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FDA Consumer magazine
VOL. 30 No. 8 OCTOBER 1996
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Features

Saving Our Children from Tobacco
Every day, almost 3,000 young people start smoking. Nearly 1,000 of them
will have their lives cut short due to smoking-related illness. To
protect America's children from this number one cause of preventable
death and illness, FDA has issued a landmark regulation intended to make
cigarettes and smokeless tobacco less available to kids, and less
alluring.

New Devices Aim at Improving Pap Test Accuracy
Methods to improve diagnostic accuracy of Pap tests are among the tools
for fighting cervical cancer, a very curable disease if caught early.

Colds and Flu: Time Only Sure Cure
Chicken soup, vitamin C, hand-washing, and cough and cold medications
are among the many ways some folks say can prevent or treat colds and
flu. Which ones work?

Help for People with Paget's Disease
Many people dismiss symptoms of this bone disease as part of the aging
process. But effective treatments are available and are best begun
early.

Inside FDA: Office of Women's Health
This FDA office has funded more than 50 projects since it was
established in 1994. And its $2 million annual budget promises further
support for research and education on a number of women's health topics.

Probing the Pancreas
Diabetes and cystic fibrosis are just two of the diseases that involve
the pancreas. Various treatments are available for these conditions.


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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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Saving Our Children from Tobacco

President Clinton announced on Aug. 23 the nation's first comprehensive
program to prevent children and adolescents from smoking cigarettes or
using smokeless tobacco and beginning a lifetime of nicotine addiction.
The president's announcement came a little more than a year after the
Food and Drug Administration issued its proposed rule to reduce the
access and appeal of tobacco products for children and adolescents.

The FDA rule-making on children and tobacco prompted the largest
outpouring of public response in the agency's history, with more than
95,000 individual comments received, totaling more than 700,000 pieces
of mail when form letters are counted. The final rule was published in
the Federal Register of Aug. 28, 1996. For more information on the final
rule and related documents, see FDA's Children and Tobacco Home Page.

Each day, almost 3,000 young people in the United States become regular
smokers, and nearly 1,000 of them will die prematurely from diseases
related to tobacco use. Each year, more than 400,000 Americans die from
smoking-related diseases, more Americans than are killed each year by
AIDS, alcohol, car accidents, murders, suicides, illegal drugs, and
fires combined.

In the last four years, the United States has experienced dramatic
increases in tobacco use by youngsters. Between 1991 and 1995, the
percentage of eighth- and 10th-graders who smoke increased 34 percent.
In 1995, more than a third of 12th-graders reported smoking in the past
month, and daily smoking in that group was up to 21.6 percent. Among
10th-graders, current use was up to 27.9 percent, and daily use was up
to 16.3 percent.

President Clinton's goal is to cut in half tobacco use by children and
adolescents over the next seven years.

"This is the most important public health initiative of our generation,"
said Health and Human Services Secretary Donna E. Shalala. "Our
children's futures are at stake. President Clinton's action will ensure
that children get their information about tobacco from their
parents--and not from Joe Camel."

The president's initiative to protect children is based on the final FDA
rule that will make it harder for young people to buy cigarettes and
smokeless tobacco and will reduce the appeal of tobacco products to
children under 18. The rule is based on the agency's finding that
cigarettes and smokeless tobacco products are delivery devices for
nicotine, an addictive drug. In addition to the rule, FDA will propose
to require tobacco companies to educate children and adolescents about
the health risks of tobacco use as part of the president's initiative.
This national mass media campaign would be monitored for its
effectiveness.

Cigarettes and smokeless tobacco products remain legal products that can
be marketed and sold to adults, 18 years and older.

"Nicotine addiction is a pediatric disease that often begins at 12, 13,
and 14 only to manifest itself at 16 and 17 when these children find
they cannot quit," said Commissioner of Food and Drugs David A. Kessler,
M.D. "By then our children have lost their freedom and face the prospect
of lives shortened by terrible diseases."

The president's initiative follows the recommendations of major medical
and scientific organizations such as the American Medical Association
and National Academy of Science's Institute of Medicine. It is a
prevention strategy based on reducing children's access to tobacco
products and limiting the appeal of these products to children. The
tobacco industry spends more than $6 billion annually on advertising and
promotion.

Besides the final rule, FDA will propose to require tobacco companies to
provide strong educational messages for children on the real dangers of
smoking and using smokeless tobacco. This national multimedia campaign
would include television spots, and it would be monitored for its
effectiveness. FDA intends to begin consultations about this campaign
with the nation's six tobacco companies with a significant share of
sales to children. Under Section 518 of the Federal Food, Drug, and
Cosmetic Act, the FDA may require companies to inform consumers about
the unreasonable health risks of their products.

"We have to tell our children the truth about the diseases caused by
smoking," Kessler said. "For too long we have sent conflicting messages
to our children and then have acted surprised when they begin to smoke."

In reviewing the public comments and developing a final rule, FDA made a
number of changes to more narrowly tailor provisions to children. For
instance, there was little evidence presented that mail-order sales are
used by children and adolescents, while they are used by adults in rural
areas. Similarly, vending machines in facilities totally inaccessible to
persons under 18 will accommodate adults while preventing easy access by
young people.

The FDA rule reduces children's easy access to tobacco products by:

 * Requiring age verification by photo ID for anyone under the age of 27
   purchasing tobacco products.

 * Banning vending machines and self-service displays except in "adult"
   facilities where children are not allowed, such as certain nightclubs
   totally inaccessible to anyone under 18.

 * Banning free samples and the sale of single cigarettes and packages
   containing fewer than 20 cigarettes.

The FDA rule limits the appeal of tobacco products to children by:

 * Prohibiting billboards within 1,000 feet of schools and playgrounds.
   Other advertising is restricted to black-and-white text only; this
   includes all billboards, signs inside and outside of buses, and all
   advertising in stores. Advertising inside "adult only" facilities
   like nightclubs can have color and imagery.

 * Permitting black-and-white text-only advertising in publications with
   significant youth readership (under 18). Significant youth readership
   means more than 15 percent or more than 2 million readers under 18;
   there are no restrictions on print advertising below these
   thresholds.

 * Prohibiting sale or giveaways of products like caps or gym bags that
   carry cigarette or smokeless tobacco product brand names or logos.

 * Prohibiting brand-name sponsorship of sporting or entertainment
   events (including teams and entries), but permitting it in the
   corporate name.

These provisions will be phased in between six months and two years from
the date of publication in the Federal Register to give businesses
adequate time to comply.


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Final Rule Summary

 * minimum age of 18 to buy tobacco products

 * ban vending machines and self-service displays, except in certain
   nightclubs and other "adult only" facilities totally inaccessible to
   persons under 18

 * ban "kiddie" packs, "loosies," or free samples

 * mail-order sales permitted

 * Ban billboards within 1,000 feet of schools and playgrounds.

 * Other billboards and outdoor and in-store advertising limited to
   black-and-white text-only, except color, imagery permitted in "adult
   only" facilities if not visible from outside and not removable.

 * Advertising in publications with significant youth readership (more
   than 15 percent or 2 million) limited to black-and-white text only.

 * Ban brand-name sponsorship of sporting or other events, including
   cars and teams; only corporate name sponsorship permitted.

 * Ban brand names on hats, t-shirts, gym bags, etc.


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Legal Issues Relating to FDA Rule
On Children and Tobacco


FDA Jurisdiction

FDA has concluded that cigarettes and smokeless tobacco are delivery
devices for nicotine, a drug that causes addiction and other significant
pharmacological effects. The Federal Food, Drug, and Cosmetic Act
provides that a product is a drug or device if it is an article (other
than food) "intended to affect the structure or any function of the
body."

Nicotine in cigarettes and smokeless tobacco does "affect the structure
or any function of the body" because nicotine in these products:

 * causes and sustains addiction

 * causes other mood-altering effects, including tranquilization and
   stimulation

 * controls body weight.

Manufacturers of cigarettes and smokeless tobacco "intend" these effects
because:

 * The addictive and pharmacological effects are so widely known and
   accepted, a reasonable manufacturer can foresee the products will be
   used by consumers for these effects.

 * Consumers use these products predominantly for pharmacological
   purposes.

 * Manufacturers know that nicotine in their products causes
   pharmacological effects and that consumers use their products
   primarily to obtain these effects.

 * Manufacturers of these products design the products to provide
   consumers with a pharmacologically active dose of nicotine.

 * An inevitable consequence of the design of these products to provide
   consumers with a pharmacologically active dose of nicotine is to
   sustain consumers' addiction to nicotine.


