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FDA Consumer magazine

VOL. 30 No. 4 MAY 1996
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Features

Taking a Shot at Allergy Relief
Is spring one long sneeze? Does owning a dog or cat bring tears to your
eyes and a drip to your nose? Allergy shots may help.

New Hope for People with Sickle Cell Anemia
In the past, individuals with sickle cell anemia often died in
childhood. Today, many with this inherited disease live at least into
their 40s thanks to early diagnosis, drugs, and other therapies. And new
treatments are on the horizon.

OTC Options: Help for Cuts, Scrapes and Burns
Nonprescription products used on the skin help kill or weaken bacteria
that might cause infection in minor cuts and scrapes.

Medications Can Aid Recovery from Alcoholism
Though some alcoholics can recover without drug treatment, others are
being helped by medications. One such treatment is a drug previously
used to treat narcotic dependency.

Chemical Photosensitivity: Another Reason to Be Careful in the Sun
Many drugs and cosmetics have the potential to lessen the time it takes
to get a sunburn or can foster some other type of reaction to sunlight
and indoor tanning devices.


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Departments



Updates

The latest information on FDA-related issues, gathered from FDA Press
Releases, Talk Papers, and other sources.



Notebook

A potpourri of items of interest gathered from the Federal Register and
other sources.



Investigators' Reports

Selected cases illustrating regulatory and administrative actions--such
as inspections, recalls, seizures, and court proceedings--by FDA's
regional and district offices across the country



Summaries of Court Actions

Cases involving seizure, criminal and injunction proceedings.






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Taking a Shot at Allergy Relief

by Isadora B. Stehlin

Isn't it a beautiful spring day?

Those words used to drive me insane. Beautiful spring days in Maryland
mean warm sunshine and gentle breezes. But drifting in those spring
breezes is pollen. So much pollen, mostly from trees, that the air
becomes hazy, making life miserable for people with pollen allergies
like my son Paul.

Two years ago, sunny spring days didn't mean riding bikes and playing
ball for 5-year-old Paul. They meant recess in the school library, a box
of tissues at his desk, and eyes nearly swollen shut by the end of the
school day. Once home, he took off his pollen-covered clothes, put on
clean clothes, and spent his afternoons inside a closed house with air
conditioning running even if it was a balmy 70 degrees Fahrenheit (21
degrees Celsius) outside.

Only rainy days were beautiful spring days to Paul.

But last spring wasn't as bad for him, and this spring--after nearly two
years of allergy shots--he may finally be able to enjoy sunny spring
days outdoors.

One treatment for people with allergies is injections of small amounts
of the substances they're allergic to. This is called immunotherapy.
Over time as the dose is increased, the patient becomes hyposensitized
(less allergic) to the allergens because the body, for reasons not yet
fully understood, becomes more tolerant to the offending substances. The
symptoms, including sneezing and watery eyes--and the need for
medication--are reduced or disappear.

People of any age can develop allergies. Heredity and allergen exposure
are important influences in whether allergies develop. Moving from one
part of the country to another, especially if the climates, and
therefore the native plants, are different, can influence the severity
and seasonality of allergic symptoms.

The Food and Drug Administration regulates the biological extracts in
allergy shots. The extracts are used both to treat and to test
individuals to determine exactly what causes their allergic reactions.

In addition to treating pollen allergy from trees, grasses and weeds,
immunotherapy is also used to treat allergies to house dust mites, pets,
molds found indoors and outside, and stinging insects such as honey
bees, yellow jackets, hornets, and wasps.

Who Should Get Shots?

From the time he was 12 months old, Paul was miserable in the spring
and, to a lesser degree in the fall, with a runny nose, watery eyes, and
itchy skin. By his third birthday, the pollen allergies also triggered
asthma attacks. Prescription medications didn't help much to relieve his
symptoms, even with constant use.

All this made Paul a good candidate for injections.

"Shots work extremely well in patients that clearly have allergic
symptoms, either allergy in their nose like allergic rhinitis or
bronchial asthma, where outdoor allergens like tree, weed and grass
pollens seem to be a major cause," says Stanley P. Galant, M.D., an
allergist in Orange County, Calif., and a clinical professor and
director of pediatric allergy at the University of California, Irvine.

Patients with allergies to molds, house dust mites (microscopic insects
that feed on human skin cells found on furniture, bedding and carpets),
and animal dander (tiny skin flakes animals continually shed) don't
respond quite as well to shots as those allergic to outdoor allergens,
he says. But standardization of extracts for cat dander and dust mites
and overall better preparations have increased effectiveness even for
these patients, he adds.

Immunotherapy doesn't begin until after skin tests or blood tests have
determined the exact culprits.

"You have to show that [the patients] have IgE antibodies to the
allergens in question," says John Yunginger, M.D., a member of FDA's
Allergenic Products Advisory Committee and a pediatric allergist at the
Mayo Clinic, Rochester, Minn.

The first time an allergic person is exposed to an allergen, the immune
system produces a kind of antibody called immunoglobulin E--IgE for
short. (But it is rare for a first exposure to cause allergic symptoms.
Only on subsequent exposures do typical allergic symptoms, such as
sneezing, coughing and rash, appear.) Overproduction of IgE is
characteristic of allergy reactions.

Deciding which allergens to test "depends very much on the patient's
history," says Yunginger. "In somebody who has fairly straightforward
classical seasonal symptoms they may get as few as 15 or 20 [skin]
tests. Someone with more extensive perennial disease may get 75 or 80."

Each individual skin test consists of a small amount of the suspect
allergen scratched onto the skin, usually on the back. If a hive with
surrounding redness appears within 15 minutes, allergy to the substance
is probable. The doctor also takes into account the dose of allergen and
the size of the response.

Two controls, standards against which experimental observations may be
evaluated, are also used to make sure skin-test reactions are caused by
the allergens. One of the controls, which should not cause a reaction
(no hive), is simply the diluting solution. The other control contains
histamine, a naturally occurring substance that causes a hive in almost
everyone.

According to Galant, the patient's history is as significant as the
testing. "The history is really what tells me whether to put the patient
on shots," he says. "Training as a specialist helps me interpret the
data from the history and correlate that with the testing and come up
with a solution."

While skin tests give quick results and can be done in the doctor's
office, there are some cases where a blood test is preferable, says
Marshall Plaut, M.D., chief of the allergic mechanisms section in the
National Institute of Allergy and Infectious Diseases, National
Institutes of Health. Individuals with skin problems or skin diseases
are not good candidates for skin tests, he says.

Shot Schedule

Once the problem allergens are identified, the allergist prepares a
treatment solution containing those allergens to begin the process of
desensitization.

"If the patient is very sensitive to a certain allergen, that allergen
should be given separately so local and systemic [whole body] responses
can be carefully monitored," says Galant. "For example, some people are
astronomically allergic to grass pollen." If the grass pollens are in
the treatment solution with other allergens, the desensitization to the
other allergens might be delayed if reactions to the grass pollens mean
maintaining or reducing the solution dose, he explains.

It turned out that Paul was equally and highly sensitive to every tree,
weed and grass pollen on the Eastern seaboard as well as dust mites and
mold. Only animal dander wasn't a problem. Because he was allergic to so
much, he had to get two shots--one containing the pollens, the other
with the molds and mites.

The amount of allergen in the first solution the allergist prepares is
very dilute. The first shot from that solution is usually 0.05
milliliters, resulting in a minute amount of allergen actually being
injected. This cautious approach decreases the chance of adverse
reactions.

The shots are given subcutaneously (under the skin) in the back of the
upper arm. The regimen usually starts with shots twice a week, gradually
increasing the doses as long as no serious reactions occur.

A little bit of redness, itching or swelling (less than 2 centimeters,
or the size of a nickel) around the injection site is all right, and the
dose may be increased at the next visit. Cold compresses, oral
antihistamines, and topical corticosteroids can relieve these minor
reactions.

If the site swells more than 2 cm or allergic symptoms develop, the
allergist may decide to repeat the same dose at the next visit or even
reduce it, depending on the severity of the previous reaction.

The chances of having an adverse reaction to the injection are more
common while the doses are being increased than once a maintenance dose
is reached, says Yunginger.

Anaphylaxis--a life-threatening reaction that causes blood pressure to
plummet, the throat to swell, and airways in the lungs to constrict--is
a slight but real risk with allergy shots. A shot of epinephrine--the
same drug used to treat severe allergic reactions to bee stings--is used
to treat anaphylaxis. Anaphylactic reactions may result in death,
although this is rare.

The American Academy of Allergy and Immunology recommends that patients
remain in the doctor's office for 20 minutes after receiving the
injection, because reactions usually occur within that time. "High-risk
patients may have to wait additional time," says Richard Lockey, M.D.,
director of the division of allergy and immunology at the University of
Southern Florida College of Medicine in Tampa.

If no reactions occur, the amount of allergen in each shot is increased
until a maintenance dose is reached. For a very sensitive patient, the
maximum dose may be the amount the patient can tolerate without a
reaction. Others may be able to reach a predetermined amount that
researchers have found to be necessary for optimal allergy relief.

Once the maintenance dose has been reached, the intervals between shots
can be gradually increased to two, three and even four weeks apart.
Reaching the maintenance dose can take anywhere from six months to three
years.

The amount of time needed to reach the maintenance dose can be reduced
to as little as a few days with "rush" immunotherapy. Patients receive
increasing doses of the allergens several times a day for three or four
days. This requires close medical observation because the frequent
schedule greatly increases the risk of anaphylaxis. That risk, plus the
inconvenience of spending several days all at once at the doctor's
office or in a clinic, makes rush immunotherapy unpopular with many
patients and physicians, says Yunginger.

Shot Success

"If allergy shots are working, the patient normally feels the benefit
within a year, sometimes within six months," writes Stuart H. Young,
M.D., and colleagues, in the book Allergies (Consumer Reports Books,
1991). "It is usually necessary to continue shots for a couple of years
at least, but the idea is to continue only if the treatment is
effective, not just in the hope that someday it may help. Fruitless
treatment should not drag on for years."

Anywhere from three to five years of treatment is the usual
recommendation, says Yunginger.

"The reason for [the three to five years]--and it's not written in
concrete--is that the long-term remission of symptoms after the shots
stop seems to be better," explains Galant. "If you give a patient shots
for a year or two, even if they've had a good year, there's some
indication that the relapse rate might be higher."

Galant usually decides to stop shots if the patient has had no symptoms
or the degree of symptoms has significantly decreased for about a year.
"Generally that's between the second or third year, so when we finish
three years, I would seriously consider stopping the shots."

When Yunginger takes his patients off shots, "I have them go through the
four seasons to see if the symptoms come back. If the symptoms do come
back and can't be completely controlled with medication, then probably
the injections should be restarted."

According to Young and colleagues, after stopping shots, one-third of
patients will no longer have allergic reactions, one-third will have a
partial relapse of symptoms, and one-third will relapse completely.

Lifestyle Changes

"Shots are just one part of this therapy," says Galant. "Good avoidance
measures are very important."

Usually outdoor allergens can't be completely avoided. Most people can't
stay inside all the time, and, in any case, pollen comes inside through
open doors and windows and on people's clothes, hair and shoes. Here are
some ways to keep pollen out of the house:


 * Keep all windows closed.

 * Put a permanent air filter specially designed
   to keep out pollens and other airborne contaminants in the heating
   and cooling systems; wash the filter every month.

 * Change clothes after coming in from outside, and wash the clothes
   before wearing them again.

 * Keep dirty clothes out of the allergic person's bedroom.

 * Wash the allergic person's hair every night to avoid transferring
   pollen from hair to pillow.

<Picture: [magnified image of house dust mite]> Some indoor allergens
are also difficult to avoid, but they can be reduced. House dust mites,
although they are so tiny you can't see them with the naked eye, can
cause big allergic reactions in susceptible people. (The North American
house dust mite pictured at right is, of course, greatly magnified.)

When it comes to dust mites, "it's hard to get rid of them," says
Galant. Mites like to live in box springs, mattresses, pillows, and
carpets. To keep the mite population down, the allergic person's
mattress, box spring, and pillows should be encased in special covers
available from companies that make allergy-proof products. Washable
curtains should be the only window coverings. To kill dust mites in bed
linens and curtains, wash water must be at least 130 degrees Fahrenheit
(54 degrees Celsius). (But during all other times, keep water
temperature at 120 F [49 C] to protect children from accidental
scalding.) Carpets should be removed or treated with an anti-allergen
spray. (Ask your allergist, or contact organizations listed in
accompanying box for sources of these products.)

