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M9490504.TXT
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1994-09-24
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Document 0504
DOCN M9490504
TI Effect of dipyridamole on zidovudine pharmacokinetics and short-term
tolerance in asymptomatic human immunodeficiency virus-infected
subjects.
DT 9411
AU Hendrix CW; Flexner C; Szebeni J; Kuwahara S; Pennypacker S; Weinstein
JN; Lietman PS; Department of Infectious Diseases, Wilford Hall Medical
Center,; Lackland AFB, Texas 78236-5300.
SO Antimicrob Agents Chemother. 1994 May;38(5):1036-40. Unique Identifier :
AIDSLINE MED/94346802
AB Zidovudine delays the progression of infection and prolongs the survival
of human immunodeficiency virus (HIV)-infected patients, but these
benefits are limited by dose-related toxicity and the cost of the drug.
Dipyridamole, in micromolar concentrations, acts synergistically with
zidovudine, reducing the anti-HIV 95% inhibitory concentration of
zidovudine 5- to 10-fold in vitro. We sought to establish a
well-tolerated dose of dipyridamole for use in combination with
zidovudine and to detect clinically significant pharmacokinetic
interactions. Both objectives are essential for planning studies of the
efficacy of the zidovudine-dipyridamole combination. Eleven asymptomatic
HIV-infected subjects (median CD4+ cell count, 311 cells per mm3), 10 of
whom had been on zidovudine at 500 mg/day for at least 6 months, were
admitted to the study. Zidovudine pharmacokinetics were measured on day
1. Dipyridamole was then begun at 600 mg/day (subjects 1 to 3) or 450
mg/day (subjects 4 to 11), and zidovudine and dipyridamole
pharmacokinetics were measured on day 5. All subjects given 600 mg of
dipyridamole per day developed headache or nausea, or both. Six of eight
subjects given dipyridamole at 450 mg/day developed headache or mild
nausea that resolved after a median of 2 days. The area under the
zidovudine concentration-time curve was not significantly different on
day 1 in comparison with that on day 5 (P = 0.11). Symptoms were
significantly correlated with the maximum zidovudine concentrations,
which were achieved when dipyridamole was dosed concomitantly (p =
0.03). Total (free and protein-bound) dipyridamole trough concentrations
were near those demonstrating synergy with zidovudine against HIV in
vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
DE Adult Dipyridamole/ADVERSE EFFECTS/BLOOD/*PHARMACOLOGY Drug
Combinations Drug Interactions Human HIV
Seropositivity/COMPLICATIONS/*METABOLISM Iodine
Radioisotopes/DIAGNOSTIC USE Male Orosomucoid/METABOLISM Support,
Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Zidovudine/*ADVERSE
EFFECTS/*PHARMACOKINETICS JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).