Rule Protects Appropriate Commercial Speech

The U.S. Supreme Court has upheld restrictions on commercial speech if
certain standards are met. Given that selling cigarettes and smokeless
tobacco to children under 18 is already illegal in every state, the rule
is aimed at regulating commercial speech to ensure that an illegal
activity is not promoted. Furthermore, the rule is narrowly tailored to
meet the tests established by the U.S. Supreme Court in its opinions on
commercial speech, including 44 Liquormart, Inc. v. Rhode Island.

 * Protecting the health of children under 18 is a substantial
   government interest justifying restrictions on tobacco advertising
   that appeals to children.

 * Advertising and promotion have been shown to play a material role in
   children beginning and continuing to use tobacco products, and
   therefore the regulations directly advance the government's interest.

 * Permitting unrestricted advertising in publications primarily read by
   adults and permitting companies to sponsor events in the corporate
   name--instead the brand identifications so appealing to young
   people--are examples of how the rule is narrowly tailored to advance
   the government's interest.

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New Devices Aim at
Improving Pap Test Accuracy

by Margie Patlak

She had gotten Pap tests each year that were reported as being negative
with no abnormal cervical cells noted. But when the 38-year-old woman
bled vaginally following sexual intercourse, she returned to her
gynecologist and was surprised and dismayed to discover she had an
advanced form of cervical cancer. She died just two years later.

When her previous Pap tests were reexamined, it was discovered that
cancerous cells had not been identified in tests up to two years before
she was diagnosed with cervical cancer. This case, though not common, is
not unique. Studies done at various Pap screening laboratories in this
country show that between 5 and 50 percent of all Pap tests with
cancerous cells are inaccurately determined to be free of abnormalities,
giving what is known as "false negative" results. Such errors can spell
the difference between life and death for some women, because when
detected in its early stages nearly all cervical cancers can be cured
with minor surgery or other procedures.

In contrast, fewer than 20 percent of women with advanced cervical
cancer survive more than five years, even with treatment, according to
the National Cancer Institute. There are nearly 5,000 deaths due to
cervical cancer each year in this country. Recent data from NCI reveal
that the number of cases of cervical cancer in white women under the age
of 50 in the United States has been increasing 3 percent each year since
1986. In contrast, incidence rates are declining in black women of all
ages and in white women over age 50. According to the World Health
Organization, cervical cancer is also the most common cancer among women
in developing countries.

To help improve accuracy, FDA has recently approved two new computer
systems for rescreening Pap tests.

A Silent Cancer

Unlike many cancers that cause pain, noticeable lumps, or other early
symptoms, cervical cancer has no telltale symptoms until it is so
advanced that it is usually unresponsive to treatment. Symptoms may even
be absent at that point, although they often include abnormal vaginal
bleeding, such as following intercourse or douching, between menstrual
periods, or after menopause. Only in its late stages does cervical
cancer cause pain in the lower abdominal or back regions.

But because the cervix, which essentially is the mouth of the uterus,
can be easily accessed through the vagina, doctors can test for cervical
cancer as well as for precancerous changes in the cervix. Most cervical
cancers grow slowly over several years and often are preceded by
abnormal cells. Cervical cancer can often be prevented with the removal
of these cells that are precursors to cancer. (See accompanying
article.)

<Picture omitted: [illustration of how a Pap test is done]>

To detect abnormal or cancerous cervical cells, George Papanicolaou,
M.D., Ph.D., of Cornell University developed in the 1940s what is known
today as the Pap test. In this test, a sample of cells is taken from in
and around the cervix with a wooden scraper, cotton swab, or small
cervical brush. The specimen is smeared on a glass slide, preserved with
alcohol, and then sent to a laboratory. There cytotechnologists,
specially trained in identifying defective cells, scrutinize the
cervical cells under the microscope for any abnormal features associated
with cancerous or precancerous cervical cells. These features include
dark or irregularly shaped cell nuclei, or small or deformed cells.

The Pap test became a routine part of gynecological exams. As a result,
there was a 70 percent drop in the number of women dying from cervical
cancer between 1950 and 1970, according to NCI. But the problem of
errors remained. Such errors are understandable when considering the
magnitude of the task set before the cytotechnologist examining Pap
slides. These standard-sized laboratory slides are lined with between
50,000 to 300,000 cervical cells. Lurking in these cells may be as few
as a dozen abnormal cells. Finding such telltale cells is akin to
finding a needle in a haystack, especially at the end of the day when
cytotechnologists are likely to have examined nearly 100 Pap slides. In
addition, abnormalities in cell shape may be slight and difficult for
even the trained eye to detect, or may be masked by infection.

Computerized Rescreening

The two new systems approved by FDA show promise of substantially
improving the accuracy of Pap tests. The computers scan the images for
abnormal-looking cells.

One system, called PAPNET, uses neural net computer technology, which
its manufacturer claims was originally created to detect flying missiles
in what is known as the "Star Wars" defense strategy. PAPNET detects
abnormal cervical cells with a computer system that essentially has
learned by example. This system was created by feeding a series of
digitized images of Pap slides to a computer. From these examples, the
computer developed the guidelines for predicting abnormal cells.

PAPNET scans each Pap slide cytotechnologists have classified as normal
and chooses the 128 cells or cell clusters that are most likely to be
abnormal. Enlarged color images of these cells are then returned to the
cytotechnologist for review.

Studies have used PAPNET rescreening to reexamine previous negative Pap
smears taken from women with high-grade cervical cell abnormalities or
cervical cancers. These studies found that in about one-third of these
women, PAPNET testing detected abnormalities missed by manual screening
on previous Pap smears.

The other Pap test rescreening system is called AutoPap 300 QC. This
computerized system uses image processing and pattern recognition
techniques to classify cells as abnormal. Hundreds of features--such as
size, shape, density, and texture--are considered for each cell.
Sophisticated statistical screens use this visual information to predict
which cervical cells are abnormal. Following routine screening by a
cytotechnologist, all "normal" slides are rescreened by AutoPap 300 QC,
which selects 10 to 20 percent of slides with the highest probability of
having abnormal cells. These are then rescreened manually by the
cytotechnologist.

In one study, cytotechnologists randomly rescreening 10 percent of more
than 4,000 Pap slides they originally classified as normal detected only
about 1 of every 10 false negatives present. Cytotechnologists using
AutoPap 300 QC to rescreen the 10 percent of slides the system deemed as
being most abnormal detected up to half of all the missed abnormals.

Both PAPNET and AutoPap 300 QC can be used by laboratories, and women
can ask if the laboratories their Pap smears are sent to employ these
rescreening systems. But some labs may not yet be fully familiar with
the Pap rescreening systems.

"Laboratories are starting to evaluate these devices and determine if
and how they will use them," said Louise Magruder, of FDA's division of
clinical laboratory devices.

Although use of PAPNET and AutoPap 300 QC will considerably decrease the
likelihood of missing a diagnosis of cervical cancer, neither system is
perfect. Even if they could detect every abnormal cell on a Pap slide,
some women with cervical cancer would still be told their Pap tests were
normal because there were too few cells on the slide or the cell samples
were not taken from both the inside and surface of the cervix. Douching
or using vaginal spermicides or medicines a day or two before a Pap test
can also wash away abnormal cells and thus reduce the test's accuracy.

Also, there is a tiny percentage of women who develop a rare form of
aggressive cervical cancer that can develop to an advanced stage in less
than a year. In addition, cervical cancer will continue to occur in
women who don't receive regular gynecological exams and Pap tests. NCI
recommends that all women who are or have been sexually active or have
reached age 18 have a Pap smear and gynecological exam as frequently as
each year, but at least every three years, depending on their risk
factors for cervical cancer.

Risk Factors

Evidence collected over the past few decades suggests several risk
factors for developing cervical cancer. These include having sexual
intercourse before age 18, having several sexual partners, or having a
sexual partner who was previously married to a woman who had cervical
cancer.

Scientists are closely scrutinizing the sexually transmitted human
papillomaviruses (HPVs), some of which cause genital warts. Research
strongly suggests some types of HPVs (there are more than 60 different
types) can trigger the growth of abnormal cells in the cervix and are
likely to play a key role in the development of cervical cancer. Women
who have HPV or whose partners have HPV have a boosted risk of
developing cervical cancer.

However, many women infected with HPV do not develop cervical cancer,
and not all women with cervical cancer harbor HPV. This suggests other
factors act with HPV to cause cervical cancer. The genital herpes virus
may play a role, as may the strength of a woman's immune system. Women
infected with HIV, the virus that causes AIDS, are more likely to
develop cervical cancer, as are female organ transplant patients who
receive drugs that suppress the immune system to prevent rejection of
the new organ.