For those with allergies to pets, the simple answer, giving up a beloved
cat or dog, is often unacceptable. To increase the success of shots,
animals should be kept out of the bedroom. Giving pets a weekly bath may
help reduce the amount of dander they release into the air.

Whether it means keeping a cat or playing outside in the spring, "my
game plan for all patients is to have them live a normal life," says
Galant.

That's what I hope will be in store for Paul--time spent outdoors
enjoying the sun and spring breezes. For me, it will mean I can finally
say, "Yes, it really is a beautiful spring day."

Isadora B. Stehlin is a member of FDA's public affairs staff.


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More Information

The following organizations have more information on allergy shots and
products to reduce allergens in the home:

Asthma and Allergy Foundation of America
1125 15th St., N.W.
Suite 502
Washington, DC 20005
(1-800) 727-8462

Allergy and Asthma Network
3554 Chain Bridge Road
Suite 200
Fairfax, VA 22030
(1-800) 878-4403
E-mail:[e-mail]

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Standardizing Extracts

Biologists and chemists in FDA's Center for Biologics Evaluation and
Research are working in their labs to standardize allergenic extracts.

"Without standardization, there is no defined potency for these
extracts," says Paul Turkeltaub, M.D., acting director of the center's
division of allergenic products and parasitology. "This can reduce the
effectiveness of both diagnosis and treatment."

Stanley P. Galant, M.D., an allergist in Orange County, Calif., and a
clinical professor and director of pediatric allergy at the University
of California, Irvine, explains that different lots of nonstandardized
extracts may not be the same strength, and allergists have no way to
know if there is any variation. He says that to avoid the risk of a bad
reaction with these extracts, a patient starting a new vial of treatment
solution must get a lower dose than what the patient is on and build up
again.

"Standards for extracts improve medical management of allergies and
lessen the risk of an adverse reaction," says Turkeltaub. "Standards
should reduce the need for retesting of patients who switch physicians,
since the physicians will have access to the same extracts."

Currently, FDA scientists have developed standards for cat allergens,
dust mites, short ragweed, and several bee venoms. The venoms were among
the first to be standardized because life-threatening reactions to them
are more common.

FDA has determined, in consultation with industry and medical
professionals, the priority for other extracts to be standardized. In
most cases, higher priority went to allergens affecting the greatest
number of people.

FDA scientists are nearing completion on standards for latex and
cockroach extracts, and work is continuing on standardization of a
peanut extract and many pollens.

"Peanut is the most severe form of food allergy," says Marshall Plaut,
M.D., chief of the allergic mechanisms section, in NIH's National
Institute of Allergies and Infectious Diseases. "A high proportion of
deaths from food allergies are from peanuts, and, unlike most food
allergies, which disappear after childhood, peanut allergies tend to
last a lifetime."

The agency plans to standardize other food allergens, pollens and insect
venoms in the future.

--I.B.S.

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OTC Options:
Help for Cuts, Scrapes and Burns

by Dixie Farley

This article is part of a series on nonprescription drugs.

A half-inch scar on my left knee is a graphic reminder of a painful
scrape at age 7. Also painful was the burn of Merthiolate antiseptic,
applied as first aid to ward off infection.

Today's approved over-the-counter topical (used on the skin) first-aid
antimicrobials are less irritating and more effective than Merthiolate,
which contains the mercury drug thimerosal. The Food and Drug
Administration has approved seven topical OTC antibiotics (see "OTC
Antibiotics") and is evaluating OTC topical antiseptics under a proposed
rule. The proposal would ban numerous antiseptics, including mercurials,
as ineffective and some, including thimerosal, as also unsafe.

Antibiotics are also available by prescription as injectable and oral
medicines and medicines for the eye and ear. They are used to treat
infections. While some can kill a limited number of bacteria, other
varieties affect many bacteria.

Antiseptics weaken microbes, but don't usually kill them. Health-care
antiseptics in soaps and other products help prevent the spread of
infection in medical facilities.

OTC first-aid antibiotics and antiseptics are applied to the skin to
help prevent infection in minor cuts, scrapes and burns.

"Used topically, OTC antimicrobials inhibit the growth of bacteria, but
don't necessarily kill them all," says Audrey Love, a microbiologist
with the division of OTC drug evaluation in FDA's Center for Drug
Evaluation and Research. "If an injury is extensive," Love says, "it
should be taken care of by a doctor. But consumers have to consider for
themselves, based on reading the labeling, whether a product is
something they should use."

FDA has published rules (monographs) establishing adequate labeling for
OTC antimicrobials, and conditions under which products would be
generally recognized as safe and effective for use without medical
supervision. The final antibiotics rule (1987) and proposed antiseptics
rule (1991) specify active ingredients and concentrations, as well as
labeling information such as product identification, indications for
use, warnings, and directions for use. All drugs must meet the agency's
good manufacturing practice requirements for product identity, strength,
quality, and purity.

Some Restrictions

OTC first-aid antimicrobials are for use only up to one week. If an
injury persists or worsens after this time, the label warns consumers to
stop use and consult a doctor.

The products are not for existing infections, animal bites, sunburn,
punctures, or eye injuries. Nor should they be used for cuts, scrapes or
burns needing medical care, such as:


 * cuts that are deep, continue bleeding, or may require stitches

 * scrapes with imbedded particles that can't be flushed away

 * large wounds

 * burns more serious than a small reddened area.

Use of an antibiotic or antiseptic does not in itself constitute
first-aid treatment of a minor wound.

A panel of experts convened by FDA defined first aid as "a process that
includes initial adequate cleansing which may or may not be followed by
application of a safe, nonirritating product which does not interfere
with normal wound healing and which may reduce the bacterial numbers and
help prevent infection." (From 1972 to 1981, at FDA's request, 16
outside panels evaluated marketed OTC drugs. Their charge completed, the
panels no longer meet.)

FDA requires that labels for antibiotics advise users to first "clean
the affected area." Antiseptics also would be labeled with the advice.

Because topical antimicrobials are not totally effective in killing
bacteria, FDA does not allow firms to place the claim "Helps kill
bacteria" in the same area as the required information. FDA believes the
term "kill" implies the product will eliminate all bacteria and could be
misleading if appearing with the required term "infection" (or alternate
term "bacterial contamination") in the label's indications section. The
claim may be used, though, as additional information elsewhere in the
label.

More About Antibiotics

In its final rule, FDA listed these antibiotic active ingredients as
safe and effective: bacitracin, bacitracin zinc, chlortetracycline
hydrochloride, tetracycline hydrochloride, neomycin sulfate,
oxytetracycline hydrochloride, and polymyxin B sulfate--the latter two
only for combination products because of their limited effectiveness
against certain microorganisms when used alone.

The rule does not allow the previously marketed antibiotic gramicidin,
because it has the potential to break down red blood cells when absorbed
through fresh wounds. The agency called for a welldesigned,
double-blind study (where neither patient nor doctor knows who gets the
drug) to show gramicidin's effects.

The data on which FDA based its approval of the other antibiotics
included a well-controlled study of minor skin injuries or insect bites
in 59 children. Streptococcal infection developed in 15 of the 32
receiving a topical placebo and in three of the 27 receiving a topical
antibiotic. Twelve of the 15 eventually needed oral antibiotics, and one
of the three did.

The agency agreed with comments that many such injuries are
self-healing, but that some do not heal without treatment and it is
impossible to make this distinction at the time of injury.

Also, says FDA's Love, there's always a chance someone can be allergic
to a drug, prescription or OTC. "People who tend to be allergic," she
says, "should talk to their doctor or pharmacist before trying any OTC
medicine for the first time."

About 1 in 20 people is allergic to neomycin, according to an article in
the August 1995 Harvard Health Letter. If a reaction such as redness,
itching or burning occurs, the article advises, "Stop using the
preparation immediately, and consult a physician if symptoms worsen or
persist for more than 48 hours."

Hypersensitivity reactions may also occur with bacitracin, according to
the Handbook of Nonprescription Drugs (10th edition), published by the
American Pharmaceutical Association and The National Professional
Society of Pharmacists, Washington, D.C. The handbook also states that
tetracycline products may trigger reactions in allergic patients, "some
of whom may have severe reactions even if exposure is by topical
application only."

With repeated use on large areas, neomycin also fosters development of
neomycin-resistant strains of Staphylococci bacteria. Neomycin products
that include polymyxin B and bacitracin guard against this.

To prevent neomycin overuse, FDA limits the drug to ointments and
creams, the most likely dosage forms for small wounds. Also, all OTC
antimicrobials must be labeled for short-term use. The agency believes
short-term use of neomycin ointments or creams on small wounds would not
risk overuse. To reduce the risk even further, FDA requires labels for
ointments and creams to identify a dose as "an amount equal to the
surface area of the tip of a finger."

Another issue is the combination of a product with a local "caine"
anesthetic, such as benzocaine, as is allowed for bacitracin ointment or
a combination ointment of bacitracin, neomycin, or polymyxin B. The
review panel was concerned an anesthetic might mask symptoms of
infection, delaying treatment by a doctor. But FDA believes the required
warnings on the label adequately inform consumers when to consult a
doctor.

More About Antiseptics

In its proposed rule, FDA listed these active antiseptic ingredients as
tentatively safe and effective: ethyl alcohol (48 to 95 percent),
isopropyl alcohol, benzalkonium chloride, benzethonium chloride,
camphorated metacresol, camphorated phenol, phenol, hexylresorcinol,
hydrogen peroxide solution, iodine tincture, iodine topical solution,
povidone-iodine, and methylbenzethonium. Five ingredients listed as
tentatively effective only in combination products are ethyl alcohol
(26.9 percent), eucalyptol, menthol, methyl salicylate, and thymol.

The proposal would ban numerous mercury ingredients and cloflucarban,
fluorosalan and tribromsalan antiseptics as not generally recognized as
safe and effective for OTC use.

FDA had requested study data on whether use of topical povidone-iodine
affected thyroid function. In submitted data, iodine blood levels did
increase after two weeks' use, but returned to normal when use was
stopped. There was no effect on thyroid function.

Antiseptics would be labeled similarly to antibiotics, but with some
differences.

Labels on camphorated metacresol, camphorated phenol, and phenol, for
example, would warn, "Do not bandage."

"The drugs can be hard on the skin," says Debbie Lumpkins, a
microbiologist in FDA's division of OTC drug evaluation. She explains
that, "when bandaged, the skin gets damp, increasing absorption.
Therefore, more drug enters the skin and may cause more damage than if
you just left the wound uncovered." Labels for ethyl alcohol (48 to 95
percent) and isopropyl alcohol (50 to 91.3 percent) would warn:
"Flammable, keep away from fire or flame."

For liquid antiseptics, labels would direct users to let the product dry
before bandaging.

Comments on the proposal were minimal, Lumpkins says, emphasizing that
FDA's evaluation of the ingredients is still very much an evolving
process.

"Frequently," she says, "we find that one study or one article says one
thing, and there's another study or article on the other side. We have
to determine the facts. Literature searches that we can now do so easily
help, but we won't find everything. We rely on people to bring things to
our attention."

Recent publications advise against two currently marketed antiseptics.
The National Safety Council's 1996 First Aid Pocket Guide states: "DO
NOT use hydrogen peroxide. It does not kill bacteria, and it adversely
affects capillary blood flow and wound healing." And the Handbook on
Nonprescription Drugs states ethyl alcohol "is not a desirable wound
antiseptic because it irritates already damaged tissue. The coagulum
[crust] formed may, in fact, protect the bacteria."

The final rule will reflect FDA's evaluation of all the data, Lumpkins
says. Thus, antiseptic ingredients proposed as safe and effective could
be found unsafe or ineffective, or new ingredients could be added,
depending on new information.

Whether using an OTC antibiotic or antiseptic, consumers should realize
"there are limits to what the products can do," Lumpkins says. "People
should read the label, and use the product appropriately. If they notice
a change in their condition, or if there's redness or swelling, they
shouldn't continue to try to treat it. They should see a doctor."

Dixie Farley is a staff writer for FDA Consumer.


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Labeling Final Rule

Under the final rule, labels for topical antibiotics must:


 * state the established name of the drug

 * identify the drug as a "first-aid antibiotic"

 * state the drug's approved use--for example: "First aid to help
   protect against infection in minor cuts, scrapes, and burns."
   (Allowed alternative wording includes "help prevent skin infection"
   or "help reduce the risk of bacterial contamination." Other
   descriptive statements may be added, provided they are truthful and
   not misleading.)

 * warn:

 * "For external use only. Do not use in the eyes or apply over large
   areas of the body. In case of deep or puncture wounds, animal bites,
   or serious burns, consult a doctor."

