life of 111 hours (range 54-148 hours). Pyrimethamine and several unidentified metabolites of the drug are excreted in urine. [AHFS Drug Information 1997; p 566] DISEASES STUDIED/TREATED Used in combination with dapsone as primary and secondary prophylaxis in treating Pneumocystis carinii pneumonia (PCP). Combined with a sulfonamide for toxoplasmosis treatment. FDA approved for toxoplasmosis. [AHFS Drug Information 1997; p 566-7] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2604] OTHER MAJOR USES Treatment of malaria due to susceptible strains of plasmodia; treatment of toxoplasmosis. [PDR 1997; p 1199] SUBSTANCE INTERACTIONS Because pyrimethamine and sulfonamides both interfere with folic acid synthesis in susceptible organisms, but at different stages, these drugs act synergistically against some organisms. This synergism is used to therapeutic advantage in the treatment of malaria and toxoplasmosis. Although the clinical importance is unclear, p-aminobenzoic acid (PABA) reportedly interferes with the action of pyrimethamine and probably should not be used in patients receiving pyrimethamine. Pyrimethamine and sulfadoxine should not be administered concomitantly with other sulfonamides or with co-trimoxazole because adverse effects of the drugs may be additive. Although the clinical importance is unclear, mild hepatocytotoxicity has been reported in some patients receiving pyrimethamine and lorazepam concomitantly. [AHFS Drug Information 1997; p 569] ADVERSE EFFECTS In dosages used for the prophylaxis and treatment of malaria, adverse effects of pyrimethamine are usually mild and infrequent. However, prolonged therapy with pyrimethamine and the high dosages of the drug required for the treatment of toxoplasmosis are associated with a high incidence of adverse hematologic effects which result from folic acid deficiency. Adverse effects include the following: hematologic (folic acid depletion and reversible bone marrow depression resulting from high dosages of the drug; megaloblastic anemia, leukopenia, thrombocytopenia, agranulocytosis, and pancytopenia; hemolysis if sulfadoxine/pyrimethamine is administered to patients with glucose-6-phosphate dehydrogenase deficiency), gastrointestinal (anorexia, abdominal cramps, diarrhea, vomiting, atrophic glossitis or gastritis); nervous system (ataxia, tremors, seizures, and respiratory failure; headache, light-headedness, insomnia, depression, malaise, fatigue, and irritability rarely); hypersensitivity reactions (severe and sometimes fatal hypersensitivity reactions have occurred with pyrimethamine/sulfadoxine therapy, in most cases, fatality resulted from severe cutaneous reactions, including erythema reactions, vasculitis, urticaria, pruritus, exfoliative dermatitis, and photosensitivity in pyrimethamine/sulfadoxine therapy; dermatitis, pulmonary eosinophilia, and photosensitivity in pyrimethamine therapy); hepatic (abnormal liver functions, jaundice, hepatomegaly, and hepatitis, which can be fatal, have been reported with the pyrimethamine/sulfadoxine therapy). Other rare adverse effects include hematuria, disorders of cardiac rhythm, dryness of the mouth or throat, fever, abnormal skin pigmentation, and hyperphenylalaninemia. [AHFS Drug Information 1997; p 567-8] CONTRAINDICATIONS Contraindicated in patients with known hypersensitivity to pyrimethamine. It should be used by pregnant women only if the potential benefit justifies the potential risk to the fetus. The drug is also contraindicated in patients with documented megaloblastic anemia due to folate deficiency. [PDR 1997; p 1199-200] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Pyrimethamine is a synthetic, aminopyrimidine derivative structurally related to trimethoprim. [AHFS Drug Information 1997; p 566] CHEMICAL/PHYSICAL DATA Molecular Formula: C12-H13-Cl-N4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 248.72 [USPD 1998; p. 617] CHEMICAL/PHYSICAL DATA Melting Point: 233-234 C [Merck Index 1996; p. 1373] CHEMICAL/PHYSICAL DATA Elemental Comp: C57.95%, H5.27%, Cl14.25%, N22.53% [Merck Index 1996; p. 1373] CHEMICAL/PHYSICAL DATA Solubility: Solubility (g/L) in ethanol (about 9); dilute HCl (about 5); boiling ethanol (about 25). Very sparingly soluble in propylene glycol and dimethylacetamide at 70 C; practically insoluble in water. [Merck Index 1996; p 1373] CHEMICAL/PHYSICAL DATA Stability: Tablets should be stored at 15 C to 25 C in a tight, light resistant container. Oral suspensions prepared from the tablets are stable at room temperature for 5 to 7 days. [AHFS Drug Information 1997; p 566] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [AHFS Drug Information 1997; p 566] SUBSTANCE DELIVERY DATA DOSAGE FORM: 25 mg tablets. [PDR 1997; p 1200] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1997; p 1199] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored at 15-25 C in a tight, light-resistant container. Oral suspensions prepared from the tablets are stable at room temperature for 5-7 days. [AHFS Drug Information 1997; p 566] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97052552. Field AS, Marriott DJ, Milliken ST, Brew BJ, Canning EU, Kench JG, Darveniza P, Harkness JL. Myositis associated with a newly described microsporidian, Trachipleistophora hominis, in a patient with AIDS. J Clin Microbiol. 1996 Nov; 34(11):2803-11. MED/97138637. Ebrahimzadeh A, Bottone EJ. Persistent diarrhea caused by Isospora belli: therapeutic response to pyrimethamine and sulfadiazine. Diagn Microbiol Infect Dis. 1996 Oct; 26(2):87-9. MED/97044644. Giacometti A, Cirioni O, Scalise G. In-vitro activity of macorlides alone and in combination with artemisin, atovaquone, dapsone, minocycline or pyrimethamine against Cryptosporidium parvum. J Antimicrob Chemother. 1996 Sep; 38(3):399-408. MED/97029274. Klinker HM, Langmann P, Richter E. Pyrimethamine alone as prophylaxis for cerebral toxoplasmosis in patients with advanced HIV infection. Infection. 1996 Jul-Aug; 24(4):324-7. MED/96408180. Maggi P, de Mari M, De Blasi R, Armenise S, Romanelli C, Andreula C, Zimatore G, Angarono G. Choreoathetosis in acquired immune deficiency syndrome patients with cerebral toxoplasmosis. Mov Disord. 1996 Jul; 11(4):434-6. MED/96400675. Klinker H, Langmann P, Richter E. Plasma pyrimethamine concentrations during long-term treatment for cerebral toxoplasmosis in patients with AIDS. Antimicrob Agents Chemother. 1996 Jul; 40(7):1623-7. MED/96397036. Carlin BP, Sargent DJ. Robust Bayesian approaches for clinical trial monitoring. Stat Med. 1996 Jun; 15(11):1093-106. MED/96338349. Jacobson JM, Davidian M, Rainey PM, Haner R, Raasch RH, Luft BJ. Pyrimethamine pharmacokinetics in human immunodeficiency virus-positive patients seropositive for Toxoplasma gondii. Antimicrob Agents Chemother. 1996 Jun; 40(6):1360-5. MED/96415921. Miller RF, Le Noury J, Corbett EL, Felton JM, De Cock KM. Pneumocystis carinii infection: current treatment and prevention. J Antimicrob Chemother. 1996 May; 37 suppl B:33-53. MED/96435297. Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis. 1996 Feb; 22(2):268-75. ENTRY MONTH 199104 LAST REVISION DATE 20000801 320 UNIQUE IDENTIFIER DRG-0026 NAME OF SUBSTANCE Primaquine [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 90-34-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N4-(6-Methoxy-8-quinolinyl)-1,4-pentanediamin- e [Merck Index 1996; p 1330] PROTOCOL ID NUMBERS Complete NIAID ACTG 044 PROTOCOL ID NUMBERS Complete NIAID ACTG 108 PHARMACOLOGICAL ACTION MODE OF ACTION: The exact mechanism of antimalarial activity has not been determined, but the drug appears to interfere with the function of plasmodial DNA. Primaquine is a tissue schizonticidal agent and is active against the preerythrocytic and exoerythrocytic forms of Plasmodium falciparum, P. malariae, P. ovale, and P. vivax. Primaquine is also gametocyticidal against plasmodia, especially the gametocytes of P. falciparum. Primaquine is well absorbed from the GI tract. Following oral administration, peak plasma concentrations of the drug generally are attained within 6 hours; plasma concentrations generally are negligible after 24 hours. Primaquine appears to be widely distributed in the body, and has an apparent volume of distribution of about 150-250 L in healthy adults. Primaquine has a plasma half-life of 3.7-9.6 hours in healthy adults. Primaquine is rapidly metabolized in the liver and only a small amount of the drug is excreted unchanged in urine. The principle metabolite of primaquine is carboxyprimaquine, and plasma concentrations of the metabolite greatly exceed those of unchanged primaquine. [AHFS Drug Information 1997; p 564] DISEASES STUDIED/TREATED When used with clindamycin, it is effective for acute Pneumocystis carinii pneumonia (PCP). [USP DI 1995; p 2993] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2540] OTHER MAJOR USES Treatment of malaria; Pneumocystis carinii pneumonia. [AHFS Drug Information 1997; p 564] SUBSTANCE INTERACTIONS Potentially hemolytic drugs (e.g., sulfonamides, nitrofurans) or depressants of myeloid elements of the bone marrow (e.g. methotrexate, phenylbutazone, chloramphenicol) should not be given concurrently with primaquine. Primaquine should not be administered to patients who have recently received quinacrine, as toxicity is increased. [Physicians GenRx 1997; p II-1749] ADVERSE EFFECTS Adverse effects include the following: hematologic (acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency; hemolytic anemia in individuals with other defects of the erythrocytic pentose phosphate pathway of glucose metabolism or in patients with certain hemoglobinopathies; methemoglobinemia in patients with NADH methemoglobin reductase deficiency; mild anemia, leukocytosis, and leukopenia occasionally; and agranulocytosis rarely); gastrointestinal (nausea, vomiting, epigastric distress, and mild to moderate abdominal cramps). Other adverse effects include headache, interference with visual accommodation, and pruritus; hypertension and arrhythmias rarely. [AHFS Drug Information 1997; p 565] CONTRAINDICATIONS Primaquine is contraindicated in acutely ill patients who have systemic disease manifested by a tendency to develop granulocytopenia (e.g. rheumatoid arthritis, lupus erythematosus); in patients receiving other potentially hemolytic drugs or agents capable of depressing the myeloid elements of the bone marrow; and in pregnant women. Because quinacrine hydrochloride appears to potentiate the toxicity of antimalarial compounds which are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is contraindicated. Similarly, primaquine should not be administered to patients who have received quinacrine, as toxicity is increased. Patients with previous idiosyncratic reactions to primaquine (as manifested by hemolytic anemia, methemoglobinemia, or leukopenia), personal or family history of favism, glucose-6-phosphate dehydrogenase deficiency, or NADH methemoglobin reductase deficiency should be monitored closely for tolerance of the drug. [AHFS Drug Information 1997; p 565; Physicians GenRx 1997; p II-1749] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An 8-aminoquinoline derivative. [AHFS Drug Information 1997; p 564] CHEMICAL/PHYSICAL DATA Molecular Formula: C15-H21-N3-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 259.35 [Merck Index 1996; p. 1330] CHEMICAL/PHYSICAL DATA Elemental Comp: C69.47%, H8.16%, N16.20%, O6.17% [Merck Index 1996; p. 1330] CHEMICAL/PHYSICAL DATA Solubility: Soluble in ether (Primaquine); moderately soluble in water (Primaquine Phosphate). [Merck Index 1996; p 1330] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Viscous liquid (Primaquine); yellow crystals (Primaquine Phosphate). [Merck Index 1996; p 1330] SUBSTANCE DELIVERY DATA DOSAGE FORM: Primaquine phosphate tablets containing 15 mg of primaquine base. [AHFS Drug Information 1997; p 565] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [AHFS Drug Information 1997; p 565] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store below 40 C, preferably between 15 C and 30 C, unless otherwise specified by the manufacturer. Store in a well-closed, light-resistant container. [AHFS Drug Information 1997; p 564] MANUFACTURERS 0000001228: Sterling Winthrop Pharmaceuticals 90 Park Ave New York, NY 10016 Contact: Professional Services (800)446-6267 REFERENCES MED/97066352. Barber BA, Pegram PS, High KP. Clindamycin/primaquine as prophylaxis for Pneumocystis carinii pneumonia. Clin Infect Dis. 1996 Oct; 23(4):718-22. MED/96335109. Sin DD, Shafran SD. Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Aug; 12(5):477-81. MED/96415921. Miller RF, Le Noury J, Corbett EL, Felton JM, De Cock KM. Pneumocystis carinii infection: current treatment and prevention. J Antimicrob Chemother. 1996 May; 37 suppl B:33-53. MED/96188893. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR. Comparison of three regimens for treatment of mild-to-moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. Ann Intern Med. 1996 May; 124(9):792-802. MED/96008522. Drugs for AIDS and associated infections. Med Lett Drugs Ther. 1995 Oct; 37 (59):87-94. MED/96185167. Korraa H, Saadeh C. Options in the management of pneumonia caused by Pneumocystis carinii in patients with acquired immune deficiency syndrome and intolerance to trimethoprim/sulfamethoxazole. South Med J. 1996 Mar;89(3):272-7. AIDS/95920331. Safrin S, Black J, Finkelstein D, Slasor P, Simpson G, Frame P, Van Der Horst C, Wu A, Cheung T, Hojczyk P, et al. Double-blind randomized comparison of oral trimethoprim-sulfamethoxazole (TS), dapsone-trimethoprim (DT),and clindamycin-primaquine (CP) for treatment of mild-to-moderate pneumocystis carinii pneumonia (PCP) in AIDS patients. Natl Conf Hum Retroviruses Relat Infect (2nd). 1995 Jan 29-Feb 2;:110. MED/94368951. Black JR, Feinberg J, Murphy RL, Fass RJ, Finkelstein D, Akil B, Safrin S, Carey JT, Stansell J, Plouffe JF, et al. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044. Clin Infect Dis. 1994 Jun;18(6):905-13. MED/94002771. Toma E, Fournier S, Dumont M, Bolduc P, Deschamps H. Clindamycin/primaquine versus trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind pilot trial. Clin Infect Dis. 1993 Aug;17(2):178-84. ICA9/93336254. Toma E, Tremblay C. Passerini L. Clindamycin/primaquine for severe Pneumocysytis carinii pneumonia (PCP). Int Conf AIDS. 1993 Jun 6-11;9(1):62 (abstract no. WS-B19-6). ENTRY MONTH 199104 LAST REVISION DATE 20000801 321 UNIQUE IDENTIFIER DRG-0025 NAME OF SUBSTANCE Pentamidine isethionate [USPD 1998; p. 558] REGISTRY NUMBER 140-64-7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Benzamidine, 4,4'-(pentamethylenedioxy)di-, bis(beta-hydroxyethanesulfonate) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Nebupent [USP DI 2000; p. 2424] SYNONYMS Pentacarinat [USP DI 2000; p. 2424] SYNONYMS Pentam 300 [USP DI 2000; p. 2427] SYNONYMS Pneumopent [USP DI 2000; p. 2424] PROTOCOL ID NUMBERS Complete FDA 022A PROTOCOL ID NUMBERS Complete CC 88 CC-85 PROTOCOL ID NUMBERS Complete NIAID ACTG 021 PROTOCOL ID NUMBERS Complete NIAID ACTG 029 PROTOCOL ID NUMBERS Complete NIAID ACTG 040 PROTOCOL ID NUMBERS Complete NIAID ACTG 041 PROTOCOL ID NUMBERS Complete NIAID ACTG 048 PROTOCOL ID NUMBERS Complete NIAID ACTG 079 PROTOCOL ID NUMBERS Complete NIAID ACTG 081 PROTOCOL ID NUMBERS Complete NIAID ACTG 115 PROTOCOL ID NUMBERS Complete NIAID ACTG 189 PROTOCOL ID NUMBERS No longer recruiting FDA 022B PROTOCOL ID NUMBERS No longer recruiting FDA 022C PROTOCOL ID NUMBERS No longer recruiting FDA 022D PROTOCOL ID NUMBERS No longer recruiting FDA 022E PROTOCOL ID NUMBERS No longer recruiting FDA 023A PROTOCOL ID NUMBERS No longer recruiting FDA 023B PROTOCOL ID NUMBERS No longer recruiting FDA 053B PROTOCOL ID NUMBERS No longer recruiting FDA 227B PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting CC 91 CC-207 PROTOCOL ID NUMBERS Terminated NIAID ACTG 030 PROTOCOL ID NUMBERS Terminated NIAID CPCRA 013 PHARMACOLOGICAL ACTION MODE OF ACTION: This is not fully understood and little is known about its pharmacokinetics. In vitro studies with mammalian tissues and the protozoan, Crithidia oncopelti, indicate that this drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins. Preliminary studies in 7 patients treated with daily intramuscular injections at 4 mg/kg for 10-12 days gave drug plasma levels between .3-0.5 mcg/ml which did not appreciably change with time after injection or from day-to-day; higher plasma levels were found in patients having an elevated blood urea nitrogen level; decreasing amounts of the drug were excreted in urine up to 6-8 weeks after cessation of treatment. [Physicians GenRx 1997; p II-1646] DISEASES STUDIED/TREATED Pneumocystis carinii pneumonia (PCP). FDA approved 10/16/84 for PCP treatment (im and iv). FDA approved 6/15/89 for PCP prophylaxis (aerosol). [PDR 1995; p 1048; FDA Office of AIDS and Special Health Issues ] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 2422] SUBSTANCE INTERACTIONS No clinically significant drug interactions have been documented in patients receiving prophylactic aerosolized pentamidine. Parenteral pentamidine has interacted with blood dyscrasia-causing medications; bone marrow depressants; nephrotoxic medications (concurrent use with pentamidine may increase the risk for nephrotoxicity). Concurrent use of pentamidine with radiation therapy may increase the bone marrow-depressant effect. Combination with didanosine may result in pancreatitis; concurrent use with foscarnet may result in severe, but reversible, hypocalcemia, hypomagnesemia and nephrotoxicity. [USP DI 1995; p 2182, 2185] ADVERSE EFFECTS The most common adverse effects are nephrotoxicity or cough and bronchospasm. Adverse effects include the following: renal (nephrotoxicity manifested by an increase in serum creatinine and/or BUN, acute renal failure, mild to severe renal insufficiency, hyperkalemia); cardiovascular (moderate to severe hypotension, cardiac arrhythmias, cardiorespiratory arrest, ventricular tachycardia, atypical ventricular tachycardia (torsade de pointes) ECG abnormalities, and facial flushing); local and dermatologic (sterile abscess, pain, erythema, tenderness, and induration at the injection site, ulceration and/or necrosis occasionally; pruritus, erythema, dry skin, desquamation, rash, and urticaria in patients receiving orally inhaled drug); hypoglycemia and diabetogenic (severe and/or prolonged hypoglycemia, hyperglycemia and insulin-dependent diabetes mellitus, night sweats); hematologic (leukopenia, thrombocytopenia, and anemia rarely); gastrointestinal (nausea, vomiting, abdominal discomfort or pain, diarrhea, anorexia or decreased appetite, and an unpleasant taste sensation in the mouth or unpleasant feeling on the tongue; gingivitis, dyspepsia, gagging, oral ulcer or abscess, gastritis, gastric ulcer, splenomegaly, melena, hematochezia, esophagitis, colitis, increased sputum production (hypersalivation), xerostomia, and numb and/or chapped lips in patients receiving inhalation therapy); hepatic (hepatitis, hepatomegaly, hepatic dysfunction); respiratory (cough and bronchospasm, laryngitis, shortness of breath, chest pain or congestion, pneumothorax; rhinitis, laryngospasm, heperventilation, hemoptysis, gagging, eosinophilic or interstitial pneumonitis, pleuritis, cyanosis, tachypnea, and rales in patients receiving inhalation therapy); nervous system (neuralgia, confusion or hallucinations, and dizziness; tremors, confusion, anxiety, memory loss, seizure, neuropathy, paresthesia, insomnia, hypoesthesia, drowsiness, emotional lability, vertigo, paranoia, neuralgia, hallucinations, depression, unsteady gait, and loss of taste or smell in patients receiving inhalation therapy). Other adverse effects include hypocalcemia, fever, Jarisch-Herxheimer-like reaction, anaphylactoid reactions with shock, extrapulmonary pneumocystosis, conjunctivitis, eye discomfort, blurred vision, blepharitis, hypertensive reactions, chills, headache, myalgia, arthralgia, edema, and incontinence. [AHFS Drug Information 1997; p 667-8] CONTRAINDICATIONS Inhalation solution: Nebupent is contraindicated in patients with a history of an anaphylactic reaction to inhaled or parenteral pentamidine isethionate. Injection: once diagnosis of Pneumocystis carinii pneumonia has been firmly established, there are no absolute contraindications to the use of pentamidine isethionate. [Physicians GenRx 1997; p II-1647] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Aromatic diamidine derivative. [AHFS Drug Information 1997; p 661] CHEMICAL/PHYSICAL DATA Molecular Formula: C19-H24-N4-O2.2(C2-H6-O4-S) [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Melting Point: 180 C [Merck Index 1996; p. 1224] CHEMICAL/PHYSICAL DATA Elemental Comp: C67.04%, H7.11%, N16.46%, O9.40% (base) [Merck Index 1996; p. 1224] CHEMICAL/PHYSICAL DATA Solubility: (Pentamidine Isethionate): Soluble in water (about 1:10 at 25 C; about 1:4 at 100 C); soluble in glycerol (solubility increases on warming); slightly soluble in alcohol; insoluble in ether, acetone, chloroform, and liquid petroleum. [Merck Index 1996; p 1224] CHEMICAL/PHYSICAL DATA Stability: Sterile solutions (in water) are stable for 48 h at room temperature and protected from light; 5% dextrose solutions are stable for 24 h at room temperature and protected from light; diluted solutions in PVC bags are stable for 48 h under fluorescent light at 22-26 C. [AHFS Drug Information 1997; p 662] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Pentamidine isethionate: white or almost white crystals or powder; hygroscopic; odorless or a slight butyric odor. [Merck Index 1996; p 1224; AHFS Drug Information 1997; p 661] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials - 300 mg lyophilized product, formulated in USP sterile water or 5% dextrose for injection/infusion. [AHFS Drug Information 1997; p 671] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral inhalation via nebulization, deep intramuscular injection, or slow intravenous infusion. The drug should not be administered by rapid intravenous injection, or slow intravenous infusion. [AHFS Drug Information 1997; p 670] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Powder should be stored at 15-30 C; injections are stable for 48 h (in sterile water), or 24 h (in 5% dextrose) at room temperature; solutions (in sterile water) for oral inhalation are stable for 48 h in original vial at room temperature; and protected from light. Diluted solutions in PVC bags are stable for 48 h under fluorescent light at 22-26 C. [AHFS Drug Information 1997; p 662] MANUFACTURERS 0000001023: LyphoMed Inc 10401 West Touhy Ave Rosemont, IL 60018 Contact: Dr Don Ebersman (708)291-1067 MANUFACTURERS 0000003335: Fujisawa Healthcare Inc Parkway Center North / 3 Parkway North Deerfield, IL 600152548 Contact: Medical Information (800)727-7003 MANUFACTURERS 0000001190: Rhone - Poulenc Rorer 500 Arcola Road Collegeville, PA 19426 Contact: Unspecified (800)727-7003 MANUFACTURERS 0000001023: LyphoMed Inc 10401 West Touhy Ave Rosemont, IL 60018 Contact: David Lester (610)454-5399 MANUFACTURERS 0000005231: Medeva Pharmaceuticals Inc PO Box 1710 Rochester, NY 14603 Contact: John Petillo (610)454-5476 REFERENCES HTA/96358344. Rawji A, Lee-Pack LR, Favell K, Chan CK. Lack of desensitization to aerosol pentamidine with long-term use. J Aerosol Med. 1996; 9(2):241-8. MED/96285243. Yeung KT, Chan M, Chan CK. The safety of i.v. pentamidine administered in an ambulatory setting. Chest. 1996 Jul; 110(1):136-40. MED/96279846. Principi N, Marchisio P, Onorato J, Gabiano C, Galli L, Caselli D, Morandi B, Campelli A, Clerici M, Gattinara GC. Long-term administration of aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia in infants and children with symptomatic human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Jun; 12(2):158-63. MED/96385620. Ewig S, Schafer H, Rockstroh JK, Pikenhain A, Luderitz B. Effect of long-term primary aerosolized pentamidine prophylaxis on breakthrough Pneumocystis carinii pneumonia. Eur Respir J. 1996 May; 9(5):1006-12. MED/96332632. Rizzardi GP, Lazzarin A, Musicco M, Frigerio D, Maillard M, Lucchini M, Moroni M. Risks and benefits of aerosolized pentamidine and cotrimoxazole in primary prohylaxis of Pneumocystis carinii penumonia in HIV-1-infected patients: a two-year Italian multicentric randomized controlled trial. J Infect. 1996 Mar; 32(2):123-31. MED/96185167. Korraa H, Saadeh C. Options in the management of pneumonia caused by Pneumocystis carinii in patients with acquired immune deficiency syndrome and intolerance to trimethoprim/sulfamethoxazole. South Med J. 1996 Mar; 89(3):272-7. MED/96342596. Conte JE Jr, Golden JA. Intrapulmonary and systemic pharmacokinetics of aerosolized pentamidine used for prophylaxis of pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus. J Clin Pharmacol. 1995 Dec; 35(12):1166-73. MED/96188309. Antinori A, Murri R, Ammassari A, De Luca A, Linzalone A, Cingolani A, Damiano F, Maiuro G, Vecchiet J, Scoppettuolo G. Aerosolized pentamidine, cotrimoxazole and dapsone-pyrimethamine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis [see comments]. AIDS. 1995 Dec; 9(12):1343-50. [Comment in AIDS. 1996 Aug; 10(9):1045-6.] MED/96116154. Rizzard GP, Lazzarin A, Musicco M, Frigerio D, Maillard M, Lucchini M, Moroni M. Better efficacy of twice-monthly than monthly aerosolized pentamidine for secondary prophylaxis of Pneumocytis carinii pneumonia in patients with AIDS. An italian multicenter randomized controlled trial. J Infect. 1995 Sep; 31(2):99-105. MED/96002826. Simonds RJ, Hughes WT, Feinberg J, Navin TR. Preventing Pneumocystis carinii penumonia in persons infected with human immunodeficiency virus. Clin Infect Dis. 1995 Aug; 21 suppl 1 :S44-8. ENTRY MONTH 199104 LAST REVISION DATE 20000801 322 UNIQUE IDENTIFIER DRG-0024 NAME OF SUBSTANCE Methotrexate [USPD 1998; p. 462] REGISTRY NUMBER 59-05-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N-(4-(((2,4-Diamino-6-pteridinyl)methyl) methylamino) benzoyl)-L-glutamic acid [Merck Index 1996; p 1025] SYNONYMS Folex (disodium salt) [USP DI 2000; p. 2103] SYNONYMS Folex-Pfs [USP DI 2000; p. 2103] SYNONYMS Mexate (disodium salt) [USP DI 2000; p. 2103] SYNONYMS Rheumatrex [USP DI 2000; p. 2103] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-207 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 013 PROTOCOL ID NUMBERS Terminated NIAID ACTG 009 PHARMACOLOGICAL ACTION MODE OF ACTION: Methotrexate inhibits dihydrofolic acid reductase, thereby inhibiting the reduction of dihydrofolates to tetrahydrofolates in the process of DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of the methotrexate. When cellular proliferation in malignant tissue is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within 1-2 hours with oral absorption, and 30-60 minutes with intramuscular injection. Approximately 50% of the drug is reversibly bound to serum proteins. After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidine synthetase. Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80-90% of the administered dose is excreted unchanged in the urine within 24 hours. Renal excretion occurs by glomerular filtration and active tubular secretion. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. The terminal half-life reported for methotrexate is approximately 3-10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is 8-15 hours. [PDR 1997; p 1323] DISEASES STUDIED/TREATED Use in mixed drug therapy of patients with AIDS-associated lymphoma. [Protocol ID: ACTG 074 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p. 2093] CLASSIFICATION CODE Antipsoriatic [USP DI 2000; p. 2100] CLASSIFICATION CODE Antirheumatic [USP DI 2000; p. 2100] OTHER MAJOR USES In treating trophoblastic neoplasms (choriocarcinoma, choriocarcinoma, chorioadenoma destruens, hydatiform mole); in palliative treatment of acute leukemias in conjunction with other chemotherapeutic regimens; in the treatment of breast cancer, alone or in combination chemotherapy; in the symptomatic control of severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy; in the management of active stage of severe classical or definite rheumatiod arthritis; high-dose MTX followed by leucovorin is used in combination chemotherapy for nonmetastatic osteosarcoma. [AHFS Drug Information 1997; p 828-30] SUBSTANCE INTERACTIONS Adverse effects of methotrexate include the following: hemotologic (leukopenia, thrombocytopenia, anemia, and hemorrhage from various sites); oral and intestinal (gingivitis, glossitis, pharyngitis, stomatitis, enteritis, ulcerations and bleeding of the mucous membranes of the mouth, or other portions of the GI tract, abdominal distress, anorexia, nausea, vomiting, hematemesis, diarrhea, and melena); hepatic (acute and chronic hepatotoxicity manifested as hepatic frbrosis, chrrhosis, or other histologic changes in the liver which may precede any symptoms of hepatotoxicity or abnormal liver functions); pulmonary (pneumonitis, pulmonary fibrosis manifested as fever, dry and nonproductive cough, dyspnea, chest pain, hypoxemia, and/or radiographic evidence of pulmonary infiltrates); dermatologic (erythematous rashes, pruritus, dermatitis, urticaria, folliculitis, vasculitis, photosensitivy, erythema multiforme, toxic epidermal necrolysis, Steven-Johnson syndrome, depigmentation, hyperpigmentation, petechiae, ecchomoses, telangiectasia, acne, furunculosis, and alopecia occasionally). Following intrathecal administration of methotrexate, acute chemical arachnoiditis manifested as headache, back pain, nuchal rigidity, and/or fever; subcute myelopathy manifested by paraparesis/paraplegia involving one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, and occasionally seizures and coma; and increased CSF pressure have increased. Systemic adverse effects include headache, drowsiness, blurred vision, eye discomfort, conjunctivitis, severe visual changes of unknown etioloty, tinnitus, malaise, undue fatigue, dizziness, chills and fever, sweating, arthalgia, mualagia, decreased resistance to infection, septicemia, upper respiratory infection, osteoporosis including aseptic necrosis of the femoral head\hypoglammaglobunia, cystitis, dysuria, vaginal discharge, diabetes, abnormal tissue changes and even [AHFS Drug Information 1997; p 830-1] ADVERSE EFFECTS Due to the possibility of fatal/serious toxic reactions, the drug should be used only by physicians experienced in antimetabolite chemotherapy; may cause marked depression of bone marrow, anemia, leukopenia, thrombocytopenia, bleeding, hepatotoxicity, liver atrophy, necrosis, cirrhosis, periportal fibrosis, fetal death and/or congenital anomalies, diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and intestinal perforation. The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other adverse reactions include anaphylaxis, malaise, undue fatigue, chills and fever, dizziness, decreased resistance to infection. Adverse reactions have been reported for various body systems (skin and alimentary, urogenital, pulmonary, central nervous systems). Use with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. The high potential toxicity of this drug is usually dose-related. Large doses may cause convulsions. [PDR 1995; p 1166-67] CONTRAINDICATIONS Mehtotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis; nursing mothers; patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease; patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes; patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia; and patients with known hypersensitivity to methotrexate. [PDR 1997; p 1324] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Folic acid antagonist. [Merck Index 1996; p 1025] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H22-N8-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 454.45 [USPD 1998; p. 462] CHEMICAL/PHYSICAL DATA Elemental Comp: C52.86%, H4.88%, N24.66%, O17.60% [Merck Index 1996; p. 1025] CHEMICAL/PHYSICAL DATA Solubility: Soluble in alkaline solutions with decomposition. [Merck Index 1996; p 1025] CHEMICAL/PHYSICAL DATA Stability: A diluted solution of methotrexate sodium injection maintains 90% of its labeled potency if stored for 24 hours at 21 C to 25 C. Preservations solutions should be diluted immediately prior to use, any unused portions should be discarded. [USP DI 1995; p 1823] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Orange-brown crystalline powder. [AHFS Drug Information 1997; p 828] SUBSTANCE DELIVERY DATA DOSAGE FORM: Lyophilized powder for parenteral injection (sodium form, presertive-free; 20 mg, 50 mg, 1 g per vial); isotonic liquid for parenteral injection (sodium form, 25 mg/ml; presertive-free: 2, 4, 8, 10 ml per vial, with presertive: 2, 10 ml per vial); tablets (sodium form; 2.5 mg of methotrexate). [PDR 1997; p 1326-7] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, intravenous, intramuscular, intra-arterial, or intrathecal administration. [PDR 1997; p 1325] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Lyophilized powder and isotonic liquid should be stored between 15-25 C (59-77 F). Tablets should be stored at controlled room temperature between 15-30 C (59-86 F). All preparations should be protected from light. [PDR 1997; p 1433] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Dr Jan Agosti (206)389-4321 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)466-8639 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001022: Lederle Laboratories North Middletown Rd Pearl River, NY 10965 Contact: Unspecified (800)432-4702 REFERENCES MED/97156553. Tosi P, Gherlinzoni F, Mazza P, Visani G, Coronado O, Costiglio P, Raise E, Mazzetti M, Gritti F, Tura S. 3'-Azido 3'deoxythymidine + methotrexate as a novel antineoplastic combination in the treatment of human immunodeficiency virus-related non-Hodgkin's lymphomas. Blood 1997 Jan; 89(2):419-25. MED/96320583. Levine AM, Tulpule A, Espina B, Boswell W, Buckley J, Rasheed S, Stain S, Parker J, Nathwani B, Gill PS. Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma. Effect on human immunodeficiency virus and serum interleukin-6 levels over time. Cancer. 1996 Aug; 78(3):517-26. MED/96194193. Berenbaum F, Duvivier C, Prier A, Kaplan G. Successful treatment of Reiter's syndrome in a patient with AIDS with methotrexate and corticosteriods [letter]. Br J Rheumatol. 1996 Mar; 35(3):295. MED/95218170. Kaplan LD, Shiramizu B, Herndier B, Hahn J, Meeker TC, Ng V, Volberding PA, McGrath MS. Influence of molecular characteristics on clinical outcome in human immunodeficiency virus-associated non-Hodgdin's lymphoma: identification of a subgroup with favorable clinical outcome. Blood. 1995 Apr 1;85(7):1727-35. MED/96122066. Stein ME, Lachter J, Spencer D, Bezwoda WR. Chemotherapy for AIDS-related and endemic African Kaosi's sarcoma in southern Africa. Int J Dermatol. 1995 Oct;34(10):729-32. MED/95212522. Schurmann D, Grunewald T, Weiss R, Jautzke G, Pohle HD, Ruf B. Intensive treatment of AIDS-related non-Hodgkin's lymphomas with the MACOP-B protocol. Eur J Haematol. 1995 Feb; 54(2):73-7. MED/95399331. Jost LM, Jacky E, Dommann-Scherrer C, Honegger HP, Maurer R, Sauter C, Stahel RA. Short-term weekly chemotherapy followed by high-dose therapy with autologous bone marrow transplantation for lymphoblastic and Burkitt's lymphomas in adult patients. Ann Oncol. 1995 May;6(5):445-51. MED/94332776. Greenberg AL, Droller DG. Successful treatment of a patient with seropositive human immunodeficiency virus with high risk Burkitt's leukemia. Cancer. 1994 Aug 15;74(4):1261-4. MED/94308359. Maurer TA, Zackheim HS, Tuffanelli L, Berger TG. The use of methotrexate for treatment of psoriasis in patients with HIV infection. J Am Acad Dermatol. 1994 Aug;31(2 Pt 2):372-5. MED/94015218. Chamberlain MC, Dirr L. Involved-field radiotherapy and intra-Ommaya methotrexate/cytarabine in patients with AIDS-related lymphomatous meningitis. J Clin Oncol. 1993 Oct;11(10):1978-84. ENTRY MONTH 199104 LAST REVISION DATE 20000801 323 UNIQUE IDENTIFIER DRG-0023 NAME OF SUBSTANCE Methadone hydrochloride [USPD 1998; p. 459] REGISTRY NUMBER 1095-90-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 3-Heptanone, 6-(dimethylamino)-4,4-diphenyl-, hydrochloride [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Dolophine [USP DI 2000; p. 2323] SYNONYMS Methadose [USP DI 2000; p. 2323] PROTOCOL ID NUMBERS Complete NIAID ACTG 055 PROTOCOL ID NUMBERS Complete NIAID ACTG 262 PROTOCOL ID NUMBERS Complete NIAID ACTG 401 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 030 PHARMACOLOGICAL ACTION MODE OF ACTION: An opioid agonist analgesic, which like morphine, exerts its activity by binding to the stereospecific receptors in the central nervous system. A 10 mg intramuscular dose or 20 mg oral dose is equivalent to 10 mg of intramuscular morphine. Protein binding is high. Half-life is 15-25 hours. The onset of action is 10-20 minutes (IM), 30-60 minutes (oral). The duration of action is 4-5 hours (IM),3-4 hours (IV), 4-6 hours (oral). This duration may increase with chronic use. Excretion is primarily via the kidneys. [USP DI 1995; p 2065, 2074-5] DISEASES STUDIED/TREATED Maintenance therapy of AIDS patients who were former drug abusers. [Protocol ID: ACTG 055 ] CLASSIFICATION CODE Analgesic [USP DI 2000; p. 2311] CLASSIFICATION CODE Suppressant, narcotic abstinence syndrome [USP DI 2000; p. 2311] OTHER MAJOR USES Oral solution is used to relieve severe, chronic pain (e.g., in terminally ill patients). Concentrate oral solution is used for the relief of severe pain, and in detoxification treatment and maintenance treatment as an oral substitute for heroin or other morphine-like drug to suppress the opiate-agonist abstinence syndrome in patients who are dependent on these drugs. [AHFS Drug Information 1997; p 1576] SUBSTANCE INTERACTIONS Patients who are on a methadone maintenance program (or who are addicted to heroin) may experience withdrawal symptoms when given pentazocine; concurrent administration of rifampin (an antituberculosis agent) may reduce the blood concentration of methadone (possibly through the enhancement of microsomal drug-metabolized enzymes) sufficient to produce withdrawal symptoms. Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or in patients who have received such agents within 14 days - similar reactions have not yet been reported with methadone, but if methadone is used for such patients, a sensitivity test should be performed using small incremental doses of methadone over the period of several hours while monitoring the patient's condition and vital signs. Methadone should be used with caution and in reduced dosage in patients concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, tricyclic antidepressants, and other central nervous system depressants (including alcohol), since respiratory depression, hypotension, and profound sedation or coma may result. [PDR 1997; p 2358] ADVERSE EFFECTS Major hazards of methadone include respiratory depression, circulatory depression, respiratory arrest, shock, and cardiac arrest. Most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. Other adverse reactions include the following: central nervous system (euphoria, dysphoria, weakness, headache, insomnia, agitation, disorientation, visual disturbances); gastrointestinal (dry mouth, anorexia, constipation, biliary tract spasm); cardiovascular (flushing of the face, bradycardia, palpitation, faintness, syncope); genitourinary (urinary retention or hesitancy, antidiuretic effect, reduced libido and/or potency); allergic (pruritus, urticaria, other skin rashes, edema, hemorrhagic urticaria (rarely)); and hematologic (reversible thrombocytopenia (narcotic addiction with chronic hepatitis)). May cause exaggerated elevation of cerebrospinal-fluid pressure (in patients having increased intracranial pressure), apnea (in patients with asthma and other respiratory conditions), severe hypotension, and impairment of mental and/or physical abilities (ambulatory patients). Methadone can produce drug dependence of the morphine type, and therefore has the potential for being abused, causing psychic and physical dependence and tolerance. [AHFS Drug Information 1997; p II-1373] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to methadone. Should be used with caution and in reduced dosage in the elderly or debilitated, and in patients with severe impairment of hepatic/renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture. Contraindicated for obstetrical analgesia, since its long duration of action increases the risk of neonatal respiratory depression. [USP DI 1997; p 2357-8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Methadone hydrochloride is a synthetic diphenylheptane derivative opiate agonist. [AHFS Drug Information 1997; p 1575] CHEMICAL/PHYSICAL DATA Molecular Formula: C21-H27-N-O.Cl-H [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 345.91 [USPD 1998; p. 449] CHEMICAL/PHYSICAL DATA Elemental Comp: C72.92%, H8.16%, Cl10.25%, N4.05%, 04.63% [Merck Index 1996; p. 1015] CHEMICAL/PHYSICAL DATA Solubility: Solubility of hydrochloride (g/100 ml): water (12), alcohol (8), isopropanol (2.4); practically insoluble in ether, glycerol; the free base is precipitated from aqueous solution above pH 6. [Merck Index 1996; p 1016] CHEMICAL/PHYSICAL DATA Stability: Injections incompatible with solutions containing aminophylline, ammonium chloride, amobarbital sodium, chlorothiazide sodium, phenytoin sodium, heparin sodium, methicillin sodium, nitrofurantoin sodium, pentobarbital sodium, phenobarbital sodium, sodium bicarbonate, and thiopental sodium. [AHFS Drug Information 1997; p 1576] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Colorless crystals or white, crystalline powder. [AHFS Drug Information 1997; p 1575] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral solutions (5 mg or 10 mg/5ml), concentrated oral solutions for dilution (10 mg/ml), dispersible tablets (40 mg) and regular tablets (5 mg and 10 mg), and solution for parenteral injection (10 mg/ml). [USP DI 1997; p 1578] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral, intramuscular or subcutaneous injection. [AHFS Drug Information 1997; p 1577] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Dispersible tablets should be stored in well-closed containers at controlled room temperature (15-30 C or 59-86 F); concentrate or a solution should be stored at controlled room temperature (15-30 C) in tight, light-resistant containers. [PDR 1997; p 2356-7] MANUFACTURERS 0000001072: Roxane Laboratories Inc 1809 Wilson Rd / PO Box 16532 Columbus, OH 432288601 Contact: Clinical and Medical Info (800)327-4865 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Information (800)520-1631 MANUFACTURERS 0000001160: Eli Lilly and Co Lilly Corporate Center Indianapolis, IN 46285 Contact: Medical Department (800)545-5979 MANUFACTURERS 0000005351: Mallinckrodt Inc 675 McDonnell Blvd / PO Box 5840 St Louis, MO 63134 Contact: Patient Assistance (800)274-8651 REFERENCES MED/96308538. Gourevitch MN, Wasserman W, Panero MS, Selwyn PA. Successful adherence to observed prophylaxis and treatment of tuberculosis among drug users in a methadone program. J Addict Dis. 1996; 15(1):93-104. MED/97035009. Wimbush J, Amicarelli A, Stein MD. Does HIV test result influence methadone maintenance treatment retention? Subst Abuse. 1996; 8(2):263-9. MED/97068266. Wells EA, Calsyn DA, Clark LL, Saxon AJ, Jackson TR. Retention in methadone maintenance is associated with reductions in different HIV risk behaviors for women and men. Am J Drug Alcohol Abuse. 1996 Nov; 22(4):509-21. MED/95386247. Nurco DN, Primm BJ, Lerner M, Stephenson P, Brown LS, Ajuluchukwu DC. Changes in locus-of-control attitudes about drug misuse in a self-help group in a methadone maintenance clinic. Int J Addict 1995 May;30(6):765-78. MED/95317197. Wall TL, Sorensen JL, Batki SL, Delucchi KL, London JA, Chesney MA. Adherence to zidovudine (AZT) among HIV-infected methadone patients: a pilot study of supervised therapy and dispensing compared to usual care. Drug Alcohol Depend. 1995 Mar;37(3):261-9. MED/95331901. Dansereau DF, Joe GW, Simpson DD. Attentional difficulties and the effectiveness of a visual representation strategy for counseling drug-addicted clients. Int J Addict. 1995 Mar;30(4):371-86. MED/95155246. Levinson I, Galynker II, Rosenthal RN. Methadone withdrawal psychosis. J Clin Psychiatry. 1995 Feb;56(2):73-6. MED/94193310. Moolchan ET, Hoffman JA. Phases of treatment: a practical approach to methadone maintenance treatment. Int J Addict. 1994 Jan;29(2):135-60. MED/95188742. De Leon G, Staines GL, Perlis TE, Sacks S, McKendrick K, Hilton R, Brady R. Therapeutic community methods in methadone maintenance (Passages): an open clinical trial. Drug Alcohol Depend. 1995 Jan;37(1):45-57. MED/95252986. Hasson AL, Grella CE, Rawson R, Anglin MD. Case management within a methadone maintenance program. A research demonstration project for HIV risk reduction. J Case Manag. 1994 Winter;3(4):167-72. ENTRY MONTH 199104 LAST REVISION DATE 20001107 324 UNIQUE IDENTIFIER DRG-0022 NAME OF SUBSTANCE Globulin, Immune [USPD 1998; p. 342] SYNONYMS Gamimune N [USP DI 2000; p. 1763] SYNONYMS Gammagard S/D [USP DI 2000; p. 1764] SYNONYMS Gammar-P I.V. [USP DI 2000; p. 1764] SYNONYMS Iveegam [USP DI 2000; p. 1764] SYNONYMS Polygam S/D [USP DI 2000; p. 1764] SYNONYMS Sandoglobulin [USP DI 2000; p. 1764] SYNONYMS Venoglobulin-I [USP DI 2000; p. 1764] SYNONYMS Venoglobulin-S [USP DI 2000; p. 1764] PROTOCOL ID NUMBERS Complete NICHD 045 PROTOCOL ID NUMBERS Complete NIAID ACTG 051 PROTOCOL ID NUMBERS No longer recruiting FDA 079A PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 185 PHARMACOLOGICAL ACTION MODE OF ACTION: IGIM and IGIV are used to provide passive immunity by increasing an individual's antibody titer and antigen-antibody reaction potential. IgG antibodies, present in IGIM and IGIV, help to prevent or modify certain infectious diseases in susceptible individuals. The mechanism by which IGIV increases platelet counts in the treatment of idiopathic thrombocytopenic purpura has not been fully elucidated. It has been suggested that IGIV may saturate Fc (crystallizable fragment) receptors on cells of the reticuloendothelial system, resulting in a decrease in Fc-mediated phagocytosis of antibody-coated cells. This Fc-receptor blockade may occur in bone marrow, spleen, and other parts of the heticuloendothelial system and may occur through competition for Fc receptors by increased serum concentrations of IgG or by circulating immune complexes. Altered Fc-receptor affinity for IgG or suppression of antiplatelet antibody production may also be involved. Following intramuscular administration of IGIM, serum concentrations of IgG peak within 2 days. IgG present in IGIM is rapidly and evenly distrubted between intravascular and extravascular spaces. The half-life of IgG in individuals with normal serum IgG concentrations is reportedly about 23 days. Following intravenous administration of IGIV, IgG appears in serum immediately; serum concentrations of IgG attained with IGIV appear to be directly related to the dose. IGIV reportedly has a half-life of about 21-29 days following IV administration; however, interindividual variation in the half-life has been reported, especially in patients with immunodeficiencies. [AHFS Drug Information 1997; p 2537] DISEASES STUDIED/TREATED Primary HIV infection - used for maintenance treatment of patients unable to produce sufficient IgG antibodies and patients with thrombocytopenia. Can prevent or modify certain infections in adult and pediatric patients. FDA Approved 12/27/93 in HIV-infected children as prophylactic therapy against certain bacterial infections. [USP DI 1995; p 1506] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 1759] CLASSIFICATION CODE Antipolyneuropathy agent [USP DI 2000; p. 1759] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1759] CLASSIFICATION CODE Immunizing agent, passive [USP DI 2000; p. 1759] CLASSIFICATION CODE Platelet count stimulator [USP DI 2000; p. 1759] OTHER MAJOR USES IGIM is used to provide passive immunity to hepatitis A, hepatitis B, parenterally transmitted non-A, non-B hepatitis, measles, and rubella, and as an alternative to varicella zoster immune globulin in the prophylaxis of varicella infection in susceptible leukemic, lymphomatous, immunosuppressed or other immunoincompetent children exposed to the disease. IGIV is used to promote passive immunity in patients with congenital agammaglobulinemia, common variable hypogammaglobulinemia, X-linked immunodeficiency with hyper-IgM, and combined immunodeficiency including Wiskott-Aldrich syndrome. [AHFS Drug Information 1997; p 2537-40] SUBSTANCE INTERACTIONS Antibodies contained in immune globulin may interfere with the immune response to certain live virus vaccines (e,g., measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live). Administration of vaccines containing measles virus vaccine live should be deferred for at least 3 months following administration of IGIM used for preexposure or postexposure prophylaxis of hepatitis A infection; for at least 5-6 months following administration of IGIM used for measles prophylaxis in immunocompetent individuals; for at least 8 months following administration of IGIV for replacement therapy of immunodeficiencies; for at least 8-10 months following administration of IGIV for the treatment of idiopathic thrombocytopenic purpura; and for at least 11 months following administration of IGIV for Kawasaki syndrome. [AHFS Drug Information 1997; p 2542] ADVERSE EFFECTS Pain, tenderness, and muscle stiffness generally occur at the intramuscular injection site and persist for several hours following administration of IGIM. Local inflammation, urticaria, and angioedema occur occasionally and headache, malaise, fever, arthralgia, and nephrotic syndrome have also been reported. Repeated injections of IGIM, especially in allergic individuals, may result in sensitization which is usually manifested as fever, chills, and sweating. Severe local and systemic reactions, including anaphylactic shock, have been reported in patients hypersensitive to IGIM. Inadvertent IV administration of IGIM may the result in severe hypersensitivity reactions, systemic reactions and anaphylactic shock following administration of IGIM may be result of formation of IgG aggregates and the resultant activation of complement. Mild chest, hip, joint, or back pain; leg cramps; myalgia; nausea; vomiting; chills; irritability; fever; pallor; malaise; fatigue; a feeling of faintness or lightheadedness; headache; anxiety; pruritis; urticaria; flushing; hypertension; chest tightness; dyspnea; wheezing; and cyanosis have been reported following administration of IGIV. Most adverse reactions to IGIV appear to be related to the rate of administration rather than the dose, and may be relieved by decreasing the rate of administration or by temporarily stopping the infusion. [AHFS Drug Information 1997; p 2540-1] CONTRAINDICATIONS IGIM and IGIV are contraindicated in individuals who have had anaphylactic or severe systemic reaction to immune globulin or any ingredients in the formulations (e.g., thimerosal, maltose). IGIM and most IGIV preparations (i.e., Gamimune N 5% and 10%; Gammar-P IV; Iveegam; Sandoglobulin; Venoglobulin-I and Venoglobulin-S) are contraindicated in individuals with selective IgA deficiences, since these individuals may have serum antibodies to IgA (or develop antibodies following administration of IGIM or IGIV) and anaphylaxis could result following administration of IGIM or IGIV or other blood products containing IgA. IGIV occasionally causes a precipitous fall in blood pressure and the clinical manifestations of anaphylaxis in patients with agammagalobulinemia or extreme hypogammaglobulinemia who have not previously received IGIM or IGIV or who have received one of these drugs within the preceding 8 weeks. IGIM should be used with extreme caution in individuals with severe thrombocytopenia or any bleeding disorder, since bleeding may occur following intramuscular administration of the drug. Gamimune N 5% and 10% have a pH0 of 4-4.5 and consideration should be given to the effect of the additional acid load if the drug is used in patients with limited or compromised acid-base compensatory mechanisms. [AHFS Drug Information 1997; p 2541] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Immune globulin is a sterile, nonpyrogenic solution of globulins containing many antibodies normally present in adult human blood. Immune globulin is commerically available for IM administration as immune globulin IM (IGIM) and for IV administration as immune globulin IV (IGIV). IGIM and IGIV are prepared by cold alcohol fractionation of large pools of human plasma and purification steps that are highly effective in removing and/or inactivating HIV. Some preparations for IGIV (e.g., Gammagard S/D, Polygam S/D, Venoglobulin-S) undergo chemical (solvent/detergent) treatment procedures during manufacture to reduce the risk of transmission of viral infection. [AHFS Drug Information 1997; p 2536] SUBSTANCE DELIVERY DATA DOSAGE FORM: IGIM solution for injection (165+ 15 mg of protein per ml); IGIV powders for injection (1, 2.5, 3, 5, 6, 10, 12g of protein); IGIV solution for injection (50, 100mg of protein per ml). [AHFS Drug Information 1997; p 2544-5] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion, and intramuscular injection. [AHFS Drug Information 1997; p 2542] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store IVIG solutions at 2 C to 8 C unless otherwise specified by the manufacturer, protect from freezing; store powders for reconstitution at temperatures not exceeding 25 C unless otherwise specified by the manufacturer. Protect diluent from freezing. [AHFS Drug Information 1997; p 2537] MANUFACTURERS 0000001118: Cutter Biological Inc 800 Dwight Way Berkeley, CA 94710 Contact: Dr Ralph Rousell (510)420-5120 MANUFACTURERS 0000005230: Bayer Corporation 400 Morgan Lane West Haven, CT 065164175 Contact: Unspecified (800)288-8371 MANUFACTURERS 0000005211: Baxter Healthcare Corporation Hyland Immuno Division / 550 North Brand Blvd Glendale, CA 91203 Contact: Unspecified (800)423-2090 MANUFACTURERS 0000005212: Centeon 1020 First Avenue King of Prussia, PA 194061310 Contact: Unspecified (800)504-5434 MANUFACTURERS 0000005228: Immuno Inc 1200 Parkdale Road Rochester, MI 483071744 Contact: Unspecified (800)423-2090 MANUFACTURERS 0000005210: American Red Cross National Headquarters Biomedical Services Arlington, VA 222093100 Contact: Unspecified (800)446-8883 MANUFACTURERS 0000003968: Novartis Pharmaceuticals Corp 59 Route 10 East Hanover, NJ 07936 Contact: Dr John Miligeni (201)503-6687 MANUFACTURERS 0000005207: Alpha Therapeutic Corporation 5555 Valley Boulevard Los Angeles, CA 900323520 Contact: Unspecified (888)669-6682 MANUFACTURERS 0000005207: Alpha Therapeutic Corporation 5555 Valley Boulevard Los Angeles, CA 900323520 Contact: Unspecified (800)421-0008 REFERENCES MED/96215415. Young, NS. Parvovirus infection and its treatment. Clin Exp Immunol. 1996 May; 104 suppl 1:26-30. MED/96126000. Mofenson LM, Korelitz J, Pelton S, Moye J Jr, Nugent R, Bethel J. Sinustis in children infected with human immunodeficiency virus: clinical characteristics, risk factors, and prophylaxis. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. Clin Infect Dis. 1995 Nov;21(5):1175-81. MED/95166796. Vittecoq D, Chevret S, Morand-Joubert L, Heshmati F, Audat F, Bary M, Dusautoir T, Bismuth A, Viard JP, Barre-Sinoussi F, et al. Passive immunotherapy in AIDS: a double-blind randomized study based on transfusions of plasma rich in anti-human immunodeficiency virus 1 antibodies vs. transfusions of seronegative plasma. Proc Natl Acad Sci USA. 1995 Feb 14;92(4):1195-9. MED/95112439. Zuhrie SR, Webster AD, Davies R, Fay AC, Wallington TB. A prospective controlled crossover trial of a new heat-treated intravenous immunoglobulin. Clin Exp Immunol. 1995 Jan;99(1):10-5. MED/95021560. Spector SA, Gelber RD, McGrath N, Wara D, Barzilai A, Abrams E, Bryson YJ, Dankner WM, Livingston RA, Connor EM. A controlled trial of intravenous immune globulin for the prevention of serious bacterial infections in children receiving zidovudine for advanced human immunodeficiency virus infection. Pediatric AIDS Clinical Trials Group [see comments]. N Engl J Med. 1994 Nov 3;331(18):1181-7. MED/95002918. Levy J, Youvan T, Lee ML. Passive hyperimmune plasma therapy in the treatment of acquired immunodeficiency syndrome: results of a 12-month multicenter double-blind controlled trial. The Passive Hyperimmune Therapy Study Group [see comments]. Blood. 1994 Oct 1;84(7):2130-5. MED/94378275. Jahnke L, Applebaum S, Sherman LA, Greenberger PA, Green D. An evaluation of intravenous immunoglobulin in the treatment of human immunodeficiency virus-associated thrombocytopenia. Transfusion. 1994 Sep;34(9):759-64. MED/94359769. Mofenson LM, Moye J Jr, Korelitz J, Bethel J, Hirschhorn R, Nugent R. Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections and reduction of hospitalizations in human immunodeficiency virus-infected children. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. Pediatr Infect Dis J. 1994 Jun;13(6):477-84. MED/94281815. Jablonowski H, Sander O, Willers R, Adams O, Bartmann P, Wahn V. The use of intravenous immunoglobulins in symptomatic HIV infection. Results of a randomized study. Clin Investig. 1994 Feb;72(3):220-4. MED/94243239. Wintergerst U, Niinivaara-Kreuzer K, Notheis G, Auberger K, Bruckmann C, Gandenberger S, Belohradsky BH. High-dose intravenous immunoglobulins in the treatment of adolescent and adult HIV-infected hemophiliacs. Clin Investig. 1994 Jan;72(2):122-6. ENTRY MONTH 199103 LAST REVISION DATE 20000801 325 UNIQUE IDENTIFIER DRG-0021 NAME OF SUBSTANCE Aldesleukin [USPD 2000; p 28] REGISTRY NUMBER 110942-02-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 2-133-Interleukin 2 (human reduced), 125-L-serine- [USPD 2000; p 28] SYNONYMS Proleukin [USP DI 2000; p 49] PROTOCOL ID NUMBERS Complete CC 88 I-170 PROTOCOL ID NUMBERS Complete NIAID ACTG 024 PROTOCOL ID NUMBERS Complete NIAID ACTG 042 PROTOCOL ID NUMBERS Complete NIAID ACTG 067 PROTOCOL ID NUMBERS Complete NIAID ACTG 080 PROTOCOL ID NUMBERS No longer recruiting FDA 085A PROTOCOL ID NUMBERS No longer recruiting FDA 086A PROTOCOL ID NUMBERS No longer recruiting CC 91 CC-143 PROTOCOL ID NUMBERS No longer recruiting CC 93 CC-113 PROTOCOL ID NUMBERS No longer recruiting CC 93 I-205 PROTOCOL ID NUMBERS No longer recruiting CC 94 I-202 PROTOCOL ID NUMBERS No longer recruiting CC 94 I-76 PROTOCOL ID NUMBERS No longer recruiting CC 95 C-183 PROTOCOL ID NUMBERS No longer recruiting CC 95 CC-114 PROTOCOL ID NUMBERS No longer recruiting CC 95 I-0133 PROTOCOL ID NUMBERS No longer recruiting CC 96 I-46 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 248 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 328 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5051 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 059 PROTOCOL ID NUMBERS No longer recruiting NIAID IL-2 SC PROTOCOL ID NUMBERS No longer recruiting NIAID IL-2 UK PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PROTOCOL ID NUMBERS No longer recruiting NIAID SQ 1 ARG PROTOCOL ID NUMBERS No longer recruiting NIAID SQIL-2 PROTOCOL ID NUMBERS No longer recruiting NIAID THAILAND PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG A5088 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 006 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 299 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 402 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5024 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5102 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-01-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-06-001 PROTOCOL ID NUMBERS Recruiting FDA B007 PROTOCOL ID NUMBERS Recruiting FDA B012 PROTOCOL ID NUMBERS Recruiting NIAID ESPRIT 001 PHARMACOLOGICAL ACTION Aldesleukin is a lymphokine produced by recombinant DNA technology using a genetically engineered E. coli strain that contains an analogue of the human interleukin-2 (IL-2) gene. It has been shown to possess the biological activities of human native interleukin-2. In vitro studies performed on human cell lines have revealed multiple immunological effects including enhanced lymphocyte mitogenesis and stimulation of long-term growth of human IL-2 dependent cell lines; enhancement of lymphocyte cytotoxicity; induction of killer cells; and production of cytokines, such as tumor necrosis factor, IL-1, and gamma interferon. High plasma concentrations of aldesleukin are seen immediately following a short intravenous (IV) infusion, with observed serum concentrations proportional to the dose. There is rapid and extensive distribution into the extravascular space and only approximately 30% of the administered dose is detectable in plasma at the end of the infusion. Greater than 80% of the drug presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. Aldesleukin is cleared from the circulation by both glomerular filtration and peritubular extraction in the kidney, a process that may account for the preservation of clearance in patients with rising serum creatinine values. Little or no bioactive protein is excreted in the urine. Following a 5-minute IV infusion of aldesleukin, cancer patients demonstrated a distribution and elimination half-life of 13 and 85 minutes, respectively. In cancer patients, the mean clearance rate was 268 ml/min. The relatively rapid clearance of aldesleukin necessitates dosage schedules characterized by frequent and short infusions. [PDR 2000; p 938; USP DI 2000; p 45] DISEASES STUDIED/TREATED The use of aldesleukin in the treatment of HIV/AIDS patients is not approved by the FDA. However, aldesleukin has been shown to increase the CD4+ T cell count in HIV-infected individuals, without an associated increase in viral load. Patient response appears to be linked to the severity of HIV-induced immunosuppression. Studies show aldesleukin, in combination with antiretroviral medications, significantly increases CD4+ cell counts in patients with pretreatment counts less than 200 cells per cubic millimeter. Studies are needed to determine whether aldesleukin, alone or in combination with current anti-HIV therapy, can improve the immune system and delay the progression of HIV disease. [Am J Health Syst Pharm (AHSP) 1998 Jul 15;55(14):1520-3] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 44] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 44] OTHER MAJOR USES Aldesleukin is used for treatment of metastatic renal cell carcinoma and melanoma. [AHFS Drug Information 2000; p 820] SUBSTANCE INTERACTIONS There are no significant effects of food on aldesleukin absorption and bioavailability. Because aldesleukin may affect central nervous function, interactions are possible with concomitant administration of psychotropic drugs. Concurrent use of drugs causing nephrotoxic, hepatotoxic, cardiotoxic, or myelotoxic effects may increase toxicity in these organ systems. In addition, reduced kidney and liver function secondary to aldesleukin therapy may alter the pharmacokinetics of other drugs. Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis, appears to be increased in patients receiving aldesleukin and interferon-alfa concurrently. This combination of agents can also cause or exacerbate autoimmune and inflammatory disorders such as crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. Beta-blockers and other antihypertensive drugs may potentiate the hypotension associated with aldesleukin. Finally, individuals treated with aldesleukin may have an increased chance of acute, atypical adverse reactions to iodinated radiographic contrast media. A review of the literature reveals that such reactions occurred in approximately 13% (range 11-28%) of interleukin-2 recipients and occurred up to 4 weeks or longer after IL-2 treatment. Symptoms manifested within 1 to 4 hours following the administration of contrast media and included fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. These reactions resemble the immediate side effects caused by interleukin-2 administration. The reason for these contrast reactions after interleukin-2 therapy is unknown. [PDR 2000; p 939-40] ADVERSE EFFECTS Adverse events associated with aldesleukin therapy are common and sometimes serious. The frequency and severity of these reactions appear to be dependent on dose, method of administration, and dosing schedule. Aldesleukin dosages used in HIV clinical trials are generally lower than those currently used for approved indications. (See specific trial information.) Aldesleukin administration in patients infected with HIV has been associated with capillary leak syndrome (CLS). In one study, 57% of patients experienced CLS characterized by reduced vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion, which may be severe and can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, and mental status changes. Aldesleukin treatment is associated with impaired neutrophil function (reduced chemotaxis) and with an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Consequently, pre-existing bacterial infections should be adequately treated prior to initiation of therapy. Patients with indwelling central lines are particularly at risk for infection with gram positive microorganisms. The most frequently reported toxicities associated with administration of aldesleukin to patients with HIV include anorexia, asthenia, chills, fever, diarrhea, nausea, and vomiting. Most events are self-limiting and reverse within 2 to 3 days of stopping therapy. Although subcutaneous administration and lower-dose continuous intravenous infusion seem to be better tolerated than earlier regimens, careful monitoring is required. [AHFS Drug Information 2000; p 822; PDR 2000; p 939-40; Am J Health Syst Pharm (AHSP) 1998 Jul 15;55(14):1520-3; PDR 2000; p 939-40; Am J Health Syst Pharm (AHSP) 1998 Jul 15;55(14):1520-3] CONTRAINDICATIONS Aldesleukin is contraindicated in patients with a history of hypersensitivity to interleukin-2 or any component of the formulation. It also is contraindicated in patients with abnormal thallium stress or pulmonary function test results and in patients with organ allografts. Retreatment is contraindicated in patients who experienced the following adverse effects on prior use of the drug: sustained ventricular tachycardia (5 or more beats); cardiac arrhythmias not controlled or unresponsive to management; chest pain with ECG changes consistent with angina or myocardial infarction; cardiac tamponade; intubation for longer than 72 hours; renal failure requiring dialysis longer than 72 hours; coma or toxic psychosis lasting longer than 48 hours; repetitive or difficult-to-control seizures; bowel ischemia/perforation; or gastrointestinal bleeding requiring surgery. [PDR 2000; p 938] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Aldesleukin is a lymphokine produced by a recombinant DNA process and is structurally related to naturally occurring interleukins. Lymphokines, also known as cytokines, are hormone-like glycoproteins that are released by T cells upon activation by a foreign body. [USP DI 2000; p 44-5] CHEMICAL/PHYSICAL DATA Molecular Formula: C690-H1115-N177-O203-S6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 15,600 [USPD 2000; p 28] CHEMICAL/PHYSICAL DATA Stability: Reconstituted solutions should be used within 48 hours. [PDR 2000; p 940-1] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white lyophilized cake [PDR 2000; p 938] SUBSTANCE DELIVERY DATA DOSAGE FORM: Aldesleukin is available commercially as a vial for injection. Each vial contains 22 million IU (1.3 mg) aldesleukin powder, to be reconstituted aseptically with 1.2 ml of Sterile Water for Injection, USP, resulting in a final concentration of 18 million IU (1.1 mg) per ml. [USP DI 2000; p 49-50] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Aldesleukin can be administered by intravenous infusion or subcutaneous injection. [USP DI 2000; p 49-50] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Powder, reconstituted vials, and diluted solutions should be stored at between 2 and 8 C (36 and 46 F). Freezing should be avoided. [PDR 2000; p 940-1] MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 Contact: Professional Services (800)244-7668 MANUFACTURERS 0000001116: Chiron Corp 4560 Horton Street Emeryville, CA 946082916 REFERENCES GWAIDS/0003949. Alcami J, Pedraza MA, Martin-Serrano J, Rullas J. Interleukin-2 is a poor inducer of HIV reactivation in peripheral blood T-lymphocytes. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. ThPpB1492. Fisher M, Nelson M, Dykhoff A, Doggett TA, Richardson C, Janossy G, Loveday C, Sullivan A, Johnson M, Tavel J, Fosdick L, Emery S, Youle M. Randomised study of intermittent subcutaneous interleukin-2 (IL-2) therapy without anti-retrovirals versus no treatment. Int Conf AIDS. 2000 Jul 9-14;13:abstract no. LbOr28. MED/20148094. Shah MH, Baiocchi RA, Fehniger TA, Khatri VP, Gould M, Poiesz B, Bernstein ZP, Caligiuri MA. Cytokine replacement in patients with HIV-1 non-Hodgkin's lymphoma: the rationale for low-dose interleukin-2 therapy. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S45-51. Review. MED/20124632. Aldesleukin. Interleukin-2 (IL-2), IL-2 (Chiron), Macrolin, Proleukin, recombinant IL-2 (Chiron), T cell growth factor. Drugs R D. 1999 Oct;2(4):267-70. MED/20112500. Piscitelli SC, Bhat N, Pau A. A risk-benefit assessment of interleukin-2 as an adjunct to antiviral therapy in HIV infection. Drug Saf. 2000 Jan;22(1):19-31. Review. MED/99285301. Sundin DJ, Wolin MJ. Aldesleukin shows promise. Aids Patient Care STDS. 1999 May;13(5):307. MED/99094097. Sundin DJ, Wolin MJ. Toxicity management in patients receiving low-dose aldesleukin therapy. Ann Pharmacother. 1998 Dec;32(12):1344-52. Review. MED/99049787. Piscitelli SC, Forrest A, Vogel S, Chaitt D, Metcalf J, Stevens R, Baseler M, Davey RT, Kovacs JA. Pharmacokinetic modeling of recombinant interleukin-2 in patients with human immunodeficiency virus infection. Clin Pharmacol Ther. 1998 Nov;64(5):492-8. MED/98079363. Ghezzi S, Vicenzi E, Soldini L, Tambussi G, Murone M, Lazzarin A, Poli G. Experiences in immune reconstitution. The rationale for interleukin-2 administration to HIV-infected individuals. J Biol Regul Homeost Agents. 1997 Jan-Jun;11(1-2):74-8. Review. MED/97305363. Gabriel CM, Minor JR, Vogel S, Piscitelli SC. Supportive care during aldesleukin therapy for patients infected with human immunodeficiency virus. Am J Health Syst Pharm. 1997 May 15;54(10):1191-3. MED/97240670. Davey RT Jr, Chaitt DG, Piscitelli SC, Wells M, Kovacs JA, Walker RE, Falloon J, Polis MA, Metcalf JA, Masur H, Fyfe G, Lane HC. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis. 1997 Apr;175(4):781-9. MED/97042873. Piscitelli SC, Wells MJ, Metcalf JA, Baseler M, Stevens R, Davey RT Jr. Pharmacokinetics and pharmacodynamics of subcutaneous interleukin-2 in HIV-infected patients. Pharmacotherapy. 1996 Sep-Oct;16(5):754-9. MED/97011039. Kovacs JA, Vogel S, Albert JM, Falloon J, Davey RT Jr, Walker RE, Polis MA, Spooner K, Metcalf JA, Baseler M, Fyfe G, Lane HC. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med. 1996 Oct 31;335(18):1350-6. MED/95384875. Minor JR. Interleukin-2 in HIV infection. Am J Health Syst Pharm. 1995 Jun 15;52(12):1345-6. ENTRY MONTH 199103 LAST REVISION DATE 20001120 326 UNIQUE IDENTIFIER DRG-0020 NAME OF SUBSTANCE Interferon gamma-1b [USPD 2000 p. 374] REGISTRY NUMBER 98059-61-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1-139-Interferon gamma (human lymphocyte protein moiety reduced), N(sup 2)-L-methionyl- [USPD 1998; p. 381] SYNONYMS Actimmune [USP DI 2000; p. 1809, 3308] PROTOCOL ID NUMBERS Complete FDA 062A PROTOCOL ID NUMBERS Complete NHLBI 88 H-78A PROTOCOL ID NUMBERS Complete NIAID ACTG 025 PROTOCOL ID NUMBERS Complete NIAID ACTG 072 PROTOCOL ID NUMBERS Complete NIAID ACTG 211 PROTOCOL ID NUMBERS No longer recruiting FDA B013 PHARMACOLOGICAL ACTION MODE OF ACTION: Interferons are a family of functionally related, species-specific proteins, synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. Interferon gamma has potent phagocyte-activating effects not seen with the other interferons. In patients, drug has broad range of biological activities including enhancement of oxidative metabolism of tissue macrophages, enhancement of antibody-dependent cellular cytotoxicity and natural killer cell activity. Interferon gamma interacts functionally with other interleukin molecules such as interleukin-2. Interferon gamma treatment of patients with chronic granulomatous disease showed enhancement of phagocyte function. The drug is slowly absorbed after IM or subcutaneous injection; the fraction of dose absorbed was greater than 89%. The mean elimination half-life in health male subjects after IV administration of 100 mcg/square meter was 38 minutes. After IM and subcutaneous injections of the same dose, elimination half-lives were 2.9 and 5.9 hours respectively. The drug was not detected in the urine of volunteers following administration by any of those routes. Treatment with the drug is indicated for reducing the frequency and severity of serious infections associated with chronic granulomatous disease. [PDR 1997; p 1044] DISEASES STUDIED/TREATED Under investigation for treatment of Mycobacterium tuberculosis infection in HIV-positive people. [AmfAR Treat Dir 1996;8(2); p 78] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p. 1807] CLASSIFICATION CODE Immunomodulator [USP DI 2000; p. 1807] OTHER MAJOR USES FDA approved for treatment of chronic granulomatous disease. Used to reduce the frequency and severity of infections associated with chronic granulomatous disease. [PDR 1997; p 1044; AmfAR Treat Dir 1996;8(2); p 78] SUBSTANCE INTERACTIONS Interactions with other drugs have not been fully evaluated. Caution should be used in concomitant administration with other myelosuppressive agents. [PDR 1997; p 1044] ADVERSE EFFECTS The most common adverse experiences occurring with interferon gamma therapy are flu-like symptoms which may be ameliorated with acetaminophen. May cause fever, headache, rash, chills, injection site erythema, fatigue, diarrhea, nausea, or vomiting. Rarely seen effects when used in higher dosages in cases other than chronic granulomatous disease were cardiovascular effects, CNS effects, gastrointestinal effects and hematologic effects. No significant differences between treated and placebo-receiving patients were observed in laboratory studies of hematologic, coagulation, hepatic and renal functions. [PDR 1997; p 1044-5] CONTRAINDICATIONS Should be used during pregnancy only if potential benefits justify the potential risk to the fetus. In nursing mothers, a decision should be made whether to discontinue nursing or the drug, depending on importance of the drug to the mother. Safety and effectiveness in children under the age of 1 year has not been established. [PDR 1997; p 1044] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Production of ACTIMMUNE (Genentech Inc. tradename for interferon gamma-1b) is through fermentation of genetically engineered Escherichia coli with DNA that encodes for human protein. Interferon gamma is structurally unrelated to interferons alfa and beta. [PDR 1997; p 1043-4] CHEMICAL/PHYSICAL DATA Molecular Formula: C734-H1166-N204-O216-S5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 16,464.69 [USPD 2000 p. 374] CHEMICAL/PHYSICAL DATA Stability: Acid-labile. [Merck Index 1989; p 791] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Powder. [Protocol ID: ACTG 025 p 24] SUBSTANCE DELIVERY DATA DOSAGE FORM: Actimmune (Genentech, Inc. preparation of interferon gamma-1b) is a sterile, clear solution in a single vial for subcutaneous injection. Each 0.5 m1 contains 100mcg (3 million U) of interferon gamma-1b with 20mg mannitol, 0.36mg sodium succinate, and 0.05 mg polysorbate 20 in sterile water. [PDR 1997; p 1045] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection. [PDR 1997; p 1045] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Vials must be placed in a 2-8 C (36-46 F) refrigerator immediately upon receipt. Freezing and/or vigorous agitation must be avoided. Vials should not be left at room temperature longer than 12 hours before usage. [PDR 1997; p 1045] MANUFACTURERS 0000002666: Genentech Inc 1 DNA Way South San Francisco, CA 940804990 Contact: Dr Don Francis (415)255-5806 MANUFACTURERS 0000005417: InterMune Pharmaceuticals Inc 1710 Gilbreth Rd, Suite 301 Burlingame, CA 94010 Contact: Unspecified (800)821-8590 REFERENCES MED/97047896. Dallalio G, North M, Means RT Jr. Inhibition of marrow CFU-E colony formation from human immunodeficiency virus-infected patients by beta- and gamma-interferon. Am J Hematol. 1996 Oct; 53(2): 118-20. MED/95229221. Kaplan G. Cytokine regulation of disease progression in leprosy and tuberculosis. Immunobiology. 1994 Oct; 191(4-5): 564-8. MED/96273137. Lumsden AJ, Codde JP, Van der Meide PH, Gray BN. Immunohistochemical charaterisation of immunological changes at the tumour site after chemo-immunotherapy with doxorubicin, interleukin-2 interferon-gamma. Anticancer Res. 1996 May-Jun; 16(3A): 1145-54. MED/96194532. Yoshimoto K, Swain SL, Bradley LM. Enhanced development of Th2-like primary CD4 effectors in response to sustained exposure to limited rIL-4 in vivo. J Immunol. 1996 May 1; 156(9): 3267-74. MED/96298921. Han X, Becker K, Degen HJ, Jablonowski H, Strohmeyer G. Synergistic stimulatory effects of tumour necorsis factor alpha and interferon gamma on replication of human immunodeficiency virus type 1 and on apoptosis of HIV-1-infected host cells. Eur J Clin Invest. 1996 Apr; 26(4):286-92. MED/96288442. Flamminio G, Caruso A, Poiesi C, Bonfanti C, Terlenghi L Donato Canaris A, Varinacci C, Martinelli F, Garotta G, Albertini A, et al. Aspects of molecular interaction between HIV p17 and human gamma interferon. AIDS Res Hum Retroviruses. 1995 Dec; 11(12):1441-7. MED/95105718. Murray HW, Hariprashad J. Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis. J Exp Med. 1995 Jan 1; 181(1):387-91. MED/95045942. Saat-Sowti B, Debre P, Mollet L, Quint L, Hadida F, Leblond V, Bismuth G, Atran B. An inhibitor of cytotoxic functions produced by CD8+CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipeints. Eur J Immunol. 1994 Nov;24(11): 2882-8. MED/94252455. Semprini AE, Stillo A, Macozzi S, Castagna C, Fiore S, Radaelli U. Treatment with interferon for genital HPV in HIV-positive and HIV-negative women. Eur J Obstet Gynecol Record Biol. 1994 Feb; 53(2): 135-7. MED/95068041. Murray HW. Interferon-gamma and host antimicrobial defense: current and future clinical applications. Am J Med. 1994 Nov;97(5):459-67. ENTRY MONTH 199103 LAST REVISION DATE 20000801 327 UNIQUE IDENTIFIER DRG-0019 NAME OF SUBSTANCE Interferon alfa-n1 [USPD 2000; p 373] STANDARD CHEMICAL NAME Interferons, alfa- [USPD 1998; p 381] SYNONYMS Wellferon [USP DI 2000; p 1815] SYNONYMS Veldona [Protocol ID: DATRI 022 ] SYNONYMS Ferimmune [Protocol ID: DATRI 022 ] PROTOCOL ID NUMBERS Complete NIAID ACTG 013 PROTOCOL ID NUMBERS Complete NIAID ACTG 014 PROTOCOL ID NUMBERS Complete NIAID IRP 011 PROTOCOL ID NUMBERS No longer recruiting FDA 052C PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 022 PHARMACOLOGICAL ACTION The precise mechanism of action of interferon alfa-n1 is unknown. Generally, natural alfa interferons appear to produce their effects via a complex sequence of intracellular events that result in enzyme induction, inhibition of virus replication, suppression of cell proliferation, and modulation of the host immune response. Following intramuscular or subcutaneous injection, bioavailability of interferon alfa-n1 ranges from 40 to 100%. The time to reach peak concentration is 6 to 9 hours, and the elimination half-life is 7 to 10 hours. Accumulation is unlikely with multiple (three times weekly) doses. Alfa interferons are metabolized principally by the kidney. Filtration through the glomeruli is extensive and rapid proteolytic degradation occurs during renal tubular reabsorption. Metabolites are almost completely reabsorbed and only negligible amounts of unchanged alfa interferon reappear in the systemic circulation. [Glaxo Wellcome Inc Wellferon product information.; Glaxo Wellcome Inc Wellferon product information.; USP DI 2000; p 1811] DISEASES STUDIED/TREATED Parenteral interferon alfa-n1 is approved by the FDA for the treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease. The oral form of interferon alfa-n1 is approved by the FDA for the treatment of papillomavirus warts in the oral cavity of HIV-positive patients. Parenteral interferon alfa-n1 also is indicated for treatment of AIDS-related Kaposi's sarcoma in selected patients 18 years of age or older. It is used as initial therapy in patients whose disease is otherwise asymptomatic and who do not have severe immune dysfunction. Response rates are decreased in patients with prior opportunistic infections, constitutional (B) symptoms, and reduced helper/inducer T-cell counts. In addition, interferon alfa-n1 is included in a number of HIV clinical trials due to its antiproliferative and antiviral effects. [U.S. FDA. CBER. Product Approval Information. Available at: http://www.fda.gov/cber/efoi/approve.htm. Accessed 10/10/00.; U.S. FDA. List of Orphan Designations and Approvals. Available at: http://www.fda.gov/orphan/designat/list.htm. Accessed 10/10/00.; USP DI 2000; p 1810; AHFS Drug Information 2000; p 961-2; Protocol ID: DATRI 022 ] CLASSIFICATION CODE Antineoplastic [USP DI 2000; p 1810] CLASSIFICATION CODE Biological response modifier [USP DI 2000; p 1810] OTHER MAJOR USES Parenteral interferon alfa-n1 is approved by the FDA for the treatment of chronic hepatitis C, diagnosed by HCV antibody and/or a history of exposure to hepatitis C, in patients 18 years of age or older with compensated liver disease. Other uses include the treatment of laryngeal papillomatosis, condylomata acuminata, hairy cell leukemia, chronic myelocytic leukemia, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, and various carcinomas. [USP DI 2000; p 1810; U.S. FDA. List of Orphan Designations and Approvals. Available at: http://www.fda.gov/orphan/designat/list.htm. Accessed 10/10/00.; Amarillo Biosciences. Current News. Available at: http://www.amarbio.com/10news41.htm. Accessed 10/10/00.; ] SUBSTANCE INTERACTIONS There are no reported food interactions with interferon alfa-n1. Alfa interferons may inhibit the activity of hepatic cytochrome P450 isoenzymes. Data on the effects of interferon alfa-n1 is inconclusive. Caution should be used in the concomitant administration of similarly metabolized drugs, such as theophylline. Caution should also be used when combining interferon alfa-n1 and myelosuppressive agents. [Glaxo Wellcome Inc Wellferon product information.] ADVERSE EFFECTS The most common adverse effect associated with interferon alfa-n1 administration is a flu-like syndrome (fatigue, headache, fever, myalgia/arthralgia, and chills). Gastrointestinal side effects, such as nausea, diarrhea, abdominal pain, and anorexia, are common. The incidence of reported depression and suicidal behavior is 15% or higher. Other CNS reactions to interferon alfa-n1 include anxiety, sleep disturbance, dizziness, impaired thought, and paresthesia. Side effects such as dyspnea, coughing, pharyngitis, and sinusitus are frequently reported. Hair loss and skin rash also occur. Thrombocytopenia, leukopenia, and anemia have been reported occasionally. Increases in hepatic enzymes can occur following administration of interferon alfa-n1; hepatotoxicity is modest in most cases but can be severe in patients with decompensated liver disease. [Glaxo Wellcome Inc Wellferon product information.] CONTRAINDICATIONS Interferon alfa-n1 is contraindicated in patients allergic to alfa interferon or any component of the product. It is also contraindicated in patients with a history of anaphylaxis to bovine or ovine immunoglobulins, egg protein, polymyxin B, or neomycin sulfate. [Glaxo Wellcome Inc Wellferon product information.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Interferon alfa-n1 is a highly purified blend of natural human alfa interferons obtained from human lymphoblastoid cells following induction with Sendai virus. [USP DI 2000; p 1810] CHEMICAL/PHYSICAL DATA Molecular Weight: approximately 20,000 [Glaxo Wellcome Inc Product Information - Wellferon] SUBSTANCE DELIVERY DATA DOSAGE FORM: Parenteral: sterile injectable solution containing 3 million units per vial [Glaxo Wellcome Inc Wellferon product information.; Amarillo Biosciences. Current News. Available at: http://www.amarbio.com/10news41.html. Accessed 10/10/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous or intramuscular injection [Glaxo Wellcome Inc Wellferon product information.; Amarillo Biosciences. Current News. Available at: http://www.amarbio.com/10news41.html. Accessed 10/10/00.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The injectable solution should be stored at 2 to 8 C (36 to 46 F) and protected from light. Do not freeze or shake vial. [Glaxo Wellcome Inc Wellferon product information.; Amarillo Biosciences. Current News. Available at: http://www.amarbio.com/10news41.html. Accessed 10/10/00.] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000005241: Procept Inc 840 Memorial Drive Cambridge, MA 02139 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 MANUFACTURERS 0000003534: Amarillo Biosciences Inc 800 West Ninth Avenue Amarillo, TX 791013206 Contact: Medical & Consumer Relations (919)483-9959 MANUFACTURERS 0000003534: Amarillo Biosciences Inc 800 West Ninth Avenue Amarillo, TX 791013206 Contact: Medical and Consumer Relations (800)437-0992 MANUFACTURERS 0000005241: Procept Inc 840 Memorial Drive Cambridge, MA 02139 Contact: Unspecified (617)491-1100 REFERENCES MED/20097662. Alston B, Ellenberg JH, Standiford HC, Muth K, Martinez A, Greaves W, Kumi J. A multicenter, randomized, controlled trial of three preparations of low-dose oral alpha-interferon in HIV-infected patients with CD4+ counts between 50 and 350 cells/mm(3). Division of AIDS Treatment Research Initiative (DATRI) 022 Study Group. J Acquir Immune Defic Syndr. 1999 Dec 1;22(4):348-57. MED/99334358. Begemann F, Jablonowski H. Enhancing the response to interferon-alpha. J Clin Virol. 1999 Jun;13(1-2):1-7. MED/99123541. Katabira ET, Sewankambo NK, Mugerwa RD, Belsey EM, Mubiru FX, Othieno C, Kataaha P, Karam M, Youle M, Perriens JH, Lange JM. Lack of efficacy of low dose oral interferon alfa in symptomatic HIV-1 infection: a randomised, double blind, placebo controlled trial. Sex Transm Infect. 1998 Aug;74(4):265-70. MED/98227672. Krown SE. Interferon-alpha: evolving therapy for AIDS-associated Kaposi's sarcoma. J Interferon Cytokine Res. 1998 Apr;18(4):209-14. Review. MED/98196800. Farrell GC, Bacon BR, Goldin RD. Lymphoblastoid interferon alfa-n1 improves the long-term response to a 6-month course of treatment in chronic hepatitis C compared with recombinant interferon alfa-2b: results of an international randomized controlled trial. Clinical Advisory Group for the Hepatitis C Comparative Study. Hepatology. 1998 Apr;27(4):1121-7. MED/97148801. Marcellin P, Boyer N, Behamou JP, Erlinger S. Interferon-alpha therapy for chronic hepatitis C in special patient populations. Dig Dis Sci. 1996 Dec;41(12 Suppl):126S-130S. MED/95070047. Bocci V. Pharmacology and side-effects of interferons. Antiviral Res. 1994 Jul;24(2-3):111-9. Review. MED/93020177. Hulton MR, Levin DL, Freedman LS. Randomized, placebo-controlled, double-blind study of low-dose oral interferon-alpha in HIV-1 antibody positive patients. J Acquir Immune Defic Syndr. 1992;5(11):1084-90. MED/93000655. Kaiser G, Jaeger H, Birkmann J, Poppinger J, Cummins JM, Gallmeier WM. Low-dose oral natural human interferon-alpha in 29 patients with HIV-1 infection: a double-blind, randomized, placebo-controlled trial. AIDS. 1992 Jun;6(6):563-9. MED/92275814. Weber R, Bonetti A, Jost J, Vogt MW, Spacey B, Siegenthaler W, Luthy R. Low-dose zidovudine in combination with either acyclovir or lymphoblastoid interferon-alpha in asymptomatic HIV-infected patients: a pilot study. Infection. 1991 Nov-Dec;19(6):395-400. MED/92054666. Lane HC. The role of alpha-interferon in patients with human immunodeficiency virus infection. Semin Oncol. 1991 Oct;18(5 Suppl 7):46-52. Review. MED/91098825. Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet. 1990 Nov;19(5):390-9. Review. MED/91073284. Fischl MA, Uttamchandani RB, Resnick L, Agarwal R, Fletcher MA, Patrone-Reese J, Dearmas L, Chidekel J, McCann M, Myers M. A phase I study of recombinant human interferon-alpha 2a or human lymphoblastoid interferon-alpha n1 and concomitant zidovudine in patients with AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr. 1991;4(1):1-10. MED/90140742. Krown SE. Approaches to interferon combination therapy in the treatment of AIDS. Semin Oncol. 1990 Feb;17(1 Suppl 1):11-5; discussion 38-41. Review. MED/85235824. Frederick WR, Epstein JS, Gelmann EP, Rook AH, Armstrong GR, Djeu JY, Jackson L, Manischewitz JF, Enterline J, Jacob J, et al. Viral infections and cell-mediated immunity in immunodeficient homosexual men with Kaposi's sarcoma treated with human lymphoblastoid interferon. J Infect Dis. 1985 Jul;152(1):162-70. MED/85196200. Gelmann EP, Preble OT, Steis R, Lane HC, Rook AH, Wesley M, Jacob J, Fauci A, Masur H, Longo D. Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome. Clinical response and prognostic parameters. Am J Med. 1985 May;78(5):737-41. MED/85159776. Rios A, Mansell PW, Newell GR, Reuben JM, Hersh EM, Gutterman JU. Treatment of acquired immunodeficiency syndrome--related Kaposi's sarcoma with lymphoblastoid interferon. J Clin Oncol. 