Hormones may also influence the development of cervical cancer. The
labeling of oral contraceptives states that some studies have found an
increased incidence of cervical cancer in women taking birth control
pills, but that this may be related to factors other than the pill.
Women whose mothers took the estrogen-like drug diethylstilbestrol (DES)
during pregnancy to prevent miscarriage are also more likely to develop
cervical cancer. (DES was used to prevent miscarriages from about 1940
to 1970.)

Smoking also elevates the risk of cervical cancer, which rises with the
number of cigarettes a woman smokes each day and with the number of
years she has smoked. Women exposed to other people's tobacco smoke are
also more likely to develop cervical cancer.

Research suggests women can reduce their risk of cervical cancer by
using barrier methods of contraception, such as the diaphragm with
spermicide and condoms, probably because such methods decrease the risk
of being infected by a sexually transmitted disease.

At present, early detection of precancerous tissue remains the most
effective way of preventing cervical cancer. With PAPNET and AutoPap 300
QC, that pathway has just become a more reliable route for maintaining
good cervical health.

Margie Patlak is a writer in Elkins Park, Pa.


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Slow Development Gives Time for Treatment

Most cervical cancers gradually progress over a period of years without
immediately invading nearby tissue. Yet they leave telltale signposts
along their way. Even the transition from a normal to a cancerous
cervical cell is usually a gradual one, with several steps that can be
seen with the aid of a microscope.

In what is thought to be one of the first steps in the development of
cervical cancer, the nuclei of cervical cells enlarge and darken. A
patch of these abnormal cells is termed a squamous intraepithelial
lesion (SIL) because the abnormal cells are present only in the squamous
epithelial cells which line the surface of the cervix. SILs are further
classified as low-grade if the abnormal cells are of normal size, or
high-grade if the cells are smaller than normal.

Low-grade SILs are common; most spontaneously revert to normal. But
because some will progress to high-grade SILs and then to cervical
cancer, most doctors ask women with this Pap diagnosis to have Pap tests
every four to six months for about two years. After three consecutive
Pap tests come back negative, women can return to a routine screening
protocol.

If repeated Pap tests show persistent abnormalities, however, a woman's
doctor may want to confirm the low-grade SIL diagnosis by further
scrutinizing the cervix with other procedures.

Colposcopy is a widely used method to check the cervix for abnormal
areas. The doctor applies special stains to the cervix and then uses an
instrument much like a microscope (called a colposcope) to detect
abnormal cells, which turn a different color than healthy cells.

The doctor also may want to remove a small amount of cervical tissue for
examination with a biopsy. It also may be necessary to scrape more
tissue from inside the cervical opening. These procedures can be done in
the doctor's office under local anesthesia.

If the low-grade SIL diagnosis is confirmed, a doctor may ask the
patient to continue to have frequent Pap tests. Alternatively, the
doctor may prefer to destroy the abnormal area by freezing it
(cryosurgery), burning it (cauterization), or by removing it with a
laser or electrosurgical device. Such treatment may cause cramping or
other pain, bleeding, or a watery discharge.

High-grade SILs rarely regress spontaneously. Most progress to cervical
cancer over a period of 10 to 15 years, according to the National Cancer
Institute. Women who have high-grade SIL Pap reports usually are asked
to undergo a colposcopy or biopsy procedure to confirm diagnosis. Once
the high-grade SIL diagnosis is certain, doctors usually destroy the
lesion with one of the procedures described in the previous paragraph.
Or, the lesion and adjacent tissue may be surgically removed.

If a high-grade SIL progresses to the point that the cell nuclei become
jagged or irregular in shape, extremely dark, and enlarged, and the
cells themselves are strangely shaped (tadpole- or spindle-shaped, for
example, instead of round), the lesion is considered cancerous. If the
cancer is limited in scope, it may be treated with some of the same
methods used to destroy precancerous lesions. For more widespread
cancers, more involved surgery is usually done, removing a larger
portion of the cervix or the entire uterus, ovaries or fallopian tubes.
Depending on the size and location of the tumor, radiation therapy or
chemotherapy may also be necessary.

--M.P.

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Colds and Flu: Time Only Sure Cure

by Tamar Nordenberg

It's not chicken soup. Believe it or not, a much more unorthodox therapy
of warm-and-cold showers has recently been proposed--though not
proven--for the prevention of the common cold. Shower therapy joins an
ever-growing spectrum of suggested preventers and treatments for the
common cold--among them, hand washing, vitamin C, interferon, seclusion,
and various over-the-counter cough and cold medications.

"An efficient, practical and inexpensive prophylaxis [preventive
measure] against one of the most frequent (and 'expensive') diseases has
been identified at last," claims water therapy researcher Edzard Ernst,
M.D., in the April 1990 issue of Physiotherapy. Though some may doubt
his shower theory, Ernst is right about one thing--the common cold is a
frequent and expensive disease, striking some people as many as 12 times
a year and leading to some 15 million days lost from work annually in
the United States. Influenza, or flu, likewise, is a frequent and
expensive disease, reaching epidemic levels in the United States each
year.

Identify the Enemy

Flu is like the cold in many ways--most basically, they're both
respiratory infections caused by viruses. If a cold is misdiagnosed as
flu, there's no problem. At worst, a cold can occasionally lead to
secondary bacterial infections of the middle ear or sinuses, which can
be treated with antibiotics. But if the flu is misdiagnosed as a bad
cold, potentially life-threatening flu complications like pneumonia may
be overlooked.

Some of the symptoms of a cold and flu are similar, but the two diseases
can usually be distinguished. (See accompanying chart.)

Typically, colds begin slowly, two to three days after infection with
the virus. The first symptoms are usually a scratchy, sore throat,
followed by sneezing and a runny nose. Temperature is usually normal or
only slightly elevated. A mild cough can develop several days later.

Symptoms tend to be worse in infants and young children, who sometimes
run temperatures of up to 102 degrees Fahrenheit (39 degrees Celsius).
Cold symptoms usually last from two days to a week.

Signs of the flu include sudden onset with a headache, dry cough, and
chills. The symptoms quickly become more severe than those of a cold.
The flu sufferer often experiences a "knocked-off-your-feet" feeling,
with muscle aches in the back and legs. Fever of up to 104 degrees
Fahrenheit (40 degrees Celsius) is common. The fever typically begins to
subside on the second or third day, and then respiratory symptoms like
nasal congestion and sore throat appear. Fatigue and weakness may
continue for days or even weeks.

"The lethargy, achiness and fever are side effects of the body doing its
job of trying to fight off the infection," according to Dominick
Iacuzio, Ph.D., influenza program officer with the National Institutes
of Health (NIH).

Influenza rarely causes stomach upset. What is popularly called "stomach
flu"--with symptoms like nausea, diarrhea and vomiting--is technically
another malady: gastroenteritis.

Cold and flu-like symptoms can sometimes mimic more serious illnesses
like strep throat, measles, and chickenpox. Allergies, too, can resemble
colds with their runny noses, sneezing, and general miserable feeling.

If symptoms persist, become severe or localized in the throat, stomach
or lungs, or if other symptoms such as vomiting and behavioral changes
occur, consult your physician. "With the typical symptoms, it's not
necessary to contact your physician immediately," Iacuzio says.

The Treatment Arsenal

There is no proven cure for colds or flu but time. However,
over-the-counter medications are available to relieve the symptoms.

"OTC cough-cold products can make you more comfortable while you
suffer," says Debbie Lumpkins, a scientist with the Food and Drug
Administration's division of over-the-counter drug products. "They are
intended to treat the symptoms of minor conditions, not to treat the
underlying illness."

Don't bother taking antibiotics to treat your flu or cold; antibiotics
do not kill viruses, and they should be used only for bacterial
complications such as sinus or ear infections. Overuse of antibiotics
has become a very serious problem, leading to a resistance in
disease-causing bacteria that may render antibiotics ineffective for
certain conditions.

Children and teenagers with symptoms of flu or chickenpox should not
take aspirin or products containing aspirin or other salicylates. Use of
these products in young flu and chickenpox sufferers has been associated
with Reye syndrome, a rare condition that can be fatal. Because cold
symptoms can be similar to those of the flu, it's best not to give
aspirin to people under 20 with these types of symptoms.

The active ingredients FDA considers safe and effective for relieving
certain symptoms of colds or flu fall into the following categories:

 * Nasal decongestantsopen up the nasal passages. They can be applied
   topically, in the form of sprays or drops, or taken orally. But using
   sprays or drops longer than three days may cause nasal congestion to
   worsen.

 * Antitussives, also known as cough suppressants, can quiet coughs due
   to minor throat irritations. They include drugs taken orally, as well
   as topical medications like throat lozenges and ointments to be
   rubbed on the chest or used in a vaporizer.

 * Expectorants, taken orally, help loosen mucus and make coughs more
   productive.