 * "Stop use and consult a doctor if the condition persists or gets
   worse. Do not use longer than 1 week unless directed by a doctor."

 * advise to clean the area, to use a small amount one to three times
   daily, and to cover with a sterile bandage if desired

 * specify on ointments and creams to use "an amount equal to the
   surface area of the tip of a finger."

Combination products must give the established name of each active
ingredient. Labels must identify any added anesthetic as such, include
the directions and warnings in its monograph, and state: "First aid for
the temporary relief of pain [or other approved alternative] in minor
cuts, scrapes, and burns."


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OTC Antibiotics

The following antibiotic products have been approved by FDA for use
without a prescription. They are ointments unless otherwise noted:



Single-Ingredient Products

bacitracin--Baciguent

bacitracin zinc--Bacitracin Zinc

chlortetracycline hydrochloride--Aureomycin

neomycin sulfate--Neomycin, Myciguent Cream

tetracycline hydrochloride--Achromycin



Combination Products

bacitracin-neomycin--none currently marketed

bacitracin-polymyxin B aerosol--none currently marketed

bacitracin-neomycin-polymyxin B--Lanabiotic, Medi-Quik Triple
Antibiotic, Clomycin Cream (with lidocaine anesthetic), Mycitracin Plus
Pain Reliever (with lidocaine)

bacitracin zinc-neomycin--none currently marketed

bacitracin zinc-polymyxin B ointment, aerosol or powder--Polysporin,
Polysporin Powder

bacitracin zinc-neomycin-polymyxin B--Neomixin, Neosporin Original

neomycin-polymyxin B ointment or cream--Neosporin Plus Maximum Strength
Cream (with lidocaine)

oxytetracycline-polymyxin B ointment or powder--none currently marketed.

--D.F.

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New Hope for People with Sickle Cell Anemia

by Eleanor Mayfield

In tropical regions of the world where the parasite-borne disease
malaria is prevalent, people with a single copy of a particular genetic
mutation have a survival advantage. Over time, people from these regions
have migrated, had children, and in some cases married each other. Some
of their children inherit two copies of the mutation.

While inheriting one copy of the mutation confers a benefit, inheriting
two copies is a tragedy. Children born with two copies of the genetic
mutation have sickle cell anemia, a painful disease that affects the red
blood cells and is curable only in rare instances.

A recent clinical trial sponsored by the National Heart, Lung, and Blood
Institute (NHLBI) found that the drug Hydrea (hydroxyurea) significantly
reduced painful episodes in adults with a severe form of sickle cell
anemia. NHLBI is a component of the National Institutes of Health (NIH).

Hydrea is approved by the Food and Drug Administration to treat certain
types of cancer. On the basis of the new clinical trial findings, FDA is
encouraging Hydrea's manufacturer, Bristol-Myers Squibb, to apply for
approval of the drug to treat sickle cell anemia.

"FDA will consider it a priority application so that sickle cell anemia
can be added to the indications for Hydrea, if the data show that [the
drug] is indeed safe and effective," said Anthony Murgo, M.D., a medical
officer in the division of oncology at FDA's Center for Drug Evaluation
and Research.

Genetic Defect Changes Cell Shape

<Picture: [illustration of a normal red blood cell and a sickled
cell]> The genetic defect that causes sickle cell anemia affects
hemoglobin, a component of red blood cells. Hemoglobin's job is to carry
oxygen to all the cells and tissues of the body. Red blood cells that
contain normal hemoglobin (such as the one pictured top right) are soft
and round. Their soft texture enables them to squeeze through the body's
small blood vessels.

People with sickle cell anemia, however, have a type of abnormal
hemoglobin called hemoglobin S. (Normal hemoglobin is called hemoglobin
A.) A genetic error makes the hemoglobin molecules stick together in
long, rigid rods after they release oxygen. These rods cause the red
blood cells to become hard and sickle-shaped, unable to squeeze through
tiny blood vessels. The misshapen cells (like the one pictured bottom
right) can get stuck in the small blood vessels, causing a blockage that
deprives the body's cells and tissues of blood and oxygen.

When this happens "it's like having mini heart attacks throughout the
entire body," said Duane R. Bonds, M.D., leader of the sickle cell
disease scientific research group at NHLBI in Bethesda, Md.

"A heart attack is painful because the blood flow to the heart is
interrupted. In sickle cell anemia, the blood flow can be interrupted to
any of the major organs, causing severe pain and organ damage at the
site of the blood flow blockage."

These painful "crises," as they are called, damage the lungs, kidneys,
liver, bones, and other organs and tissues. Recurrence of these episodes
is the most disabling feature of sickle cell anemia. They can cause leg
ulcers, blindness, and many other health problems, depending upon where
in the body the blood flow blockage occurs. A blockage in the brain can
cause a stroke, which may result in paralysis or death.

The body, recognizing that the sickled cells are abnormal, destroys them
at a faster rate than it can replace them. This causes a type of anemia,
a shortage of red blood cells. Symptoms of anemia include extreme
fatigue and susceptibility to infection.

Penicillin Treatment

An important breakthrough occurred in 1986 when an NHLBI-sponsored study
found that young children with sickle cell anemia who took penicillin
twice a day by mouth had much lower rates of S. pneumoniae infection
than a similar group of children who received a placebo.

In 1987, an expert panel convened by NHLBI recommended that all infants
born in the United States be screened for sickle cell anemia so that
children with the disease could be identified early and offered
treatment with penicillin. Forty-two states now have newborn screening
programs, according to Bonds. NHLBI also recommends that affected
infants get daily penicillin therapy beginning by the age of 3 months.

In the first year of life, children with sickle cell anemia are
protected from blood flow blockages by the presence of fetal hemoglobin.

"Fetal hemoglobin is the hemoglobin that all of us produce before we're
born," explained Bonds. Fetal hemoglobin physically blocks hemoglobin S,
preventing it from forming the long, rigid rods that lead to sickling of
the red blood cells. Several weeks before birth, however, the fetus'
bone marrow usually begins to shut down the production of fetal
hemoglobin and starts making adult hemoglobin instead. At birth, an
infant's red blood cells contain roughly equal amounts of fetal and
adult hemoglobin.

By the time the child is 6 months old, it has usually stopped making any
fetal hemoglobin. As the level of fetal hemoglobin in the child's blood
falls, explained Bonds, there is no longer anything to prevent the red
blood cells from becoming sickle-shaped and getting stuck in the blood
vessels, causing a painful crisis.

The symptoms of a painful crisis may be relieved by giving patients
fluids and painkillers, said Lilia Talarico, M.D., a medical officer in
the division of gastrointestinal and hematologic drug products in FDA's
Center for Drug Evaluation and Research. However, no FDA-approved
treatment is currently available to prevent painful crises from
occurring.

Life Expectancy Improves

Despite the absence of an effective treatment, life expectancy for
individuals with sickle cell anemia has improved, said Bonds, as a
result of early identification through neonatal screening, early
initiation of penicillin therapy, close medical monitoring, and early
intervention to relieve the symptoms of a painful episode. A recent
study found that half of all patients with sickle cell anemia survive
into their 40s.

Rates of early death are highest among those with a severe form of the
disease. "Between 10 and 15 percent of patients will have three or more
painful crises per year," said Bonds. "The more crises you have per
year, the greater your chances of dying prematurely. Your organs become
more damaged when they are chronically not receiving enough blood and
oxygen."

Some people continue to produce fetal hemoglobin throughout their lives.
A study of the life expectancy of people with sickle cell anemia found
that adults with high levels of fetal hemoglobin lived longer than those
who had low levels.

People with sickle cell anemia who suffer strokes or infections, who are
pregnant, or who must undergo surgery may be treated with blood
transfusions. Risks of this treatment include the possibility of
acquiring a viral illness such as hepatitis and the possibility of organ
damage caused by iron overload.

Sickle cell anemia can be cured by a bone marrow transplant, which
replaces the defective red blood cells with healthy cells from a donor.
But a transplant is not a realistic option for most people with sickle
cell anemia, according to Bonds, because of a shortage of compatible
donors and because of the risks presented by the drug regimen that is
required to prepare a patient for a transplant.

"First you give drugs to kill off the patient's marrow, then you do the
transplant to replace the marrow." But the powerful drugs given to kill
the patient's bone marrow can be dangerous for someone who has had a
stroke or is at risk for stroke, she said.

In January 1995, NHLBI announced the successful conclusion of a
five-year, multicenter trial of Hydrea in the treatment of sickle cell
anemia. The study involved 299 patients ages 18 and older who were
recruited at 21 medical centers in the United States.

All patients had experienced at least three painful crises in the year
before they entered the trial. Half of the patients received Hydrea and
half received a placebo. Neither the patients nor their doctors knew who
was taking the drug and who was taking the placebo. Patients who took
Hydrea had roughly half as many painful crises as those who took the
inactive pill.

The trial had been scheduled to conclude in May 1995. However,
scientists involved found the results so compelling that they stopped
the study early and notified doctors of the results so that all patients
who might benefit could be offered the treatment. A report of the
trial's findings was published in the May 1995 New England Journal of
Medicine.

Hydrea Studies

Hydrea is approved by FDA to treat certain types of leukemia and other
cancers. Doctors have been interested in Hydrea for the treatment of
sickle cell anemia for about 10 years, since pilot studies in humans
showed that the drug could increase the level of fetal hemoglobin in red
blood cells.

Because Hydrea is already on the market for other uses, it was
unnecessary for FDA to issue a Treatment IND (investigational new drug)
to make the drug available to patients with sickle cell anemia, said
FDA's Murgo. A Treatment IND is a mechanism used by FDA to make
investigational new drugs available to patients while they are under
study.

As with other approved medications, doctors may prescribe Hydrea for
sickle cell anemia if in their professional judgment a patient will
benefit from the treatment.

"We are excited about the report [of the Hydrea clinical trial]," said
Murgo. "But until the manufacturer [of the drug] submits the detailed
data for us to review, [the agency] cannot approve the drug to treat
sickle cell anemia."

Bonds, who was the project officer for the multicenter study, cautioned
that Hydrea treatment is not appropriate for every patient.

"We only recommend it for patients over 18 who have had at least three
painful crises in the previous year. The patients have to be monitored
very carefully. They must have a blood test every two weeks to ensure
that their blood count is not depressed to a level where they might be
at risk for infection or bleeding."

Hydrea should not be prescribed for patients who are likely to become
pregnant or who are unable to follow instructions regarding treatment,
said Murgo.

Many questions about Hydrea in the treatment of sickle cell anemia
remain unanswered, said Bonds. Doctors do not know what the most
effective and least toxic dose of the drug is or whether taking it for
many years presents health risks.

Some doctors prescribe Hydrea to treat polycythemia vera, a disease in
which the number of red blood cells increases abnormally. Some evidence
suggests that the drug may cause leukemia in a few of these patients,
both Murgo and Bonds said.

However, they added, patients with polycythemia vera already have a
higher-than-average risk of getting leukemia, so it is unclear whether
the leukemia is caused by Hydrea or whether the patients would have
developed it anyway.

NHLBI is planning a five-year follow-up study of patients who took part
in the Hydrea trial to see whether any of them develop leukemia or other
problems that may result from long-term use of the drug. Another study,
which began in January 1995, is looking at the safety and effectiveness
of Hydrea in children ages 5 to 15 who have sickle cell anemia.

Research continues on other possible ways of reducing the occurrence of
painful sickle cell episodes by increasing the production of fetal
hemoglobin. For example, NIH scientists are studying whether a combined
regimen of Hydrea and erythropoietin, a hormone that increases the
production of red blood cells, is less toxic and more effective than
Hydrea alone. (Erythropoietin is licensed by FDA to treat anemia in
certain patients.) Studies are also under way to determine the safety
and efficacy of butyrate, an experimental drug that can stimulate
production of fetal hemoglobin.

NHLBI recently funded three centers that will try to develop gene
therapy for sickle cell anemia, said Bonds. "If you could replace the
abnormal genes, you could cure the disease. However, there are
significant technical problems involved in making gene therapy work."

Because of these problems, gene therapy is unlikely to be a reality for
many years, she said. Nevertheless, she said she is optimistic that new,
effective treatments for sickle cell anemia will be developed in the
future.

"I like to tell people that [the results of the Hydrea study] will one
day be likened to [the discovery of] insulin or penicillin. Those drugs
were the first major breakthroughs for the treatment of diabetes and
severe bacterial infections, although other agents have since [been
introduced] to treat those diseases."

Eleanor Mayfield is a writer in Silver Spring, Md.