1985 Apr;3(4):506-12. ENTRY MONTH 199103 LAST REVISION DATE 20001010 328 UNIQUE IDENTIFIER DRG-0018 NAME OF SUBSTANCE Ganciclovir [USPD 2000; p 331] REGISTRY NUMBER 82410-32-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed November 7,2000.] STANDARD CHEMICAL NAME 6H-Purin-6-one, 2-amino-1,9-dihydro-9-((2-hydroxy-1-(hydroxym- ethyl)ethoxy)methyl)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Cytovene [USP DI 2000; p 1621] SYNONYMS Cytovene-IV (sodium salt) [USP DI 2000; p 1622] SYNONYMS Vitrasert [USP DI 2000; p 1618] PROTOCOL ID NUMBERS Complete NEI 92 EI-169 PROTOCOL ID NUMBERS Complete NIAID ACTG 004 PROTOCOL ID NUMBERS Complete NIAID ACTG 071 PROTOCOL ID NUMBERS Complete NIAID ACTG 073 PROTOCOL ID NUMBERS Complete NIAID ACTG 085 PROTOCOL ID NUMBERS Complete NIAID ACTG 127 PROTOCOL ID NUMBERS Complete NIAID ACTG 129 PROTOCOL ID NUMBERS Complete NIAID ACTG 151 PROTOCOL ID NUMBERS Complete NIAID ACTG 183 PROTOCOL ID NUMBERS Complete NIAID ACTG 228 PROTOCOL ID NUMBERS Complete NIAID ACTG 266 PROTOCOL ID NUMBERS Complete NIAID ACTG 278 PROTOCOL ID NUMBERS Complete NIAID ACTG 350 PROTOCOL ID NUMBERS No longer recruiting FDA 005A PROTOCOL ID NUMBERS No longer recruiting FDA 017A PROTOCOL ID NUMBERS No longer recruiting FDA 029B PROTOCOL ID NUMBERS No longer recruiting FDA 029C PROTOCOL ID NUMBERS No longer recruiting FDA 029D PROTOCOL ID NUMBERS No longer recruiting FDA 029F PROTOCOL ID NUMBERS No longer recruiting FDA 029G PROTOCOL ID NUMBERS No longer recruiting FDA 037B PROTOCOL ID NUMBERS No longer recruiting FDA 037C PROTOCOL ID NUMBERS No longer recruiting FDA 059A PROTOCOL ID NUMBERS No longer recruiting FDA 059B PROTOCOL ID NUMBERS No longer recruiting FDA 059C PROTOCOL ID NUMBERS No longer recruiting FDA 059D PROTOCOL ID NUMBERS No longer recruiting FDA 059E PROTOCOL ID NUMBERS No longer recruiting FDA 059F PROTOCOL ID NUMBERS No longer recruiting FDA 079A PROTOCOL ID NUMBERS No longer recruiting FDA 251B PROTOCOL ID NUMBERS No longer recruiting FDA 268A PROTOCOL ID NUMBERS No longer recruiting CC 96 I-66 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 226 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 305 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 023 PROTOCOL ID NUMBERS No longer recruiting NIAID TX 303 PROTOCOL ID NUMBERS Terminated CC 90 CC-118 PHARMACOLOGICAL ACTION The exact mechanism of antiviral activity of ganciclovir is unknown. Ganciclovir is rapidly phosphorylated to the monophosphate form in CMV-infected cells by a CMV-encoded enzyme, then converted to the diphosphate and triphosphate forms by cellular kinases. Ganciclovir is phosphorylated more rapidly in infected cells; however, uninfected cells can also produce low levels of ganciclovir triphosphate. Once formed, ganciclovir triphosphate persists for days in the CMV-infected cell. Ganciclovir triphosphate is thought to inhibit viral DNA synthesis by competitive inhibition of viral DNA polymerases and incorporation into viral DNA, resulting in eventual termination of viral DNA elongation. Ganciclovir appears to be principally virustatic rather than virucidal in action. Ganciclovir is not effective against cytomegalovirus latent infection, often established within leukocytes or solid organ tissue, as the virus is not actively replicating. Resistance to ganciclovir has been observed in patients with AIDS and CMV retinitis who have never received ganciclovir and in patients receiving prolonged treatment with ganciclovir. Ganciclovir is poorly absorbed after oral administration. Under fasting conditions, bioavailability is about 5% and, when administered with food, 6 to 9%. Ganciclovir is widely distributed to all tissues, collecting substantially in the kidneys, lungs, and liver. The concentration of ganciclovir in cerebrospinal fluid averages about 40% of corresponding plasma concentrations. Ganciclovir also appears to have good intraocular penetration. Protein binding is very low (1 to 2%). The time to peak concentration for orally administered ganciclovir is 1.8 and 3 hours in fasting and nonfasting states, respectively. Half-life is 2.5 to 3.6 hours when administered intravenously and 3.1 to 5.5 hours when administered orally. There is little or no metabolism. Renal excretion occurs via glomerular filtration and tubular secretion, and most of the drug is recovered unchanged in the urine. Renal function impairment results in increased plasma concentrations and increased half-life. Doses and frequency of administration of the drug should be modified according to creatinine clearance. Hemodialysis reduces plasma concentrations of ganciclovir by about 50%. The intravitreal implant is designed to release ganciclovir over a period of 5 to 8 months. In a clinical trial, the average release rate in vivo was determined to be 1.40 microg/h (range 0.5 to 2.88 microg/h) and the mean vitreous drug level was 4.1 microg/ml. Another clinical trial demonstrated that median time to progression of CMV retinitis after insertion of the implant was 210 days compared to 120 days with standard induction and maintenance doses of intravenous ganciclovir. [USP DI 2000; p 1618; Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.; AHFS Drug Information 2000; p 537-8; USP DI 2000; p 1618; Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.; AHFS Drug Information 2000; p 538-9; PDR Online. PDR for Ophthalmology entry for Vitrasert Implant (Bausch & Lomb Surgical). Available at: http://physician.pdr.net/. Accessed November 17, 2000.] DISEASES STUDIED/TREATED Parenteral ganciclovir is FDA-approved for treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Oral ganciclovir is indicated only for maintenance treatment of CMV retinitis in patients who have stable retinitis after intravenous induction therapy. However, because oral ganciclovir is associated with a risk of a more rapid progression of CMV retinitis, this route should be used only when this risk is balanced by the benefit of avoiding daily intravenous infusions. Oral ganciclovir is indicated for the prophylaxis of CMV disease in patients with advanced HIV infection who are at risk for developing CMV disease. Off-label uses of parenteral ganciclovir include the treatment of severe cytomegalovirus disease, including CMV pneumonia, CMV gastrointestinal disease, CMV radiculopathy, and disseminated CMV infections, in patients with AIDS. Ganciclovir intravitreal implant is FDA-approved for the intraocular treatment of cytomegalovirus retinitis in patients with AIDS. [Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.; USP DI 2000; p 1618; USP DI 2000; p 1618; USP DI 2000; p 1616] CLASSIFICATION CODE Antiviral [USP DI 2000; p 1618] OTHER MAJOR USES Parenteral ganciclovir is FDA-approved for treatment of cytomegalovirus retinitis in immunocompromised patients. Oral ganciclovir is indicated for maintenance treatment of CMV retinitis in immunocompromised patients who have stable retinitis after intravenous induction therapy. Ganciclovir is also indicated for the prevention of CMV disease in transplant patients who are at risk for the disease. The treatment of CMV disease in immunocompromised patients is an off-label use. [USP DI 2000; p 1618] SUBSTANCE INTERACTIONS Ganciclovir capsules should be taken with food to maximize bioavailability. Drugs with potential for clinically significant interactions include bone marrow depressants, nephrotoxic medications, zidovudine, didanosine, probenecid, and imipenem-cilastatin. Concurrent use of bone marrow depressants and ganciclovir may increase bone marrow toxicity. Nephrotoxic medications used with ganciclovir may increase the chance of renal function impairment and, as a result, decrease the clearance of ganciclovir, leading to toxicity. Probenecid competes with ganciclovir for renal tubular secretion and also may decrease the clearance of ganciclovir. Use of zidovudine with ganciclovir has been associated with severe hematologic toxicity in some patients even when the dose of zidovudine was reduced to 300 mg/day. Individuals taking didanosine and ganciclovir concurrently may have increased blood levels of didanosine; however, the clinical importance of this interaction appears to be minimal. Combined therapy with imipenem-cilastatin and ganciclovir has resulted in generalized seizures. Ganciclovir has exhibited additive or synergistic antiviral activity with foscarnet against cytomegalovirus and herpes simplex virus type 2. Combined therapy may be effective in treatment of CMV resistant to either drug alone. There are no reported food or drug interactions with ganciclovir intravitreal implants. [USP DI 2000; p 1619; AHFS Drug Information 2000; p 547; PDR Online. PDR for Ophthalmology entry for Vitrasert Implant (Bausch & Lomb Surgical). Available at: http://physician.pdr.net/. Accessed November 17, 2000.] ADVERSE EFFECTS Adverse reactions to systemic ganciclovir occur frequently and may be alleviated by dosage reduction or reversed by discontinuation of the drug. The most common reactions are hematologic (leukopenia, thrombocytopenia, and anemia), which may be severe. Neutropenia usually occurs during the first 2 weeks of treatment but may occur at any time during treatment. Deaths have occurred secondary to superinfection in patients with ganciclovir-induced neutropenia. Cell counts usually begin to recover within 7 days after discontinuing the drug. Retinal detachment has been reported with ganciclovir use in up to 30% of patients with CMV retinitis. Elevated serum creatinine, hypersensitivity reactions, and phlebitis also have been reported. Common side effects include fever, diarrhea, anorexia, vomiting, and increased sweating. Nervous system effects, ranging from headache to seizures or coma, have been reported, but a causal relationship with ganciclovir is uncertain. Side effects reported with insertion of a ganciclovir intravitreal implant are probably due to the surgical procedure rather than to the medication. A decrease in visual acuity occurs in the implanted eye immediately after surgery in almost all patients. Ten to twenty percent of patients report vitreous hemorrhage, retinal detachment, or loss of 3 or more lines of visual acuity within the first 2 months after surgery. Less frequently (1 to 5%), cataract formation or lens opacities, increased intraocular pressure, macular abnormalities, or optic disk or nerve changes, hyphema, or uveitis are reported. [AHFS Drug Information 2000; p 543; USP DI 2000; p 1620; Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.; USP DI 2000; p 1617] CONTRAINDICATIONS Ganciclovir is contraindicated in patients with hypersensitivity to ganciclovir or acyclovir. Also, ganciclovir should not be administered if the absolute neutrophil count is less than 500 cells/ml or the platelet count is less than 25,000 cells/ml. Ganciclovir intravitreal implants are also contraindicated in patients with contraindications for intraocular surgery, such as external infection or severe thrombocytopenia. [Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.; PDR Online. PDR for Ophthalmology entry for Vitrasert Implant (Bausch & Lomb Surgical). Available at: http://physician.pdr.net/. Accessed November 17, 2000.] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Ganciclovir is a synthetic purine nucleoside analogue of guanine. It is structurally and pharmacologically similar to acyclovir but has increased antiviral activity against cytomegalovirus (CMV) and decreased selectivity for viral DNA. Ganciclovir also has been shown to be active against herpes simplex virus (HSV) in human clinical trials. [AHFS Drug Information 2000; p 537] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H13-N5-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed November 7, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 255.23 [USPD 2000; p 331] CHEMICAL/PHYSICAL DATA Melting Point: 250 C [Merck Index 1996; p 739] CHEMICAL/PHYSICAL DATA Elemental Comp: C42.35%, H5.13%, N27.44%, O25.07% [Merck Index 1996; p 739] CHEMICAL/PHYSICAL DATA Solubility: Ganciclovir is a polar hydrophilic compound with a solubility of 4.3 mg/ml in water at 25 C. [Merck Index 1996; p 739] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder [Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.] SUBSTANCE DELIVERY DATA DOSAGE FORM: Ganciclovir is available as: capsules (250 and 500 mg); injectable (500 mg vials for reconstitution and addition to infusion fluids); intravitreal implant (consisting of a ganciclovir tablet embedded in a non-erodible polymer-based system, delivering a minimum of 4.5 mg of the drug). Caution should be exercised in the handling and preparation of ganciclovir. Solutions of ganciclovir are alkaline (pH 11). Direct contact with the skin or mucus membranes of capsule powder of parenteral solutions should be avoided. Because ganciclovir shares some properties of anti-tumor agents, it should be handled and disposed of according to guidelines issued for cytotoxic drugs. [USP DI 2000; p 1622; PDR Online. PDR for Ophthalmology entry for Vitrasert Implant (Bausch & Lomb Surgical). Available at: http://physician.pdr.net/. Accessed November 17, 2000.; Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Ganciclovir can be administered via the oral, intravenous, and intravitreal routes. To prepare ganciclovir for intravenous injection, 10 ml of sterile water for injection (without parabens) is added to the 500 mg vial, resulting in a strength of 50 mg/ml. Once dissolved, the contents of the vial are added to compatible infusion fluids, such as sodium chloride 0.9%; dextrose 5%, Ringer's injection; and lactated Ringer's injection. Infusion concentrations greater than 10 mg/ml are not recommended. The intravitreal implant should be handled only by the suture tab and implanted in the posterior segment of the eye using aseptic surgical techniques. The procedure normally takes less than 1 hour, requires only local anesthesia, and is conducted in an outpatient setting. [USP DI 2000; p 1617, 1621; Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.; PDR Online. PDR for Ophthalmology entry for Vitrasert Implant (Bausch & Lomb Surgical). Available at: http://physician.pdr.net/. Accessed November 17, 2000.] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Capsules, unreconstituted vials, and intravitreal implants are to be stored at temperatures below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F). Products should be protected from freezing, excessive heat, and light. After reconstitution, ganciclovir injection solution retains potency for 12 hours at room temperature. Refrigeration is not recommended. After further dilution for intravenous infusion, solutions should be refrigerated and used within 24 hours to reduce the risk of bacterial contamination. [USP DI 2000; p 1622; Roche U.S. Pharmaceuticals. Cytovene: Complete Product Information. Available at: http://www.rocheusa.com/products/cytovene/pi.- html. Accessed November 17, 2000.] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Unspecified (800)526-6367 MANUFACTURERS 0000005272: Bausch & Lomb Surgical Inc 555 West Arrow Highway Claremont, CA 91711 Contact: Consumer Contact (800)910-4687 REFERENCES MED/20469958. Mouly S, Aymard G, Diquet B, Caulin C, Bergmann JF. Oral ganciclovir systemic exposure is enhanced in HIV-infected patients with diarrhea and weight loss. J Acquir Immune Defic Syndr. 2000 Aug 1;24(4):344-51. MED/20241626. Anduze-Faris BM, Fillet AM, Gozlan J, Lancar R, Boukli N, Gasnault J, Caumes E, Livartowsky J, Matheron S, Leport C, Salmon D, Costagliola D, Katlama C. Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients. AIDS. 2000 Mar 31;14(5):517-24. MED/20146727. Emery VC. Cytomegalovirus drug resistance. Antivir Ther. 1998;3(4):239-42. Review. MED/20145333. Wutoh AK, Hidalgo J, Rhee W, Bareta J, Steidl S. Survival differences associated with treatment of cytomegalovirus retinitis in Maryland patients with AIDS, 1987-1994. Am J Health Syst Pharm. 1999 Jul 1;56(13):1314-8. MED/20142931. Nichols WG, Boeckh M. Recent advances in the therapy and prevention of CMV infections. J Clin Virol. 2000 Feb;16(1):25-40. Review. MED/20087778. Eong KG, Beatty S, Charles SJ. Cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Postgrad Med J. 1999 Oct;75(888):585-90. Review. MED/20079374. Holland GN. New strategies for the management of AIDS-related CMV retinitis in the era of potent antiretroviral therapy. Ocul Immunol Inflamm. 1999 Dec;7(3-4):179-88. Review. MED/20068698. Chou S, Meichsner CL. A nine-codon deletion mutation in the cytomegalovirus UL97 phosphotransferase gene confers resistance to ganciclovir. Antimicrob Agents Chemother. 2000 Jan;44(1):183-5. MED/99432077. Grzywacz M, Deayton JR, Bowen EF, Wilson P, Emery VC, Johnson MA, Griffiths PD. Response of asymptomatic cytomegalovirus viraemia to oral ganciclovir 3 g/day or 6 g/day in HIV-infected patients. J Med Virol. 1999 Nov;59(3):323-8. MED/99415339. Walmsley S, Tseng A. Comparative tolerability of therapies for cytomegalovirus retinitis. Drug Saf. 1999 Sep;21(3):203-24. Review. MED/99271554. Anders HJ, Goebel FD. Neurological manifestations of cytomegalovirus infection in the acquired immunodeficiency syndrome. Int J STD AIDS. 1999 Mar;10(3):151-9. Review. MED/99042229. Jung D, Griffy K, Dorr A, Raschke R, Tarnowski TL, Hulse J, Kates RE. Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients. J Clin Pharmacol. 1998 Nov;38(11):1057-62. MED/98381850. McCluskey PJ, Shah R, Versace P. Outcomes of cytomegalovirus retinitis following the use of ganciclovir implants. Aust N Z J Ophthalmol. 1998 Aug;26(3):207-10. ENTRY MONTH 199103 LAST REVISION DATE 20010713 329 UNIQUE IDENTIFIER DRG-0017 NAME OF SUBSTANCE Foscarnet sodium [USPD 1998; p. 327] REGISTRY NUMBER 63585-09-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Phosphinecarboxylic acid, dihydroxy-, oxide, trisodium salt [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Foscavir [USP DI 2000; p. 1604] PROTOCOL ID NUMBERS Complete NIAID ACTG 015 PROTOCOL ID NUMBERS Complete NIAID ACTG 028 PROTOCOL ID NUMBERS Complete NIAID ACTG 053 PROTOCOL ID NUMBERS Complete NIAID ACTG 093 PROTOCOL ID NUMBERS Complete NIAID ACTG 095 PROTOCOL ID NUMBERS Complete NIAID ACTG 129 PROTOCOL ID NUMBERS Complete NIAID ACTG 136 PROTOCOL ID NUMBERS Complete NIAID ACTG 151 PROTOCOL ID NUMBERS Complete NIAID ACTG 228 PROTOCOL ID NUMBERS Complete NIAID ACTG 266 PROTOCOL ID NUMBERS No longer recruiting FDA 020A PROTOCOL ID NUMBERS No longer recruiting FDA 020B PROTOCOL ID NUMBERS No longer recruiting FDA 020E PROTOCOL ID NUMBERS No longer recruiting FDA 020F PROTOCOL ID NUMBERS No longer recruiting FDA 020G PROTOCOL ID NUMBERS No longer recruiting FDA 020H PROTOCOL ID NUMBERS No longer recruiting FDA 020I PROTOCOL ID NUMBERS No longer recruiting FDA 020J PROTOCOL ID NUMBERS No longer recruiting FDA 240A PROTOCOL ID NUMBERS No longer recruiting CC 88 EI-199 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 305 PROTOCOL ID NUMBERS Terminated CC 90 CC-118 PROTOCOL ID NUMBERS Terminated NIAID ACTG 092 PHARMACOLOGICAL ACTION MODE OF ACTION: An organic analog of inorganic pyrophosphate that inhibits replication of all known herpesviruses in vitro. Selectively inhibits the pyrophosphate binding site on virus-specific DNA polymerases and reverse transcriptases in concentrations that do not affect cellular DNA polymerases. Plasma concentrations in one study were: after 57 mg/kg infusion, 78 (average min. conc.) to 573 microM (average max. conc.). Clearance depends on renal function. Approximately 80-90% of IV FOSCAVIR (ASTRA tradename) is excreted unchanged in patients with normal renal function. Both tubular secretion and glomerular filtration account for urinary elimination of foscarnet. In one study, drug plasma half-lives of 0.45 (+/- 0.32) hours were determined following continuous infusion for 72 hours. Variable penetration - of foscarnet - of cerebral spinal fluid has been observed. Foscarnet lacks the adverse myelosuppression effect of ganciclovir. [PDR 1997; p 541-542; Protocol ID: ACTG 015 p 4, 5, 7] DISEASES STUDIED/TREATED FDA approved 9/27/91 for cytomegalovirus retinitis in AIDS patients. [AHFS Drug Information 1995; p 426; FDA Press Release ] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1601] OTHER MAJOR USES Injection form for the treatment of acyclovir-resistant herpes simplex virus in immunocomprimised patients. [Astra USA, Incorporated July 6, 1995] SUBSTANCE INTERACTIONS A possible interaction with IV pentamidine possibly causing hypocalcemia has been described. Toxicity with concomitamt use of aerosolized Pentamidne has not been reported. Because foscarnet's tendency to cause renal impairment, it should not be used with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B and IV pentamidine. Concomitant treatment with zidovudine is generally well tolerated; no evidence of increased myelosuppressions was seen, however additive effects on anemia may have occured. [PDR 1997; p 543] ADVERSE EFFECTS The major toxicity is renal impairment. This is manifested by a rise in serum creatinine concentration to 2.0 mg/dL. This is usually, but not uniformly, reversible by treatment discontinuation. Foscarnet has been assocated with changes in serum electrolytes including hypocalcemia (15% of patients in controlled studies), hypophosphatemia (8%) and hyperphosphatemia (6%), hypomagnesemia (15%) and hypokalemia (16%). Foscarnet treatment has been associated with seizures, but rate of seizures did not increase with duration of treatment. The most frequently reported events in 5 foscarnet trials were: fever (65%), nausea (47%), anemia (33%), diarrhea (30%), abnormal renal functions (27%), vomiting (26%), headache (26%) and seizure (10%). [PDR 1997; p 542-3] CONTRAINDICATIONS Has a high toxicity profile and should only be used when potential benefits outweigh the possible risks. Must be used with caution in patients with a history of renal impairment. Dosage modification according to renal function is essential. Because foscarnet has a propensity to chelate divalent metal ions and alter concentrations of calcium and other electrolytes, it should be used with caution in patients with altered baseline serum concentrations of these electrolytes, and especially in those with neurologic or cardiac abnormalities. [AHFS Drug Information 1996; p 449] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Phosphonoformic acid trisodium salt. [USAN 1997; p 320] CHEMICAL/PHYSICAL DATA Molecular Formula: C-O5-P.3Na [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 191.95 [USPD 1998; p. 327] CHEMICAL/PHYSICAL DATA Melting Point: >250 C [Merck Index 1996; p. 720] CHEMICAL/PHYSICAL DATA Elemental Comp: C6.26%, Na35.93%, O41.68%, P16.14% [Merck Index 1996; p. 720] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [PDR 1995; p 564] SUBSTANCE DELIVERY DATA DOSAGE FORM: Injection 24mg/ml for IV infusion. [PDR 1997; p 545] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Injection. [Astra USA, Incorporated July 6, 1995] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Should be stored at 15-30 C (59-86 F) and should be protected from excessive heat (above 40C) and freezing. [PDR 1997; p 545] MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Cheryl Karol (508)366-1100 MANUFACTURERS 0000001091: AstraZeneca Pharmaceuticals 725 Chesterbrook Blvd Wayne, PA 190875677 Contact: Unspecified (800)236-9933 REFERENCES MED/97189884. Bright DC. Pharmacologic management of cytomegalovirus retintis: review of current and future therapeutic modalities. J Am Optom Assoc. 1997 Jan; 68(1):11-30. MED/97143204. Segondy M, Montes B, Delmas B, Leclercq C, Janbon F, Reynes J. Changes in HIV-1 RNA plasma level in patients treated with foscarnet [letter]. - J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Jan 1; 14(1):79-80. MED/97185939. Breton G, Cremieux AC. [Treatment of cytomegalovirus infections in HIV infection]. Presse Med. 1996 Dec 14; 25(39): 1967-73. ASHM8/97153641. Clezy K. CMV infection in patients with AIDS--a clinical update. Annu conf Australas Soc HIV Med. 1996 Nov 14-17; 8:69 (abstract no. 61). MED/97075682. Sastry SM, Epps CH 3rd, Walton RC, Rana SN, Sanders RJ. Combined ganciclovir and foscarnet in pediatric cytomegalovirus retinitis. J Natl Med Assoc. 1996 Oc; 88(10):661-2. MED/97055965. Craigen JL, Grundy JE. Cytomegalovirus induced up-regulation of LFA-3 (CD58) an ICAM-1 (CD54) is a direct viral effect that is not prevented by ganciclovir or foscarnet treatment. Transplantation. 1996 Oct 27; 62(8):1102-8. MED/97028615. Drusano GL, Aweeka F, Gamertoglio J, Jacobson M, Polis M, Lane HC, Eaton C, Martin-Munley S. Relationship between foscarnet exposure, baseline cytomegalovirus (CMV) blood culture and the time to progression of CMV retinitis in HIV-positive patients. AIDS. 1996 Sep; 10(10):1113-9. MED/97028613. Mocroft A, Youle M, Gazzard B, Morcinek J, Halai R, Phillips AN. Anti-herpesvirus treatment adn risk of Kaposi's sarcoma in HIV infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group. AIDS 1996 Sep; 10(10):1101-5. ASM96/97925956. Lipson SM, Ciamician Z, Falk L, Shepp DH, Kaplan MH. The quantitative cytomegalovirus (CMV) antigenemia (CMV-Ag) assay: a marker for CMV organ specific disease and antiviral drug efficacy. Abstr Gen Meet Am Soc Microbiol. 1996 May 19-23;:16 (abstract no. C-88). ENTRY MONTH 199103 LAST REVISION DATE 20001107 330 UNIQUE IDENTIFIER DRG-0016 NAME OF SUBSTANCE Didanosine [USPD 1998; p. 233] REGISTRY NUMBER 69655-05-6 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Inosine, 2',3'-dideoxy- [USPD 1998; p 233] SYNONYMS Videx [USP DI 2000; p. 1244] PROTOCOL ID NUMBERS Complete NIAID ACTG 064 PROTOCOL ID NUMBERS Complete NIAID ACTG 091 PROTOCOL ID NUMBERS Complete NIAID ACTG 103 PROTOCOL ID NUMBERS Complete NIAID ACTG 116 PROTOCOL ID NUMBERS Complete NIAID ACTG 117 PROTOCOL ID NUMBERS Complete NIAID ACTG 118 PROTOCOL ID NUMBERS Complete NIAID ACTG 140 PROTOCOL ID NUMBERS Complete NIAID ACTG 143 PROTOCOL ID NUMBERS Complete NIAID ACTG 144 PROTOCOL ID NUMBERS Complete NIAID ACTG 152 PROTOCOL ID NUMBERS Complete NIAID ACTG 163 PROTOCOL ID NUMBERS Complete NIAID ACTG 175 PROTOCOL ID NUMBERS Complete NIAID ACTG 178 PROTOCOL ID NUMBERS Complete NIAID ACTG 187 PROTOCOL ID NUMBERS Complete NIAID ACTG 193 PROTOCOL ID NUMBERS Complete NIAID ACTG 193A PROTOCOL ID NUMBERS Complete NIAID ACTG 194 PROTOCOL ID NUMBERS Complete NIAID ACTG 199 PROTOCOL ID NUMBERS Complete NIAID ACTG 203P PROTOCOL ID NUMBERS Complete NIAID ACTG 213 PROTOCOL ID NUMBERS Complete NIAID ACTG 231 PROTOCOL ID NUMBERS Complete NIAID ACTG 239 PROTOCOL ID NUMBERS Complete NIAID ACTG 241 PROTOCOL ID NUMBERS Complete NIAID ACTG 243 PROTOCOL ID NUMBERS Complete NIAID ACTG 244 PROTOCOL ID NUMBERS Complete NIAID ACTG 245 PROTOCOL ID NUMBERS Complete NIAID ACTG 246/946 PROTOCOL ID NUMBERS Complete NIAID ACTG 260 PROTOCOL ID NUMBERS Complete NIAID ACTG 261 PROTOCOL ID NUMBERS Complete NIAID ACTG 274 PROTOCOL ID NUMBERS Complete NIAID ACTG 275 PROTOCOL ID NUMBERS Complete NIAID ACTG 276 PROTOCOL ID NUMBERS Complete NIAID ACTG 290 PROTOCOL ID NUMBERS Complete NIAID ACTG 300 PROTOCOL ID NUMBERS Complete NIAID ACTG 302 PROTOCOL ID NUMBERS Complete NIAID ACTG 306 PROTOCOL ID NUMBERS Complete NIAID ACTG 307 PROTOCOL ID NUMBERS Complete NIAID ACTG 327 PROTOCOL ID NUMBERS Complete NIAID ACTG 330 PROTOCOL ID NUMBERS Complete NIAID ACTG A5039 PROTOCOL ID NUMBERS No longer recruiting FDA 015H PROTOCOL ID NUMBERS No longer recruiting FDA 039A 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NUMBERS No longer recruiting CC 93 CC-113 PROTOCOL ID NUMBERS No longer recruiting CC 93 I-109 PROTOCOL ID NUMBERS No longer recruiting NCI 94 C-35 PROTOCOL ID NUMBERS No longer recruiting CC 94 I-76 PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-0003G PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-63 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 176 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 206 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 249 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 328 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 403 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5051 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5069 PROTOCOL ID NUMBERS No longer recruiting FDA ATLANTIC STUDY PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 002 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 007 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 003 PROTOCOL ID NUMBERS Not yet recruiting NIAID ACTG P1021 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-03-005 PROTOCOL ID NUMBERS Not yet recruiting NIAID AIEDRP AI-07-001 PROTOCOL ID NUMBERS Recruiting FDA 039F PROTOCOL ID NUMBERS Recruiting FDA 259H PROTOCOL ID NUMBERS Recruiting FDA 298C PROTOCOL ID NUMBERS Recruiting FDA 302A PROTOCOL ID NUMBERS Recruiting FDA 315A PROTOCOL ID NUMBERS Recruiting CC 99 C-0118 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 371 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5116 PROTOCOL ID NUMBERS Recruiting NIAID ACTG P1007 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-05-003 PROTOCOL ID NUMBERS Recruiting NIAID CPCRA 058 PROTOCOL ID NUMBERS Terminated FDA 292D PROTOCOL ID NUMBERS Terminated FDA 292E PROTOCOL ID NUMBERS Terminated CC 90 CC-118 PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PROTOCOL ID NUMBERS Terminated NIAID AIEDRP AI-03-001 PHARMACOLOGICAL ACTION MODE OF ACTION: Following conversion to a pharmacologically active metabolite, didanosine appears to inhibit replication of retroviruses, including HIV, by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). The antiviral activity of didanosine appears to depend on intracellular conversion to a 5'-triphosphate metabolite, dideoxyadenosine-5'-triphosphate (ddATP). Because this step depends on cellular rather than viral enzymes, conversion of the drug to the active triphosphate occurs in both virus-infected and uninfected cells. The metabolite ddATP appears to compete with deoxyadenosine-5'-triphosphate (dATP) for incorporation into viral DNA. When ddATP is incorporated, DNA synthesis is prematurely terminated because absence of the 3'-hydroxyl group prevents further 5' to 3' phosphodiester linkages. Therefore, viral DNA growth is inhibited. Didanosine is rapidly degraded at acidic pH, so the FDA-approved formulations are given with buffering agents to increase gastric pH. The manufacturer is testing an enteric-coated formulation (ddI EC) consisting of small beads coated with a methyl cellulose-based product that permits the drug to pass through the stomach and to be released in the upper portion of the small intestine. The enteric-coated formulation does not include buffering agents. Didanosine is rapidly, but incompletely, absorbed following oral administration; peak plasma concentrations are generally attained within 0.6-1 hour following a single dose in the fasting adult. Oral administration of a single dose of 300 mg as buffered tablet or 375 mg as oral solution results in plasma concentrations averaging 1.6 microg/ml. Absolute bioavailability is between 30 and 40%. The steady state volume of distribution averages 54 liters. CSF levels 1 hour after infusion of didanosine average 21% of the simultaneous plasma concentration. Serum half-life is 1.6 hours, and intracellular half-life is 25 to 40 hours. Total body clearance averages 800 ml/min. Renal clearance represents about 50% of the total body clearance, with no evidence of accumulation. In pediatric patients absorption and dose linearity data are similar to adult patient data, although both adult and pediatric patients show significant variability among patients. HIV strains with decreased in vitro susceptibility to didanosine have been isolated from patients on the drug, but the clinical importance of this is unknown. There is no evidence that concomitant didanosine-zidovudine therapy delays the appearance of zidovudine-resistant strains. The potential for cross-resistance between didanosine and HIV protease inhibitors, and didanosine and nonnucleoside reverse transcriptase inhibitors, is low because these drug systems have different mechanisms of action. [PDR 1999; p 806; AHFS Drug Information 1999; p 576-8; Protocol ID: 039F ] DISEASES STUDIED/TREATED Didanosine was the second antiretroviral agent approved by FDA for HIV infection (1991), originally for the treatment of adults with advanced HIV infection who have received prolonged prior treatment with AZT. FDA recently approved didanosine as a first-line therapy against HIV when antiretroviral therapy is warranted. Current recommendations generally advise using agents such as didanosine as part of a potent three-drug combination. [AmfAR Treat Dir 1998;9(2); p 45] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 1241] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 601] SUBSTANCE INTERACTIONS Oral antacids increase didanosine bioavailabilty. Failure of dapsone to prevent Pneumocystis carinii pneumonia was reported in 40% of HIV patients receiving didanosine. An in vitro study indicates that ganciclovir (used against cytomegalovirus infections in HIV patients) antagonizes didanosine's anti-HIV action. Concomitant oral administration of the antifungal itraconazole and didanosine has resulted in decreased serum concentration of the former. Because oral absorption of ketoconazole, some quinolone anti-infectives, or tetracyclines may be decreased by antacids, these drugs should not be administered within 2 hours of giving buffered tablets of didanosine. Ribavirin may potentiate didanosine activity against HIV. Concomitant use of didanosine and zalcitabine could exacerbate danger of peripheral neuropathy. Clinical effects of didanosine and zidovudine against HIV appear to be synergistic. Didanosine should be used with caution in patients being given other drugs associated with pancreatic toxicity. Didanosine and some HIV protease inhibitors are additive or synergistic against HIV in vitro. Concomitant administration of didanosine and ritonavir decreases the plasma concentration of didanosine but does not appear to affect the pharmacokinetics of ritonavir. Coadministration of didanosine and nelfinavir does not affect the plasma concentration of nelfinavir. [AHFS Drug Information 1999; p 582-3] ADVERSE EFFECTS The major dose-limiting toxicities of didanosine are pancreatitis and peripheral neuropathy. Other nervous system effects are headaches, insomnia, and central nervous system depression. Diarrhea, nausea, vomiting and abdominal pain, rashes, and pruritus are reported in some patients. An asymptomatic increase in serum uric acid concentration occurs in some patients. Some hematological effects (e.g., leukopenia, granulocytopenia, and anemia) are observed, as are increased serum concentrations of SGOT, SGPT, alkaline phosphatase, and bilirubin (hepatic effects). Other adverse effects such as myalgia, arthritis, hypertension, and alopecia are rare. Hyperuricemia occurs in some patients receiving didanosine. About 50% of patients with elevated serum uric acid levels prior to didanosine therapy show increased levels when didanosine therapy is initiated. Four pediatric patients demonstrated retinal depigmentation at doses above 300 mg/m2/day. [AHFS Drug Information 1999; p 580-1] CONTRAINDICATIONS Because didanosine has been associated with fatal pancreatitis, it must be used with extreme caution in patients with a prior history of the disease. If clinical signs of neuropathy occur, didanosine treatment should be discontinued. Patients with renal or hepatic impairment may be at increased risk of didanosine adverse effects. Patients with phenylketonuria should be made aware that didanosine chewable/dispersible, buffered tablets contain aspartame (NutraSweet). Animal studies with didanosine have not shown evidence of impaired fertility or harm to the fetus. Nevertheless, the drug should be used during pregnancy only if clearly needed. It is not known whether didanosine is distributed into human milk. However, the drug and/or its metabolites are distributed into milk in lactating rats. The CDC recommends that HIV-positive mothers avoid breast-feeding because HIV in the breast milk can infect the infants. [AHFS Drug Information 1999; p 581-2] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic purine dideoxynucleoside; analogue of inosine from which it differs in that the 2' and 3'-hydroxyl group on the ribose moiety have been replaced with hydrogens; absence of a free 3'-hydroxyl group results in the inability of didanosine to form phosphodiester linkages at this position (these are needed for the completion of DNA chains). [AHFS Drug Information 1999; p 575] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H12-N4-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 236.23 [USPD 1998; p. 233] CHEMICAL/PHYSICAL DATA Melting Point: 160-163 C [Merck Index 1996; p. 524] CHEMICAL/PHYSICAL DATA Elemental Comp: C50.84%, H5.12%, N23.72%, O20.32% [Merck Index 1996; p. 524] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water at 25C: 27.3mg/ml. [PDR 1999; p 806] CHEMICAL/PHYSICAL DATA Stability: Stable at neutral or slightly alkaline pH, but unstable at acidic pH. Complete hydrolysis occurs at pH 3 or less. Reconstituted pediatric oral suspension is stable for 30 days at 2-8 C. Tablets that are crushed and dispersed in water are stable for 1 h at room temperature. [AHFS Drug Information 1999; p 576] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, nonhygroscopic crystalline powder. [AHFS Drug Information 1999; p 575] SUBSTANCE DELIVERY DATA DOSAGE FORM: Buffered oral powder formulation (100, 167, and 250 mg) for reconstitution with sterile water; chewable tablets (25, 50, 100, 150, and 200 mg); pediatric powder oral formulation (2 and 4 g); a non-buffered, enteric-coated formulation recently approved by the FDA. [PDR 1999; p 809-10; Protocol ID: 039F ; U.S. FDA. CDER. New Drug Approval Packages. Available at http://www.fda.gov/cder/approval/index.htm. Accessed 11/03/00.] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 809] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store tablets in tightly closed bottles at 59 to 86 F. Store foil packets for oral dispersion at 59 to 86 F; after dissolving in water, store the solution at room temperature for up to 4 hours. Store bottles of pediatric powder for oral solution at 59 to 86 F. Store reconstituted preparations at 36 to 46 F and discard after 30 days. [PDR 1999; p 810] MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 REFERENCES MED/99359272. Palmer S, Shafer RW, Merigan TC. Hydroxyurea enhances the activities of didanosine, 9-[2-(phosphonylmethoxy)ethyl]adenine, and 9-[2-(phosphonylmethoxy)propyl]adenine against drug-susceptible and drug-resistant human immunodeficiency virus isolates. Antimicrob Agents Chemother 1999 Aug;43(8):2046-50. MED/99376519. Mobley JE, Pollard RB, Schrader S, Adler MH, Kelleher T, McLaren C. Virological and immunological responses to once-daily dosing of didanosine in combination with stavudine. AI454-143 Team. AIDS 1999 Jul 30;13(11):F87-93. MED/99391157. Kelleher T, Cross A, Dunkle L. Relation of peripheral neuropathy to HIV treatment in four randomized clinical trials including didanosine. Clin Ther 1999 Jul;21(7):1182-92. MED/99240968. Line MW, Van Dyke RB, Lindsey JC, Gwynne M, Culnane M, Diaz C, Yogev R, McKinney RE Jr, Abrams EJ, Mofenson LM. Combination therapy with stavudine (d4T) plus didanosine (ddI) in children with human immunodeficiency virus infection. The Pediatric AIDS Clinical Trials Group 327 Team. Pediatrics 1999 May;103(5):e62. MED/99125804. Floridia M, Bucciardini R, Ricciardulli D, Fragola V, Pirillo MF, Weimer LE, Tomino C, Giannini G, Galluzzo CM, Andreotti M, et al. A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease. J Acquir Immune Defic Syndr Hum Retrovirol 1999 Jan 1;20(1):11-19. MED/99125805. Simonelli C, Zanussi S, Sandri S, Comar M, Lucenti A, Talamini R, Bortolin MT, Giacca M, De Paoli P, Tirelli U. Concomitant therapy with subcutaneous interleukin-2 and zidovudine plus didanosine in patients with early stage HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1999 Jan 1;20(1):20-27. MED/99042229. Jung D, Griffy K, Dorr A, Raschke R, Tarnowski TL, Hulse J, Kates RE. Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients. J Clin Pharmacol 1998 Nov;38(11):1057-62. MED/99030033. Raffi F, Reliuet V, Auger S, Besnier JM, Chennebault JM, Billaud E, Michelet C, Perre P, Lafeuillade A, May T, et al. Efficacy and safety of stavudine and didanosine combination therapy in antiretroviral-experienced patients. AIDS 1998 Oct 22;12(15):1999-2005. MED/99030034. Schmit JC, Van Laethem K, Ruiz L, Hermans P, Sprecher S, Sonnerborg A, Leal M, Harrer T, Clotet B, Arendt V, et al. Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries. AIDS 1998 Oct 22;12(15):2007-15. AIDS/98929701. Lori F, Jessen H, Clerici M, Lieberman J, Siliciano RF, Lisziewicz J. Drugs suppressing HIV replication and cell proliferation decrease proviral DNA to undetectable levels. 5th Conf Retrovir Oppor Infect 1998 Feb 1-5:224 (abstract no. LB11). ENTRY MONTH 199103 LAST REVISION DATE 20000801 331 UNIQUE IDENTIFIER DRG-0015 NAME OF SUBSTANCE Zalcitabine [USPD 1998; p. 791] REGISTRY NUMBER 7481-89-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Cytidine, 2',3'-dideoxy- [USPD 1998; p 791] SYNONYMS Hivid [USP DI 2000; p. 3175] PROTOCOL ID NUMBERS Complete NIAID ACTG 011 PROTOCOL ID NUMBERS Complete NIAID ACTG 012 PROTOCOL ID NUMBERS Complete NIAID ACTG 047 PROTOCOL ID NUMBERS Complete NIAID ACTG 050 PROTOCOL ID NUMBERS Complete NIAID ACTG 106 PROTOCOL ID NUMBERS Complete NIAID ACTG 112 PROTOCOL ID NUMBERS Complete NIAID ACTG 114 PROTOCOL ID NUMBERS Complete NIAID ACTG 119 PROTOCOL ID NUMBERS Complete NIAID ACTG 138 PROTOCOL ID NUMBERS Complete NIAID ACTG 155 PROTOCOL ID NUMBERS Complete NIAID ACTG 163 PROTOCOL ID NUMBERS Complete NIAID ACTG 175 PROTOCOL ID NUMBERS Complete NIAID ACTG 187 PROTOCOL ID NUMBERS Complete NIAID ACTG 190 PROTOCOL ID NUMBERS Complete NIAID ACTG 193 PROTOCOL ID NUMBERS Complete NIAID ACTG 193A PROTOCOL ID NUMBERS Complete NIAID ACTG 197 PROTOCOL ID NUMBERS Complete NIAID ACTG 203P PROTOCOL ID NUMBERS Complete NIAID ACTG 229 PROTOCOL ID NUMBERS Complete NIAID ACTG 243 PROTOCOL ID NUMBERS No longer recruiting FDA 015H PROTOCOL ID NUMBERS No longer recruiting FDA 031B PROTOCOL ID NUMBERS No longer recruiting FDA 031C PROTOCOL ID NUMBERS No longer recruiting FDA 031D PROTOCOL ID NUMBERS No longer recruiting FDA 031E PROTOCOL ID NUMBERS No longer recruiting FDA 031F PROTOCOL ID NUMBERS No longer recruiting FDA 052B PROTOCOL ID NUMBERS No longer recruiting FDA 052C PROTOCOL ID NUMBERS No longer recruiting FDA 129C PROTOCOL ID NUMBERS No longer recruiting FDA 220A PROTOCOL ID NUMBERS No longer recruiting FDA 229A PROTOCOL ID NUMBERS No longer recruiting FDA 229B PROTOCOL ID NUMBERS No longer recruiting FDA 229C PROTOCOL ID NUMBERS No longer recruiting FDA 229D PROTOCOL ID NUMBERS No longer recruiting FDA 246J PROTOCOL ID NUMBERS No longer recruiting NCI 87 C-179B PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-47 PROTOCOL ID NUMBERS No longer recruiting NCI 89 C-89 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-70 PROTOCOL ID NUMBERS No longer recruiting CC 93 CC-113 PROTOCOL ID NUMBERS No longer recruiting CC 94 I-76 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 002 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 007 PHARMACOLOGICAL ACTION MODE OF ACTION: The antiviral activity of zalcitabine depends on its intracellular conversion to dideoxycytidine-5'-triphosphate (ddCTP); ddCTP appears to compete with the natural deoxycytidine triphosphate (dCTP) for viral reverse transcriptase and incorporation into viral DNA. Following incorporation of ddCTP, nucleic acid synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages. HIV strains with decreased in vitro susceptibility to zalcitabine have been isolated from patients on long-term zalcitabine therapy. Mutation of reverse transcriptase appears to be one mechanism of resistance to zalcitabine (and other dideoxynucleosides). Results of some in vitro studies show that AZT-resistant HIV strains are still susceptible to zalcitabine, and vice versa. However, some strains of AZT-resistant HIV are cross-resistant to zalcitabine and/or didanosine. Cross-resistance between zalcitabine and HIV protease inhibitors is unlikely because the drugs target different enzymes. The potential for cross-resistance between zalcitabine and NNRTIs is low since these drugs bind at different sites on the reverse transcriptase and have different mechanisms of action. Zalcitabine is well absorbed following oral administration. Food in the GI tract may decrease the extent of absorption. Peak plasma concentrations in adults are attained in 0.5-2 hours. Oral bioavailability in HIV+ adults is 70-88%. Zalcitabine is less than 4% bound to plasma proteins. It is not known whether the drug is distributed in milk. Dideoxyuridine (ddU) is the principal metabolite of zalcitabine. However, ddU accounts for less than 15% of an oral dose of zalcitabine in feces and urine. The drug is not metabolized substantially in the liver. Zalcitabine is eliminated principally in urine. Approximately 60-70% of an oral dose or 75-80% of an IV dose is eliminated unchanged in urine in 24 hours. Plasma half-life of zalcitabine in HIV+ adults averages 1.2-2 hours. In patients with impaired renal functions, zalcitabine plasma concentrations may be increased and the half-life prolonged. [AHFS Drug Information 1999; p 624-6] DISEASES STUDIED/TREATED Zalcitabine was originally approved in combination with AZT in patients with no prior antiretroviral experience. FDA approved zalcitabine as monotherapy for HIV+ people who have experienced disease progression while receiving AZT, or who are intolerant to AZT. Zalcitabine monotherapy is not as effective as AZT/zalcitabine combination therapy in prolonging the life of treatment-naive patients. Current recommendations generally advise a three-drug combination including a protease inhibitor. [AmfAR Treat Dir 1998;9(2); 1998;9(2); p 50] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 3172] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p. 660] SUBSTANCE INTERACTIONS Should not be used with other drugs with pancreatic toxicity (e.g., parenteral pentamidine), peripheral neuropathy (e.g., chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, isoniazid, nitrofurantoin, phenytoin, ribavirin, vincristine), and drugs that may decrease renal clearance of zalcitabine (e.g., aminoglycosides, amphotericin B, foscarnet, probenecid). Bioavailability of zalcitabine may be decreased 25% by antacids containing Mg or Ca. Concomitant use of zalcitabine and zidovudine against HIV appears to be synergistic. In vitro data suggest that ribavirin may antagonize the antiretroviral activity of zalcitabine, therefore concomitant use requires caution. Cimetidine has decreased the renal clearance of zalcitabine by about 23% and increased the AUC about 35%. Metoclopramide has decreased the bioavailability by about 10%. The antiviral effects of dideoxynucleoside reverse transcriptase inhibitors and HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir) are additive against HIV-1 in vitro. Treatment with zalcitabine in combination with zidovudine and saquinavir does not affect the pharmacokinetics of any of the three drugs and does not result in additive or lowered toxicities. [AHFS Drug Information 1999; p 631-2] ADVERSE EFFECTS The manufacturer's warning states: Use of HIVID (zalcitabine) has been associated with significant adverse reactions, some of which are potentially fatal. HIVID can cause severe peripheral neuropathy and because of this should be used with extreme caution in patients with preexisting neuropathy. HIVID may also rarely cause pancreatitis and patients who develop any symptoms suggestive of pancreatitis while using HIVID should have therapy suspended immediately until this diagnosis is excluded. Rare occurrences of potentially fatal lactic acidosis in the absence of hypoxemia and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues including zidovudine and HIVID. In addition, rare cases of hepatic failure and death considered possibly related to underlying hepatitis B and HIVID have been reported. Zalcitabine, at currently recommended dosages, appears generally to be well tolerated. Dose-related adverse effects include rashes and oral ulcers. Pharyngitis (in 5% of patients) and coughing, dyspnea, cyanosis, fever and flu-like manifestations (less than 1% of patients) have been reported. Severe oral ulcers, as well as esophageal ulcers, have also been reported in clinical trials. Caution should be observed in patients with a cardiomyopathy or a history of congestive heart failure. [PDR 1999; p 2681; AHFS Drug Information 1999; p 628-30] CONTRAINDICATIONS Discontinue on signs of numbness, tingling, burning, or pain of extremities; use with caution in patients with history of pancreatitis, elevated serum amylase concentration, renal impairment, baseline cardiomyopathy, or congestive heart failure. Should be used during pregnancy only when potential benefits justify possible risks to the fetus. It is not known if zalcitabine is distributed into milk, but the CDC recommends that mothers with HIV not breast-feed their infants because HIV in the breast milk can infect the infant. [AHFS Drug Information 1999; p 630-1] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A synthetic dideoxynucleoside analogue of the naturally occurring pyrimidine nucleoside cytidine in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages, which are needed for the completion of nucleic acid chains. [PDR 1999; p 2681] CHEMICAL/PHYSICAL DATA Molecular Formula: C9-H13-N3-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 211.22 [USPD 1998; p. 791] CHEMICAL/PHYSICAL DATA Melting Point: 215-217 C [Merck Index 1996; p. 1730] CHEMICAL/PHYSICAL DATA Elemental Comp: C51.18%, H6.20%, N19.89%, O22.72% [Merck Index 1996; p. 1730] CHEMICAL/PHYSICAL DATA Solubility: Aqueous solubility of 76.4 mg/ml at 25 C. [PDR 1999; p 2681] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to off-white crystalline powder. [PDR 1997; p 2287] SUBSTANCE DELIVERY DATA DOSAGE FORM: Oral tablets, 0.375 mg and 0.75 mg, film-coated (HIVID Roche's zalcitabine). Parenteral dosage form currently is not available in US. [AHFS Drug Information 1999; p 633] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [PDR 1999; p 2684] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Tablets should be stored in tightly closed bottles at 59-86 F. [PDR 1999; p 2685] MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Consumer Contact (800)910-4687 MANUFACTURERS 0000001066: Hoffmann - La Roche Inc 340 Kingsland St Nutley, NJ 071101199 Contact: Professional Services (800)526-6367 REFERENCES MED/99303109. Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trailists' Collaborative Group. Lancet 1999 Jun 12;353(9169):2014-25. MED/97323041. Adkins JC, Peters DH, Faulds D. Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection. Drugs 1997 Jun;53(6):1054-80. Review. MED/99284278. Revicki DA, Moyle G, Stellbrink HG, Barker C. Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group. AIDS 1999 May 7;13(7):851-8. MED/99250858. Jung D, AbdelHameed MH, Teitelbaum P, Dorr A, Griffy K. The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients. J Clin Pharmacol 1999 May;39(5):505-12. MED/99059878. Schapiro JM, Lawrence J, Speck R, Winters MA, Efron B, Coombs RW, Collier AC, Merigan TC. Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS clinical trials group 229. J Infect Dis 1999 Jan;179(1):249-53. MED/99067723. Cinatl J Jr, Kotchetkov R, Groschel B, Cinatl J, Driever PH, Kabickova H, Kornhuber B, Schwabe D, Doerr HW. Azidothymidine resistance of H9 human T-cell lymphoma cells is associated with decreased sensitivity to antitumor agents and inhibition of apoptosis. Int J Mol Med 1998 Dec;2(6):685-91. MED/99038179. Winters MA, Coolley KL, Girard YA, Levee DJ, Hamdan H, Shafer RW, Katzenstein DA, Merigan TC. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Invest 1998 Nov 15;102(10):1769-75. MED/99030034. Schmit JC, Van Laethem K, Ruiz L, Hermans P, Sprecher S, Sonnerborg A, Leal M, Harrer T, Clotet B, Arendt V, Lissen E, Witvrouw M, Desmyter J, De Clercq E, Vandamme AM. Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries. AIDS 1998 Oct 22;12(15):2007-15. MED/99006857. A randomized double-blind trial of the addition of lamivudine or matching placebo to current nucleoside analogue reverse transcriptase inhibitor therapy in HIV-infected children: the PENTA-4 trial. Paediatric European Network for Treatment of AIDS. AIDS 1998 Oct 1;12(14):F151-60. MED/94150516. Abrams DI, Goldman AI, Launer C, Korvick JA, Neaton JD, Crane LR, Grodesky M, Wakefield S, Muth K, Kornegay S, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. The Terry Beirn Community Programs for Clinical Research on AIDS. N Engl J Med 1994;330(10):657-62. ENTRY MONTH 199103 LAST REVISION DATE 20000922 332 UNIQUE IDENTIFIER DRG-0014 NAME OF SUBSTANCE Dextran sulfate [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] REGISTRY NUMBER 9042-14-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 060 PROTOCOL ID NUMBERS Complete NIAID ACTG 078 PROTOCOL ID NUMBERS Complete NIAID ACTG 105 PHARMACOLOGICAL ACTION MODE OF ACTION: The main mechanism of HIV inhibition by most sulfated polyanions like dextran sulfate involves the sulfated polyanion binding to a site close to the gp120 binding region of CD4, thereby disrupting gp120-CD4 interation. The higher the molecular weight of dextran sulfate, the more potent the anti-HIV effect. Dextran sulfate does not directly block gp120-CD4 interactions. The rapid increase in the amount of gp120 on the surface of the infected cells suggests that the effects of dextran sulfate include the disruption of gp120 cell surface expression resulting in inhibition of syncytia formation. Dextran sulfate blocks the cell fusion and protects the cell from death on HIV-1 env gene expressing CD4+ T and monocytoid cells. [Int Conf AIDS 1990 Jun 20-23;6(1); abstract no. Th.A. 238; Int Conf AIDS 1989 Jun 4-9;5; p 664 (abstract no. C.635); Int Conf AIDS 1994 Aug 7-12;10(1); p 105 (abstract no. PA0038)] DISEASES STUDIED/TREATED Treatment of HIV in AIDS patients. [Protocol ID: ACTG 060 ; Int Conf AIDS 1989 Jun 4-9;5; p 554 (abstract no. M.V.P. 75); USP DI 1996; p 3100] CLASSIFICATION CODE Investigational - Virion receptor binding antagonist [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CLASSIFICATION CODE Investigational - Virucidal agent [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Anticoagulant and antihyperlipoproteinemic agent. [Merck Index 1989; p 465] SUBSTANCE INTERACTIONS In combination with dideoxynucleosides, the high-molecular-weight range of dextran sulfate (500,000 Da) resulted in an antagonistic response directed against the two clinical isolates of HIV (HIV TM and SP) when the antiviral concentrations of dextran sulfate were in the ineffective range. Additive or synergistic effects were seen with the other three HIV isolates and all 5 HIV isolates when the low molcular weight range of dextran sulfate was used. Dextran sulfate application did neither enhance adverse drug effects of Zidovudine nor induce severe disorders of blood coagulation. The beneficial effect of castanospermine (CSP) and dextran sulfate (DS) on CD4+ T cells is counteracted by the observation that both drugs also permit the growth of in vivo HIV-infected CD4+ T cells. The expansion of the population of HIV-infected cells may cause an undesirable increase in the viral load in the host. Thus both drugs may have to be used in combination with drugs that prevent virus replication. [Biochem Soc Trans 1992 May;20(2); p 163S] ADVERSE EFFECTS May cause diarrhea or abdominal bloating, neutropenia, thrombocytopenia, elevation in hepatic transaminases, dysphoric mental hyperactivity, and insomnia. Intravenous infusion may cause nausea, anorexia, arthralgias, skin eruptions, transient alopecia, and headache. [Protocol ID: ACTG 060 p 4; Protocol ID: ACTG 078 p 16] CONTRAINDICATIONS Should not be used by pregnant or nursing women. [Protocol ID: ACTG 060 p 8] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Sulfated polysaccharide containing up to three sulfate groups per glucose unit. [Merck Index 1989; p 465] CHEMICAL/PHYSICAL DATA Molecular Formula: H2-O4-S.x-Unspecified [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 5,000-500,000 [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] CHEMICAL/PHYSICAL DATA Elemental Comp: Molecular composition: 17-20% sulfur content [Protocol ID: ACTG 060 p. 3] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water. [Merck Index 1989; p 465] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White powder. [Merck Index 1989; p 465] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (300 mg); sterile solution (225 mg/20 ml normal saline). [Protocol ID: ACTG 060 p 10; Protocol ID: ACTG 078 p 10] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous infusion. [Protocol ID: ACTG 078 p 9-10] MANUFACTURERS 0000001218: Ueno Fine Chemicals Industry Ltd 1133 Sixth Ave / 27th Floor New York, NY 10036 Contact: Unspecified (212)935-2323 REFERENCES MED/97030931. Fletcher CV. Pharmacologic considerations for antiviral drug development [see comments in Ann Pharmacother 1996 Sep; 30(9):964-6]. Ann Pharmacother. 1996 Sep; 30(9):972-7. MED/96342050. Choi YS, Yoshida T, Mimura T, Kaneko Y, Nakashima H, Yamamoto N, Uryu T. Synthesis of sulfated octadecyl ribo-oligosaccharides with potent anti-AIDS virus activity by ring-opening polymerization of a 1, 4-anhydroribose derivative. Carbohydr Res. 1996 Feb 28; 282(1):113-23. MED/96435129. Pearce-Pratt R, Phillips DM. Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of human immunodeficiency virus-1. Biol Reprod. 1996 Jan; 54(1):173-82. MED/95376342. Neyts J, De Clercq E. Effect of polyanionic compounds on intracutaneous and intravaginal herpesvirus infection in mice: impact on the search for vaginal microbicides with anti-HIV activity. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Sep 1;10(1):8-12. MED/96078228. Gordon LM, Waring AJ, Curtain CC, Kirkpatrick A, Leung C, Faull K, Mobley PW. Antivirals that target the amino-terminal domain of HIV type 1 glycoprotein 41. AIDS Res Hum Retroviruses. 1995 Jun;11(6):677-86. MED/96093892. Okada T, Gurney ME. Single basic amino acid substitutions at position 302 or 320 in the V3 domain of HIV type 1 are not sufficient to alter the antiviral activity of dextran sulfate and heparin. AIDS Res Hum Retroviruses. 1995 May;11(5):571-5. MED/95251713. Okada T, Patterson BK, Gurney ME. Inhibition of anti-V3 domain antibody binding to human immunodeficiency virus type-1-infected cells by sulfated polysaccharides. Biochem Biophys Res Commun. 1995 Apr 26;209(3):850-8. MED/95178505. Carrie V, Mbemba E, Letourneur D, Jozefonvicz J, Gattegno L. Interactions of HIV-1 envelope glycoproteins with derivatized dextrans. Biochim Biophys Acta. 1995 Feb 23; 1243(2): 175-80. MED/95209324. Meylan PR, Kornbluth RS, Zbinden I, Richman DD. Influence of host cell type and V3 loop of the surface glycoprotein on susceptibility of human immunodeficiency virus type 1 to polyanion compounds. Antimicrob Agents Chemother. 1994 Dec;38(12):2910-6. MED/95036234. Bergamini A, Perno CF, Dini L, Capozzi M, Pesce CD, Ventura L, Cappannoli L, Falasca L, Milanese G, Calio R, et al. Macrophage colony-stimulating factor enhances the susceptibility of macrophages to infection by human immunodeficiency virus and reduces the activity of compounds that inhibit virus binding. Blood. 1994 Nov 15;84(10);3405-12. ENTRY MONTH 199103 LAST REVISION DATE 20000801 333 UNIQUE IDENTIFIER DRG-0013 NAME OF SUBSTANCE Dexamethasone [USPD 1998; p. 222] REGISTRY NUMBER 50-02-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Decadron [USP DI 2000; p. 1052] SYNONYMS Dexameth [USP DI 2000; p. 1052] SYNONYMS Dexasone [USP DI 2000; p. 1037] PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 202 PROTOCOL ID NUMBERS Terminated NIAID ACTG 009 PROTOCOL ID NUMBERS Terminated NIAID ACTG 252 PHARMACOLOGICAL ACTION MODE OF ACTION: Corticosteroids (including dexamethasone) diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA, and stimulate transcroption of messenger RNA and subsequent responsible for two categories of effects of systemic coricosteroids. Corticosteroids cause profound and varied metabolic effects and modify the body's immune responsiveness to varied stimuli; dexamethasone exhibits potent anti-inflammatory effects in disorders of many organ systems. Oral dosing produces a plasma peak concentration in 1-2 hours, with a duration of action of 2.75 days (respective intramuscular injection values for Dexamethasone acetate are 8 hours and 6 days); Dexamethasone exhibits high protein binding and plasma and tissue half-lives of 3-4.5 and 36-54 hours, respectively. [PDR 1993; p 1496-1511; USP DI 1996; p 979] DISEASES STUDIED/TREATED Acquired autoimmune hemolytic anemia. [PDR 1997; p 1677] CLASSIFICATION CODE Anti-inflammatory [USP DI 2000; p. 1037] CLASSIFICATION CODE Antiemetic [USP DI 2000; p. 1037] CLASSIFICATION CODE Corticosteroid [USP DI 2000; p. 1037] CLASSIFICATION CODE Immunosuppressant [USP DI 2000; p. 1037] OTHER MAJOR USES Treatment of inflammation in disorders of many organ systems, including the treatment of adrenocortical function abnormalities, allergic disorders, collagen disorders, and various other disorders (dermatologic, gastrointestinal, hematologic, nonrheumatic inflammation, neurologic, ophthalmic, oral, respiratory, rheumatic), hepatitis, and certain neoplastic diseases. [PDR 1997; p 1677] SUBSTANCE INTERACTIONS Phenytoin, phenobarbital, ephedrine, and rifampin may enhance metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiologic activity. False-negative results in the dexamethasone suppression test in patients treated with indomethacin have been reported. Corticosteroids have been reported to alter prothrombin time in patients also receiving anticoagulants. When corticosteroids are given concomitantly with potassium-depleting diuretics, patients should be observed for hypokalemia. [PDR 1997; p 1677-8] ADVERSE EFFECTS May cause sodium and fluid retention, congestive heart failure, potassium loss, hypokalemic alkalosis, hypertension, muscle weakness, steroid myopathy, osteoporosis, muscle mass loss, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, long bone fracture, tendon rupture, peptic ulcer with possible hemorrhage, small/large bowel perforation, pancreatitis, abdominal distention, ulcerative esophagitis, impaired wound healing, thin fragile skin, petechiae and ecchymoses, erythema, increased sweating, cutaneous reactions, convulsions, increased intracranial pressure with papilledema, vertigo, headache, menstrual irregularities, development of cushingoid state, growth suppression in children, secondary adrenocortical and pituitary unresponsiveness, decreased carbohydrate tolerance, latent diabetes manifestations, increased need for insulin/oral hypoglycemic agents in diabetics, hirsutism, posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos, negative nitrogen balance due to protein catabolism, myocardial rupture following recent myocardial infarction, hypersensitivity, thromboembolism, weight gain, increased appetite, nausea, malaise, psychic disturbances. [PDR 1997; p 1678] CONTRAINDICATIONS Contraindicated in patients with systemic fungal infections or hypersensitivity to dexamethasone. [PDR 1997; p 1677] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Glucocorticoid; Synthetic adrenocortical steroid. [PDR 1997; p 1677] CHEMICAL/PHYSICAL DATA Molecular Formula: C22-H29-F-O5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 392.47 [USPD 1998; p. 222] CHEMICAL/PHYSICAL DATA Melting Point: 262-264 C [Merck Index 1996; p. 499] CHEMICAL/PHYSICAL DATA Elemental Comp: C67.33%, H7.45%, F4.84%, O20.38% [Merck Index 1996; p. 499] CHEMICAL/PHYSICAL DATA Solubility: Soluble in water(25 C): 10mg/100ml. Soluble in acetone, ethanol, chloroform. [Merck Index 1989; p 464] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, odorless crystalline powder. [PDR 1997; p 1676] SUBSTANCE DELIVERY DATA DOSAGE FORM: Elixir (0.1 mg/ml); oral solution (0.5-1 mg/ml); tablets (0.25 mg, 0.5 mg, 1.5 mg, 4 mg, and 6 mg); solution for injection (4 mg/ml); 0.05% ophthalmic ointment; aerosol for inhalation; 0.1% topical cream; intranasal aerosol. [PDR 1997; p 1677-1690] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral (Dexamethasone); intra-articular or soft-tissue injection (Dexamethasone acetate or Dexamethasone sodium phosphate); inhalation; topical; intranasal administration. [PDR 1997; p 1678] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store elixir, oral solution, and parenteral dosage forms in tight container at 15-30 C (59-86 F) and protect from freezing and from light; store tablets in well-closed container at 15-30 C (59-86 F). [PDR 1997; p 1677-1690] MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)672-6372 MANUFACTURERS 0000001024: Merck & Co Inc PO Box 4 West Point, PA 194860004 Contact: Unspecified (800)642-1232 MANUFACTURERS 0000002862: Major Pharmaceuticals Inc 31778 Enterprise Drive Livonia, MI 48150 Contact: Unspecified (800)528-3144 MANUFACTURERS 0000005219: Legere Pharmaceuticals 7326 East Evans Road Scottsdale, AZ 85260 REFERENCES MED/97091415. Komaba Y, Kitamura S, Terashi A, Tamotsu M, Nakatani Y, Hara A. Human T-cell lymphotropic virus type-I associated myelopathy complicated by optic neuritis. Nippon Ika Daigaku Zasshi. 1996 Oct; 63(5):414-8. MED/97047548. Kaufmann T, Nisce LZ, Coleman M. A comparison of survival of patients treated for AIDS-related central nervous system lymphoma with and without tissue diagnosis. Int J Radiat Oncol Biol Phys. 1996 Sep 1; 36(2):429-32. MED/96320583. Levine AM, Tuplule A, Espina B, Boswell W, Buckley J, Rasheed S, Stain S, Parker J, Nathwani B, Gill PS. Low dose methotrexate, bleomycib, doxorubicin, cyclophosphamdie, vinciristine, and dexamthasone with zalcitabine in patients with aquired immunodeficiency syndrome-related lymphoma. Effect on human immunodeficiency virus and serum interleukin-6 levels over time. Cancer. 1996 Aug 1; 78(3):517-26. MED/97031825. Guizani L, Perrin-Wolff M, Bread J, Binetruy B, Bertoglio J. Mechanisms in interleukin-2 protection against glucocorticoid-induced apoptosis: regulation of AP-1 and glucocorticoids receptor transcriptional activities. J Interferon Cytokine Res. 1996 Aug; 16(8):601-9. MED/96272884. Norbiato G, Bevilacqua M, Vago T, Clerici M. Glucocorticoids and interferon-alpha in the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1996 Jul; 81(7):2601-6. MED/96316065. Campbell BG, Hurley J, Zimmerman RD. False-negative single-photon emission CT in AIDS lymphoma: lack of effect of steroids [letter; comment]. AJMR Am J Neuroradiol. 1996 May; 17(5): 1000-2. MED/96180193. Ramierz F, Fowell DJ, Puklavec M, Simmonds S, Mason D. Glucocorticoids promote a TH2 cytokine reponse by CD4+ T cells in vitro. J Immunol. 1996 Apr 1; 156(7): 2406-12. MED/96235996. Kawa SK, Thompson EB. lymphoid cell resistance to glucocorticoids in HIV infection. J Steroid Biochem Mol Biol. 1996 Mar; 57(5-6):259-63. MED/96223415. Schultz C, Scott C, Sherman W, Donahue B, Fields J, Murray K, Fisher B, Abrams R, Meis-Kindblom J. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamthasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol. 1996 Feb; 14(2): 556-64. MED/96397201. Caceres W. Non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome. Bol Asoc Med P R. 1995 Oct-Dec; 87(10-12): 158-61. ENTRY MONTH 199103 LAST REVISION DATE 20001107 334 UNIQUE IDENTIFIER DRG-0012 NAME OF SUBSTANCE Sargramostim [USPD 1998; p. 656] REGISTRY NUMBER 123774-72-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Colony-stimulating factor 2 (human clone pHG25 protein moiety), 23-L-leucine- [USPD 1998; p. 656] SYNONYMS Leukine [USP DI 2000; p. 980] PROTOCOL ID NUMBERS Complete CC 88 I-181 PROTOCOL ID NUMBERS Complete NIAID ACTG 065 PROTOCOL ID NUMBERS Complete NIAID ACTG 073 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 090 PROTOCOL ID NUMBERS Complete NIAID ACTG 094 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 387 PROTOCOL ID NUMBERS Complete NIAID AVEG 033 PROTOCOL ID NUMBERS No longer recruiting FDA 005A PROTOCOL ID NUMBERS No longer recruiting FDA 067A PROTOCOL ID NUMBERS No longer recruiting FDA 067B PROTOCOL ID NUMBERS No longer recruiting FDA 067C PROTOCOL ID NUMBERS No longer recruiting FDA 067D PROTOCOL ID NUMBERS No longer recruiting FDA 067E PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-130 PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-177 PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5041 PHARMACOLOGICAL ACTION MODE OF ACTION: GM-CSF is a multilineage colony-stimulating factor that principally affects proliferation, differentiation, and activation of granulocytes and macrophage pathways. Endogenous human GM-CSF is produced by both hematologic and tissue cells. It acts on various progenitor target cells by binding to GM-CSF-specific binding sites on their surfaces; biosynthetic GM-CSF products have similar mechanisms of action. The increase in leukocyte count in response to GM-CSF therapy is dose dependent. Serum concentrations appear to decline in a biphasic manner. Elimination characteristics of the drug, including possible metabolic pathways and/or excretion mechanisms remain to be fully explored. In vitro, Leukine (Immunex tradename for yeast-derived GM-CSF) increases the cytotoxicity of monocytes towards certain neoplastic cell lines and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells. Following IV infusion over 2 hours of 250 microgram per square meter doses, serum concentrations were 0.12-1.5 nanogram per ml immediately after completion of the infusion and remained 0.1 nanogram/ml for 6 hours. [AHFS Drug Information 1996; p 1057; PDR 1997; p 1317] DISEASES STUDIED/TREATED Used to correct or minimize HIV-associated neutropenia and/or drug-induced neutropenia(i.e., due to treatment with zidovudine, interferon alfa, or cytotoxic chemotherapy). Used to increase neutrophil counts in patients with CMV infection who develop neutropenia while on ganciclovir, and in patients with nonmalignant conditions who develop neutropenia while on myelosuppressive drugs. FDA approved 3/5/91 for cancer patients with lymphomas or leukemia who are receiving bone marrow transplants. [AHFS Drug Information 1996; p 1060] CLASSIFICATION CODE Antineutropenic [USP DI 2000; p. 975] CLASSIFICATION CODE Hematopoietic stimulant [USP DI 2000; p. 975] CLASSIFICATION CODE Immunomodulator [NIAID DAIDS Anti-HIV Compounds Database. Available at: http://www.niaid.nih.gov/daids/dtpdb/default.- htm. Accessed: June 30, 2000.] OTHER MAJOR USES Used to accelerate myeloid recovery in adults with non-Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia or Hodgkin's disease undergoing cytotoxic chemotherapy and autologous bone marrow transplantation (BMT). Also used in adults with chronic myelogenous leukemia, acute nonlymphocytic leukemia or severe aplastic anemia undergoing allogenic BMT. [AHFS Drug Information 1996; p 1059-1061] SUBSTANCE INTERACTIONS Safety and efficacy of concomitant administration with radiation therapy or with myelosuppressive antineoplastic agents have not been established. Because specific studies have not been performed to evaluate the additive effects of myeloproliferative drugs, such combinations should be used with caution in patients receiving GM-CSF. In vitro studies indicate that GM-CSF may potentiate the antiretroviral activity of zidovudine. [AHFS Drug Information 1996; p 1064] ADVERSE EFFECTS GM-CSF is generally well tolerated. In some patients with preexisting renal or hepatic dysfunctions, administration of the drug caused elevation of serum creatinine or bilirubin and hepatic enzymes. In some patients there were reports of headache, arthralgia, myalgia, fever, bone pain, and chills. These effects were generally mild or moderate and could be alleviated with drugs such as acetaminophen. [PDR 1997; p 1320] CONTRAINDICATIONS Contraindicated in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (>10%). Should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates, or cardiac disease. It should also be used with caution in patients with preexisting renal or hepatic dysfunctions. The drug should be given to pregnant women or nursing mothers only if clearly needed. The drug does not exhibit any greater toxicity in children (4 months to 18 years of age) than in adults. [PDR 1997; p 1319; AHFS Drug Information 1996; p 1063] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A single chain, glycosylated polypeptide of 127 amino acid residues expressed from Saccharomyces cervesiae. The glycoprotein is represented by three molecular species having relative molecular weights of approximately 19,500, 16,800, and 15,500 due to different levels of glycosylation. [USAN 1997; p 641] CHEMICAL/PHYSICAL DATA Molecular Formula: C639-H1002-N168-O196-S8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 15,500-19,500 daltons [USPD 1998; p. 656] CHEMICAL/PHYSICAL DATA Solubility: In water. [PDR 1997; p 1321] CHEMICAL/PHYSICAL DATA Stability: To avoid physical and chemical incompatibilities do not mix with other drugs in infusion solutions. [PDR 1997; p 1321] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Sterile lyophilized powder. [PDR 1997; p 1321] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vials containing 250 or 500 mcg. [PDR 1997; p 1321] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Subcutaneous injection, intravenous infusion. [PDR 1997; p 1320; AHFS Drug Information 1996; p 1064-5] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: The sterile powder, the reconstituted solution, and the diluted solutions for injection should be refrigerated at 2-8 C (36-46 F). Do not shake or freeze. Discard any unused solution after 6 hours. [PDR 1997; p 1321] MANUFACTURERS 0000002641: Schering - Plough Corp 2000 Galloping Hill Rd Kenilworth, NJ 070330530 Contact: Dr Jan Agosti (206)389-4321 MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Dr Janice Albrecht (908)298-7985 MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Unspecified (800)466-8639 REFERENCES MED/96116037. Aweeka FT, Mak M al-Uzri A, Petr K, Dett C, Franco J, Affrime M, Guerciolini R, Cutler DL, Kahn J, et al. Oral and intravenous zidovudine pharmacokinetics: the effecct of granulocyte-macrophage colony stimulating factor. J Clin Pharmacol. 1995 Sep; 35(9):856-64. MED/97128018. Meyer CN, Neilsen H. Priming of neutrophil and moncyte actvation in human immunodeficiency virus infection. Comparison of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and interferon-gamma. APMIS. 1996 Sep; 104(9):640-6. MED/97000989. Scadden DT, Pickus O, Hammer SM, Strecher B, Bresnahan J, Gere J, McGrath J, Agosti JM. Lack of in vivo effect of granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 1996 Aug 10; 12(12):1151-9. MED/96404537. Manfredi R, Mastroianni A, Coronado o, Chiodo F. Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in leukopenic patients with advanced HIV disease. J Chmeother. 1996 Jun; 8(3):214-20. MED/96188315. Capetti A, Bonfanti P, Magni C, Milazzo F. Employment of recombinant human granulocyte-macrophage colony stimulating factor in oesophageal candidiasis in AIDS patients [letter]. AIDS 1995 Dec; 9(12):1378-9. MED/96107355. Hill AD, Naama HA, Calvano SE, Daly JM. The effect of granulocyte-macrophage colony-stimulating factor on myeloid cells and its clinical applications. J Leukoc Biol. 1995 Dec;58(6):634-42. MED/96103541. Castello G, Mela G, Cerruti A, Mencoboni M, Lerza R. Azidothymidine and interferon-alpha in vitro effects on hematopoiesis: protective in vitro activity of IL-1 and GM-CSF. Exp Hematol. 1995 Dec;23(13):1367-71. MED/96089210. Matsuda S, Akagawa K, Honda M, Yokota Y, Takebe Y, Takemori T. Suppression of HIV replication in human monocyte-derived macrophages induced by granulocyte/macrophage colony-stimulating factor. AIDS Res Hum Retroviruses. 1995 Sep;11(9):1031-8. MED/96051001. Manfredi R, Cariani T, Latini F, Chiodo F. Recombinant granulocyte-macrophage colony-stimulating factor in the treatment of HIV-related leucopenia. Acta Paediatr. 1995 Aug;84(8):943-4. MED/95087232. Price P, Johnson RP, Scadden DT, Jassoy C, Rosenthal T, Kalams S, Walker BD. Cytotoxic CD8+ T lymphocytes reactive with human immunodeficiency virus-1 produce granulocyte/macrophage colony-stimulating factor and variable amounts of interleukins 2,3, and 4 following stimulation with the cognate epitope. Clin Immunol Immunopathol. 1995 Jan;74(1):100-6. ENTRY MONTH 199103 LAST REVISION DATE 20000801 335 UNIQUE IDENTIFIER DRG-0011 NAME OF SUBSTANCE Clindamycin [USPD 1998; p. 177] REGISTRY NUMBER 18323-44-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME L-threo-alpha-D-galacto-Octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-(((1-methyl-4-propy- l-2-pyrrolidinyl)carbon yl)amino)-1-thio-, (2S-trans)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Cleocin (hydrochloride) [USP DI 2000; p. 929] SYNONYMS Cleocin Injectable (phosphate) [USP DI 2000; p. 929] SYNONYMS Cleocin Pediatric (palmitate hydrochloride) [USP DI 2000; p. 929] PROTOCOL ID NUMBERS Complete NIAID ACTG 044 PROTOCOL ID NUMBERS Complete NIAID ACTG 077 PILOT PROTOCOL ID NUMBERS Complete NIAID ACTG 108 PROTOCOL ID NUMBERS No longer recruiting FDA 021A PHARMACOLOGICAL ACTION MODE OF ACTION: Clindamycin may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of the infection and the susceptibility of the infecting organism. Clindamycin palmitate, hydrochloride or phosphate are inactive until hydrolyzed to free clidamycin; this occurs very rapidly in vivo. Clindamycin appears to inhibit protein synthesis in suceptible organisms by binding to 50S ribosomal subunits; the primary effect is inhibition of peptide bond formation. Clindamycin hydrochloride is rapidly absorbed after oral administration, reaching a mean peak serum level of 2.50 mcg/ml in 45 minutes, with a reduction therafter to 1.51 and 0.70 mcg/ml in 3 and 6 hours respectively. Clindamycin is widely distributed in body fluids and tissue (including bone); but no significant levels are attained in cerebrospinal fluid. Approximately 10% of the bio-activity is excreted in the urine and 3.6% in the feces; the remainder is excreted as bio-inactive metabolites. Clostridia toxin(s) appear to be the primary cause of Clindamycin-associated colitis. Cholestyramine and colestipol resins have been shown to bind the toxin in vitro. [PDR 1995; p 2524-2525; AHFS Drug Information 1996; p 375] DISEASES STUDIED/TREATED Treatment of mild-moderate Pneumocystis carinii pneumonia (PCP) and toxoplasmosis in AIDS patients. [AHFS Drug Information 1996; p 377] CLASSIFICATION CODE Antibacterial [USP DI 2000; p. 926] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 926] OTHER MAJOR USES Treatment of serious infections by susceptible anaerobic bacteria. Used against infections due to streptococci, pneumococci, and staphylococci. Should be reserved for penicillin-allergic patients. [PDR 1997; p 2069; AHFS Drug Information 1996; p 377] SUBSTANCE INTERACTIONS Antagonism has been demonstrated between clindamycin and erythromycin. Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore it should be used with caution in patients receiving such agents. The following drugs are physically incompatible with clindamycin phosphate (IV preparation): ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.Combination therapy with clindamycin and quinine has been reported as beneficial in the treatment of cryptosporidiosis; clindamycin in combination with pyrimethamine has been used against cerebral and/or ocular toxoplasmosis in immunocompromised patients. [PDR 1995; p 2524, 2528] ADVERSE EFFECTS Has been associated with severe colitis (usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus), which may end fatally; also may cause esophagitis, nausea, vomiting, rashes, jaundice and liver function abnormalities, renal dysfunction, transient neutropenia (leukopenia) and eosinophilia, and agranulocytosis and thrombocytopenia. LD-50 (mice): 2618 mg/kg (oral); 361 mg/kg (ip); 245 mg/kg IV). [PDR 1997; p 2068-2069] CONTRAINDICATIONS Should not be used in patients with a history of hypersensitivity to preparations containing clindamycin or lincomycin. Use of clindamycin may cause overgrowth of nonsusceptible organisms, particularly fungi. Patients with preexisting Candida infection should receive concomitant antifungal treatment. Clindamycin should be used with caution in patients with a history of GI disease, and with severe renal and/or hepatic impairment. [PDR 1997; p 2069; AHFS Drug Information 1996; p 377] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A lincomycin derivative; lincosamine antibiotic. [PDR 1997; p 2067] CHEMICAL/PHYSICAL DATA Molecular Formula: C18-H33-Cl-N2-O5-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 424.99 [USPD 1998; p. 177] CHEMICAL/PHYSICAL DATA Elemental Comp: C50.87%, H7.83%, Cl8.34%, N6.59%, O18.82%, S7.55% [Merck Index 1996; p. 397] CHEMICAL/PHYSICAL DATA Solubility: In water, pyridine, ethanol, dimethylformamide. [Merck Index 1989; p 367] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow amorphous solid; white crystals from ethanol-ethyl acetate. [Merck Index 1989; p 367] SUBSTANCE DELIVERY DATA DOSAGE FORM: Vial of sterile solution of clindamycin phosphate, equivalent to 150 mg clindamycin/ml; clindamycin hydrochloride (75m 150, and 300 mg capsules); clindamycin palmitate hydrochloride granules for oral (15 mg/ml) solution; topical solution (10 mg/ml). Topical gel, lotion, solution, and vaginal cream. [PDR 1997; p 2068, 2070; AHFS Drug Information 1996; p 378-379] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Clindamycin hydrochloride and clindamycin palmitate hydrochloride are administered orally; clindamycin phosphate is administered by IM injection or by IV infusion. [AHFS Drug Information 1996; p 378] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Solution (clindamycin phosphate, IV) and capsules or granules: store at controlled room temperature, 15-30 C (59- 86 F). [PDR 1997; p 2070] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Unspecified (800)432-4702 REFERENCES MED/97066352. Barber BA, Pergram PS, High KP. Clindamycin/primaquine as prophylaxis for Pneumocytis carinii pneumonia. Clin Infect Dis. 1996 Oct; 23(4): 718-22. MED/97030415. Laing RB, Flegg PJ, Brettle RP, Leen CL, Burns SM. Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients. Int J STD AIDS. 1996 Jul; 7(4):258-64. MED/96300524. Flaherty JF Jr, Gatti G, White J, Bubp J, Borin M, Gambertoglio JG. Protein binding of clindamycin in sera of patients with AIDS. Antimicrob Agents Chemother. 1996 May; 40(5):1134-8. MED/96188893. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR. Comparison of three regimens for treatment of mild to moderalte Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trail of oral trimethorpim-sulfamethoxazole, dapson-trimethoprim, ad clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med. 1996 May 1; 124(9): 792-802. MED/96435297. Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis. 1996 Feb; 22(2):268-75. MED/96077391. Caumes E, Bocquet H, Guermonprez G, Rogeaux O, Bricaire F, Katlama C, Gentilini M. Adverse cutaneous reactions to pyrimethamine/sulfadiazine and pyrimethamine/clindamycin in patients with AIDS and toxoplasmic encephalitis. Clin Infect Dis. 1995 Sep;21(3):656-8. MED/96131195. Behbahani R, Moshfeghi M, Baxter JD. Therapeutic approaches for AIDS-related toxoplasmosis. Ann Pharmacother. 1995 Jul-Aug;29(7-8):760-8. MED/96004910. Winstanley P. Drug treatment of toxoplasmic encephalitis in acquired immunodeficiency syndrome. Postgrad Med J. 1995 Jul;71(837):404-8. MED/95075284. Rabaud C, May T, Amiel C, Katlama C, Leport C, Ambroise-Thomas P, Canton P. Extracerebral toxoplasmosis in patients with HIV. A French National Survey. Medicine (Baltimore). 1994 Nov;73(6):306-14. MED/94368951. Black JR, Feinberg J, Murphy RL, Fass RJ, Finkelstein D, Akil B, Safrin S, Carey JT, Stansell J, Plouffe JF, et al. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044. Clin Infect Dis. 1994 Jun;18(6):905-13. ENTRY MONTH 199103 LAST REVISION DATE 20001107 336 UNIQUE IDENTIFIER DRG-0010 NAME OF SUBSTANCE AS-101 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] REGISTRY NUMBER 106566-58-9 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Tellurate(1-), (1,2-ethanediolato(2-)-O,O')trichloro-, ammonium, (SP-5-22)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed Nov 6, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 046 PROTOCOL ID NUMBERS No longer recruiting FDA 045A PROTOCOL ID NUMBERS No longer recruiting FDA 045B PROTOCOL ID NUMBERS No longer recruiting FDA 045C PROTOCOL ID NUMBERS No longer recruiting CC 89 CC-75 PHARMACOLOGICAL ACTION MODE OF ACTION: Enhances production of colony stimulating factor and interleukin-2 (IL-2) in murine splenocytes and human peripheral blood mononuclear cells and stimulates mitogenesis and increases the percentages of cells with receptors for IL-2. Increases gamma interferon and natural killer cell activity, and tumor necrosis factor production; suppresses growth of methylcholanthrene-induced sarcoma (animal studies); may restore immune function in mice immunosuppressed by irradiation. [AmfAR Treat Dir 1989 May; p 33; Nat Immun 1993 Jan-Feb;12(1); p 50-5; Int J Immunopharmacol 1992 May;14(4); p 613-9] DISEASES STUDIED/TREATED Treatment of patients with low CD4 cells and HIV infection. [Protocol ID: ACTG 046 p 14] CLASSIFICATION CODE Immunomodulator [Int J Immunopharmacol 1992 May;14(4); p 613-9] ADVERSE EFFECTS May cause transient microscopic hematuria and asymptomatic transient temperature increases, fever, rash, proteinuria, and hypotension. Persistent garlic odor in AIDS/ARC patients. Less frequently seen side effects are nausea, vomiting, and diarrhea. Seven subjects receiving 13 mg/m2 IV tiw have experienced a greying of their skin color. [Protocol ID: ACTG 046 p 5; AmfAR Treat Dir 1989 May; p 39] CONTRAINDICATIONS Should not be used by pregnant women or nursing mothers. [Protocol ID: ACTG 046 p 18] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Chemically synthesized organotellurium salt. [Nat Immun 1993 Jan-Feb;12(1); p 50-5] CHEMICAL/PHYSICAL DATA Molecular Formula: C2-H4-Cl3-O2-Te.H4-N [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 312 [Protocol ID: ACTG 046 p. 5] CHEMICAL/PHYSICAL DATA Stability: When placed in solution, it is hydrated and converted to tellurous acid, tellurium salts, and a small amount of ethylene glycol (about 20% of AS-101). [Protocol ID: ACTG 046 p 13] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Crystalline white powder. [Protocol ID: ACTG 046 p 5] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile solution (50 mcg/ml in 100 ml vial). [Protocol ID: ACTG 046 p 18] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion. [Protocol ID: ACTG 046 p 15, 18] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Refrigerate under dry conditions; is converted to tellurous acid, tellurium salts, and a small amount of ethylene glycol when hydrated. [Protocol ID: ACTG 046 p 13] MANUFACTURERS 0000002865: Wyeth - Ayerst Research PO Box 8299 Philadelphia, PA 19101 Contact: General Information (610)688-4400 REFERENCES ICDB/96633128. Kalechman Y, Tichler T, Shani A, Albeck M, Sredni B. Differential effect of the immunomodulator AS101 on B7-1 and B7-2 costimulatory molecules: role in Th1 predominance and in the antitumoral effects of Proc Annu Meet Am Assoc Cancer Res; 37:A3128 1996. ICA8/92401170. Amarante JM, Levi GC, Pedro RJ, Galvao PA, Scheinberg M, Levy DS. A double blind controlled study with AS-101 in patients infected with HIV. Int Conf AIDS. 1992 Jul 19-24;8(2):B160 (abstract no. PoB 3439). ICA8/92403352. Lewi DS, Acceturi CA, Diaz RS, Lofty C, Sader H. AS 101: tolerability, safety and clinical efficacy in HIV positive patients with advanced disease. Int Conf AIDS. 1992 Jul 19-24;8(3):100 (abstract no. PuB 7310). MED/92385164. Vonsover A, Loya S, Sredni B, Albeck M, Gotlieb-Stematsky T, Araf O, Hizi A. Inhibition of the reverse transcriptase activity and replication of human immunodeficiency virus type 1 by AS 101 in vitro. AIDS Res Hum Retroviruses. 1992 May;8(5):613-23. MED/90368122. Sredni B, Kalechman Y, Albeck M, Gross O, Aurbach D, Sharon P, Sehgal SN, Gurwith MJ, Michlin H. Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin. Immunology. 1990 Aug; 70(4):473-7. ICA6/30049290. Falloon J, Ogata-Arakaki D, Baseler M, Davey R, Polis M, Kovacs J, Zurlo J, Zunich K, Lane HC, Masur H. Therapy of HIV infection with AS-101 and zidovudine. Int Conf AIDS. 1990 Jun 20-23;6(3):209 (abstract no. S.B.492). MED/90318427. Shani A, Tichler T, Catane R, Gurwith M, Rozenszajn LA, Gezin A, Levi E, Schlesinger M, Kalechman Y, Michlin H, et al. Immunologic effects of AS101 in the treatment of cancer patients. Nat Immune Cell Growth Regul. 1990;9(3):182-90. ICA5/00309789. Vonsover A, Kalechman Y, Oron M, Shalit F, Albeck M, Sredni B. The immunomodulating and antiviral effects of AS101, an organotellurium compound. Int Conf AIDS. 1989 Jun 4-9;5:590 (abstract no. T.C.P.142). ICA5/00200989. Laporte JP, Lebas J, Gonzales G, Meyohas M, Srenndi B, Najman A. AS-101, a new immunomodulating compound in the treatment of AIDS. Int Conf AIDS. 1989 Jun 4-9;5:399 (abstract no. W.B.P.283). ICA5/00204689. Laporte JP, Frottier J, Dormont D, Imbert JC, Albeck M, Najman A. As 101 in associaton with azt in AIDS patients: a phase I pilot study. Int Conf AIDS. 1989 Jun 4-9;5:405 (abstract no. W.B.P.320). ENTRY MONTH 199103 LAST REVISION DATE 20000801 337 UNIQUE IDENTIFIER DRG-0009 NAME OF SUBSTANCE AL 721 [Merck Index 1996; p. 37] REGISTRY NUMBER 99751-63-0 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME AL 721 [CHEMLINE ] PROTOCOL ID NUMBERS Complete NIAID ACTG 022 PHARMACOLOGICAL ACTION MODE OF ACTION: Reduces the cholesterol content of certain membranes, causing membrane fluidization, which affects the viral membrane organization and protein structure; postulated that it could interfere with the attachment, penetration, and release of HIV. [Protocol ID: ACTG 022 p 4; Proc Annu Meet Am Soc Clin Oncol 1988;7; A18] DISEASES STUDIED/TREATED Persistent generalized lymphadenopathy (PGL) and symptomatic HIV infection. [Protocol ID: ACTG 022 ] CLASSIFICATION CODE Nutritional supplement [Merck Index 1996; p. 37] OTHER MAJOR USES Nutritional supplement. [Merck Index 1989; p 34] ADVERSE EFFECTS May cause gastrointestinal disturbances (diarrhea, nausea, vomiting, abdominal pain) in patients at higher doses. Considered to be nontoxic and safe at single oral doses up to 60 g. [Protocol ID: ACTG 022 p 4-7; Int Conf AIDS 1989 Jun 4-9;5; p 403] CONTRAINDICATIONS Should not be used by pregnant or lactating women or by people with significant cardiac, liver, renal, or neurologic disorder. [Protocol ID: ACTG 022 p 12] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Lipid mixture of neutral glycerides, phosphatidylcholine, and phosphatidylethanolamine in a 7:2:1 ratio. [Protocol ID: ACTG 022 p 4] SUBSTANCE DELIVERY DATA DOSAGE FORM: Polyethylene-lined aluminum foil sachets, reconstituted in orange juice. [Protocol ID: ACTG 022 p 12] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: ACTG 022 p 13] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store in freezer until reconstitution. [Protocol ID: ACTG 022 p 13] MANUFACTURERS 0000005385: Intervention provided by participating unit , REFERENCES MED/91366573. Mildvan D, Buzas J, Armstrong D, Antoniskis D, Sacks HS, Rhame FS, Mosbach FW, Pettinelli C. An open-label, dose-ranging trial of AL 721 in patients with persistent generalized lymphadenopathy and AIDS-related complex. J Acquir Immune Defic Syndr. 1991;4(10):945-51. ICA7/3216791. Yust I, Vardinon N, Zacut V, Hasner A, Burke M. AL721 reduces HIV antigenemia in seropositive asymptomatic subjects. Int Conf AIDS. 1991 Jun 16-21;7(2):223 (abstract no. W.B.2167). MED/91241636. Wolf R, Ophir J, Yust I. Atopic dermatitis provoked by AL721 in a patient with acquired immunodeficiency syndrome. Ann Allergy. 1991 May;66(5):421-3. MED/90258571. Shinitzky M, Skornick Y. Suppression of HIV antigenaemia by AL721 [letter; comment]. Lancet. 1990 May 26;335(8700):1281-2. MED/90173578. Peters BS, Bennett JM, Jeffries DJ, Knox K, Kocsis A, Pinching AJ. Ineffectiveness of AL721 in HIV disease [letter]. Lancet. 1990 Mar 3;335(8688):545-6. MED/90186144. Yust I, Vardinon N, Skornick Y, Zakuth V, Hasner A, Shinitzky M. Reduction of circulating HIV antigens in seropositive patients after treatment with AL-721. Isr J Med Sci. 1990 Jan;26(1):20-6. ICA5/00203889. Mildvan D, Armstrong D, Antoniskis D, Sacks H, Balfour H, Buzas J, Pettinelli C. An open label dose-ranging trial of al721 in pgl and ARC. Int Conf AIDS. 1989 Jun 4-9;5:403 (abstract no. W.B.P.312). ENTRY MONTH 199103 LAST REVISION DATE 20000801 338 UNIQUE IDENTIFIER DRG-0008 NAME OF SUBSTANCE Acyclovir [USPD 1998; p. 23] REGISTRY NUMBER 59277-89-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 6H-Purin-6-one, 2-amino-1,9-dihydro-9-((2-hydroxyethoxy)methy- l)- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Zovirax [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 010 PROTOCOL ID NUMBERS Complete NIAID ACTG 063 PROTOCOL ID NUMBERS Complete NIAID ACTG 070 PROTOCOL ID NUMBERS Complete NIAID ACTG 095 PROTOCOL ID NUMBERS Complete NIAID ACTG 169 PROTOCOL ID NUMBERS Complete NIAID ACTG 204 PROTOCOL ID NUMBERS No longer recruiting FDA 018A PROTOCOL ID NUMBERS No longer recruiting FDA 033A PROTOCOL ID NUMBERS No longer recruiting FDA 104A PROTOCOL ID NUMBERS No longer recruiting FDA 104B PROTOCOL ID NUMBERS No longer recruiting FDA 130A PROTOCOL ID NUMBERS No longer recruiting FDA 270A PROTOCOL ID NUMBERS No longer recruiting NCI 89 C-89 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 020 PHARMACOLOGICAL ACTION MODE OF ACTION: Acyclovir is converted to acyclovir monophosphate, a nucleotide analogue, by Herpes simplex virus-coded thymidine kinase. The monophosphate is converted to diphosphate by cellular guanylate kinase, and to triphosphate by various cellular enzymes. The triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits DNA replication. In one trial capsules were administered in doses of 200 to 1000mg every 4 hours, 6 times daily for 5 days. Steady state plasma levels were reached on the second day of dosing. Mean plasma concentrations after the final 200mg and 800mg dose were 0.49 microgram/ml and 1.8 microgram/ml, respectively. Mean plasma half-life ranges from 2.5 to 3.3 hours. The only urinary metabolite identified is 9-((carboxymethoxy)methyl)guanine. Half-life and total body clearance are dependent on renal function. [PDR 1997; p 1187-8] DISEASES STUDIED/TREATED Initial treatment and management of recurrent Herpes virus (genitalis; simplex; zoster) infections and chickenpox infections in immunocompromised patients. [PDR 1997; p 1188; USP DI 1996; p 21-2] CLASSIFICATION CODE Antiviral [USP DI 2000; p. 25] OTHER MAJOR USES Initial treatment and management of recurrent Herpes virus (genitalis; simplex; zoster) infections in nonimmunocompromised patients. [PDR 1997; p 1188] SUBSTANCE INTERACTIONS Administration of nephrotoxic drugs with intravenous acyclovir may increase the potential for nephrotoxicity, especially in patients with renal function impairment. Probenecid may decrease tubular excretion of intravenous acyclovir, which may produce increased serum or cerebral spinal fluid concentrations and possible increased toxicity. [USP DI 1996; p 23] ADVERSE EFFECTS The most frequent adverse effects reported include nausea, diarrhea, inflammation or phlebitis at the injection site, transient elevations of serum creatinine, and rash or hives. Less frequent adverse reactions include hematuria, diaphoresis, and increased blood urea nitrogen in patients with impaired renal function. [PDR 1997; p 1189] CONTRAINDICATIONS Acyclovir should not be used by patients who are allergic to any component of the formulation. [PDR 1997; p 1188, 1193] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Synthetic acyclic purine nucleoside analogue. [PDR 1997; p 1187] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H11-N5-O3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 225.21 [USPD 1998; p. 23] CHEMICAL/PHYSICAL DATA Melting Point: 256.5-257 C [Merck Index 1996; p. 27] CHEMICAL/PHYSICAL DATA Elemental Comp: C42.67%, H4.92%, N31.10%, O21.31% [Merck Index 1996; p. 27] CHEMICAL/PHYSICAL DATA Solubility: Acyclovir has maximum solubility in water of 2.5 mg/m1 at 37 C; the sodium salt has a solubility in water exceeding 100 mg/m1. [PDR 1995; p 827, 831] CHEMICAL/PHYSICAL DATA Stability: After reconstitution with sterile water for injection, solutions at concentrations of 50 mg/ml retain their potency for 12 hours at 15 to 25 C. Solutions for intravenous infusion diluted with electrolytes or dextrose retain their potency for 24 hours at 15 to 25 C. [USP DI 1996; p 26] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline powder. [PDR 1997; p 1187] SUBSTANCE DELIVERY DATA DOSAGE FORM: Sterile powder for intravenous infusion (500 mg/vial); ointment (5% formulation); 200 mg capsules; 800 mg tablets; banana-flavored syrup containing 200 mg/tsp. [PDR 1997; p 1189, 1191] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion; topical application; oral. [PDR 1997; p 1189] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store at 15-25 C (59-77 F), and protect from light. [PDR 1997; p 1189, 1191, 1193] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 REFERENCES MED/97012208. Borrego L, Castro I, Frances A, Gimeno C, Soler E. Treatment of acyclovir-resistant perianal herpetic ulceration with intramuscular interferon alfa. Arch Dermatol. 1996 Oct; 132(10):1157-8. MED/97030930. Whitley RJ. The past as prelude to the future: history, status, and future of antiviral drugs. Ann Pharmacother. 1996 Sep; 30 (9):967-71. MED/97006454. Amin AR, Robinson MR, Smith DD, Swenson CF, Luque AE. Trifluorothymidine 0.5% ointment in the treatment of aciclovir-resistant mucocutaneous herpes simplex in AIDS [letter]. AIDS. 1996 Aug; 10(9):1051-3. MED/96420841. Becker BN, Schulman G. Nephrotoxicity of antiviral therapies. Curr Opin Nephrol Hypertens. 1996 Jul; 5(4):375-9. MED/96113365. Fazal BA, Turett GS, Justman JE, Hall G, Telzak EE. Stevens-Johnson syndrome induced by treatment with acyclovir. Clin Infect Dis. 1995 Oct;21(4): 1038-9. MED/96188396. Rodriguez A, Power WJ, Neves RA, Foster CS. Recurrence rate of herpetic uveitis in patients on long-term oral acyclovir. Doc Ohphthalmol. 