The effectiveness against cold symptoms of another category of
over-the-counter drugs called "antihistamines" is being studied.
Currently, OTC antihistamines are approved only for use by sufferers of
hay fever and some other allergies.

Most nonprescription cough-cold remedies contain a combination of
ingredients to attack multiple symptoms. These combination products
often contain antipyretics to reduce fever and analgesics to relieve
minor aches, pains and headaches.

Users of OTC medicines should carefully follow the labeling instructions
and warnings. To help people understand the OTC labels, FDA is working
with industry on new labeling that would use more consumer-friendly
language and standardize the placement of important information from
product to product.

The Cold War

OTC cough and cold medication sales totaled 3.2 billion dollars in 1995,
according to a national industry survey. That's no surprise, considering
Americans endure about 1 billion colds each year.

Children get the most colds--six or eight a year. By contrast, adults
average two to four a year, with a greater frequency in the parents of
children.

The high rate in children is blamed on their lack of a built-up
resistance to infection and the close contacts with other kids in
schools and day care. Women's closer contact with children may also
explain the greater prevalence of colds in women than in men.

Adults over 60 usually suffer less than one cold a year, probably
because they have built up a natural immunity.

Most colds strike Americans in the fall and winter. Contrary to what
many people believe, the increased rate of colds during this time is
actually not due to the cold weather. So why do more people feel "under
the weather" during the winter months? Probably, say researchers at
NIH's National Institute of Allergy and Infectious Diseases, because of
the greater time spent indoors in cold weather, increasing the
opportunity for viruses to spread among people. Also, the lower humidity
during the colder months helps cold-causing viruses to thrive and may
dry the lining of the nasal passages, making them more susceptible to
infection.

Because the symptoms of the common cold are caused by more than 200
different viruses--most by the so-called "rhinoviruses" (from the Greek
rhin, meaning "nose")--the development of a vaccine isn't feasible. To
minimize the spread of colds, people should try to keep their defenses
up and their exposure down.

First Line of Defense

Cold viruses can be transmitted in one of two ways: by touching
respiratory secretions on a person's skin (when shaking hands, for
example) or on environmental surfaces (like doorknobs or handrails) and
then touching the eyes, nose or mouth, or by inhaling infectious
particles in the air (like respiratory secretions from a cough or
sneeze).

The best way to break the chain of infection? Hand washing is the key,
according to Iacuzio, along with not touching the nose, eyes or mouth.

"Your mucus membranes are your first line of defense against infection,"
according to Iacuzio. "Interference with the constant passage of mucus
raises the chances for entry of the virus." That's why drinking liquids
and maintaining a humid environment with a vaporizer may lower
susceptibility.

To minimize the spread, other helpful measures include avoiding close,
prolonged exposure to people with colds, and always sneezing or coughing
into a facial tissue and immediately throwing it away. Cleaning
environmental surfaces with a virus-killing disinfectant is also
recommended.

The Flu Fighters

Flu typically affects 20 to 50 percent of the U.S. population each
winter. It's a highly contagious disease, spreading mostly by direct
person-to-person contact. "With the flu, coughing--even more than
sneezing--is the most effective method of transmission," Iacuzio says.

The flu virus can linger in the air for as long as three hours. In close
quarters, conditions are ripe for the spread of the virus. That explains
why the highest incidence of the flu is in 5- to 14-year-olds, who spend
much of their time in school, in close contact with their classmates.
The most serious complications occur in older adults, however.

Years ago, there were no practical tools to protect people from flu. In
1918-1919, a global flu epidemic, or pandemic, struck half the world's
population and claimed the lives of 20 million. Still today, 10,000 to
20,000 Americans--almost all of them elderly, newborns, or chronically
ill--die each year from flu complications, usually pneumonia.

The challenge for scientists trying to protect us from the disease is
that influenza viruses can change themselves, or mutate, to become
different viruses. Scientists have classified flu viruses as types A, B
and C. Type A is the most common and leads to the most serious
epidemics. Type B can cause epidemics, but usually produces a milder
disease than type A. Type C viruses have never been associated with a
large epidemic.

Vaccine a Powerful Weapon

The most important tool for fighting the everchanging flu virus is
immunization by a killed virus vaccine licensed by FDA. The vaccine is
made from highly purified, egg-grown viruses that have been made
noninfectious.

Vaccination is available to anyone who wants to reduce their chances of
getting the flu. Studies have shown the vaccine's effectiveness rate to
be 70 to 90 percent in healthy young adults. In the elderly and in
people with certain chronic illnesses, the vaccine sometimes doesn't
prevent illness altogether, but it does reduce its severity and the risk
of complications.

The government's Advisory Committee on Immunization Practices strongly
recommends vaccination for the following high-risk groups:

 * people aged 65 or older

 * residents of nursing homes and other facilities that provide care for
   chronically ill persons

 * people over the age of 6 months, including pregnant women, who have
   certain underlying medical conditions that required hospitalization
   or regular doctors' visits during the preceding year. These
   conditions include:

 * asthma, anemia, metabolic disease such as diabetes, or heart, lung or
   kidney disease

 * impaired immune system due to HIV infection, treatment with drugs
   such as long-term steroids, or cancer treatment with radiation or
   chemotherapy

 * children and teenagers (6 months to 18 years) who must take aspirin
   regularly and therefore may be at risk of developing Reye syndrome if
   they get the flu.

To reduce the risk of transmitting flu to high-risk persons--and to
protect themselves from infection--the advisory committee recommends flu
shots for people with regular close contact with high-risk groups. Such
people include health-care workers, nursing home personnel, home-care
providers, and children. Police, firefighters, and other community
service providers may also find vaccination useful.

Because it takes the immune system about six to eight weeks to respond
to vaccination, the best time to get the flu vaccine is mid-October to
mid-November, before the December-to-March U.S. flu season hits.

The vaccine's most common side effect is soreness at the vaccination
site for up to two days. Some people may experience post-shot fever,
malaise, sore muscles, and other symptoms resembling the flu that can
last for one to two days. Actually, the flu vaccine can't cause flu
because it contains only inactivated viruses.

Some people--but not many--should avoid the flu shot. People allergic to
eggs and people with certain other allergies and medical problems like
bronchitis or pneumonia should consult a doctor before getting a flu
shot. And those with a high fever should not receive the vaccine until
they feel better.

Pregnant women who have a high-risk condition should be immunized
regardless of the stage of pregnancy; healthy pregnant women may also
want to consult their health-care providers about being vaccinated.

In the rare cases when the vaccine is not advisable, two prescription
drugs are available for flu prevention: Symmetrel (amantadine), approved
by FDA in 1976, and Flumadine (rimantadine), approved by FDA in 1993.
Either drug also can be used to reduce symptoms and shorten the illness
if administered within 48 hours after symptoms appear.

Individuals opting for the vaccine should be immunized annually, since
the immunity is believed to last only about a year, and because the
vaccine's composition changes each year based on the flu strains
scientists expect to be most common.

To decide which strains of influenza virus should be incorporated into
the vaccine for the coming flu season, FDA's Vaccines and Related
Biologicals Advisory Committee meets in late January each year to
consider reports from national and international surveillance systems. A
World Health Organization panel meets in Geneva in mid-February to make
final recommendations for the next season's flu vaccine.

The strains are labeled by their type (A, B or C) and the place where
the strain was isolated. In 1996, the predominant strains were
A/Johannesberg, A/Texas, and B/Beijing. The anticipated strains for the
1996-1997 flu season are largely the same: A/Texas, A/Wuhan-like, and
B/Beijing.

"In the not-too-distant future," says Iacuzio, "consumers may have
alternatives to the flu shot, including different delivery methods like
nasal drops or a spray." Major pharmaceutical companies, in cooperation
with scientists representing NIH, FDA's Center for Biologics Evaluation
and Research, and academia, are making significant strides, also, toward
an even more protective vaccine.

First Do No Harm

If, despite precautions, you do get a cold or flu, besides taking an OTC
medication if needed and as directed, drink fluids and get plenty of bed
rest. "Your body is trying to attack the virus," Iacuzio says. "Give in,
and give your body a chance to fight off the infection. It takes energy
to do that."

Many people are convinced that vitamin C can prevent colds or relieve
symptoms. There is no conclusive evidence of this, but the vitamin may
reduce the severity or duration of symptoms, according to the National
Institute of Allergy and Infectious Diseases. But taking vitamin C in
large amounts over long periods can be harmful, sometimes causing
diarrhea and distorting common medical tests of the urine and blood.

Another proposed therapy, interferon-alpha nasal spray, can prevent
infection and illness but causes unacceptable side effects like
nosebleeds, according to the institute.