------------------------------------------------------------------------


Sickle Cell Inheritance

<Picture: [chart showing incidence of sickle cell disease among various
ethnic groups in the United States]>In the United States, sickle cell
anemia is most common among African Americans. Every year, about 1 in
400 African-American infants is born with the disease after inheriting
the genetic mutation from both parents.

People who have only one copy of the mutation are said to have sickle
cell trait. It is estimated that 1 in 12 African Americans has sickle
cell trait. People with sickle cell trait are usually healthy, although
they can pass the mutation on to their children.

A child conceived by two people with sickle cell trait has one chance in
two of also having sickle cell trait, one chance in four of having
sickle cell anemia, and one chance in four of inheriting neither the
trait nor the disease, according to Lilia Talarico, M.D., a medical
officer in the division of gastrointestinal and hematologic drug
products in FDA's Center for Drug Evaluation and Research.

The disease can also occur among non-African Americans. "People whose
ancestors came from parts of the world where malaria was prevalent are
potentially carriers of the sickle gene," said Duane R. Bonds, M.D., of
the National Heart, Lung, and Blood Institute. "In addition to people of
African descent, people whose ancestors came from the Mediterranean
basin-Greece, Italy, Sardinia-may also carry the gene. The sickle gene
is also found in parts of India and the Arabian peninsula."

In the past, individuals with sickle cell anemia often died in
childhood. A 1973 study estimated that half of those with the disease
died by the age of 14. A frequent cause of death was bacterial infection
by the organism Streptococcus pneumoniae. Children with sickle cell
anemia are highly susceptible to infections because they lose the
function of their spleen, which provides protection against bacterial
infections.

--E.M.

------------------------------------------------------------------------

Medications Can Aid
Recovery from Alcoholism

by Paula Kurtzweil

The number 13 represents bad luck for some people, but for Floyd McCrory
of Rockville, Md., it's a sign of continuing good fortune.

This year, he celebrates 13 years of sobriety.

"Best thing I ever did," he said about quitting drinking. "It turned my
whole life around."

McCrory, 63, realized he was an alcoholic in 1983. That was the year he
got so sick from alcohol-induced pancreatitis, he swore he'd never drink
again. He went into a 28-day treatment program and now attends as many
as 12 Alcoholics Anonymous meetings a week, he said.

In addition, he serves as volunteer director of the Rockville (Md.)
Metro Group. As director, he helps other people overcome their addiction
to alcohol.

He's rarely short of work because, according to the most recent
estimates from the federal government's National Institute on Alcohol
Abuse and Alcoholism, in 1992, 6.3 percent of men and 2.6 percent of
women were alcoholics. That translates to nearly 8 million alcoholics in
the United States. As many as 1.5 million of them seek treatment each
year.

Many follow McCrory's example: They enroll in inpatient and outpatient
alcoholism treatment programs and supplement that with regular
attendance at AA and other self-help group meetings.

Others find success with AA and other self-help groups alone. Some turn
to psychotherapy. Some quit drinking completely on their own.

In some cases, recovering alcoholics are aided by two drugs specifically
for treating alcoholism, one of which was approved by the Food and Drug
Administration in December 1994.

Like McCrory, many alcoholics who seek treatment find success--they
learn to abstain totally from alcohol. But the majority--as many as 90
percent, according to NIAAA--relapse at least once during the four years
following treatment. Fifty percent relapse within the first few months.
Subsequent treatment attempts may or may not prove successful.

What Is Alcoholism?

Alcoholism is a complex disease with physical, social and psychological
consequences--not only for alcoholics but also for people closest to
them.

In the past, alcoholism was often viewed as a moral weakness or
character flaw; it was thought that the person could stop drinking if he
or she really wanted to. It wasn't until 1970, with the establishment of
NIAAA and a national public education effort, that people began to
understand and accept that alcoholism is a life-threatening, chronic
disease involving psychological and physical dependence on alcohol.

Based on the American Psychiatric Association's 4th edition of
Diagnostic and Statistical Manual of Mental Disorders, NIAAA recognizes
four signs of alcoholism:


 * Loss of control over drinking. Alcoholics may intend to have two or
   three drinks, but before they know it, they are on their 10th.

 * Continued use of alcohol despite social, medical, family, and work
   problems.

 * Increased alcohol tolerance over time--that is, needing more alcohol
   to become intoxicated.

 * Withdrawal symptoms when alcoholics stop drinking after a period of
   heavy drinking. The symptoms include anxiety, agitation, increased
   blood pressure, and, in extreme cases, seizures. These symptoms may
   persist for several days.

People do not need to have all four signs to be diagnosed as alcoholic.
Those who have significant problems controlling their drinking and
functioning in social situations because of alcohol may be considered
alcoholics without the physical signs, tolerance and withdrawal.

The APA manual distinguishes between alcoholism and alcohol abuse. The
latter is a less severe problem; unlike alcoholics, alcohol abusers do
not develop physical withdrawal or compulsive alcohol use. However, like
alcoholics, their drinking has negative health, economic and social
effects. Both alcoholics and alcohol abusers need treatment, although
the goals differ. In most cases of alcohol abuse, the goal is to limit
drinking, while for alcoholism, it is to stop drinking altogether.

Why some people become alcoholics remains a mystery, although most
scientists now agree that a combination of genetic and environmental
factors increases a person's vulnerability.

Based on the results of Swedish adoption studies, some researchers
divide alcoholism into two types. Type I, the most common, occurs in
both men and women and is associated with adult-onset alcohol
dependence. This form, also known as "milieu-limited" alcoholism,
appears to be the result of "genetic predisposition and environmental
provocation," according to NIAAA's 1991 publication Alcohol Research:
Promise for the Decade--that is, the development of alcoholism in these
cases is an interaction between inherited predisposition and the
person's life situations.

Type II, or male-limited, alcoholism, on the other hand, is due mainly
to genetics. It occurs only in men, usually with early onset in the teen
years, and is more difficult to treat. Type II alcoholics tend to
exhibit antisocial, aggressive behavior.

A study in a 1992 Journal of Studies on Alcohol (Volume 53, Number 2)
suggests there may be a third type similar to Type II but without the
antisocial behavior.

People often realize a friend or family member has alcoholism through
the consequences of drinking, such as arrests for drunk driving or
problems at work, including chronic absenteeism. Alcoholics' spouses may
demand they leave the house. Later in the disease, they may be
hospitalized for liver disease or pancreatitis.

Denial of these and other negative effects of alcohol in their lives is
common in alcoholics and those close to them, according to the National
Council on Alcoholism and Drug Dependence. But sometimes the negative
occurrences can serve as a catalyst for getting the alcoholic into
treatment. More usually, an ultimatum from the spouse or other family
member, boss, doctor, or judge is the driving force.

McCrory sought treatment after his wife, son and daughter told him he
needed help. A bout with acute pancreatitis (inflammation of the
pancreas) also helped convince him. "The pains were so severe, I wanted
to die," he said. "I never want to go through that again."

Conventional Treatment

For some alcoholics, treatment begins with "detoxification"--that is,
medical management of acute alcohol withdrawal. This can be done in the
hospital or on an outpatient basis and usually lasts one to seven days.

FDA has approved two anti-anxiety drugs, Valium (diazepam) and Librium
(chlordiazepoxide), for treating alcohol withdrawal effects. Some
doctors also prescribe other drugs in the same chemical class, also
approved to treat anxiety. These drugs help decrease the symptoms of
alcohol withdrawal, including anxiety and tremors, and reduce the risk
of serious consequences of withdrawal, such as seizure and delirium.
Dosages are based on the severity of patients' symptoms. Use of these
drugs beyond the withdrawal phase is not advised for alcoholics because
of the drugs' abuse potential and alcoholics' addictive inclination.

Because heavy drinking often results in nutritional deficiencies,
vitamins, particularly thiamin and other B vitamins, also may be given.

Once sober, patients can begin rehabilitation. Many enroll in
hospital-based or freestanding alcoholism treatment centers. According
to a 1991 survey by the U.S. Department of Health and Human Services,
nearly 575,000 people were treated in 8,298 facilities in the United
States on Sept. 30, 1991. Of those, 12 percent were treated as
inpatients, 88 percent as outpatients.

While enrolled, patients attend classes, hear lectures, and participate
in individual, group and family counseling sessions. The activities aim
to educate patients about alcoholism, help them recognize that they have
the disease, and help them adjust to a life without alcohol. Patients
often are introduced to self-help groups, such as AA. Family members
often get involved, too, and may be referred to Al-Anon, a self-help
group for family members of alcoholics.

Following this intensive program, patients are often encouraged to
continue with some type of aftercare program for at least one year. This
might include AA, individual or group psychotherapy, or a
center-sponsored program that continues on a smaller scale the same type
of activities offered during the intensive treatment.

For example, at an addiction treatment center in Bethesda, Md.,
aftercare consists of a 15-week program, in which participants meet
twice a week for one hour. They hear lectures and participate in group
therapy. This is followed by ongoing group therapy of up to one year for
patients with a history of relapse.

"This is a powerful enough disease that a great number of people are
going to [drink] one more time, at least," said Larry Goodwin, a
licensed social worker and director of the Addiction Treatment Center at
Montgomery General Hospital in Olney, Md. "And sometimes that's a
necessary part because they find out, 'I don't like the results. I've
tried it again, and [the experts] are right.'"

Drug Treatment

Alcoholics also may be helped in their recovery with one of two drugs
approved for discouraging alcohol intake. Antabuse (disulfiram), sold by
Wyeth-Ayerst Laboratories Division, has been marketed since 1948. When
combined with alcohol, even small amounts, this drug causes unpleasant
effects, such as facial flushing, throbbing headache, nausea, vomiting,
and increased blood pressure and heart rate.

The drug's effectiveness depends on patient motivation. Those who want
to drink simply stop taking the drug.

A 1986 study found that Antabuse did not improve abstinence rates,
length of time to relapse, or psychosocial functioning any more than
counseling alone. But, patients on Antabuse who continued to drink drank
less frequently than relapsed patients who did not receive the
medication.

The second drug, ReVia (naltrexone), approved by FDA in December 1994
for treating alcoholism, acts on the opioid receptor in the brain to
help prevent relapse and reduce alcohol cravings in those who drink.
ReVia was developed by The DuPont Merck Pharmaceutical Co., which
previously marketed naltrexone under the trade name Trexan for treating
narcotic dependency. The drug remains available for treating narcotic
dependency but under the new brand name, ReVia.

In a 12-week study of 70 alcoholic men, 23 percent of the ReVia-treated
patients relapsed, compared with 54 percent of those receiving placebo.
Of those who drank during the study, 50 percent of those on ReVia
relapsed to heavy drinking, compared with 95 percent of those receiving
placebo.

A study of 104 alcoholic men and women found that patients who took
ReVia were about twice as successful in quitting drinking as patients
who received placebo.

However, because ReVia was tested in conjunction with supportive
therapy, FDA approved its use only as an adjunct to supportive therapy
(such as group therapy) in treating alcoholism.

Studies show the drug is nonaddictive. But it can cause liver toxicity
when given at doses higher than recommended. Therefore, it is not
recommended for people with active hepatitis and other liver diseases.

NIAAA is sponsoring additional studies to determine which patients are
best suited for treatment with ReVia, as well as what dose, therapy
combinations, and treatment duration work best.

Research Continues

Though treatments are helping make controlling alcoholism easier, a cure
is more elusive. The disease is so complex, said Richard Fuller, M.D.,
director of NIAAA's division of clinical and prevention research, that
it may be unlikely one single drug to treat alcoholism will be
discovered. Instead, he said, research will continue to focus on finding
drugs that can treat various aspects of alcoholism.

"I really see alcoholism as a chronic relapsing disease, like
arthritis," he said. "And just as with arthritis, in which various
inflammatory agents can be used to treat an acute episode, there will be
more drugs developed to help alcoholics get and stay on the road to
recovery."

Current NIAAA research efforts focus on developing drugs to:

 * induce sobriety in intoxicated patients
 * treat long-lasting withdrawal symptoms, which often lead to relapse
 * control alcohol craving
 * improve mental abilities of patients with alcohol-induced mental damage
 * decrease alcohol consumption by treating coexisting psychiatric disorders.

But the advent of these drugs is not likely to diminish the importance
of behavioral therapies. Self-help programs, like AA, will continue to
play an important role for many alcoholics.

One person who is a firm believer in such programs is AA member McCrory.
"These people have been there," he said. "They tell it like it is:
Alcoholism will never be cured, but there will be good days and good
times if you stay sober."

Paula Kurtzweil is a member of FDA's public affairs staff.