1995; 90(40)331-40. MED/96034253. Pottage JC Jr, Kessler HA. Herpes simplex virus resistance to acyclovir: clinical relevance. Infect Agents Dis. 1995 Sep; 4(3):115-24. MED/95348530. Gallant JE, Moore RD, Keruly J, Richman DD, Chaisson RE. Lack of association between acyclovir use and survival in patients with advanced human immunodeficiency virus disease treated with zidovudine. Zidovudine Epidemiology Study Group. J Infected Dis. 1995 Aug; 172(2):346-52. MED/95162796. Drew WL, Anderson R, Lang W, Miner RC, Davis G, Lalezari J. Failure of high-dose oral acyclovir to suppress CMV viruria or induce ganciclovir-resistant CMV in HIV antibody positive patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Mar 1; 8(3):289-91. MED/95358532. About I, Capdeville J, Bernard P, Massip P. [Chronic herpes resistant to acyclovir in a patient with AIDS.] Ann Dermatol Venereol. 1994; 121(11):810-3. ENTRY MONTH 199103 LAST REVISION DATE 20001107 339 UNIQUE IDENTIFIER DRG-0007 NAME OF SUBSTANCE Acetaminophen [USPD 1998; p. 18] REGISTRY NUMBER 103-90-2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME N-(4-Hydroxyphenyl)acetanilide [Merck Index 1989; p 8] SYNONYMS Panadol [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Tempra [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Tylenol [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 032 PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PHARMACOLOGICAL ACTION MODE OF ACTION: of Acetaminophen not fully determined, but may act (a) predominantly by inhibiting prostaglandin synthesis in the central nervous system, or (b) to a lesser extent by blocking pain impulse generation through a peripheral action; the peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation. Mechanism of antipyretic action probably is due to the drug acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation, resulting in increased blood flow through the skin, sweating, and heat loss; the centralization probably involves inhibition of prostaglandin synthesis in the hypothalamus. Oral doses of the drug are rapidly and almost completely absorbed; about 90-95% of the drug is metabolized in the liver, principally via conjugation with glucuronic acid, H2SO4, and cysteine; an intermediate metabolite (which may accumulate in overdose after the primary metabolic pathways become saturated) is hepatotoxic and possibly nephrotoxic. The drug exhibits a half-life of 1-4 hours, which does not change with renal failure but may be prolonged in acute overdose, some forms of hepatic disease, the elderly, and the neonate, and may be somewhat shortened in children. Peak plasma levels of 5-20 mcg/ml from doses up to 650 mg are attained in 0.5-2 hours, with the peak effect attained in 1-3 hours and the duration of action lasting for 3-4 hours. Elimination of the drug is principally renal, as metabolites (principally as conjugates), with about 3% of a dose excreted unchanged. [USP DI 1996; p 4] DISEASES STUDIED/TREATED Treatment of mild to moderate fever and pain. [AHFS Drug Information 1996; p 1509] CLASSIFICATION CODE Analgesic [USP DI 2000; p. 8] CLASSIFICATION CODE Antipyretic [USP DI 2000; p. 8] OTHER MAJOR USES Treatment of fever; relief of minor aches and pains. [USP DI 1996; p 3; PDR 1993; p 1415] SUBSTANCE INTERACTIONS Acetaminophen may increase hepatotoxicity risk when administered in chronic alcohol abuse or with hepatotoxic medications or hepatic enzyme inducers; the drug may increase the anticoagulant effect of coumarin- or indandione- derivative anticoagulants; prolonged concurrent use of the drug with a salicylate may increase the risk of analgesic nephropathy, renal papillary necrosis, end-stage renal disease, and kidney and bladder cancer; prolonged concurrent use with other nonsteroidal anti-inflammatory analgesics may also increase the risk of adverse renal effects; Diflunisal may increase the plasma Acetaminophen level by 50%, leading to increased risk of Acetaminophen-induced hepatotoxicity. [USP DI 1996; p 4-5] ADVERSE EFFECTS Rare adverse events include agranulocytosis, anemia, allergic dermatitis, renal colic, renal failure, sterile pyruria and thrombocytopenia. Overdose symptoms include gastrointestinal upset, increased sweating and hepatotoxicity. [USP DI 1996; p 5] CONTRAINDICATIONS Should not be used by patients who have demonstrated an intolerance to Acetaminophen. Risk-benefit should be considered for patients with alcoholism, hepatic disease, viral hepatitis, or severe renal function impairment. [USP DI 1996; p 5] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Acetamido-substituted phenol. [Merck Index 1989; p 8] CHEMICAL/PHYSICAL DATA Molecular Formula: C8-H9-N-O2 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 151.17 [USPD 1998; p. 18] CHEMICAL/PHYSICAL DATA Melting Point: 169-170.5 C [Merck Index 1996; p. 9] CHEMICAL/PHYSICAL DATA Elemental Comp: C63.56%, H6.00%, N9.27%, O21.17% [Merck Index 1996; p. 9] CHEMICAL/PHYSICAL DATA Solubility: Soluble in methanol, ethanol, dimethyl-formamide, ethylene dichloride, acetone, ethyl acetate; slightly soluble in ether; very slightly soluble in cold water, considerably more soluble in hot water; insoluble in petroleum ether, pentane, benzene. [Merck Index 1989; p 8] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White, odorless crystalline powder with a slightly bitter taste. [PDR 1993; p 2287] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules, tablets, solutions and suppositories. [USP DI 1996; p 8-9] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral;rectal. [USP DI 1996; p 7-8] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store below 40 C (104 F), preferably at 15-30 C (59-86 F) in tight container and protect from freezing. [USP DI 1996; p 8-9] MANUFACTURERS 0000001072: Roxane Laboratories Inc 1809 Wilson Rd / PO Box 16532 Columbus, OH 432288601 Contact: Clinical and Medical Info (800)327-4865 MANUFACTURERS 0000004003: SmithKline Beecham Pharmaceuticals One Franklin Plaza / P O Box 7929 Philadelphia, PA 19101 Contact: Drug Information (800)366-8900 MANUFACTURERS 0000001225: Warner-Lambert 201 Tabor Rd Morris Plains, NJ 07950 Contact: Information (800)520-1631 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Patient Assistance (800)274-8651 MANUFACTURERS 0000005220: McNeil Consumer Healthcare 7050 Camp Hill Road Ft Washington, PA 19034 Contact: Unspecified (800)962-8364 REFERENCES MED/94301428. Burger DM, Meenhorst PL, Underberg WJ, van de Heijde JF, Koks CH, Beijnen JH. Short-term, combined use of paracetamol and zidovudine does not alter the pharmacokinetics of either drug. Neth J Med. 1994 May;44(5):161-5. MED/94250987. Burger DM, Meenhorst PL, Koks CH, Beijnen JH. Pharmacokinetics of zidovudine and acetaminophen in a patient on chronic acetaminophen therapy. Ann Pharmacother. 1994 Mar;28(3):327-30. MED/93377694. Ameer B. Acetaminophen hepatotoxicity augmented by zidovudine]. Am J Med. 1993 Sep;95(3):342. ICA10/94371469. Gonzales M, Esteban A, Mora A, Priego M, Boix V, Portilla J, Perez-Mateo M. Acetaminophen (A) metabolism in HIV infection. Int Conf AIDS. 1994 Aug 7-12;10(2):208 (abstract no. PBO844). MED/92328062. Shriner K, Goetz MB. Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. Am J Med. 1992 Jul;93(1):94-6. MED/91286869. Nicholas SW. Guidelines for the care of children and adolescents with HIV infection. Management of the HIV-positive child with fever. J Pediatr. 1991 Jul;119(1 (Pt 2)):S21-4. MED/91221416. Sattler FR, Ko R, Antoniskis D, Shields M, Cohen J, Nicoloff J, Leedom J, Koda R. Acetaminophen does not impair clearance of zidovudine. Ann Intern Med. 1991 Jun 1;114(11):937-40. MED/90278711. Steffe EM, King JH, Inciardi JF, Flynn NF, Goldstein E, Tonjes TS, Benet LZ. The effect of acetaminophen on zidovudine metabolism in HIV-infected patients. J Acquir Immune Defic Syndr. 1990;3(7):691-4. ICA5/00291889. Steffe E, Inciardi J, King J, Flynn N, Goldstein E, Tanjes T. Analysis of the effect of acetaminophen on zidovudine pharmacokinetics in HIV infected patients. Int Conf AIDS. 1989 Jun 4-9;5:560 (abstract no. M.C.P.113). ICA5/00130189. Pazin GJ, Ptachcinski RJ, Sheehan M, Ho M. Interactive pharmacokinetics of zidovudine and acetaminophen. Int Conf AIDS. 1989 Jun 4-9;5:278 (abstract no. M.B.P.338). ENTRY MONTH 199103 LAST REVISION DATE 20000801 340 UNIQUE IDENTIFIER DRG-0006 NAME OF SUBSTANCE Amphotericin B [USPD 1998; p. 51] REGISTRY NUMBER 1397-89-3 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Amphotericin B [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Amphocin [USP DI 2000; p. 117] SYNONYMS Fungizone [USP DI 2000; p. 117] PROTOCOL ID NUMBERS Complete FDA 051A PROTOCOL ID NUMBERS Complete NIAID ACTG 026 PROTOCOL ID NUMBERS Complete NIAID ACTG 059 PROTOCOL ID NUMBERS Complete NIAID ACTG 159 PROTOCOL ID NUMBERS Complete NIAID ACTG 202 PROTOCOL ID NUMBERS Complete NIAID ACTG 295 PROTOCOL ID NUMBERS No longer recruiting FDA 001A PROTOCOL ID NUMBERS No longer recruiting FDA 012D PROTOCOL ID NUMBERS No longer recruiting FDA 012F PROTOCOL ID NUMBERS No longer recruiting FDA 012G PROTOCOL ID NUMBERS No longer recruiting FDA 012H PROTOCOL ID NUMBERS No longer recruiting FDA 012N PROTOCOL ID NUMBERS No longer recruiting FDA 131A PROTOCOL ID NUMBERS No longer recruiting FDA 254A PROTOCOL ID NUMBERS No longer recruiting CC 97 I-0164 PROTOCOL ID NUMBERS No longer recruiting FDA B013 PHARMACOLOGICAL ACTION MODE OF ACTION: The metabolic pathways are unknown, however antifungal action is probably due to binding to sterols in the fungal cell membrane, changing membrane permeability that allows loss of potassium and small molecules from the cell. Amphotericin B distributes to lungs, liver, spleen, kidneys, adrenal glands, muscle, and other tissues at potentially therapeutic concentrations, but is usually undetectable in cerebrospinal fluid. The drug circulating in plasma appears to be highly bound (above 90%) to plasma proteins and is poorly dialyzable. Initial intravenous injection of 1-5 mg/day gradually increased to 0.4-0.6 mg/kg/day produced peak plasma levels ranging from about 0.5-2 mcg/ml; after a rapid initial fall, a plasma level plateau was attained at about 0.5 mcg /ml; an elimination half-life of about 15 days followed an initial plasma half-life of about 24 hours. Amphotericin B is excreted slowly by the kidneys, with 2-5% of the dose excreted in its biologically active form; cumulative urinary output over 7 days amounts to about 40% of the amount of the drug infused. [USP DI 1996; p 98; PDR 1997; p 507] DISEASES STUDIED/TREATED Acute cryptococcal meningitis. [AHFS Drug Information 1996; p 74] CLASSIFICATION CODE Antifungal [USP DI 2000; p. 107] CLASSIFICATION CODE Antiprotozoal [USP DI 2000; p. 107] OTHER MAJOR USES Used in treatment of patients with progressive, potentially fatal fungal infections, including cryptococcosis (torulosis); North American blastomycosis; disseminated forms of moniliasis, coccidioidomycosis, and histoplasmosis; mucormycosis (phycomycosis) caused by species of the genera Mucor, Rhizopus, Absidia, Entomophthora, and Basidiobolus; sporotrichosis; and aspergillosis. [PDR 1997; p 508] SUBSTANCE INTERACTIONS May interact with antineoplastic agents (e.g., nitrogen mustard), corticosteroids and corticotropin (ACTH), digitalis glycosides, flucytosine, other nephrotoxic medications, skeletal muscle relaxants (e.g., Tubocurarine) and imidazoles (e.g., fluconazole). [PDR 1997; p 508] ADVERSE EFFECTS May induce fever (often with shaking chills), headache, anorexia, weight loss, nausea, vomiting, diarrhea, muscle and joint pains, reversible renal dysfunction, hypokalemia, anemia, irregular heartbeat, blurred vision, polyneuropathy, ear ringing, seizures, troubled breathing, skin rash, agranulocytosis, leukopenia, and thrombocytopenia. [PDR 1997; p 508; USP DI 1996; p 98; AmfAR Treat Dir 1993;6(3); p 45] CONTRAINDICATIONS Contraindicated in patients with hypersensitivity to amphotericin B. [PDR 1997; p 508] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: An antimycotic polyene antibiotic. [PDR 1997; p 704] CHEMICAL/PHYSICAL DATA Molecular Formula: C47-H73-N-O17 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 924.10 [USPD 1998; p. 51] CHEMICAL/PHYSICAL DATA Elemental Comp: C61.09%, H7.96%, N1.52%, O29.43% [Merck Index 1996; p. 99] CHEMICAL/PHYSICAL DATA Solubility: 0.1 mg/ml in water at pH2 or pH 11; dimethylformamide (DMF) to 2-4 mg/ml; DMF plus HCl to 60-80 mg/ml; dimethylsulfoxide (DMSO) to 30-40 mg/ml; insoluble in water at pH 6-7; Amphotericin B for injection USP yields a colloidal dispersion in water [Merck Index 1989; p 93] CHEMICAL/PHYSICAL DATA Stability: Solids and solutions appear stable for long periods between pH 4-10 when stored at moderate temperatures out of contact with light and air; decomposes gradually above 170 C. UV max (methanol): 406, 382, 363, 345 nm. [Merck Index 1989; p 93] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Yellow to orange lyophilized cake. [PDR 1997; p 509] SUBSTANCE DELIVERY DATA DOSAGE FORM: Initial concentrate of 5mg/ml is first prepared by expressing 10ml sterile water without a bacteriostatic agent directly into the lyophilized cake. Shake the vial immediately untill colloidal solution is clear. The infusion solution of 0.1mg amphotericin B is obtained by futher dilution (1:50) with 5% dextrose. [PDR 1997; p 509] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Slow intravenous infusion. [PDR 1997; p 508] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Prior to reconstitution, store at 2-8 C (36-46 F) in the dark; protect solutions prepared for intravenous infusion from light during administration. [USP DI 1996; p 100; PDR 1997; p 509] MANUFACTURERS 0000001001: Pharmacia & Upjohn 100 Route 206 North Peapack, NJ 07977 Contact: Dr Donald M Demke (616)833-8586 MANUFACTURERS 0000001199: Schering - Plough Research 2000 Galloping Hill Rd Kenilworth, NJ 07033 Contact: Professional Information (800)526-4099 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)432-4702 MANUFACTURERS 0000002711: Bristol - Myers Squibb Co PO Box 4500 Princeton, NJ 085434500 Contact: Unspecified (800)321-1335 REFERENCES MED/97193057. More new drugs for HIV and associated infections. Med Lett Drugs Ther. 1997 Feb 14; 39(994):14-6. MED/97153227. Kelly SL, Lamb DC, Kelly DE, Manning NJ, Loeffler J, Hebart H, Schumacher U, Einsele H. Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation. FEBS Lett. 1997 Jan 2; 400(1):80-2. MED/97046181. Aberg JA, Powderly WG. Cryptococcosis. Adv Pharmacol. 1997; 37:215-51. MED/97081589. Barlows TG 3rd, Luber AD, Jacobs RA, Guglielmo BJ. Hypothermia following the intravenous administration of amphotericin B. Clin Infect Dis. 1996 Nov; 23(5):1187-8. MED/97032328. Gonzalez CE, Shetty D, Lewis LL, Mueller BU, Pizzo PA, Walsh TJ. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1996 Sep; 15(9):796-800. MED/97011461. Petit N, Parola P, Dhiver C, Gastaut JA. Efficacy and tolerance of amphotericin B in a lipid emulsion in the treatment of visceral leishmaniasis in AIDS patients [letter]. J Antimicrob Chemother. 1996 Jul; 38(1):154-7. MED/97011453. Joly V, Geoffray C, Reynes J, Goujard C, Mechali D, Maslo C, Raffi F, Yeni P. Amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients. J Antimicrob Chemother. 1996 Jul; 38(1):117-26. MED/97060079. Ghannoum MA, Rex JH, Galgiani JN. Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome. J Clin Micorbiol. 1996 Mar; 34(3):489-95. ENTRY MONTH 199103 LAST REVISION DATE 20001107 341 UNIQUE IDENTIFIER DRG-0005 NAME OF SUBSTANCE Fluconazole [USPD 2000; p 308] REGISTRY NUMBER 86386-73-4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME 1H-1,2,4-Triazole-1-ethanol, alpha-(2,4-difluorophenyl)-alpha-(1H-1,2,4-tr- iazol-1-ylmethyl)- [USPD 1998; p. 314] SYNONYMS Diflucan [USP DI 2000; p 319] PROTOCOL ID NUMBERS Complete NIAID ACTG 026 PROTOCOL ID NUMBERS Complete NIAID ACTG 059 PROTOCOL ID NUMBERS Complete NIAID ACTG 159 PROTOCOL ID NUMBERS Complete NIAID ACTG 174 PROTOCOL ID NUMBERS Complete NIAID ACTG 202 PROTOCOL ID NUMBERS Complete NIAID ACTG 981 PROTOCOL ID NUMBERS No longer recruiting FDA 012A PROTOCOL ID NUMBERS No longer recruiting FDA 012B PROTOCOL ID NUMBERS No longer recruiting FDA 012C PROTOCOL ID NUMBERS No longer recruiting FDA 012D PROTOCOL ID NUMBERS No longer recruiting FDA 012F PROTOCOL ID NUMBERS No longer recruiting FDA 012G PROTOCOL ID NUMBERS No longer recruiting FDA 012H PROTOCOL ID NUMBERS No longer recruiting FDA 012I PROTOCOL ID NUMBERS No longer recruiting FDA 012J PROTOCOL ID NUMBERS No longer recruiting FDA 012K PROTOCOL ID NUMBERS No longer recruiting FDA 012L PROTOCOL ID NUMBERS No longer recruiting FDA 012M PROTOCOL ID NUMBERS No longer recruiting FDA 012N PROTOCOL ID NUMBERS No longer recruiting FDA 012P PROTOCOL ID NUMBERS No longer recruiting FDA 012Q PROTOCOL ID NUMBERS No longer recruiting FDA 012R PROTOCOL ID NUMBERS No longer recruiting FDA 120 PROTOCOL ID NUMBERS No longer recruiting FDA 213A PROTOCOL ID NUMBERS No longer recruiting FDA 226A PROTOCOL ID NUMBERS No longer recruiting FDA 236A PROTOCOL ID NUMBERS No longer recruiting FDA 288A PROTOCOL ID NUMBERS No longer recruiting FDA 305A PROTOCOL ID NUMBERS No longer recruiting CC 95 CC-102 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 283 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 323 PROTOCOL ID NUMBERS No longer recruiting FDA B013 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 010 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 030 PROTOCOL ID NUMBERS Recruiting CC 96 I-0108 PHARMACOLOGICAL ACTION Fluconazole is fungistatic. It works by inhibiting fungal cytochrome P450 activity necessary for the demethylation of sterol C-14. This depletes ergosterol, the principal sterol in the fungal cell membrane, and produces alterations in membrane function and permeability. While fluconazole has a weak affinity for mammalian P-450 enzymes, the degree of enzyme inhibition or induction is variable. Fluconazole appears to have minimal effect on human steroid synthesis. The pharmacokinetic properties of fluconazole are similar following administration by oral or intravenous routes. Orally administered fluconazole is over 90% bioavailable. Peak plasma concentrations occur one to two hours after oral administration in fasted, healthy subjects. The rate and extent of absorption is not affected by the presence of food or stomach acid. Steady-state concentrations are reached within 5 to 10 days following once-daily oral doses. Onset of steady state can occur in as little as 2 days if a loading dose equal to twice the usual daily dose is given. Protein binding is low (11-12%). The apparent volume of distribution approximates that of total body water. Fluconazole distributes readily throughout the body with good penetration into urine and skin (approximately 10 times the plasma concentration); distribution into saliva, sputum, nails, and vaginal tissue occurs in concentrations approximately equal to that of plasma. In patients with fungal meningitis, concentrations in cerebrospinal fluid can reach approximately 80% of the corresponding plasma concentration. The terminal elimination half-life of fluconazole is approximately 30 hours (range: 20-50 hours). The primary route of elimination is renal, with about 80% of the dose appearing in urine as unchanged drug. Therefore, the pharmacokinetics of fluconazole are markedly affected by a reduction in renal function. Results of a few limited studies indicate that HIV-infected adults may have a smaller apparent volume of distribution, longer plasma half-life, and reduced renal clearance of fluconazole relative to healthy adults. [PDR 2000; p 2338; USP DI 2000; p 320; AHFS Drug Information 2000; p 90; AHFS Drug Information 2000; p 90; PDR 2000; p 2338; AHFS Drug Information 2000; p 90; PDR 2000; p 2338; AHFS Drug Information 2000; p 90; PDR 2000; p 2338; AHFS Drug Information 2000; p 90] DISEASES STUDIED/TREATED Fluconazole is FDA-approved for the treatment and suppression of meningitis caused by Cryptococcus neoformans in patients with AIDS. It is also approved for the treatment of vulvovaginal, oropharyngeal, and esophageal infections, as well as more serious systemic infections (candidemia, peritonitis, pneumonia, and urinary tract infections) caused by Candida species. Although not an FDA-approved use, fluconazole is indicated in the treatment of severe, chronic extensive mucocutaneous Candida infections. Other off-label uses are the treatment, suppression, or primary prophylaxis of infections in select HIV-infected populations. Susceptible species include Candida, Cryptococcus, Coccidioides, Histoplasma, Blastomyces, and Aspergillosis. [USP DI 2000; p 319; USP DI 2000; p 319; AHFS Drug Information 2000; p 92-6] CLASSIFICATION CODE Antifungal [USP DI 2000; p 319] OTHER MAJOR USES Fluconazole is FDA-approved for the treatment of vaginal, oropharyngeal, and esophageal candidiasis, as well as serious systemic infections (peritonitis, pneumonia, and urinary tract infections) caused by Candida species. It also is approved for prevention of candidiasis in patients undergoing bone marrow transplant who receive cytotoxic chemotherapy or radiation therapy. Non-approved indications include treatment of onychomycosis caused by Trichophyton and Candida species and treatment of tinea corporis, cruris, pedis, and manuum. [USP DI 2000; p 319] SUBSTANCE INTERACTIONS There are no reported effects of food on fluconazole. Clinically or potentially significant drug interactions between fluconazole and cisapride, terfenadine, zidovudine, warfarin, oral hypoglycemic agents, theophylline, phenytoin, carbamazepine, cyclosporine, tacrolimus, rifampin, and rifabutin have been reported. Because of the risk of serious cardiac arrhythmias caused by prolongation of the QT interval, coadministration with cisapride is contraindicated. When fluconazole is given in doses of 400 mg or greater, administration with terfenadine also is contraindicated. In the absence of more information about the effect of astemizole on the QT interval, caution should be used when combining the drugs. Coadministration of fluconazole and zidovudine results in a 20% mean increase in the zidovudine area-under-the-concentration-time curve (range: 27 to 104%). Patients taking fluconazole and warfarin concomitantly may have an increased prothrombin time. Fluconazole can increase the plasma concentrations of oral hypoglycemic agents, such as tolbutamide, glyburide, or glipizide, resulting in hypoglycemia. Plasma concentrations of theophylline, phenytoin, carbamazepine, cyclosporine, and tacrolimus can also increase, leading to possible toxicity. Rifampin increases the metabolism of fluconazole, which may necessitate an increase in fluconazole dose. There have been reports of uveitis in patients taking rifabutin and fluconazole concurrently. [PDR 2000; p 2340] ADVERSE EFFECTS Serious hepatotoxicity, including death, has been associated occasionally with the use of fluconazole. There is no apparent relationship to the total daily dose, duration of therapy, gender, or patient age. Fluconazole should be stopped if a patient develops clinical signs and symptoms consistent with hepatic disease. Rare cases of anaphylaxis and exfoliative skin disorders, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients with AIDS, Stevens-Johnson syndrome and toxic epidermal necrolysis have resulted in death. Other common adverse effects include abdominal pain, diarrhea, headache, nausea, vomiting, skin rash, and alopecia. The overall incidence of adverse effects with fluconazole use has been reported to be higher in patients infected with HIV compared to those not infected. However, many patients in these studies were also receiving other medications known to be associated with hepatotoxicity or exfoliative skin disorders, making a causal association with fluconazole difficult. [PDR 2000; p 2341; USP DI 2000; p 322; AHFS Drug Information 2000; p 97; USP DI 2000; p 322] CONTRAINDICATIONS Coadministration of fluconazole with cisapride or terfenadine is contraindicated. Also, fluconazole is contraindicated in patients who are allergic to fluconazole or to any of its ingredients. There is no information regarding cross sensitivity with the other azole antifungal agents. [PDR 2000; p 2340] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Fluconazole is a synthetic triazole antifungal agent. [PDR 2000; p 2338] CHEMICAL/PHYSICAL DATA Molecular Formula: C13-H12-F2-N6-O [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 306.3 [USPD 2000; p 308] CHEMICAL/PHYSICAL DATA Melting Point: 138-140 C [Merck Index 1996; p 698] CHEMICAL/PHYSICAL DATA Elemental Comp: C50.98%, H3.95%, F12.41%, N27.44%, O5.22% [Merck Index 1996; p 698] CHEMICAL/PHYSICAL DATA Solubility: Slightly soluble in water (8mg/ml at 37 C) and soluble in alcohol (25mg/ml at 20 C) [AHFS Drug Information 2000; p. 90] CHEMICAL/PHYSICAL DATA Stability: The oral suspensions retain their potency for 14 days after reconstitution. [PDR 2000; p 2342] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White crystalline solid [PDR 2000; p. 2338] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (50, 100, and 200 mg); powder for oral suspension (35ml bottles containing 10 or 40 mg/ml when reconstituted); intravenous solutions (100ml and 200ml volumes containing 2 mg/ml, packaged in glass or Viaflex containers) [PDR 2000; p 2342] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous injection [PDR 2000; p 2342] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store tablets and powder for oral suspension below 30 C (86 F). Store reconstituted oral suspension between 5-30 C (41-86 F); protect from freezing. Store injection in glass bottles between 5-30 C (41-86 F). Store injection in Viaflex containers between 5-25 C (41-77 F). Brief exposure up to 40 C (104 F) does not adversely affect the product. Protect injection from freezing. [PDR 2000; p 2342] MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Professional Information (800)438-1985 MANUFACTURERS 0000001186: Pfizer Inc 235 East 42nd Street New York, NY 100175755 Contact: Unspecified (800)438-1985 REFERENCES Clin Mgmt Vol 6 - Fungal infections. Medscape Web Site. Available at: http://www.medscape.com/Medscape/HIV/Clinical- Mgmt/CM.v06/public/inde x-CM.v06.html. Accessed May 8, 2000. MED/20053523. Martin MV. The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. J Antimicrob Chemother. 1999 Oct;44(4):429-37. Review. MED/99162009. Saag MS, Cloud GA, Graybill JR, Sobel JD, Tuazon CU, Johnson PC, Fessel WJ, Moskovitz BL, Wiesinger B, Cosmatos D, Riser L, Thomas C, Hafner R, Dismukes WE. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1999 Feb;28(2):291-6. MED/99085535. Havlir DV, Dube MP, McCutchan JA, Forthal DN, Kemper CA, Dunne MW, Parenti DM, Kumar PN, White AC Jr, Witt MD, Nightingale SD, Sepkowitz KA, MacGregor RR, Cheeseman SH, Torriani FJ, Zelasky MT, Sattler FR, Bozzette SA. Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS. Clin Infect Dis. 1998 Dec;27(6):1369-75. MED/98275558. Manfredi R, Chiodo F. Role of fluconazole in the management of AIDS-related cryptococcosis, according to daily dosing. Chemotherapy. 1998 May-Jun;44(3):206-14. MED/97330766. van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, Johnson PC, Tuazon CU, Kerkering T, Moskovitz BL, Powderly WG, Dismukes WE. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997 Jul 3;337(1):15-21. MED/97148120. Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD, Gallant JE. Infection due to fluconazole-resistant Candida in patients with AIDS: prevalence and microbiology. Clin Infect Dis. 1997 Jan;24(1):28-34. MED/96100759. Tett S, Moore S, Ray J. Pharmacokinetics and bioavailability of fluconazole in two groups of males with human immunodeficiency virus (HIV) infection compared with those in a group of males without HIV infection. Antimicrob Agents Chemother. 