Many patients have their own, unproven theories about what works. "As
long as it's not harmful, why not try it?" says Iacuzio. "But be
skeptical of something that hasn't been clinically proven in a
well-designed, placebo-controlled study." So what about chicken soup? It
may soothe a sore throat, unstuff clogged passageways, and hydrate a
thirsty body. At the very least, according to Iacuzio, "It's good TLC.
Psychologically, that's important when you're sick."

Tamar Nordenberg is a staff writer for FDA Consumer.


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


Is It a Cold or the Flu?

 Symptoms             Cold                Flu

fever                     rare                 characteristic, high (102-104F);
                                              lasts 3-4 days

headache             rare                 prominent

general aches,pains      slight                 usual; often severe

fatigue,weakness     quite mild         can last up to 2-3 weeks

extreme exhaustion     never                 early and prominent

stuffy nose             common                 sometimes

sneezing             usual                 sometimes

sore throat             common                 sometimes

chest discomfort,        mild to moderate    common;can become severe
cough                    hacking cough


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

Help for People with Paget's Disease

by Paula Kurtzweil

Something weighs heavily on Jan Brown's head every day. Something called
Paget's disease of bone, and it affects her skull. She feels the effects
constantly, like 5 pounds of pressure, she says.

"It's always there," the 57-year-old Rockville, Md., woman says. "I can
feel it right now as I speak."

Sometimes she takes Tylenol (acetaminophen) for the pain.

Seventy-two-year-old Kenneth Halstead, of Raleigh, N.C., also has
Paget's disease. It affects his skull, as well as his spine, hips,
pelvis, and right leg. It's evident from his right leg, which is bowed.
On his right foot, he wears a "built-up" shoe to compensate for the half
an inch his leg has shrunk. He also wears a hearing aid.

A 78-year-old woman from Washington, D.C., who asked that her name not
be used, also has the disease. She, too, wears a hearing aid, and her
head is pushed forward and down, preventing her from tilting her head
back to look up.

Paget's disease is the second most common bone disease in the United
States. Osteoporosis is No. 1. Paget's disease can cause pain,
deformities, hearing loss, and limits on activity. The disease, which
affects people in different ways, also can cause arthritis and other
serious consequences.

Many people may dismiss these disabilities as a natural part of aging.
The average age of diagnosis is 58 (although the disease actually may
begin much earlier). But the disease is treatable, and with newer drugs
on the market--including two approved by the Food and Drug
Administration in 1991 and 1995--there is greater opportunity for
patients with Paget's disease to find pain relief, limit the progression
of their disease, and, in some cases, reverse bone damage.

The challenge now, experts say, is to identify patients early and, if
feasible, start treatment promptly. It's estimated that 3 percent of the
American population over 40 is affected. The problem is that many people
with Paget's disease don't know they have it because often it develops
without symptoms.

Bone Gone Awry

Paget's disease gets its name from Sir James Paget, an English doctor
who served as surgeon to Queen Victoria. He first described the
disease's characteristics in 1876.

Many years later, scientists realized Paget's disease is a disruption in
the normal activity of bone tissue.

Bone is constantly being broken down by cells called osteoclasts and
rebuilt by cells called osteoblasts. This is called bone turnover, and
throughout the entire skeleton, this process is normally in precise
balance.

In Paget's disease, the process goes awry. In discrete portions of bone,
overly large osteoclasts dissolve bone too quickly--as much as 50 times
faster than normal. Osteoblasts try to compensate for the increased pace
by rapidly depositing new bone. But, in the hurried process, the newly
deposited bone is loose and bulky in structure, rather than strong,
compact, and neatly arranged.

Over time, pagetic bone becomes weak and soft and can easily bend,
actually shortening the part of the body affected: for example, a leg or
the spine. The bone may enlarge in diameter, though, and it can become
painful and break easily.

Any bone can be affected, but the most common sites are the spine,
skull, pelvis, and legs. Some patients may have only one affected bone,
while others may have two or more. The disease usually does not spread
to unaffected bones.

Common deformities include bowed legs, an enlarged head or pelvis, and a
curved back. Pagetic bone can affect other parts of the body, causing
added problems. For example, it can change bones around joints, causing
arthritis. If in the skull and the temporal bone (the bone surrounding
the inner ear), Paget's disease can affect hearing. When it affects the
facial bones, it can cause dental problems.

Because of changes to the bone, pagetic bones often contain more blood
vessels than normal, increasing blood flow to affected bones. Because
the heart has to work harder to pump the extra blood, Paget's patients
with heart disease may be at even greater risk for heart failure.

Paget's disease is rarely fatal. However, fewer than 1 percent of
patients may develop osteosarcoma, a form of bone cancer, and other
sarcomas. Most Paget's patients die from causes unrelated to Paget's
disease.

Causes

No one knows what causes Paget's disease, although genetics may play a
role. Several studies indicate that 15 to 30 percent of Paget's patients
have family members with the disease. Those with a first-degree
relative--parent, sibling or child--with Paget's disease are seven times
more likely to develop the disease than those without an affected
first-degree relative.

"It clearly runs in families," says Ethel Siris, M.D., an
endocrinologist at Columbia University College of Physicians and
Surgeons in New York City. She says the risk increases if the
first-degree relative has more severe disease and an early age at
diagnosis. Paget's disease is rarely diagnosed in people under 40,
although there have been cases. Siris says she's treated patients in
their late 20s and early 30s.

The family history related by several patients seems to bear out Siris'
conclusions: Evelyn Nef, 83, of Washington, D.C., who was diagnosed with
Paget's disease in 1962, says her brother and sister also suffer from
the disease. Halstead, who was diagnosed in his 30s, says his two
brothers have the disease and his mother, who is 102, was diagnosed
three years ago.

The role of genetics also is supported by observations that certain
ethnic groups have higher rates of Paget's disease. According to the
Paget Foundation, Paget's disease is most common in Caucasian people of
Anglo-Saxon and European descent, but it also occurs in African
Americans. It is rare in people of Asian descent.

Research by Frederick Singer, M.D., an endocrinologist with the John
Wayne Cancer Institute at Saint John's Hospital and Health Center in
Santa Monica, Calif., may eventually yield proof of a genetic role.
Studying an Iowa family with a history of Paget's disease, Singer and
his colleagues traced a genetic abnormality to chromosome 18. The
precise gene has yet to be identified, Singer says, but when it is,
genetic tests may be able to predict who will get the disease. "I think
that's coming pretty fast," he says.

Many experts, Singer included, also suspect that a slow virus may play a
role. The theory is that the virus infects a person early in life,
without causing symptoms for many years. This theory is based on studies
identifying viral-like particles in osteoclasts from pagetic bone.
According to Sakamuri Reddy, Ph.D., assistant professor at the
University of Texas Health Science Center at San Antonio, these
particles react with antibodies that detect a group of viruses which
includes the measles and canine distemper viruses. Reddy and his group
also have shown that osteoclasts from patients with Paget's disease
contain the measles virus messenger RNA. Osteoclasts of people without
Paget's disease do not contain this RNA.

This isn't to say that measles is the cause, though, says Leo Lutwak,
M.D., Ph.D., an endocrinologist and medical reviewer in FDA's division
of metabolism and endocrine drug products. "The agent may be related to
the measles virus," he says.

How do the viral theory and genetics' role fit together? Experts in
Paget's disease surmise that heredity may put people at risk for the
suspected Paget's virus.

"It may be that some people inherit the tendency to have this virus
affect their osteoclasts, while other people are, due to their own
genetic makeup, more resistant," Siris writes in the Paget Foundation
publication A Patient's Guide to Paget's Disease of Bone.

Accidental Diagnoses

Many patients, especially those with mild cases, first learn they have
Paget's disease when a routine blood test reveals an abnormally high
blood level of total alkaline phosphatase, an enzyme produced by
osteoblasts, as well as cells of the intestine and liver.

When osteoblasts are more numerous or are especially active, the amount
of alkaline phosphatase throughout the skeleton is increased. The
increased bone alkaline phosphatase spills over into the blood,
increasing the serum alkaline phosphatase.

A normal serum alkaline phosphatase ranges from 20 to 141 units per
liter (U/L). Patients with severe Paget's disease may have six to 10
times that range. Halstead recalls that at one point his serum alkaline
phosphatase rose to nearly 2,000 U/L. Jan Brown of Rockville recalls her
alkaline phosphatase was more than 1,000 U/L when she was first
diagnosed. "The doctor said he had never seen such a high alkaline
phosphatase in as young a person," recalls Brown, who was 52 when
diagnosed with Paget's disease.

Sometimes, Paget's patients first learn about their diagnosis when an
x-ray taken for other reasons reveals pagetic bone.