------------------------------------------------------------------------


More Information

For more information on alcoholism and its treatment, contact:

National Institute on Alcohol Abuse and Alcoholism
Office of Scientific Affairs
Willco Building, Suite 409
6000 Executive Blvd., MSC 7003
Bethesda, MD 20892-7003
[phone]

National Clearinghouse for Alcohol and Drug Information
(1-800) 729-6686 (Se habla Espa±ol)
TDD for hearing impaired callers: (1-800) 487-4889

Center for Substance Abuse Treatment's National Drug and Alcohol
Treatment Routing Service
(1-800) 662-HELP (662-4357)

National Council on Alcoholism and Drug Dependence Inc.'s Hope Line
(1-800) NCA-CALL (622-2255)

National Association for Families and Addiction Research and Education
(1-800) 638-2229.

To find the nearest Alcoholics Anonymous meeting place, call your local
AA organization, listed in the white and yellow pages of your telephone
directory.

To find the nearest Al-Anon group (for family members of alcoholics),
call (1-800) 245-4656.


------------------------------------------------------------------------


Raw Oyster Risk for Alcoholics

Eating raw oysters can be dangerous for alcoholics (just as it can be
for people with suppressed immune systems).

Raw oysters can carry the bacterium Vibrio vulnificus, which, if
ingested, can cause serious illness--even death. This bacterium occurs
naturally in marine waters and is often found in oysters from the Gulf
of Mexico. People with liver disease, which is common among alcoholics,
are 200 times more likely to die from this bacterium than those without
liver disease.

According to the National Institute on Alcohol Abuse and Alcoholism, 90
to 100 percent of heavy drinkers show evidence of fatty liver, the
earliest signs of liver disease. Ten to 30 percent develop alcoholic
hepatitis, inflammation of the liver. And 10 to 20 percent develop
cirrhosis, end-stage liver disease.

If you are unsure of your risk, check with your doctor. Or eat your
oysters fully cooked because cooking kills all the bacteria.

For more information, call the FDA Seafood Hotline at (1-800) FDA-4010.

--P.K.

------------------------------------------------------------------------


Drug Photosensitivity
Another Reason to Be Careful in the Sun

by Craig D. Reid, Ph.D.

Since childhood, my brother Blair always developed a dark tan without
ever sunburning. Now a college soccer coach in Iowa, he is constantly
outside practicing in the sun. Recently, Blair suffered a severe sunburn
after only 45 minutes of sun exposure on a cool, partly sunny morning.
Consulting his physician, he learned that the commonly prescribed
colitis medication Azulfidine (sulfasalazine), which he was using at the
time for a colon infection, was the cause of his problems.

Azulfidine is one of the many medications included in the Food and Drug
Administration's most recent listing of medications that increase
sensitivity to light and can cause a wide variety of health problems
known as photosensitivity disorders. In some individuals, these
medications can produce adverse effects when the person is exposed to
sunlight and other types of ultraviolet (UV) light of an intensity or
for a length of time that would not usually give the person problems.
Some products are more likely to cause reactions than others. And not
everyone who uses the products will be affected.

Photoreactions

Chemicals that produce a photoreaction (reaction with exposure to UV
light) are called photoreactive agents or, more commonly,
photosensitizers. After exposure to UV radiation either from natural
sunlight or an artificial source such as tanning booths or even those
"purple-lighted" mosquito zappers, these photosensitizers cause chemical
changes that increase a person's sensitivity to light, causing the
person to become photosensitized. Medications, food additives, and other
products that contain photoreactive agents are called photosensitizing
products.

FDA has also reported that photoreactive agents have been found in
deodorants, antibacterial soaps, artificial sweeteners, fluorescent
brightening agents for cellulose, nylon and wool fibers, naphthalene
(mothballs), petroleum products, and in cadmium sulfide, a chemical
injected into the skin during tattooing.

Photoreactive agents, such as Azulfidine, can cause both acute and
chronic effects. Acute effects, from short-term exposure, include
exaggerated sunburn-like skin conditions, eye burn, mild allergic
reactions, hives, abnormal reddening of the skin, and eczema-like rashes
with itching, swelling, blistering, oozing, and scaling of the skin.
Chronic effects from long-term exposure include premature skin aging,
stronger allergic reactions, cataracts, blood vessel damage, a weakened
immune system, and skin cancer.

Widely used medications containing photoreactive agents include
antihistamines, used in cold and allergy medicines; nonsteroidal
anti-inflammatory drugs (NSAIDs), used to control pain and inflammation
in arthritis; and antibiotics, including the tetracyclines and the
sulfonamides, or "sulfa" drugs.

Sometimes this quality can be put to good medical use. For example, two
well-known photoreactive chemicals, psoralens and coal-tar dye creams,
are used together with UV lamps to treat psoriasis, a chronic skin
condition characterized by bright red patches covered with silvery
scales.

Pioneering Research

European scientists pioneered photosensitivity disorder research during
the 1960s. In 1967, Danish researchers attributed strange skin lesions
(any abnormal change on the skin) on women to perfumed soap. In 1967,
British researchers discovered that sandalwood oil in sunscreens and
facial cosmetics caused photoallergies and later reported that
quindoxin, a food additive in animal feed also caused phototoxic
erythemal skin patches on British farmers handling the feed.

Shortly thereafter, French scientists demonstrated that bergamot oil in
sunscreens caused photosensitivity disorders. German researchers
isolated photoreactive agents in colognes, perfumes and oral
contraceptives.

In 1972, American scientists linked sunlight-activated aniline compounds
(found in drugs, varnishes, perfumes, shoe polish, and vulcanized
rubber) to hives and skin conditions such as dermatitis and dandruff.

Scientists were soon publishing laundry lists of photoreactive agents
found in these substances as well as those in hair dyes, hair styling
creams, and household items such as shoe polish and mothballs. Current
research focuses on identifying what photoreactive agents are found in
which medicinal products and how to control photosensitivity disorders.

Photosensitizers can cause either photoallergic or phototoxic reactions.

Photoallergies

In photoallergic reactions, which generally occur due to medications
applied to the skin, UV light may structurally change the drug, causing
the skin to produce antibodies. The result is an allergic reaction.
Symptoms can appear within 20 seconds after sun exposure, producing
eczema-like skin conditions that can spread to nonexposed parts of the
body. But sometimes, photoallergic reactions can be delayed. For
example, Yuko Kurumaji reported in the October 1991 issue of Contact
Dermatitis that photoallergic sensitivity disorders to the topically
applied NSAID Suprofen (not approved for use in the United States) took
up to three months to develop.

Other regularly used products that can cause photoallergic reactions are
cosmetics that contain musk ambrette, sandalwood oil, and bergamot oil;
some quinolone antibacterials; and the over-the-counter (OTC) NSAID pain
relievers Advil, Nuprin and Motrin (ibuprofen), and Aleve (naproxen
sodium).



Phototoxicity

Phototoxic reactions, which do not affect the body's immune system, are
more common than photoallergic reactions. These reactions can occur in
response to injected, oral or topically applied medications.

In phototoxic reactions, the drug absorbs energy from UV light and
releases the energy into the skin, causing skin cell damage or death.
The reaction occurs from within a few minutes to up to several hours
after UV light exposure. Though sunburn-like symptoms appear only on the
parts of the body exposed to UV radiation, resulting skin damage can
persist.

For example, Henry Lim, M.D., reported in the March 1990 issue of
Archives of Dermatology that several patients previously exposed to
photoallergens continued to have phototoxic skin eruptions up to 20
years after discontinuing medication use, even though they avoided
further exposure to the photoallergens.

Frequently prescribed medications that cause phototoxic reactions
include tetracycline antibiotics, NSAIDS, and Cordarone (amiodarone),
used to control irregular heartbeats.

Because drug-induced photosensitivity disorder symptoms mimic sunburns,
rashes and allergic reactions, many cases go unreported. Also, although
research has shown that the numbers of photosensitized individuals may
be high, most people do not associate the sun's light with the
development of their skin eruptions.

Photophobia

Some medications can cause photophobia. Although literally, photophobia
is fear of light, photophobic photosensitivity disorder patients avoid
light not because they're afraid of it but because their eyes are
painfully sensitive to it.

Some medications that induce photophobia include several drugs
prescribed for irregular heartbeat, such as Crystodigin (digitoxin) and
Duraquin (quinidine), and several drugs for diabetes, such as Tolinase
(tolazamide) and Orinase (tolbutamide).

Who Gets a Reaction?

The degree of photosensitivity varies among individuals. Not everyone
who uses medications containing photoreactive agents will have a
photoreaction. In fact, a person who has a photoreaction after a single
exposure to an agent may not react to the same agent after repeated
exposures.

On the other hand, people who are allergic to one chemical may develop
photosensitivity to another related chemical to which they would
normally not be photosensitive. In such cross-reaction, photosensitivity
to one chemical increases a person's tendency for photosensitivity to a
second. For example, J.L. deCastro reported in the March 1991 issue of
Contact Dermatitis that 17 patients allergic to the antiseptic
thimerosal, used in some contact lens preparations, developed
photosensitivity to the NSAID Feldene (piroxicam), yet none of them had
had any previous photoreaction to Feldene.

Although those with fair skin are more susceptible to photosensitizing,
it is not uncommon for dark-skinned individuals to have chronic
photodermatitis.

People infected with HIV, the virus that causes AIDS, are more
susceptible to photosensitive disorders so they need to exercise special
care in UV light exposure. In a study published in the May l994 Archives
of Dermatology, Amy Pappert, M.D., reported that if apparently healthy
patients exhibit certain photodistributed skin problems of unknown
origin, the possibility of HIV infection should be considered.

What is termed a "photo-recall" can take place when a non-photoreactive
product prompts the repeat of a previous reaction to a photoreactive
agent.

Photoreactive products can also aggravate existing skin problems like
eczema, herpes, psoriasis and acne, and can inflame scar tissue. They
can also precipitate or worsen autoimmune diseases, such as lupus
erythematosus and rheumatoid arthritis, in which the body's immune
system mistakenly destroys itself.

A Few Common Photosensitizers

These are just a few of the more commonly used drugs that can cause
photosensitivity reactions in some people.


Brand Name         Generic Name        Therapeutic Class

Motrin             ibuprofen            NSAID, antiarthritic
Crystodigin         digitoxin            antiarrhythmic
Sinequan         doxepin            antidepressant
Cordarone         amiodarone         antiarrhythmic
Bactrim          trimethoprim        antibiotic
Diabinese         chlorpropamide        antidiabetic (oral)
Feldene          piroxicam            NSAID, antiarthritic
Vibramycin         doxycycline        antibiotic
Phenergan         promethazine        antihistamine


Do Sunscreens Help?

Does using sunscreens help protect against photosensitivity? The answer
is not clear. Sunscreens do lessen the effects of UV radiation, but some
contain ingredients that themselves may cause photosensitivity in some
people. Also, most sunscreens protect only from short-wave UV light
(UVB), whereas most phototoxic compounds are activated by longer
wavelengths of UV light (UVA). Sunscreens containing bergamot oil,
sandalwood oil, benzophenones, PABA, cinnamates, salicylates,
anthranilates, PSBA, mexenone, and oxybenzone can all cause
photosensitivity reactions. Titanium dioxide is the least likely
sunscreen to cause photosensitivity disorders.

Before going out in the sun, it's a good idea to check with your doctor
to see if any of the medications you're taking is likely to cause
problems and decide how to best avoid such reactions. Read the labels of
OTC drugs and note if they may be photosensitizing.

If you get symptoms after being out in the sun, you may want to consider
what drugs and chemicals you are using and contact your doctor
immediately for advice.

Craig D. Reid, Ph.D., is a writer in New Haven, Conn.


------------------------------------------------------------------------


Tanning Booths Bigger Problem

<Picture: [picture of tanning booth]> Tanning booths and the use of
indoor tanning products can be more of a problem than natural sunlight,
and this is true with photosensitivity reactions as well as in general.
FDA enforces policies in which sunlamp product manufacturers must
develop an exposure schedule and establish a maximum recommended
exposure time (and therefore the maximum timer interval) based on the
characteristics of their particular products. This information must
appear on the product's warning label and is no way to be considered as
a safe limit.

FDA warns that some tanning operators may claim that UVA sunlamps are
safer than the sun and UVB lamps. This is not true. In fact, exposure to
the UV radiation from sunlamps adds to the total amount of UV radiation
you get from the sun during your lifetime, further increasing your risk
of cancer.

For further information on the dangers of indoor tanning, write to FDA
(HFZ-342), 5600 Fishers Lane, Rockville, MD 20857 and ask for DHHS
Publication No. (FDA) 87-8272.