1995 Aug;39(8):1835-41. MED/96002836. Pinner RW, Hajjeh RA, Powderly WG. Prospects for preventing cryptococcosis in persons infected with human immunodeficiency virus. Clin Infect Dis. 1995 Aug;21 Suppl 1:S103-7. Review. MED/95157588. Powderly WG, Finkelstein D, Feinberg J, Frame P, He W, van der Horst C, Koletar SL, Eyster ME, Carey J, Waskin H, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995 Mar 16;332(11):700-5. ENTRY MONTH 199103 LAST REVISION DATE 20001024 342 UNIQUE IDENTIFIER DRG-0004 NAME OF SUBSTANCE Zidovudine [USPD 1998; p. 793] REGISTRY NUMBER 30516-87-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Thymidine, 3'-azido-3'-deoxy- [USPD 1998; p 793] SYNONYMS component of Combivir [Protocol ID: 280A ] SYNONYMS component of Trizivir [Protocol ID: 308A ] SYNONYMS Retrovir [USP DI 2000; p. 3181] PROTOCOL ID NUMBERS Complete FDA 014A PROTOCOL ID NUMBERS Complete FDA 014B PROTOCOL ID NUMBERS Complete FDA 014C PROTOCOL ID NUMBERS Complete FDA 014D PROTOCOL ID NUMBERS Complete FDA 014K PROTOCOL ID NUMBERS Complete FDA 246G PROTOCOL ID NUMBERS Complete CC 88 I-181 PROTOCOL ID NUMBERS Complete CC 91 CC-0019 PROTOCOL ID NUMBERS Complete NIAID ACTG 001 PROTOCOL ID NUMBERS Complete NIAID ACTG 002 PROTOCOL ID NUMBERS Complete NIAID ACTG 003 PROTOCOL ID NUMBERS Complete NIAID ACTG 004 PROTOCOL ID NUMBERS Complete NIAID ACTG 005 PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 010 PROTOCOL ID NUMBERS Complete NIAID ACTG 013 PROTOCOL ID NUMBERS Complete NIAID ACTG 014 PROTOCOL ID NUMBERS Complete NIAID ACTG 016 PROTOCOL ID NUMBERS Complete NIAID ACTG 017 PROTOCOL ID NUMBERS Complete NIAID ACTG 019 PROTOCOL ID NUMBERS Complete NIAID ACTG 021 PROTOCOL ID NUMBERS Complete NIAID ACTG 024 PROTOCOL ID NUMBERS Complete NIAID ACTG 027 PROTOCOL ID NUMBERS Complete NIAID ACTG 032 PROTOCOL ID NUMBERS Complete NIAID ACTG 033 PROTOCOL ID NUMBERS Complete NIAID ACTG 036 PROTOCOL ID NUMBERS Complete NIAID ACTG 037 PROTOCOL ID NUMBERS Complete NIAID ACTG 042 PROTOCOL ID NUMBERS Complete NIAID ACTG 043 PROTOCOL ID NUMBERS Complete NIAID ACTG 047 PROTOCOL ID NUMBERS Complete NIAID ACTG 049 PROTOCOL ID NUMBERS Complete NIAID ACTG 050 PROTOCOL ID NUMBERS Complete NIAID ACTG 051 PROTOCOL ID NUMBERS Complete NIAID ACTG 052 PROTOCOL ID NUMBERS Complete NIAID ACTG 053 PROTOCOL ID NUMBERS Complete NIAID ACTG 055 PROTOCOL ID NUMBERS Complete NIAID ACTG 057 PROTOCOL ID NUMBERS Complete NIAID ACTG 061 PROTOCOL ID NUMBERS Complete NIAID ACTG 062 PROTOCOL ID NUMBERS Complete NIAID ACTG 063 PROTOCOL ID NUMBERS Complete 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PROTOCOL ID NUMBERS No longer recruiting FDA 264D PROTOCOL ID NUMBERS No longer recruiting FDA 280A PROTOCOL ID NUMBERS No longer recruiting FDA 281B PROTOCOL ID NUMBERS No longer recruiting NCI 86 C-174 PROTOCOL ID NUMBERS No longer recruiting NCI 86 C-175 PROTOCOL ID NUMBERS No longer recruiting NCI 87 C-179B PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-102 PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-177 PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-47 PROTOCOL ID NUMBERS No longer recruiting NCI 88 C-92 PROTOCOL ID NUMBERS No longer recruiting CC 88 EI-199 PROTOCOL ID NUMBERS No longer recruiting CC 88 I-172 PROTOCOL ID NUMBERS No longer recruiting NCI 89 C-89 PROTOCOL ID NUMBERS No longer recruiting CC 89 CC-75 PROTOCOL ID NUMBERS No longer recruiting CC 89 I-139 PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting CC 90 CC-04 PROTOCOL ID NUMBERS No longer recruiting CC 90 I-15 PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-01 PROTOCOL ID NUMBERS No longer recruiting NCI 91 C-18 PROTOCOL ID NUMBERS No longer recruiting CC 91 CC-143 PROTOCOL ID NUMBERS No longer recruiting CC 91 I-112 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-155 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-192 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-207 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-21 PROTOCOL ID NUMBERS No longer recruiting NCI 93 C-70 PROTOCOL ID NUMBERS No longer recruiting CC 93 CC-113 PROTOCOL ID NUMBERS No longer recruiting CC 93 I-109 PROTOCOL ID NUMBERS No longer recruiting NCI 94 C-35 PROTOCOL ID NUMBERS No longer recruiting CC 94 I-76 PROTOCOL ID NUMBERS No longer recruiting NCI 95 C-163 PROTOCOL ID NUMBERS No longer recruiting NCI 95 C-83 PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-0003G PROTOCOL ID NUMBERS No longer recruiting NCI 96 C-63 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 176 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 185 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 328 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 331 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 332 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 338 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 353 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 354 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 364 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 366 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 370 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 372 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 375 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 384 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG 400 PROTOCOL ID NUMBERS No longer recruiting NIAID ACTG A5051 PROTOCOL ID NUMBERS No longer recruiting NIAID CPCRA 007 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 002 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 003 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 012 PROTOCOL ID NUMBERS No longer recruiting NIAID DATRI 013 PROTOCOL ID NUMBERS No longer recruiting NIAID HIVNET 012 PROTOCOL ID NUMBERS No longer recruiting NIAID SPIRAT 3 PROTOCOL ID NUMBERS No longer recruiting NIAID TX 304 PROTOCOL ID NUMBERS Recruiting FDA 259H PROTOCOL ID NUMBERS Recruiting CC 97 I-082 PROTOCOL ID NUMBERS Recruiting CC 99 I-0032 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 317 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 321 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 345 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 356 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 358 PROTOCOL ID NUMBERS Recruiting NIAID ACTG 386 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5062 PROTOCOL ID NUMBERS Recruiting NIAID ACTG A5095 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-02-001 PROTOCOL ID NUMBERS Recruiting NIAID AIEDRP AI-04-008 PROTOCOL ID NUMBERS Suspended NIAID ACTG 324 PROTOCOL ID NUMBERS Suspended NIAID ACTG P1022 PROTOCOL ID NUMBERS Terminated CC 90 I-114 PROTOCOL ID NUMBERS Terminated NIAID ACTG 009 PROTOCOL ID NUMBERS Terminated NIAID ACTG 020 PROTOCOL ID NUMBERS Terminated NIAID ACTG 088 PROTOCOL ID NUMBERS Terminated NIAID ACTG 131 PROTOCOL ID NUMBERS Terminated NIAID ACTG 133 PROTOCOL ID NUMBERS Terminated NIAID ACTG A5025 PHARMACOLOGICAL ACTION MODE OF ACTION: Following conversion to a pharmacologically active triphosphate metabolite, zidovudine inhibits in vitro replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). Neither zidovudine nor its monophosphate (an intermediate in the formation of the biologically active triphosphate) has in vitro activity against HIV. Because phosphorylation of zidovudine depends on cellular rather than viral enzymes, conversion to the active triphosphate derivative occurs in HIV-infected and uninfected cells. Zidovudine triphosphate appears to compete with thymidine triphosphate for the reverse transcriptase and incorporation into viral DNA. After incorporation of the zidovudine triphosphate, DNA synthesis is prematurely terminated because the 3'-azido group in the zidovudine molecule prevents further 5' to 3' phosphodiester linkages. The major metabolite of zidovudine, 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranosylt- hymidine, has no antiviral activity. Zidovudine is rapidly absorbed from the GI tract. Further studies are needed to determine the effect the presence of food or milk has on GI absorption of zidovudine. Following IV infusion of zidovudine over 1 hr of a single 2.5 mg or 5 mg dose in HIV+ adults, plasma concentrations range from 1.07-1.6 or 1.6-2.7 microgram/ml respectively. The drug appears to be widely distributed in the body. It is distributed into plasma and CSF; 34-38% is bound to plasma proteins. The drug and its glucuronide metabolite cross the human placenta. The drug is also distributed into human milk. The plasma half-life of zidovudine in adults is approximately 1 hr following oral administration, and 1.1 hr following IV administration. Some 14-18% of unchanged zidovudine and 72-74% of the drug as its major metabolite, are eliminated through the urine. Strains of HIV-1 with in vitro resistance to zidovudine have been isolated. Resistance is most likely to develop in patients with advanced HIV infection and in those on prolonged zidovudine therapy. Laboratory studies showed that HIV strains resistant to zidovudine also were resistant to other 3'-azido nucleoside antiviral agents. Some resistant strains may also be cross-resistant or have decreased susceptibility to other dideoxynucleoside reveres transcriptase inhibitors (e.g., didanosine, lamivudine, stavudine, zalcitabine). Cross-resistance between zidovudine and HIV protease inhibitors is unlikely since the drugs have different target enzymes. The potential of cross-resistance between zidovudine and NNRTIs is also considered to be low since the drugs bind at different sites on the reverse transcriptase and have different mechanisms of action. [AHFS Drug Information 1999; p 633-7] DISEASES STUDIED/TREATED Zidovudine is approved for the treatment of all HIV positive people with a CD4 count less than 500. Results of numerous clinical trials indicate that zidovudine is most effective when used in combination with other antiretroviral drugs. At its peak effectiveness in treatment-naive patients, zidovudine reduces HIV RNA levels by roughly 70%, and as a monotherapy cannot control viral replication in the majority of HIV infected patients. [AmfAR Treat Dir 1998:9(2); p 51] CLASSIFICATION CODE Antiretroviral [U.S. FDA. Office of Special Health Issues. Available at: http://www.fda.gov/oashi/aids/status.html. Accessed: June 30, 2000.] CLASSIFICATION CODE Antiviral [USP DI 2000; p 3176] CLASSIFICATION CODE Nucleoside reverse transcriptase inhibitor [AHFS Drug Information 2000; p 669] SUBSTANCE INTERACTIONS Concomitant ganciclovir or interferon alfa therapy has resulted in hematologic toxicity. Probenecid may increase zidovudine levels by inhibiting glucuronidation and/or by reducing renal excretion. Some patients on concomitant probenecid therapy have developed flu-like symptoms consisting of myalgia, malaise, and/or fever and maculopaplular rash. Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine. In methadone maintenance patients the zidovudine AUC was increased 43% without any adverse clinical effects. Atovaquone decreased zidovudine oral clearance by 24% in HIV patients and resulted in a 35% increase in plasma zidovudine AUC. Coadministration of zidovudine and fluconazole has been reported to interfere with the oral clearance and metabolism of zidovudine. The anti-HIV effects of zidovudine and foscarnet are additive in vitro. Some nucleoside analogs affecting DNA replication, such as ribavirin antagonize the in vitro anti-HIV effect of zidovudine. Concomitant use of such drugs should be avoided. Valproic acid decreased the urinary excretion ratio of zidovudine and its primary metabolite without affecting zidovudine plasma half-life. However, this interaction may increase zidovudine bioavailability and these patients should be monitored for possible zidovudine related adverse effects. Caution should be observed with drugs that affect the renal excretion or hepatic blood flow and decrease zidovudine clearance. Drugs that are nephrotoxic, cytotoxic or myelosuppressive, e.g., amphotericin B, co-trimoxazole, dapsone, doxorubicin, flucytosine, interferon, pentamidine, vinblastine, vincristine, should be used with caution during zidovudine therapy. [PDR 1999; p 1204-5] ADVERSE EFFECTS Reversible bone marrow toxicity, causing anemia or leukopenia, is the major dose-limiting adverse effect of zidovudine treatment. Fatigue, rashes, severe muscle pain and inflammation (myopathy), nausea, insomnia, and headaches are also associated with zidovudine treatment. Side effects are generally more pronounced in patients with advanced HIV disease. In one study, enlarged fatty liver has been reported in 11 patients (10 of them were women and 7 of them were obese) receiving zidovudine, the effect was fatal in 8 of these patients. Potentially fatal lactic acidosis and severe hepatomegaly with steatosis have been reported rarely in patients on zidovudine. The manufacturer suggests that obese women and patients with risk factors for liver disease be followed closely while receiving zidovudine, and that lactic acidosis be considered when patients develop tachypnea, dyspnea, or decreased bicarbonate levels. [AmfAR Treat Dir 1998:9(2); p 53; AHFS Drug Information 1999; p 641] CONTRAINDICATIONS Zidovudine should be used with caution in patients with bone marrow compromise as evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5g/dL. Frequent blood counts are strongly recommended in patients on zidovudine with advanced HIV disease. Zidovudine treatment should be suspended when tachypnea, dyspnea or fall in serum bicarbonate levels develop until the diagnosis of lactic acidosis has been excluded. In patients with severely impaired renal functions, zidovudine dosage reduction is recommended. Patients with severely impaired hepatic functions may be at greater risk of zidovudine-induced toxicity. [PDR 1999; p 1204] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Zidovudine is a dideoxynucleoside reverse transcriptase inhibitor. The compound is a thymidine analog, which contains a 3'-azido group instead of thymidine's 3'-hydroxyl group. This modification prevents the formation of phosphodiester linkages at this position; these are needed for the completion of nucleic acid chains. [MeSH ] CHEMICAL/PHYSICAL DATA Molecular Formula: C10-H13-N5-O4 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 267.25 [USPD 1998; p. 793] CHEMICAL/PHYSICAL DATA Melting Point: 106-112 C [Merck Index 1996; p. 1732] CHEMICAL/PHYSICAL DATA Elemental Comp: C44.94%, H4.90%, N26.21%, O23.95% [Merck Index 1996; p. 1732] CHEMICAL/PHYSICAL DATA Solubility: 25 mg/ml in water at 25C [Merck Index 1996; p 1732] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: White to beige, odorless, crystalline solid. [PDR 1999; p 1202] SUBSTANCE DELIVERY DATA DOSAGE FORM: Tablets (300 mg), capsules (100 mg), syrup (50 mg/5 ml) in bottle of 240 ml. For IV infusion, 10 mg/ml in 20 ml single-use vials. [PDR 1999; p 1207, 1211] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral; intravenous injection. [AHFS Drug Information 1999; p 633] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store oral and intravenous dosage forms at 15-25 C and protect from light; protect capsules from moisture. [AHFS Drug Information 1999; p 633] MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Medical & Consumer Relations (919)483-9959 REFERENCES MED/99094949. Van Dyke RB, Korber BT, Popek E, Macken C, Widmayer SM, Bardeguez A, Hanson IC, Wiznia A, Luzuriaga K, Viscarello RR, et al. The Ariel Project: A prospective cohort study of maternal-child transmission of human immunodeficiency virus type 1 in the era of maternal antiretroviral therapy. J Infect Dis. 1999 Feb;179(2):319-28.. MED/99094950. Rinaldo Jr CR, Liebmann JM, Huang XL, Fan Z, Al-Shboul Q, McMahon DK, Day RD, Riddler SA, Mellors JW. Prolonged suppression of human immunodeficiency virus type 1 (HIV-1) viremia in persons with advanced disease results in enhancement of CD4 T cell reactivity to microbial antigens but not to HIV-1 antigens. J Infect Dis. 1999 Feb;179(2):329-36. MED/99134816. Paul SM, Jorden V, Costa SJ, Ziskin LZ. Recommendations for occupational exposures to HIV. N J Med. 1999 Jan;96(1):41-6. MED/99119001. Chan EF, Dowdy YG, Lee B, McKenna WG, Fox KR, Levy RJ, Wasik MA, Rook AH. A novel chemotherapeutic regimen (interferon alfa, zidovudine, and etretinate) for adult T-cell lymphoma resulting in rapid tumor destruction. J Am Acad Dermatol. 1999 Jan;40(1):116-21. MED/99120767. Baleta A. Huge percentage of women volunteer for zidovudine project [news]. Lancet. 1999 Jan 16;353(9148):219. MED/99125804. Floridia M, Bucciardini R, Ricciardulli D, Fragola V, Pirillo MF, Weimer LE, Tomino C, Giannini G, Galluzzo CM, Andreotti M, et al. A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Jan 1;20(1):11-9. MED/99125805. Simonelli C, Zanussi S, Sandri S, Comar M, Lucenti A, Talamini R, Bortolin MT, Giacca M, De Paoli P, Tirelli U. Concomitant therapy with subcutaneous interleukin-2 and zidovudine plus didanosine in patients with early stage HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Jan 1;20(1):20-7. MED/99045103. Andreoni M, Sarmati L, Nicastri E, Ventura L, Ercoli L, Parisi SG, Giannini G, Galluzzo C, Vella S. Saquinavir delays the emergence of zidovudine resistance in HIV-1 seropositive patients treated with combination therapy. J Med Virol. 1998 Dec;56(4):332-6. AIDS/99703987. Updated postexposure guidelines stress need for expert advice. AIDS Alert. 1998 Jul;13(7):73-5. MED/99074463. Atlante A, Passarella S. AZT side effect on mitochondria does not depend on either inhibition of electron flow or mitochondrial uncoupling. Int J Mol Med. 1998 Mar;1(3):601-3. ENTRY MONTH 199103 LAST REVISION DATE 20000921 343 UNIQUE IDENTIFIER DRG-0003 NAME OF SUBSTANCE Cysteamine [USPD 2000 2000; p 198] REGISTRY NUMBER 60-23-1 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] STANDARD CHEMICAL NAME Ethanethiol, 2-amino- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 11/07/00.] SYNONYMS Cystagon [USP DI 2000; p. 3297] PROTOCOL ID NUMBERS No longer recruiting FDA 211A PHARMACOLOGICAL ACTION MODE OF ACTION: The effect of cysteamine (mercaptoethylamine, MEA) on HIV-1 replication has been studied in vitro. This study concluded that (1) MEA at non-toxic concentrations inhibits HIV-1 replication in mononuclear cell systems; (2) virus which emerges in drug treated H9 cells remains inhibitable by MEA; (3) MEA acts synergistically with ZDV, DDI and DDC versus HIV-1; and (4) the mechanism of action is unclear but may involve disruption of disulfide bonds in the HIV Env. [Int Conf AIDS 1993 Jun 6-11;9(1); 230 (abstract no. PO-A25-0571); Prog Abst Intersci Conf Antimicrob Agents Chemother 1994 Oct; p 93] DISEASES STUDIED/TREATED Primary HIV infection. [Int Conf AIDS 1993 Jun 6-11;9(1); 230 (abstract no. PO-A25-0571)] CLASSIFICATION CODE Antiurolithic [USPD 2000; p 198] OTHER MAJOR USES Antidote to acetaminophen. Treatment of nephropathic cystinosis. [USP DI 1995; p 2971] SUBSTANCE INTERACTIONS MEA acts synergistically with ZDV versus HIV-1 in vitro. [Int Conf AIDS 1993 Jun 6-11;9(1); 230 (abstract no. PO-A25-0571)] ADVERSE EFFECTS Produces acute and chronic duodenal ulcers in rats (cysteamine given 3 times within 8 hours produced ulcers in female SIV infected rats). Abdominal pain; anorexia; diarrhea; fever; lethargy; nausea or vomiting; skin rash. [Merck Index 1989; p 436; Scand J Gastroenterol Suppl 1984;92; p 121-4; USP DI 1996; suppl. p 195] CONTRAINDICATIONS Risk-benefits should be considered when the following problems exist: blood disorders; hepatic function impairment; seizures. [USP DI 1996; suppl. p 195] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: A sulfhydryl compound with a variety of biological effects. [Merck Index 1989; p 436] CHEMICAL/PHYSICAL DATA Molecular Formula: C2-H7-N-S [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 77.15 [USPD 1998; p. 205] CHEMICAL/PHYSICAL DATA Melting Point: 97-98.5 C [Merck Index 1996; p. 470] CHEMICAL/PHYSICAL DATA Elemental Comp: C31.14%, H9.15%, N18.16%, S41.56% [Merck Index 1996; p. 470] CHEMICAL/PHYSICAL DATA Solubility: Freely soluble in water, alkaline reaction. [Merck Index 1989; p 436] CHEMICAL/PHYSICAL DATA Stability: Oxidizes to cystamine on standing in air. [Merck Index 1989; p 436] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsule. [Protocol ID: 211A ] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Oral. [Protocol ID: 211A ] MANUFACTURERS 0000002795: Mylan Laboratories Inc 1030 Century Building / 130 Seventh St Pittsburgh, PA 15222 Contact: (412)232-0100 MANUFACTURERS 0000002795: Mylan Laboratories Inc 1030 Century Building / 130 Seventh St Pittsburgh, PA 15222 Contact: Kristine Hartman (800)858-8490 REFERENCES MED/96262018. Bergamini A, Ventrua L, Mancino G, Capozzi M, Placido R, Salanitro A, Cappannoli L, Faggioli E, Stoler A, Rocchi G. In vitro inhibition of the replication of human immunodeficiency virus type 1 by beta-mercaptoethylamine (cysteamine). J Infect Dis. 1996 Jul;174 (1):214-8. MED/95358905. Ho WZ, Zhu XH, Song L, Lee HR, Cutilli JR, Douglas SD. Cystamine inhibits HIV type 1 replication in cells of monocyte/macrophage and T cell lineages. AIDS Res Hum Retroviruses. 1995 Apr;11(4):451-9. AIDS/95920791. Gunnarsson G, Ladd E, McGrath J, Thoene J, Hammer S. Effect of combinations of cysteamine (mercaptoethylamine, MEA) and nucleoside reverse transcriptase (RT)inhibitors on HIV-1 replication in vitro. Program Abstr Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7;:93. ICA10/94371011. Ho WZ, Zhu XH, Song L, Cutilli J, Douglas SD. Cysteamine and cystamine inhibit HIV-1 replication in cells of monocyte/macrophage and T cell lineages. Int Conf AIDS. 1994 Aug 7-12;10(2):103 (abstract no. PA0292). ICA9/93334041. Gunnarsson G, Hammer S, McGrath J, Ladd E, Thoene J. Effect of cysteamine (mercaptoethylamine, MEA) on HIV-1 replication in vitro. Int Conf AIDS. 1993 Jun 6-11;9(1):230 (abstract no. PO-A25-0571). ENTRY MONTH 199103 LAST REVISION DATE 20001107 344 UNIQUE IDENTIFIER DRG-0002 NAME OF SUBSTANCE Leucovorin calcium [USPD 1998; p. 414] REGISTRY NUMBER 1492-18-8 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] SYNONYMS Leucovorin Calcium [USP DI 2000; p. 3311] SYNONYMS Wellcovorin [USP DI 2000; p. 1951] PROTOCOL ID NUMBERS Complete CC 88 CC-85 PROTOCOL ID NUMBERS Complete CC 89 CC-02 PROTOCOL ID NUMBERS Complete NIAID ACTG 008 PROTOCOL ID NUMBERS Complete NIAID ACTG 018 PROTOCOL ID NUMBERS Complete NIAID ACTG 029 PROTOCOL ID NUMBERS Complete NIAID ACTG 031 PROTOCOL ID NUMBERS Complete NIAID ACTG 039 PROTOCOL ID NUMBERS Complete NIAID ACTG 074 PROTOCOL ID NUMBERS Complete NIAID ACTG 077 PILOT PROTOCOL ID NUMBERS Complete NIAID ACTG 102 PROTOCOL ID NUMBERS Complete NIAID ACTG 142 PROTOCOL ID NUMBERS Complete NIAID ACTG 154 PROTOCOL ID NUMBERS Complete NIAID ACTG 156 PROTOCOL ID NUMBERS Complete NIAID ACTG 237 PROTOCOL ID NUMBERS Complete NIAID NS 401 PROTOCOL ID NUMBERS No longer recruiting FDA 056A PROTOCOL ID NUMBERS No longer recruiting FDA 132A PROTOCOL ID NUMBERS No longer recruiting FDA 132B PROTOCOL ID NUMBERS No longer recruiting FDA 132C PROTOCOL ID NUMBERS No longer recruiting FDA 132D PROTOCOL ID NUMBERS No longer recruiting FDA 224A PROTOCOL ID NUMBERS No longer recruiting CC 89 CC-59 PROTOCOL ID NUMBERS No longer recruiting NCI 90 C-34 PROTOCOL ID NUMBERS No longer recruiting NIAID TX 301 PROTOCOL ID NUMBERS Terminated NIAID ACTG 009 PROTOCOL ID NUMBERS Terminated NIAID ACTG 030 PHARMACOLOGICAL ACTION MODE OF ACTION: Leucovorin is a reduced form of folic acid which is readily converted to other reduced folic acid derivatives. Because it does not require reduction by dihydrofolate reductase as does folic acid, leucovorin is not affected by blockage of this enzyme by folic acid antagonists. This allows purine and thymidine synthesis and thus DNA, RNA, and protein systhesis to occur. Leucovorin given at appropriate time rescues bone marrow and gastrointestinal cell from methotrexate but has no apparent effect on pre-existing methotrexate nephrotoxicity. [USP DI 1996; p 1882] DISEASES STUDIED/TREATED Prevention of mucositis and bone marrow toxicity associated with Trimetrexate when the latter is used for treatment of Pneumocystis carinii pneumonia (PCP) in AIDS patients. [Protocol ID: ACTG 039 p 3] CLASSIFICATION CODE Antianemic [USP DI 2000; p 1948] CLASSIFICATION CODE Antidote (to folic acid antagonists) [USP DI 2000; p.1948] CLASSIFICATION CODE Antineoplastic adjunct [USP DI 2000; p 1948] OTHER MAJOR USES Treatment of toxicity and adverse effects of inadvertently administered overdoses of folic acid antagonists; treatment of megaloblastic anemias due to sprue, nutritional deficiency, pregnancy, and infancy. Treatment of advanced colorectal cancer. [PDR 1997; p 1204; USP DI 1996; p 1882] SUBSTANCE INTERACTIONS Leucovorin may interact with barbiturate or hydantoin anticonvulsants, primidone, and central nervous system depressants. Leucovorin is a specific antidote for the hematopoietic toxicity of methotrexate and other strong inhibitors of dihydrofolate reductase. May enhance the toxicity of fluorouracil. The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV was associated with increased rates of treatment failure and morbidity in a placebo-controlled study [USP DI 1996; p 1882] ADVERSE EFFECTS May cause allergic reactions. [PDR 1997; p 1204] CONTRAINDICATIONS Should not be used for treating pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12; a hematologic remission may occur while neurologic manifestations remain progressive. [PDR 1997; p 1204] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Reduced form of folic acid. [PDR 1995; p 1158] CHEMICAL/PHYSICAL DATA Molecular Formula: C20-H21-Ca-N7-O7 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Molecular Weight: 511.51 [USPD 1998; p. 414] CHEMICAL/PHYSICAL DATA Solubility: In water; insoluble in alcohol. [Merck Index 1989; p 660] CHEMICAL/PHYSICAL DATA Stability: Reconstituted solutions prepared with bacteriostatic water for injections (preserved with benzyl alcohol) should be used within 7 days. Intravenous solutions containing leucovorin calcium in 10% dextrose injection, 10% dextrose in 0.9% sodium chloride injection, lactated Ringer's injection. [USP DI 1996; p 1885] SUBSTANCE DELIVERY DATA DOSAGE FORM: Parental 50, 100, 350 mg vials for reconstitution; tablets (5, 10, 15, 25 mg). [USP DI 1996; p 1884] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion; intramuscular; oral. [USP DI 1996; p 1882-3] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Store parenteral vials prior to reconstitution below 40 C, preferably between 15 and 30 C, unless otherwise specified by the manufacturer; protect from light. Store tablets below 40 C, preferably between 50 and 30 C, in a well closed container, unless otherwise specified by the manufacturer; protect from light. [USP DI 1996; p 1884] MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Abacavir Information (888)825-5249 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Debbie Thomas (919)483-9959 MANUFACTURERS 0000004386: Immunex Corporation 51 University Street Seattle, WA 98101 Contact: Dr Jan Agosti (206)389-4321 MANUFACTURERS 0000004417: Glaxo Wellcome Inc Five Moore Dr Research Triangle Park, NC 27709 Contact: Jaime Hernandez (919)483-6300 REFERENCES MED/95150090. Bozzette SA, Forthal D, Sattler FR, Kemper C, Richman DD, Tilles JG, Leedom J, McCutchan JA. The tolerance for zidovudine plus thrice weekly or daily trimethoprim-sulfamethoxazole with and without leucovorin for primary prophylaxis in advanced HIV disease. California Collaborative Treatment Group. Am J Med. 1995 Feb;98(2):177-82. MED/95016043. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis 1994 Oct;170(4):912-7. MED/94284632. Sattler FR, Frame P, Davis R, Nichols L, Shelton B, Akil B, Baughman R, Hughlett C, Weiss W, Boylen CT, et al. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis 1994 Jul;170(1):165-72. ICA9/93335828. Crine L, Corfmat Y, Julien C, Echard M, et al. Plasma levels of leucovorin (LV) stereoisomers in Pneumocystis carinii pneumonia (PCP) of AIDS patients treated with trimethoprim-sulfamethoxazole (TMP-SMX). Int Conf AIDS. 1993 Jun 6-11;9(1):502 (abstract no. PO-B30-2204). MED/93274105. Masur H, Polis MA, Tuazon CU, Ogata-Arakaki D, et al. Salvage trial of Trimetrexate-leucovorin for the treatment of cerebral toxoplasmosis in patients with AIDS. J Infect Dis 1993 Jun;167(6):1422-6. ICA8/92400861. Taillan B, Pesce A, Garnier G, Vinti H, Fuzibet JG, Cassuto JP, Dujardin P. AIDS related malignant lymphoma: results of MACOP B chemotherapy. Int Conf AIDS. 1992 Jul 19-24;8(2):B108 (abstract no. PoB 3127). ICA6/10039990. Falloon J, Kovacs J, Allegra C, O'Neill D, Tuazon C, Frame P, Dohn M, Joseph P, Feuerstein I, LaFon S, et al. A pilot study of piritrexim (PTX) with leucovorin (LCV) for the treatment of pneumocystis pneumonia. Int Conf AIDS 1990 Jun 20-23;6(1):221 (abstract no. Th.B.399). MED/90111802. Schneider AM, Straus DJ, Schluger AE, Lowenthal DA, Koziner B, Lee BJ, Wong G, Clarkson BD. Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin's lymphomas. J Clin Oncol. 1990 Jan;8(1):94-102. MED/90111282. Sattler FR, Allegra CJ, Verdegem TD, Akil B, Tuazon CU, Hughlett C, Ogata-Arakaki D, Feinberg J, Shelhamer J, Lane HC, et al. Trimetrexate-leucovorin dosage evaluation study for treatment of Pneumocystis carinii pneumonia. J Infect Dis 1990 Jan;161(1):91-6. ENTRY MONTH 199103 LAST REVISION DATE 20000801 345 UNIQUE IDENTIFIER DRG-0001 NAME OF SUBSTANCE Ampligen [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000] REGISTRY NUMBER 38640-92-5 [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] PROTOCOL ID NUMBERS Complete NIAID ACTG 038 PROTOCOL ID NUMBERS Complete NIAID ACTG 054 PROTOCOL ID NUMBERS Complete NIAID ACTG 056 PROTOCOL ID NUMBERS No longer recruiting FDA 073A PHARMACOLOGICAL ACTION MODE OF ACTION: May have dual mode, direct antiviral action and various indirect, immunomodulatory actions. Acts through a number of pathways to stimulate intracellular antiviral activity and to increase the effective cellular and other activities of the immune system. Stimulates interferon production, activates the 2'-5' oligoadenylate synthetase (2-5A) RNase L pathway, stimulates natural killer cell activity, and, in general, acts as a nonmitogenic stimulator of the immune system. Ampligen inhibits replication of HIV in vitro. After intravenous injection of 200 mg of Ampligen in humans, its plasma half-life was estimated at 23 minutes. [Protocol ID: ACTG 054 p 5, 7] DISEASES STUDIED/TREATED Primary HIV infection (stimulation of immune system). [Protocol ID: ACTG 054 p 5] CLASSIFICATION CODE Investigational - Antiviral [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] OTHER MAJOR USES Treatment of renal carcinoma; chronic fatigue syndrome; invasive metastatic melanoma. [USP DI 1995; p 2990] SUBSTANCE INTERACTIONS May act synergistically with zidovudine (AZT). [J Infect Dis 1992 Oct;166(4); p 717-22] ADVERSE EFFECTS May cause mild flu-like symptoms; mild fatigue; fever; hypersensitivity skin reactions. A flushing reaction, characterized by at least one occurrence of reddening of the face and chest, has been observed in about 10% of patients when the drug was prepared in plastic IV bags. This flushing reaction was not observed when glass IV bottles were used. Other less frequently occurring adverse effects include nausea, diarrhea, photophobia, rash and transient visual disturbances. [Protocol ID: ACTG 054 p 8; Lancet 1987 Jun 6; p 1286-92; USP DI 1995; p 2992] CONTRAINDICATIONS Should not be used by pregnant or lactating women or by patients requiring antineoplastic therapy. [Protocol ID: ACTG 054 p 14] CHEMICAL/PHYSICAL DATA DRUG DESCRIPTION: Polynucleotide derivative of poly I - poly C with occasional uracil residues in the polypyrimidine strand; a synthetic mismatched, double-stranded RNA molecule. [Protocol ID: ACTG 054 p 4.] CHEMICAL/PHYSICAL DATA Molecular Formula: (C10-H13-N4-O8-P)x-.(C9-H14-N3-O8-P.C9-H13-N2- -O9-P)x- [ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed May 15, 2000.] CHEMICAL/PHYSICAL DATA Solubility: Disperses in water. [Protocol ID: ACTG 054 p 15] CHEMICAL/PHYSICAL DATA PHYSICAL DESCRIPTION: Freeze-dried powder. [Protocol ID: ACTG 054 p 15] SUBSTANCE DELIVERY DATA DOSAGE FORM: Capsules (30) mg; sterile aqueous solution. [Protocol ID: ACTG 054 p 15] SUBSTANCE DELIVERY DATA MODE OF DELIVERY: Intravenous infusion; oral. [Protocol ID: ACTG 054 p 15; Int Conf AIDS 1990 Jun 20-23;6(2); p 208 (Abstract No. SB 490)] SUBSTANCE DELIVERY DATA STORAGE INSTRUCTIONS: Do not store in solution for more than 3 hours. [Protocol ID: ACTG 054 p 15] MANUFACTURERS 0000001134: HEM Research Inc 1617 JFK Blvd / One Penn Ctr / Suite 660 Philadelphia, PA 19103 Contact: Unspecified (215)988-0080 REFERENCES MED/97027989. Thompson KA, Strayer DR, Salvato PD, Thompson CE, Klimas N, Molavi A, Hamill AK, Zheng Z, Ventura D, Carter WA. Results of a double-blind placebo-controlled study of the double-stranded RNA drug polyI:polyC12U in the treatment of HIV infection. Eur J Clin Microbiol Infect Dis. 1996 Jul; 15(7):580-7. AIDS/96701606. New ThetaSwitch drug may increase long-term survival in HIV disease. J Int Assocc Physicians AIDS Care. 1996 Apr; 2(4):59. MED/95101981. Gillespie D, Hubbell HR, Carter WA, Midgette P, Elsasser W, Mullaney R, Strayer DR. Synergistic inhibition of AZT-resistant HIV by AZT combined with poly(I):poly(C12U), without synergistic toxicity to bone marrow progenitor cell elements. In Vivo. 1994 May-Jun; 8(3):375-81. ICA7/3213691. Pazin GJ, Armstrong JA, Rinaldo CR, McMahon DK, Huang XL, Gupta P, Winkelstein A, Ho M. A synthetic double-stranded RNA (rIn:r(C12U)n) stabilizes CD4+ lymphocyte counts in volunteers with early HIV disease. Int Conf AIDS. 1994 Jun 16-21(2):216 (abstract no. W.B.2136). MED/94208071. Schroder HC, Kelve M, Schacke H, Pfleiderer W, Charubala R, Suhadolnik RJ, Muller WE. Inhibition of DNA topoisomerase I activity by 2',5'-oligoadenylates and mismatched double-stranded RNA in uninfected and HIV-1 infected H9 cells. Chem Biol Interact. 1994 Feb; 90(2):169--83. MED/94198386. Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994 Jan; 18 Suppl 1:S88-95. MED/94143075. Sinet M, Pocidalo JJ. [Are immunomodulators capable to improve the activity of nucleoside antiretroviral agents?]. Pathol Biol (Paris). 1993 Oct; 41(8 Pt 2):794-8. MED/94096550. Gohchi K, Matsuda J. [Immunotherapy for HIV carrier]. Nippon Rinsho. 1993 Sep; 51 Suppl:338-42. MED/93370886. Sidwell RW, Morrey JD, Okleberry KM, Burger RA, Warren RP. Immunomodulator effects on the Friend virus infection in genetically defined mice. Ann NY Acad Sci. 1993 Jun 23; 685:432-46. ICA9/93334049. Muller WE, Schroder HC, Ushijima H, Pfleiderer W, Charubala R, Suhadolnik RJ. Mismatched double-stranded RNA (Ampligen) acts synergistically with inhibitors of reverse transcriptase or inhibitors of HIV-1 regulatory proteins on HIV-1 production. Int Conf AIDS. 1993 Jun 6-11; 9(1):231 (abstract no. PO-A25-0577). ENTRY MONTH 199103 LAST REVISION DATE 20001011 SS 2 /C?