Usually, bone pain is the first complaint of patients with symptoms.
Bone deformities, arthritic pain, and hearing loss are other complaints
that may lead patients to seek medical attention.

Laboratory tests, such as the serum alkaline phosphatase and urinary
hydroxyproline (a measure of bone breakdown), may offer evidence of
Paget's disease, but x-rays give the definitive diagnosis. Bone scans
also may be taken to determine the extent and activity of Paget's
disease. Bone scans involve less radiation and are more sensitive than
x-rays in detecting areas of pagetic bone.

Treatments

Safe drugs for treating Paget's disease of bone became available only in
the last 25 years. FDA approved the first two, calcitonin and Didronel
(etidronate disodium), in the mid-1970s.

Salmon calcitonin (Calcimar and Miacalcin) and human calcitonin
(Cibacalcin) are synthetic substances similar to the human hormone
calcitonin. Synthetic calcitonin preparations help inhibit bone
breakdown by decreasing the activity of osteoclasts. Only injectable
calcitonin is approved for patients with Paget's disease, although
nasal-spray calcitonin, which is approved for other uses, is under study
for Paget's disease also, according to the Paget Foundation.

Didronel is taken orally in the middle of a four-hour fast. It is a
bisphosphonate, a class of drugs that slows bone turnover.

Two newer bisphosphonates, Aredia (pamidronate disodium for injection)
and Fosamax (alendronate sodium tablets), appear to achieve more
effective results--as measured by laboratory tests--according to
studies, and usually in smaller doses because they are more potent.
Aredia, approved by FDA in October 1991, is given intravenously over
four hours daily for three consecutive days.

Fosamax, approved by FDA in October 1995, is taken orally. Because this
medicine is poorly absorbed, patients should take Fosamax with a glass
of water first thing in the morning, then wait at least 30 minutes
before taking other medications, eating, or drinking anything other than
water. Also, to help prevent esophageal irritation and to ease delivery
of the medicine to the stomach, patients should drink a glass of water
and not lie down for at least 30 minutes after taking Fosamax.

In clinical studies, patients receiving Fosamax had a 20 to 25 percent
greater drop in serum alkaline phosphatase levels than those receiving
Didronel. The drop was up to 65 percent greater compared with placebo,
which had little effect on alkaline phosphatase levels. Bone tissue
studies indicated that normal bone was produced during treatment with
Fosamax, even where preexisting bone had the abnormally disorganized
pattern characteristic of Paget's disease.

Fosamax and Didronel usually are taken for no longer than six months at
a time. If symptoms worsen or laboratory tests indicate a worsening of
the disease, the drugs may be restarted after at least a six-month break
from the medications.

Additional Therapies

According to the Paget Foundation, several more bisphosphonate drugs are
undergoing clinical tests. These drugs may offer greater ease of use,
says Charlene Waldman, executive director of the Paget Foundation.

Because new bone formation occurs as part of the process of repair in
pagetic bone, it is important that along with calcitonin and the
bisphosphonates to inhibit abnormal bone breakdown, patients eat a diet
that provides 1,000 to 1,500 milligrams of calcium and 400 International
Units of vitamin D daily. These nutrients are needed for proper bone
formation.

Calcium can be obtained by eating a well-balanced diet that includes
foods that are good sources of calcium--for example, milk and milk
products, dark-green leafy vegetables (such as mustard greens and kale),
and canned fish with soft bones (such as sardines and salmon). Dietary
supplements of calcium may be another source.

Some Paget's patients, especially those with severe bowing of legs,
fractures, and degenerative arthritis, may need splints, braces, and
other devices such as canes and walkers. Patients also may receive
physical therapy.

Although uncommon, surgery may be required, especially in cases of
fractured bones, severe arthritis, and progressive deformity of leg
bones.

Exercise is important for patients with Paget's disease, just as it is
for everyone. Because patients with Paget's disease are prone to bone
fractures, they should consult their doctors or physical therapists
before starting an exercise program.

Various laboratory tests monitor the progression of Paget's disease. The
most common is the total alkaline phosphatase. FDA has cleared two
tests--Hybritech Ostase in 1994 and Metra Alkphase-B in 1995--that
measure only the alkaline phosphatase from bone, since the enzyme in the
blood can come from other organs, too.

A possible future test, which is still under research, would measure
osteocalcin, a byproduct of osteoblasts, to determine bone turnover
rates.

Deciding When to Treat

For many years, doctors generally treated patients with Paget's disease
only if they had symptoms. In recent years, with the availability of a
wider range of drugs, doctors have begun treating patients without
symptoms, as well, hoping that the drugs may prevent the effects of
Paget's disease. Factors to consider in deciding whether to treat
patients without symptoms, according to Siris, are the location of the
disease and the likelihood of its progression. Diseased bone near
joints, in the spine or skull, or in the leg bones are particularly "bad
spots," she says, and may indicate the need for drug therapy.

Patients who are told they have Paget's disease may want to seek a
medical specialist in that condition. The Paget Foundation recommends
endocrinologists (doctors who specialize in hormonal and metabolic
disorders) or rheumatologists (doctors who specialize in joint and
muscle disorders). Orthopedic doctors (who specialize in bone problems),
neurologists (doctors who specialize in nerve disorders), and
otolaryngologists (eye, ear, nose, and throat specialists) also may be
called on to evaluate specific symptoms.

Siris and Michael McClung, M.D., an endocrinologist and director of the
Oregon Osteoporosis Center in the Oregon Health Sciences University in
Portland, say that too often doctors who aren't specialists in the
disease fail to follow up on laboratory tests or x-rays that indicate
Paget's disease. "They might tell patients: 'Forget about it. You'll
just end up in a wheelchair,'" Siris says. She believes that many
doctors aren't aware of current treatments because effective drugs for
Paget's disease weren't available when they were trained.

Since Paget's disease often runs in families, medical experts recommend
that people with a family history of Paget's disease have their serum
alkaline phosphatase measured after age 40, since the disease rarely
shows up in people under 40. The laboratory test can be done as part of
the routine medical exam.

With prompt medical attention and treatment, when needed, people with
Paget's disease may be able to avoid some of the disease's serious,
often painful effects.

Maryland resident Brown hopes that will be true for her. "[The disease]
is foremost in my mind," she says. "I wonder: 'Am I going to suffer any
deformities from this?' I don't know. But I must be treated or so many
things could happen."

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


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


More Information

The Paget Foundation for Paget's Disease of Bone and Related Disorders
200 Varick St., Suite 1004
New York, NY 10014-4810
(1-800) 23-PAGET
E-mail:[e-mail]
World Wide Web: http://www.housecall.com/

Osteoporosis and Related Bone Diseases National Resource Center
1150 17th St., N.W., Suite 500
Washington, DC 20036-4603
(1-800) 624-BONE
TTY for hearing-impaired callers: [phone]
E-mail:[e-mail]
World Wide Web: http://www.osteo.org/

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

Inside FDA: Office of Women's Health

by Isadora B. Stehlin

This is one in a series of articles on FDA activities and concerns.

When FDA's Office of Women's Health announced that 1995 annual funds
were available for agency research projects, Mary Lou Tortorello, a
microbiologist with FDA's Center for Food Safety and Applied Nutrition,
knew just the project to propose. She wanted to develop a rapid test for
Listeria monocytogenes, a microorganism widespread in the environment
that may contaminate many types of foods. She thought the test could
have a major impact on women's health, since Listeria can cause
miscarriages and stillbirths in pregnant women.

"By current standard methods, it takes at least four days to detect
Listeria in food, and that's only if everything works as it is supposed
to," says Tortorello. "A rapid test could really enhance food safety."

Tortorello's research is one of more than 50 projects within the agency
that have been funded by the Office of Women's Health since it was
established in July 1994.

The office, with a $2 million annual budget, promotes testing of
FDA-regulated products in women, supports research and education to
increase knowledge of women's health issues, and forms partnerships with
other government agencies and advocacy groups to advance women's health
objectives.

Women's health issues of particular concern to OWH include:

 * cardiovascular disease
 * cancer screening and treatment
 * sexually transmitted diseases, including HIV
 * contraception, pregnancy and childbirth
 * hormone replacement therapy for menopause
 * osteoporosis and other diseases affecting older women
 * autoimmune diseases.

Central to the office's mission are increasing the number of women in
clinical trials and analyzing data for important effects that vary with
gender.

Historically, women have been neglected in clinical trials for new
drugs, devices, and biological products. Attention to remedying this
situation was integral to the genesis of the Office of Women's Health
and is one of its major issues, explains Audrey Sheppard, acting
director of the office.