------------------------------------------------------------------------


Updates



Public Can Comment on PPA Proposal

Because of a possible link between phenylpropanolamine (PPA), an
ingredient in certain over-the-counter (OTC) drug products, and a type
of stroke, FDA recently proposed new warning labels for these products.

The public has until May 14 to send written comments on the proposal to:
FDA Dockets Management Branch, HFA-305, Rockville, MD 20857. The
proposal was in the Feb. 14, 1995, Federal Register.

FDA officials are concerned it may be harmful to take more than the
recommended dose of PPA, an ingredient in OTC weight control,
cough-cold, allergy, and nasal decongestant drug products. PPA affects
the central nervous system and the cardiovascular system.

Some data indicate that PPA in OTC drugs may increase the risk of
hemorrhagic stroke, which results from bleeding into the brain. Although
FDA agrees that, to date, there is no definite link between using OTC
drugs containing PPA and hemorrhagic strokes, the agency believes
further safety data are needed. FDA awaits these data from an
industry-sponsored PPA safety study.

The new labels would warn consumers not to take more than one
PPA-containing drug at a time, or at the same time as a drug containing
phenylephrine, pseudoephedrine or ephedrine--whose effects are similar
to PPA's. Labels on weight-control products containing PPA would also
warn that the products are for adult use only.

PPA interacts with certain antidepressants known as monoamine oxidase
inhibitors, which when combined with PPA, can cause life-threatening
adverse effects. Also, people with high blood pressure, heart or thyroid
disease, or diabetes should not use PPA-containing products without
consulting a doctor. Labels already include this information.



FDA Requires Folic Acid Fortification

Most enriched grain products marketed in the United States will be
fortified with folic acid, under a new FDA rule intended to reduce the
risk of certain birth defects.

Folic acid, or folate, reduces the risk of neural tube birth defects,
such as spina bifida, when consumed in adequate amounts by women before
and during early pregnancy. Spina bifida is a common disabling birth
condition resulting from failure of the spinal cord to close.

In 1992, the Public Health Service recommended that all women of
childbearing age eat 0.4 milligrams (mg) of folic acid daily because
over half of all pregnancies are unplanned and because these defects
occur in the developing fetus before most women know they are pregnant.

"By fortifying grain products, we are making it easier for women of
childbearing age to achieve adequate folic acid levels in their diets,"
said FDA Commissioner David A. Kessler, M.D.

In addition to eating fortified foods, women of childbearing age should
eat a diet rich in leafy green vegetables, citrus fruits and juices, and
lentils or take a multivitamin a day to ensure adequate levels of folic
acid, Kessler said.

Under FDA's rule, food manufacturers must fortify their enriched bread
products, flour, corn grits, cornmeal, farina, rice, macaroni, and
noodles with 0.43 mg to 1.4 mg of folic acid per pound of product.
Breakfast cereals can have up to 0.4 mg of added folic acid per serving.
These amounts are designed to keep daily intakes of folic acid below 1
mg because intakes above that amount may mask symptoms of pernicious
anemia, a form of vitamin B12 deficiency that primarily affects older
people. If untreated, pernicious anemia can lead to severe permanent
nerve damage.

The rule allows food manufacturers to make claims on the labels of
fortified products that adequate intake of the nutrient has been shown
to reduce the risk of neural tube birth defects.

FDA published a final rule in the March 5, 1996, Federal Register. (See
"To Reduce Birth Defects, FDA Proposes Folic Acid Fortification" in the
May 1994 FDA Consumer.)



Smoking Cessation Aid Available OTC

Nicorette gum (nicotine polacrilex) became the first over-the-counter
smoking cessation aid when FDA recently switched the drug from
prescription to OTC status.

FDA approved Nicorette gum for adults last Feb. 9 in both 2-mg and 4-mg
strengths, based on recommendations by the agency's Nonprescription
Drugs and Drug Abuse Advisory committees. Previously available by
prescription only, Nicorette will now be sold OTC as a 12-week smoking
cessation treatment that includes a user's guide and audio tape.

When used according to directions, Nicorette delivers a low level of
nicotine that helps reduce craving and other withdrawal symptoms.

Almost half of those who use Nicorette are able to stop smoking for at
least a few days, but many start smoking again. The one-month quit rates
among smokers who use Nicorette and who seek no additional treatment
(such as support groups) is less than 10 percent. Approximately 45
million to 50 million U.S. adults are addicted to nicotine.

People with heart disease should consult their doctors before using
Nicorette.

SmithKline Beecham Consumer Healthcare of Pittsburgh markets Nicorette
gum.

(For more information on quitting smoking, see "Prescriptions to Help
Smokers Quit" in the December 1992 FDA Consumer.)



Rogaine Now Available OTC

Rogaine Topical Solution (minoxidil 2%) was recently approved as the
first over-the-counter drug to treat common hereditary hair loss. It was
previously available by prescription only.

More than 40 million men and 20 million women experience hair loss or
thinning at any given time, usually due to heredity. In patients with
hereditary hair loss, Rogaine promotes gradual hair growth and may take
at least four months before producing noticeable results. Hair regrowth
varies by person, and not everyone responds to the drug. Rogaine has not
been shown to help treat hair loss caused by nonhereditary factors.

About 25 percent of men and 20 percent of women attain at least moderate
hair growth with the product, meaning new individual hairs cover some or
all thinning areas. A larger fraction of users achieve growth of some
new hairs, though not enough to cover thinning areas.

In some cases, Rogaine users have reported itching and other skin
irritations of treated scalp areas. The product should not be used on
children or babies. Pregnant or nursing women should see a health
professional before using the drug. Users should discontinue the drug
and see a health professional if they have chest pains, rapid heartbeat,
faintness or dizziness, sudden unexplained weight gain, swollen hands or
feet, or redness or irritation.

FDA granted Rogaine's OTC status last Feb. 12 following recommendations
from two of the agency's advisory committees.

Upjohn Pharmaceuticals of Kalamazoo, Mich., markets Rogaine.

(For more on hair loss and its treatment, see "Hair! From Personal
Statement to Personal Problem" in the December 1991 FDA Consumer.)



AIDS Drug Approved in 72 Days

The second in a new class of AIDS drugs was approved by FDA in only 72
days, the fastest approval of any AIDS drug so far.

FDA approved the protease inhibitor Norvir (ritonavir) last March 1 for
use alone or in combination with nucleoside analog medicines, such as
AZT (zidovudine, marketed as Retrovir), in people with advanced HIV
infection. Both types of drugs inhibit HIV development, but at different
points in the replication process.

Ritonavir may also be used for less advanced HIV infection under FDA's
accelerated approved mechanism. Under this mechanism, the agency bases
early marketing approval on improved laboratory markers--such as CD4
cell counts, an indicator of immune system strength, and viral load, a
measure of virus level detectable in the bloodstream. Longer term data
must be collected on clinical endpoints, such as disease progression and
deaths.

Clinical researchers studied the new drug alone and in combination with
nucleoside analogs in people at various stages of HIV infection.

None of the studies included clinical endpoints for patients with less
advanced HIV infection. However, in people with advanced disease, the
studies showed ritonavir not only increased CD4 cell counts and
decreased viral load, but also reduced disease progression and deaths.

In the largest study, the cumulative death rate among patients on
ritonavir was about 40 percent of that among patients on placebo.
Treated patients also had a 50 percent greater reduction in disease
progression during the six-month study.

Adverse events associated with ritonavir treatment included diarrhea,
nausea, vomiting, weakness, tingling, liver inflammation, elevated lipid
levels, and taste disturbance.

FDA worked with the manufacturer, Abbott Laboratories, to ensure that
potentially severe drug interactions with Norvir are clearly highlighted
in the package label and that education materials are available to
patients.



Thalidomide Studied for Treating AIDS

Several trials are ongoing to determine the safety and effectiveness of
thalidomide in treating conditions related to AIDS and HIV infection.

Thalidomide was marketed in Europe and other parts of the world in the
1950s and 1960s as a tranquilizer and for nausea in pregnancy before it
was discovered that it causes severe birth defects. The drug was never
approved in the United States.

AIDS-related conditions for which clinical studies of thalidomide are
under way include:


 * Aphthous ulcers (painful, open sores in the mouth and throat). Two
   protocols: AIDS Clinical Trial Group (ACTG) 251, and single-patient
   INDs.

 * Wasting syndrome. Two protocols: a randomized, placebo-controlled
   study in which participants who receive placebo are switched to
   thalidomide if their condition doesn't improve after eight weeks; for
   patients who do not qualify for the first study, a compassionate use
   study has been initiated by the drug's manufacturer, Celgene Corp.

 * Tuberculosis and other mycobacterial infections: a pilot study under
   the direction of Gilla Kaplan, M.D., of Rockefeller University in New
   York City.

 * HIV infection: an early placebo-controlled study (ACTG 267) limited
   to 36 participants to determine the safety, antiviral activity, and
   tolerability of thalidomide in people with HIV.

For more information about these and other AIDS drug clinical trials,
call (1-800) TRIALS-A.


Cholesterol Filter Approved

A medical device that filters harmful cholesterol from blood has been
approved by FDA for use in people who have extremely high blood
cholesterol levels that cannot be lowered with a low-fat diet and
cholesterol-lowering medicines.

The Liposorber LA-15 System was approved Feb. 21 for treating the
estimated 4,000 Americans with a genetic disorder causing extremely high
cholesterol. These people are at very high risk for early heart disease,
heart attacks, and death.

The Liposorber removes low density lipoprotein (LDL) ("bad" cholesterol)
from the blood through a plastic tube inserted into the arm and
connected to the filtering machine. The process, similar to kidney
dialysis, takes about three hours and is done at a medical facility.
Patients who receive the treatment should remain on a low-fat diet and
continue to take cholesterol-lowering medication, even though these
therapies may have little effect.

In a study of 74 patients at 11 U.S. sites, the treatment with the
Liposorber immediately reduced blood levels of LDL in all patients. The
patients were on cholesterol-lowering drugs and diet, which had not had
much effect on their cholesterol levels.

Because patients' LDL levels returned to their pretreatment values 14 to
30 days after treatment, the treatment must be repeated every one to two
weeks.

The study was not designed to, nor did it, show whether the treatment
has long-term benefits, such as reducing angina, heart attacks, and
death. To help determine long-term risks and benefits, FDA is requiring
the manufacturer, Kaneka America Corp., of New York City, to establish a
patient registry to continue to monitor the conditions of patients who
receive this treatment.



Low-Risk Devices Exempt from FDA Review

To speed patient access to new medical devices, FDA has exempted 122
categories of low-risk devices from premarket review, adding to the 450
categories already exempted.

New exemptions include gas pressure gauges, oxygen masks, pacemaker
chargers, dental floss, pneumatic tourniquets, patient scales,
examination lights, and therapeutic massagers.

The revised policy, which went into effect Feb. 15, reclassifies 111
categories of devices from class II (medium risk) to class I (low risk)
and exempts 11 device categories already in class I. Nearly
three-fourths of all class I devices, or one-third of all classified
medical devices, are now exempt from premarket review.

FDA will continue to regulate these products, which are still subject to
good manufacturing practice regulations, factory inspections, and other
general controls. But manufacturers no longer need agency clearance
before marketing the products. FDA notified device makers with premarket
clearances pending for the 122 categories that their devices are now
exempt.

The exemptions are part of drug and medical device reforms included in
the Clinton administration's National Performance Review.



Free Spanish, English Pubs

Teenage smoking, childhood poisoning, and stomach upsets are the topics
of free new FDA Consumer reprints. The smoking reprint is available in
both Spanish and English.

Also available are a brochure, in Spanish, about using medicine safely
and a backgrounder about commenting on FDA rules.

The new publications and their pub numbers are:

 * On the Teen Scene: Young People Talk with FDA Commissioner About
   Smoking (FDA) 96-1232

 * Jovenes Conversan con el Comisionado de la FDA Sobre el Problema del
   Uso del Tabaco (FDA) 96-1232S

 * Preventing Childhood Poisoning (FDA) 96-1233

 * Taming Tummy Turmoil (FDA) 96-3219

 * Las Medicinas: Como Usarlas Con Confianza (FDA) 96-3201S

 * Making Your Voice Heard at FDA: How to Comment on Proposed
   Regulations and Submit Petitions (BG 96-2)

To order single copies of the brochure and reprint, write to FDA,
HFE-88, Rockville, MD 20857. To order single copies of the backgrounder
or 2 to 100 copies of the brochure and reprints, write to FDA, HFI-40,
at the same address, or fax your order to [phone]. Include the
publication number.


------------------------------------------------------------------------


Notebook


The Notebook: a potpourri of items of interest gathered from FDA news
releases, other news sources, and the Federal Register (designated FR,
with date of publication). The Federal Register is available in many
public libraries.


Wine bottle necks can no longer be covered with tin-coated lead foil
capsules, according to an FDA final rule effective last Feb. 8. During
use, the lead in the capsules may become a component in the wine and be
consumed, exposing the drinker to lead. (FR Feb. 8)

Color additive certification fees have been increased to cover the cost
of FDA's color certification program, according to an FDA final rule
effective last March 4. The new fee is 30 cents per pound, a 5-cent
increase. (FR Feb. 1)

Computerized information is now available from the national Centers for
Disease Control and Prevention. "CDC WONDER for the PC" provides
menu-driven access to more than 25 public health databases, including
data on diseases, deaths, hospitalizations, and CDC health policies.
Users need a computer, modem, CDC software, and user identification.
"CDC WONDER on the Web" provides free access to much of the same
information as CDC WONDER for the PC. It can be accessed at
http://wonder.cdc.gov/. "The CDC Prevention Guidelines on CD-ROM"
provides more than 400 documents on public health topics. For more
information on access and costs, which vary, contact Dianne Wylie,
Public Health Information Systems Branch, CDC, 4770 Buford Highway,
N.E., Mailstop F-51, Atlanta, GA 30341-3724; telephone [phone];
E-mail [e-mail]. (FR Feb. 14)

Food Chemicals Codex, an 880-page reference, is now available. It
provides standards for the identity, strength and purity of more than
900 food-grade ingredients. Copies may be purchased for $195, plus $4
for shipping and handling, from the National Academy Press, 2101
Constitution Ave., N.W., Lockbox 285, Washington, DC 20055; telephone
[phone] or (1-800) 624-6242; Internet address:
http://www.nas.edu/nap/bookstore/.

A seafood safety arrangement was signed by FDA and New Zealand last Dec.
20. The countries arranged to acknowledge one another as competent
authorities and recognize that each has systems to ensure safe,
wholesome, and truthfully labeled fish and fishery products. (FR Feb.
26)

A battery charger for computer notebooks was recalled by the
manufacturer and the Consumer Product Safety Commission. Texas
Instruments' battery charger for TravelMate 4000M notebook computers was
recalled because some chargers may have a defect in a small electronic
component that could cause fire if consumers cover or insulate the
external charger during use. The chargers, sold from November 1994
through January 1996, are labeled "Texas Instruments ... P/N
9792543-0001 ... Type BTC 01 ..." Owners of the chargers should call
(1-800) 730-4235 or send an E-mail with their name, address, and
telephone number to [e-mail]. Texas Instruments will replace
the charger or refund the purchase price.

Biotechnology product quality is the topic of a final guideline prepared
by FDA for the International Conference on Harmonization. "Analysis of
the Expression Construct in Cells Used for Production of r-DNA Derived
Protein Products" describes the information needed to assess the
structure of cells used to make recombinant deoxyribonucleic acid
(r-DNA) derived proteins. For a free copy, write to Division of
Communications Management (HFD-210), Center for Drug Evaluation and
Research, Rockville, MD 20855; telephone [phone]. An electronic
version of the guideline is available at ftp://cdvs2.cder.fda.gov/. (FR
Feb. 23)

------------------------------------------------------------------------


Investigators' Reports


Laser Light Shows Nixed Until Fixed

by Paula Kurtzweil

A glitch in the glitter over Las Vegas has temporarily turned off some
of the city's well-known glitz.

Last December, FDA declared a temporary moratorium on outdoor laser
light shows within a 20-mile radius of the three Las Vegas-area airports
because the lights were "flash blinding" and distracting airline pilots
during takeoffs and landings there.

The lights can go back on when the hotel casinos can demonstrate to FDA
and the Federal Aviation Administration that their laser light shows
will not distract and temporarily impair aircraft personnel's vision
during critical and sensitive flight periods.

In late 1995, the FAA reported to FDA that 52 incidents of aircraft
"illuminations" from laser lights had occurred in or near Las Vegas
since 1993. Eleven incidents resulted in temporary blindness of flight
crew members, and 24 took place during critical flight times.

Although no aircraft accidents occurred, FDA said the temporary ban is
necessary to protect public safety. "We must all do our parts to prevent
the occurrence of a tragedy that could cost hundreds of lives," FDA said
in the moratorium issued Dec. 11, 1995.

FDA also said it would not "hesitate to extend" the moratorium to other
cities or nationwide if problems arise in other locations. The ban
mainly affects three hotel casinos that hold variances, or permits, from
FDA to display laser light shows in the sky. FDA regulates laser light
shows, along with all other laser equipment--from surgical instruments
to grocery store checkout scanners--under the Radiation Control for
Health and Safety Act and the Medical Device Amendments to the federal
Food, Drug, and Cosmetic Act.

According to Gary Zaharek, an FDA electrooptics specialist, outdoor
high-power laser light displays became popular in Las Vegas about three
years ago as a way to attract tourists and customers. Competition had
been intense among operators, he said.

FAA began receiving pilot complaints about Las Vegas-area outdoor laser
lights in late 1993. The first report involved a pilot who took off from
Las Vegas and was treated for corneal irritation at his destination,
Phoenix, Ariz. His condition may have been caused when the pilot rubbed
his eyes after the laser light incident.

In early 1994, Ralph Kirch, another FDA electrooptics specialist,
investigated Las Vegas hotel casinos displaying laser light shows. One
was operating without a variance. After several visits by Kirch, the
casino agreed to stop showing the laser light shows.

The other three, while variance holders, were not following proper
procedures. Among their violations were failing to:

 * employ people as aircraft "spotters" to warn laser operators of
   incoming and outgoing planes

 * maintain documented quality control procedures

 * provide certificates of proper operator training.

The operators also were allowing unnecessary laser light in areas where
the public could be present.

In 1994 and 1995, Kirch and Zaharek made a number of follow-up visits to
the laser light show operations and found many repeat violations.

Then, on Oct. 30, 1995, a Southwest Airlines' pilot in control of a
flight departing McCarran International Airport in Las Vegas was
temporarily blinded by a laser light. According to news reports, the
incident was serious enough to force the plane's captain to take control
until the pilot regained his sight. "Had it hit me and the other pilot
simultaneously, I shudder to think what would have happened," the pilot
told reporters.

Under the moratorium, manufacturers and operators will be permitted to
beam their laser light shows into the sky only if they can demonstrate
that their shows comply with FAA's recommended interim rules. They also
must develop and follow quality assurance programs that, among other
things, specify radiant power and energy, beam divergence, and pointing
accuracy of lasers.

Since the ban, only one variance holder has received FDA's permission to
project an outdoor laser light show. That show, a special two-day event,
did not include beams into the sky.

At press time in April, FDA was working with FAA, laser industry groups,
the U.S. Army and Air Force, the Society of Automotive Engineers, and
others to develop final guidelines on projecting laser light shows into
airspace.

Paula Kurtzweil is a member of FDA's public affairs staff.


------------------------------------------------------------------------



From Barnyard to Breakfast Table,
Court Recognizes FDA's Jurisdiction

Is a hog being raised for food just an animal until the moment of
slaughter? Or is it a breathing bacon? In a precedent-setting court
case, a federal judge decided that when it comes to the federal
government's food safety enforcement, "a hog is food."

On May 18, 1995, U.S. Judge Walter H. Rice, Southern District of Ohio,
Western Division, ruled that live animals, raised for food and intended
for slaughter are food under the Federal Food, Drug, and Cosmetic Act.
Rice's ruling broke judicial ground because it was the first time a
court officially recognized FDA's jurisdiction over live animals
intended for slaughter. The judge also reaffirmed that any party who has
purchased an adulterated article--including live food animals--may be
held liable for introduction of the article into interstate commerce.

Such was the case with two Ohio livestock dealers who, FDA charged, had
bought and sold live hogs with illegal amounts of drugs in the animals'
tissues.

On Oct. 5, 1995, livestock dealers Ronald Tuente and Roger Tuente,
owners of Tuente Livestock Inc., Yorkshire, Ohio, went out of business
after signing a consent order of injunction prohibiting them from buying
and selling livestock.

FDA's investigation of the Tuentes and their firm began in September
1987 after the U.S. Department of Agriculture found illegal residues of
the animal antibiotic sulfamethazine in the tissue of hogs the Tuentes
had sold for slaughter. Sulfamethazine in animals sold for human
consumption may cause allergic and other adverse reactions in some
people. In addition, it is a potential carcinogen.

Under the Food, Drug, and Cosmetic Act, FDA can hold responsible any
party in the distribution chain who introduces an adulterated product
into interstate commerce. This includes both the party that actually
adulterated the product and any other party that distributes the product
after adulteration has occurred.

To ensure that the livestock sold for slaughter do not have illegal
residues of drugs, FDA advises livestock dealers to do business with
producers who issue drug-free certificates or supply other documentation
of animals' medication history. The agency requires the certificates
when companies' livestock test positive for illegal drug residues. In
addition, FDA requires dealers to segregate each producer's animals or
tattoo or tag each animal with a distinct producer's identification.
This allows FDA to trace violations to the source.

After inspecting the firm on Sept. 9, FDA's Cincinnati district issued a
Notice of Adverse Findings because the firm lacked guarantees from
producers that the animals bought were free of illegal levels of drug
residues and did not properly identify hogs so that contaminated animals
could be traced to the producers.

In a Feb. 9, 1988, letter, Ronald Tuente notified FDA that he was
telling his producers about their responsibilities to ensure their
animals were drug-free when sold. The agency responded that the only way
for Tuente Livestock to waive its responsibility was to get drug-free
certificates from its hog producers.

From October 1988 through December 1993, USDA found illegal
sulfamethazine drug residues in tissues from 17 hogs Tuente Livestock
had sold for slaughter. The department issued several warning letters to
Tuente Livestock about the illegal residues and the company's lack of
producer identification, such as tattoos.

During that time, FDA inspected the firm several times. During those
inspections, investigators observed some animals being tattooed. Ronald
Tuente claimed that all animals were tattooed but could not explain why
the Agriculture Department was unable to find the tattoos. In addition,
Ronald Tuente told FDA investigators he would not ask for drug-free
guarantees because he was sure the producers would refuse and sell their
animals to someone else.

On Jan. 24, 1994, the Cincinnati district office recommended to FDA's
Center for Veterinary Medicine that Tuente Livestock be permanently
enjoined from shipping swine in interstate commerce. On April 12, the
agency asked the Justice Department to initiate injunction proceedings
against Tuente. The department filed the complaint on Aug. 15.

On Sept. 22, Tuente Livestock filed a motion to dismiss the complaint
for injunction. The firm sought to dismiss the charges by arguing that
living animals are not food and, therefore, FDA had no jurisdiction. The
firm also argued that even if livestock were food, FDA still did not
have jurisdiction over Tuente because the firm was merely a middleman
and did not introduce the animals into commerce.

FDA and the Department of Justice continued to investigate Tuente
Livestock's activities by interviewing slaughterhouse employees and USDA
veterinarians in Ohio, Michigan, Virginia, and Maryland. Two of the
veterinarians told FDA that they had examined shipments of hogs Tuente
was selling and found a significant number did not have producer
tattoos. In one shipment of 100 hogs, more than half lacked tattoos.

On May 18, 1995, Judge Rice denied Tuente Livestock's motion to dismiss.

During August and September 1995, the Justice Department sought a
voluntary consent agreement with Tuente. But the firm refused to obtain
drug-free certificates required of dealers whose hogs tested positive
for illegal drug residues because, the company argued, FDA did not
require that of all dealers.

On Oct. 5, the Tuentes signed a consent order under which they agreed to
cancel their state livestock dealer's licenses, and withdraw their
registration and bond with the Agriculture Department's Packers and
Stockyards Administration. They also notified the court that they had
leased their hog-buying facilities to an unrelated third party and were
no longer doing business as livestock dealers.

--Isadora B. Stehlin


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Rodent-Contaminated Food Destroyed

Nearly 450,000 kilograms (1 million pounds) of food, valued at almost $1
million, was destroyed after an FDA investigation found serious rat and
mouse infestation in a Chicago warehouse where the products were stored.

La Hacienda Brands, Inc., Chicago, destroyed on Dec. 5, 1995, over
12,103 kg (over 26,000 pounds) of flour, fava beans, coriander seeds,
and other nonperishable items contaminated with rodent filth. Almost two
years earlier, the firm had destroyed over 437,800 kg (over 973,000
pounds) of perishable food in its inventory for the same reason.