One of the first projects the office funded in 1994 was a study to
determine how women newly diagnosed with breast cancer obtained clinical
trial information. "There's a great misunderstanding about the National
Cancer Institute's Physician Data Query [PDQ] clinical trial database,"
says Patty Delaney, project coordinator and cancer liaison in FDA's
Office of AIDS and Special Health Issues. Not every trial is included,
she explains, only trials sponsored by NCI and a few others submitted
voluntarily by nongovernment sponsors. "If a manufacturer is conducting
one on its own, it is likely not to be in NCI's database."

The project, conducted by a contractor for FDA, involved calling more
than 100 different telephone numbers that supplied cancer information.
Results showed there was no simple, comprehensive way to find out about
all the current clinical trials on breast cancer. University medical
centers and other research sites often only offered information on
studies they were conducting, and when asked where someone could get
information on other studies, callers were usually referred to NCI's
cancer hot line, (1-800)4-CANCER.

Because there is no centralized source for information on all current
clinical trials, "patients and their doctors have trouble finding
suitable trials, and manufacturers have trouble filling trials," says
Marietta Anthony, Ph.D., a microbiologist with the Office of Women's
Health.

Based on these conclusions, the National Action Plan on Breast Cancer,
an organization funded by both private groups and the Department of
Health and Human Services, awarded FDA $100,000 to assist NCI in getting
drug, biologics and device manufacturers to voluntarily add their breast
cancer clinical trials to the PDQ database.

The office has also funded research projects and studies to:

 * Develop a computer model to simulate the potential for a virus to
   break through a protective barrier such as latex, used in surgical
   gloves and condoms.

 * Develop a pilot tracking system to monitor the participation of women
   in clinical trials.

 * Examine the effects of the anti-breast cancer drug tamoxifen
   (marketed as Nolvadex) on the rat uterus. Preliminary studies of
   women taking tamoxifen, which can delay or prevent relapse in
   patients who have undergone surgery for breast cancer, have shown
   that the drug poses an increased risk of cancer of the uterus.

 * Determine if changes in female sex hormone levels that occur during
   the menstrual cycle, pregnancy and menopause affect the activities of
   cytokines (hormone-like proteins that act as communicators between
   cells). Limited evidence suggests that the cause of systemic lupus
   erythematosus, an immune-system disease that mainly affects women,
   may be linked to the interaction of these cells.

In addition to funding research, the office has also supported education
projects that address women's health issues. One of these efforts, "The
Minority Women's Health Empowerment Project," attracted nearly 500
participants. Theresa Holmes, a public affairs specialist with FDA's
Philadelphia office, and Joan Lytle, a public affairs specialist with
the agency's Newark office, developed the project and six half-day
workshops held during the fall of 1995. Four were held in different New
Jersey cities, one in Philadelphia, and one in Wilmington, Del.

"These workshops provided really practical nuts and bolts information on
diseases and conditions, prevention and diagnosis, and remedies," says
Sheppard.

Some critical health problems of minority women include cervical cancer,
which is approximately three times higher among black women than white
women; heart disease, which is the leading cause of death in Latino
women; and hypertension, stroke, diabetes, lupus, and other chronic
diseases, which are responsible for a disproportionate number of deaths
in young African-American women.

Other education projects funded by the Office of Women's Health include:

 * Mammography Quality Standards Act brochure for consumers

 * Mammography Quality Standards Act speakers kit to help FDA and state
   radiation control personnel explain MQSA requirements, as well as
   FDA's programs and policies for mammography facility accreditation
   and inspection

 * Women of Color Outreach project to expand minority women's
   involvement in the FDA policy development process

 * Hispanic Women's Health Conference in Miami on May 9 and 10, 1996

 * Asian Pacific Islander Group outreach to encourage use screening
   tests such as mammograms and pap smears. Asian language translations
   of FDA educational materials were distributed at health conferences,
   community activities, and medical centers in California.

 * Women's Health Internet Initiative to provide information about
   women's health issues related to food safety, nutrition and
   cosmetics. Its World Wide Web address is
   http://vm.cfsan.fda.gov/~dms/wh-toc.html.

OWH also coordinates working groups that bring together agency experts.
For example, for the working group on older women's issues, "the office
is bringing together people throughout the agency who have a piece of
the osteoporosis puzzle--the people who approve the drugs, the people
who approve the bone measurement devices, and the people who know all
about calcium and other foods," explains Sheppard.

In partnership with women's organizations, the office is initiating a
new public education campaign titled "Women's Health: Take Time to
Care." The campaign will target middle-aged and older women, with
special emphasis on women who are medically underserved.

As the Office of Women's Health continues to define its role, "we really
do see ourselves as not just coordinating and educating," says Sheppard,
"but also determining where there needs to be advances in thinking, in
policy, and in regulation."

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


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


Probing the Pancreas

by Craig D. Reid, Ph.D.

The human pancreas, an elongated, flattened gland behind the stomach, is
involved in or affected by a number of diseases, including diabetes
mellitus, cystic fibrosis, pancreatitis, and pancreatic cancer. These
conditions are diagnosed and treated with products regulated by the Food
and Drug Administration.

The pancreas is composed of two major types of tissues:

 * exocrine tissue (acini), which secretes digestive enzymes via the pancreatic duct into the duodenum (part of the small intestine leading from the stomach)

 * endocrine tissue (islets of Langerhans), which produces and secretes
   the hormones insulin and glucagon directly into the blood. Endocrine
   tissue contains alpha, beta and delta cells. Beta cells produce
   insulin and alpha cells produce glucagon. These hormones regulate
   blood glucose levels. Delta cells secrete the hormone somatostatin,
   which inhibits insulin and glucagon secretion.

Diabetes

A deficiency of insulin in the body results in diabetes mellitus, which
affects about 13 million individuals in the United States. It is
characterized by a high blood glucose (sugar) level and glucose spilling
into the urine due to a deficiency of insulin. As more glucose
concentrates in the urine, more water is excreted, resulting in extreme
thirst, rapid weight loss, drowsiness, fatigue, and possibly
dehydration. Because the cells of the diabetic cannot use glucose for
fuel, the body uses stored protein and fat for energy, which leads to a
buildup of acid (acidosis) in the blood. If this condition is prolonged,
the person can fall into a diabetic coma, characterized by deep labored
breathing and fruity-odored breath.

There are two types of diabetes. In Type I diabetes, formerly called
juvenile-onset diabetes, the pancreas cannot produce insulin. People
with Type I diabetes must have daily insulin injections. But they need
to avoid taking too much insulin because that can lead to insulin shock,
which begins with a mild hunger. This is quickly followed by sweating,
shallow breathing, dizziness, palpitations, trembling, and mental
confusion. As the blood sugar falls, the body tries to compensate by
breaking down fat and protein to make more sugar. Eventually, low blood
sugar leads to a decrease in the sugar supply to the brain, resulting in
a loss of consciousness. Eating a sugary food can prevent insulin shock
until appropriate medical measures can be taken.

Type II diabetes, formerly called adult-onset diabetes, can occur at any
age. The pancreas can produce insulin, but the cells do not respond to
it.

For many years, treatment was insulin therapy for Type I and oral
sulfonylureas and/or insulin therapy for Type II.

Metformin (glucophage) was the first antidiabetic drug approved by FDA
(May 1995) for the treatment of Type II diabetes since the oral
sulfonylureas were introduced in 1984. Metformin promotes the use of
insulin already in the blood. This May 1995 approval was followed by the
September 1995 approval of another antidiabetic drug, Acarbose
(precose), in September 1995. It slows down the digestion and absorption
of complex sugars, which reduces blood sugar levels after meals.

Before 1982, insulin was purified from beef or pork pancreas. This was a
problem for those diabetics allergic to animal insulin. Researchers
produced a synthetic insulin called humulin. Approved by FDA in 1982, it
was the first genetically engineered consumer health product
manufactured for diabetics. Synthetic insulins can be produced in
unlimited quantities.

Another possible treatment for diabetes includes surgically replacing
the pancreas' endocrine tissues (islets of Langerhans) with healthy
islet of Langerhans tissue grafts. Since 1988, 45 patients worldwide
have undergone successful transplantation.

Cystic Fibrosis

The major problem of cystic fibrosis, the number one genetic killer
disease of children in the United States, is that the body overproduces
thick, sticky mucus. The mucus blocks the pancreatic ducts, which
impedes the flow of the pancreatic juices from the pancreas into the
duodenum of the small intestines. Food cannot be properly digested.
Without treatment, children with cystic fibrosis suffer from
malnutrition and constant diarrhea; their average life expectancy is 21.
Pancreatic enzyme preparations are usually used to minimize the
disease's effects on the pancreas.