FDA's Chicago district investigators first found the rodent infestation
during a routine inspection of the firm Jan. 26 to Feb. 2, 1994,
according to Paul Boehmer, district compliance officer.

"We found mouse and rat excreta on all four floors, and our
investigators saw live mice on the third floor on two different
occasions during the inspection," Boehmer said.

FDA's investigators collected numerous product samples during the
inspection, and sent them to the district's laboratory. The lab
identified rodent hair and excrement in all samples, as well as places
where rodents had gnawed on food.

The Chicago Department of Health on Jan. 27 placed an embargo on the
sale of all food stored in the warehouse.

The U.S. attorney filed a civil suit on Feb. 11 in the U.S. District
Court for the Northern District of Illinois, Eastern Division, seeking
the forfeiture and destruction of the products. Three days later, on
Feb. 14, the U.S. Marshal's Office, at FDA's request, seized the
products stored in the warehouse.

Over the next several weeks, the firm destroyed in a local landfill all
of the perishable items that had been stored in the warehouse, including
fresh yams, onions, eggs, ham, and sausage.

The firm signed a consent decree of condemnation on Nov. 1, 1994, that
required the firm to recondition or destroy the remaining nonperishable
foods.

Boehmer said that the firm had difficulty raising the $88,000 bond the
court required before the products could be released for reconditioning,
and a year lapsed before the case progressed.

La Hacienda posted the bond on Nov. 14, 1995, and the products were
released from federal custody. According to Boehmer, La Hacienda decided
it wasn't worthwhile reconditioning the products, and FDA investigators
witnessed the firm's destruction of the foods last Dec. 5.

FDA plans to inspect the firm again.

--Kevin L. Ropp


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Tons of Rotten Shrimp to Be Destroyed

After determining that about 131,820 kilograms (290,000 pounds) of raw,
frozen shrimp owned by one of the largest U.S. shrimp importers was
decomposed and unfit to eat, FDA took steps to seize and dispose of it
all.

The shrimp, property of Vernon, Calif.-based seafood importer Red
Chamber Co., was being stored at Mercury Cold Storage Inc., a public
warehouse in Dover, Fla.

FDA's discovery of the spoiled shrimp in June 1995 stemmed from a tip
received in FDA's Florida district office that decomposed shrimp from
India might be stored in a Tampa-area warehouse.

The resulting investigation led to Mercury Cold Storage, which FDA's
Tampa Bay resident post inspected on June 6, 1995. FDA inspectors
noticed the facility was storing immense quantities of imported shrimp.
A list provided by the warehouse showed that about 75 percent of the
stored shrimp came from China and the rest from India, Malaysia, and
other Asian countries.

One week later, FDA Tampa Bay resident post inspector Erny Clausnitzer
returned to Mercury Cold Storage and collected five samples of Chinese
shrimp stored under Red Chamber's account. FDA's Atlanta laboratory
found four of the five specimens decomposed. Based on the analysis, FDA
officials believed that the majority of the shrimp at Mercury could be
decomposed. But before taking any action, they needed to know the true
extent of decomposition.

"We couldn't sample all of it," says Clausnitzer. "Literally tons and
tons of it were in the warehouse." So FDA devised a statistical method
for testing a small group of samples that would represent Red Chamber's
entire shrimp inventory at Mercury Cold Storage.

On July 18, five FDA officials collected a sample from each of 33 lots
of frozen shrimp. Of these, 21 were decomposed, and one contained
potentially dangerous Salmonella bacteria. Combining this outcome with
analysis results from the previous month, FDA officials concluded that
27 of 38 lots of Red Chamber's stored shrimp--or 71 percent--violated
federal law by being decomposed or tainted with bacteria.

Meanwhile, Florida state officials placed a "stop sale" on the 27 lots
of Red Chamber's product confirmed to be decomposed or contaminated,
which barred the shrimp from being moved from the warehouse without
state permission. Red Chamber exported the rest of the shrimp stored at
the warehouse that was not under the state's stop sale order.

On Aug. 29, deputy U.S. marshals seized the 27 lots, weighing almost 132
metric tons (145 tons). At press time in April, the shrimp, worth an
estimated $900,000, was in frozen storage at Mercury Cold Storage
awaiting destruction.

--John Henkel


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Summaries of Court Actions



Summaries of Court Actions are given pursuant to Section 705 of the
Federal Food, Drug, and Cosmetic Act. Summaries of Court Actions report
cases involving seizure proceedings, criminal proceedings, and
injunction proceedings. Seizure proceedings are civil actions taken
against goods alleged to be in violation, and criminal and injunction
proceedings are against firms or individuals charged to be responsible
for violations. The cases generally involve foods, drugs, devices, or
cosmetics alleged to be adulterated or misbranded or otherwise violative
of the law when introduced into and while in interstate commerce.

Summaries of Court Actions are prepared by Food and Drug Division,
Office of the General Counsel, HHS, and are published by direction of
the Secretary of Health and Human Services.



SEIZURE ACTIONS



Food/Contamination, Spoilage, Insanitary Handling

PRODUCT: Articles of food, at Chicago Heights, Ill. (N.D.Ill.); Civil
No. 95C-0452.

CHARGED 1-24-95: While held for sale after shipment in interstate
commerce at U.S. Spice, in Chicago Heights, Ill., the articles were
adulterated in that they were stored under insanitary conditions whereby
they might have been contaminated with filth--402(a)(4).

DISPOSITION: A default decree of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 67057; S. No. 95-741-369; S.J. No.
1)



PRODUCT: Baby Don't Be Bald Medicated Shampoo, Mallard's Tail and Mane
Hair and Scalp Treatment, Arthur's Pro-Grow Protein Enriched
Conditioning Shampoo Maximum Strength, and other OTC topical
preparations, at Mobile, Ala. (S.D.Ala.); Civil No. 95-0339-BH-S.

CHARGED 4-26-95: While held for sale after shipment of one or more of
their components in interstate commerce at Mallard Enterprises (a.k.a.
Branton Laboratory) and Arthur's Beauty Lab, Inc. (a.k.a. Jessica's
Beautee Internationale, Inc.), in Mobile, Ala., the articles were
adulterated in that the methods used in, and the facilities and controls
used for, their manufacture, processing, packing, and holding did not
conform to and were not operated and administered in conformity with
current good manufacturing requirements--501(a)(2)(B). The articles were
unapproved new drugs--505(a). The articles contained unsafe color
additives, for coloring purposes only, which were intended for use in
drugs--501(a)(4)(A) and (B). The articles were misbranded in that their
labeling failed to bear adequate directions for use--502(f)(1).

DISPOSITION: A default decree of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 67039; S. No. 94-679-282; S.J. No.
2)


PRODUCT: Basmati Rice, Lentils, and Mung Beans, at Elk Grove Village,
Ill. (N.D.Ill.); Civil No. 93C-6467.

CHARGED 10-22-93: While held for sale after shipment in interstate
commerce at the House of Spices, Inc., in Elk Grove Village, Ill., the
articles were adulterated in that they were held under insanitary
conditions whereby they might have been contaminated with
filth--402(a)(4).

DISPOSITION: Claimant entered into a consent decree, and resumed
business upon compliance. (F.D.C. No. 66799; S. No. 94-710-287; S.J. No.
3)



Drugs/Human Use

PRODUCT: Hydrosol Medicated Ointment, Hydrosol Hemorrhoidal Ointment,
and raw material components, at Miamitown, Ohio (S.D.Ohio); Civil No.
C-1-95-007.

CHARGED 1-5-95: While held for sale after shipment of one or more of
their components in interstate commerce at Hydrosol Manufacturing
Company in Miamitown, Ohio, the articles were adulterated in that the
methods used in, and the facilities and controls used for, their
manufacture, processing, packing, and holding did not conform to and
were not operated and administered in conformity with current good
manufacturing requirements--501(a)(2)(B).

DISPOSITION: A consent decree of condemnation was entered providing for
reconditioning of the seized articles. Some of the articles were
released for sale in contradiction to the decree, and a recall was
instituted. The reconditioning was completed, and the articles were
released. (F.D.C. No. 66966; S. No. 94-670-115; S.J. No. 4)



PRODUCT: Liquid Oxygen, at Bloomsberg, Pa. (M.D.Pa.); Civil No.
4:CV-94-0644.

CHARGED 8-17-94: While held for sale after shipment in interstate
commerce at Respiratory Support System, Inc., in Bloomsberg, Penn., the
articles were adulterated in that the methods used in, and the
facilities and controls used for, their manufacture, processing,
packing, and holding did not conform to and were not operated and
administered in conformity with current good manufacturing
requirements--501(a)(2)(B).

DISPOSITION: A consent decree of condemnation ordered the articles
destroyed. (F.D.C. No. 66965; S. No. 93-633-774; S.J. No. 5)



PRODUCT: Nifedipine, capsules, at Newark, N.J. (D.N.J.); Civil No.
94-4880 (NHP).

CHARGED 10-14-94: While held for sale after shipment of one or more of
their components in interstate commerce at Chase Laboratories in Newark,
N.J., the articles were adulterated in that the methods used in, and the
facilities and controls used for, their manufacture, processing,
packing, and holding did not conform to and were not operated and
administered in conformity with current good manufacturing
requirements--501(a)(2)(B). The articles were also unapproved new drugs
introduced into interstate commerce--505(a).

DISPOSITION: A consent decree of condemnation was filed, and all but
eight lots of the articles were destroyed. The claimant was permitted to
attempt to bring these lots into compliance. Four lots were authorized
for release, and the others were destroyed. (F.D.C. No. 66914; S. No.
93-675-794; S.J. No. 6)



Drugs/Veterinary

PRODUCT: Articles of drugs for veterinary use, at Perry, Iowa
(C.D.Iowa); Civil No. 4-93-CV-80420.

CHARGED 6-8-93: While held for sale after shipment of one or more of its
components in interstate commerce at Immuno-Dynamics, Inc., in Perry,
Iowa, the articles were adulterated in that they were unapproved new
animal drugs--501(a)(5).

DISPOSITION: The products were seized, and the government filed a motion
for summary judgment, which was denied. The district court returned a
verdict in favor of the defendants, and the appellate court affirmed the
district court's decision. (F.D.C. No. 66672; S. No. 93-636-092; S.J.
No. 7)



CRIMINAL ACTIONS

DEFENDANTS: Dr. Leon Silverstone, at Denver, Colo. (D.Colo.); Criminal
No. 93-CR-251.

CHARGED 8-3-93: Counts 1 and 2: Defendant Dr. Leon Silverstone submitted
used false studies to support a premarket application for an electronic
dental anesthesia device made by SION Technology--301(q)(2), 303(a)(1),
and 18 U.S.C. Section 2.

DISPOSITION: Guilty plea; ordered to pay a $5,000 fine and sentenced to
six months of prison and a year of supervised release. (F.D.C. No.
66510; S.J. No. 8)



INJUNCTION ACTIONS

DEFENDANT: George Plantenga d/b/a Western Sky Dairy, at Corona, Calif.
(C.D.Calif.); Civil No. 92-4186-RSWL(EEx).

CHARGED 7-16-92: While held for sale at Western Sky Dairy in Corona,
Calif., the defendant introduced adulterated food into interstate
commerce--301(a). The food was adulterated in that the cattle sold for
slaughter contained unsafe new animal drugs--402(a)(2)(D).

DISPOSITION: The defendant entered into a consent decree of permanent
injunction and was authorized to resume business upon compliance. (Inj.
No. 1289; S. No. 92-567-555/556; S.J. No. 9)



MISCELLANEOUS ACTIONS

ACTION: Bae v. Shalala, at Chicago, Ill. (7th Cir.); Civil No. 94-1373.

CHARGED 1-4-95: In 1993, FDA debarred the defendant, the former
president of a generic drug manufacturer, from providing services in any
capacity to a person with an approved or pending drug product
application. The defendant was debarred for a felony conviction. The
defendant appealed the debarment, alleging the order was punitive and
that its retroactive application violated the Constitution.

DISPOSITION: The appellate court rejected the defendant's arguments and
held that the debarment was a remedial act intended to safeguard the
integrity of the generic drug industry. (Misc. No. 1015; S.J. No. 10)

------------------------------------------------------------------------


FDA Consumer is the official magazine of the U.S. Food and Drug
Administration. Each issue contains in-depth feature articles written
for the general public on FDA-related health issues. The magazine also
includes reports from FDA's own investigators that go behind the scenes
to show how the agency protects the public from unsafe or worthless
products.

FDA Consumer is published monthly, except for combined issues for
July-August and January-February. Subscriptions are available for $15
per year by writing:

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Government Printing Office
Washington, DC 20402-9371.

------------------------------------------------------------------------