Pancreatic juices contain enzymes for digesting all three major food
types (proteins, carbohydrates and fats), as well as quantities of
bicarbonate ions, which play an important role in neutralizing the acid
emptied by the stomach into the duodenum. The most important enzyme for
fat digestion is pancreatic lipase, which is capable of changing fat
into glycerol fatty acids and cholesterol. Hormones regulate pancreatic
secretions. Food enters the small intestine. The hormones secretin and
cholecystokinin cause the pancreas to create large quantities of fluid
containing bicarbonate ions, which neutralizes the acid stomach
contents.

Pancreatitis

Another common disease associated with the exocrine function of the
pancreas is pancreatitis (inflammation of the pancreas), which can be
either acute or chronic.

The most common cause of acute pancreatitis is blockage by a gallstone
of the main secretory duct from the pancreas as well as the common bile
duct. When this happens, large quantities of pancreatic secretions pool
in the pancreas and can digest the entire pancreas within a few hours.
But because the islets of Langerhans are not adversely affected, the
pancreas can continue secreting insulin. Acute pancreatitis is a
condition demanding immediate medical attention. It is characterized by
abdominal pain, vomiting, abdominal swelling and gas, fever, muscle
aches, and a drop in blood pressure. When appropriately treated, the
effects of acute pancreatitis usually calm down within five to seven
days. Treatment includes stopping oral consumption and providing
nourishment only with intravenous fluids.

Chronic pancreatitis occurs when acute pancreatitis continues until
pancreatic function is greatly diminished. Symptoms include persistent
pain in the upper abdomen which can radiate to the back and last for
days or weeks, with mild jaundice (yellow skin and eyes) and rapid
weight loss. A person can have recurrent attacks over several years.
This may result in secondary bacterial infections of the pancreas,
calcium deficiencies, and Type II diabetes.

Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer deaths in the
United States, affecting about 27,000 persons yearly. It is second only
to colon cancer as a cause of death from gastrointestinal malignancy. It
affects men twice as frequently as women and is more likely to develop
after the age of 40. Pancreatic cancer risks increase with chronic
pancreatitis, diabetes mellitus, genetic factors (more common in blacks
than whites), smoking, excess alcohol consumption, high-fat diets, and
exposure to industrial chemicals such as urea, naphthalene or benzidine.
Symptoms include weight loss, abdominal pain, nausea, loss of appetite,
itching, jaundice, and constipation. Abdominal stress may improve or
worsen after eating, and the pain may increase after lying down. Because
its symptoms mimic many other common health problems, it often goes
undetected until it is too late to treat effectively.

When early diagnosis and early treatment are possible, however, survival
chances increase. Imaging with endoscopic ultrasound may aid early
diagnosis. Researchers are also rapidly building a library of potential
genetic markers that indicate the onset of pancreatic cancer. Treatment
includes chemotherapeutic drugs and traditional surgical techniques.

The most commonly used chemotherapeutic agents are 5-Fluorouracil (5-FU)
and the recently approved Gemzar (gemcitabine), a nucleoside analog that
mimics DNA building blocks. FDA's approval of Gemzar last May was based
on two clinical studies in patients with cancer that was locally
advanced or had spread beyond the pancreas. These studies found
improvement with Gemzar in what is termed "clinical benefit response"--a
measure including changes in patients' use of painkillers, pain
intensity, and body weight.

The first study, conducted with patients who had never before received
chemotherapy, showed that when compared to patients receiving 5-FU
therapy, patients treated with Gemzar had a statistically significant
improvement in clinical benefit (23.8 percent versus 4.8 percent) and in
median survival (5.6 months versus 4.2 months).

A second study conducted in 63 patients previously treated with 5-FU
therapy and then given Gemzar showed a clinical benefit response of 27
percent and a median survival of 3.8 months.

Before its approval, FDA authorized Gemzar's manufacturer, Eli Lilly and
Company, to make the drug available through a Treatment IND
(investigational new drug) program. More than 2,800 patients received
the drug under this program between February 1995 and May 1996.
Treatment INDs allow drug developers to give patients access to drugs
before they are approved for marketing in cases of immediately
life-threatening or otherwise serious diseases.

Cryosurgery, a type of surgery in which extremely low temperatures are
employed either locally or generally to destroy tissue, is also being
investigated for use in pancreatic cancer. The technique involves
specific time length and time interval applications by a probe
containing liquid nitrogen to freeze the cancer cells to death. The
advantages of cryosurgery are that it is inexpensive, requires shorter
hospital stays, and causes less blood loss.

Pancreatic diseases are among the most common and most deadly diseases
that affect Americans today. Due to genetics and the pancreas' inability
to cope with disease, having one pancreatic disease primes the body to
contract or develop a second pancreatic disease. Although scientists
have made considerable progress in the treatment of diabetes, early
detection and treatments for cystic fibrosis and pancreatic cancer don't
always guarantee the patient will live a long normal life. However,
researchers are constantly searching for new and improved methods to
complement or replace current therapies in an attempt to at least
improve the patient's quality of life.

Craig D. Reid, a writer in Los Angeles, was diagnosed with cystic
fibrosis more than 30 years ago.

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


Updates

New Pertussis Vaccine Safer for Infants

An acellular vaccine recently licensed by FDA protects infants against
pertussis, or "whooping cough," while causing fewer side effects than
whole-cell pertussis vaccines.

Acellular pertussis vaccines contain only parts of the pertussis
bacterium thought to be important for immunity, while whole-cell
vaccines contain the whole, killed bacterium.

Currently, children in the United States receive a whole-cell pertussis
vaccine in combination with diphtheria-tetanus toxoid, or DTP, at 2, 4
and 6 months of age, with additional doses of either a DTP or DT vaccine
with an acellular pertussis component (DTaP) between 12 and 18 months
and before entering elementary school.

The acellular vaccine licensed July 31 for the first three doses is one
of two DTaP vaccines already approved for the fourth and fifth doses.

Pertussis is a highly communicable respiratory disease that can be
especially serious for infants. The coughing and choking that occur make
breathing difficult and can last for several weeks. Occasionally,
infants can die from the disease.

According to the national Centers for Disease Control and Prevention, in
1994 and 1995 a total of approximately 9,500 cases of pertussis were
reported in the United States. The World Health Organization reports
that pertussis causes approximately 350,000 deaths worldwide.

Safety data from a number of studies indicate that the DTaP vaccines
cause fewer adverse reactions than DTP vaccines in the first three
doses. Reactions can include local redness or swelling, as well as
fever, drowsiness, irritability, or prolonged, high-pitched crying.
Studies are in progress to help determine the extent of these reactions
when children receive the acellular pertussis vaccine for all five
doses. Infrequent, serious events such as seizures have been reported
after immunizations with both DT P and DTaP.

Two clinical studies were conducted to assess the efficacy of the
pertussis component of this DTaP vaccine for infants. In these studies,
the acellular pertussis vaccine was estimated to be between 69 and 80
percent effective in preventing pertussis, depending on the way the
study was designed and completed. (The whole-cell vaccine is about 80
percent effective.)

Children who have begun their immunizations with DTP should continue to
receive their fourth and fifth doses as DTaP. For those children who
will now receive DTaP at 2, 4 and 6 months, a fourth dose of DTaP is
recommended in the second year of life. Studies are being planned to
help determine recommendations for the fifth dose.

The acellular pertussis component of the vaccine is produced by the
Research Foundation for Microbial Diseases of Osaka University in Japan.
It is combined with diphtheria and tetanus toxoids by Connaught
Laboratories, Inc., Swiftwater, Pa., and is sold under the trade name
Tripedia.

(See also "New Pertussis Vaccine Offers Prevention Alternative," in the
September 1992 FDA Consumer.)

Nicotine Patches Available OTC

Two different nicotine patches to help smokers quit the habit have made
the switch. Formerly available by prescription only, the smoking
cessation aids have been approved by FDA for over-the-counter marketing.

The Nicotrol Transdermal System was approved as an OTC drug product for
adults last July. The NicoDerm CQ was switched for adult use last
August. When used according to directions, the patches deliver a
continuous low level of nicotine that helps reduce nicotine craving and
other withdrawal symptoms.

About 35 million to 45 million U.S. adults are addicted to nicotine due
to cigarette smoking.

The six-week Nicotrol cessation aid includes an audiotape and other user
information. The one-month quit rate among smokers who use the patch and
accompanying materials is about 20 percent. Many smokers who use the
Nicotrol patch stop smoking for at least a few days but may start
smoking again. Most smokers quit several times before they completely
stop.

The NicoDerm eight-to-ten-week treatment includes an audiotape, other
user information, and a child-resistant disposal tray. It comes in
7-milligram, 14-mg, and 21-mg strengths as part of a "step-down" plan to
gradually reduce the nicotine level as treatment progresses. Heavy
smokers (more than 10 cigarettes a day) start with 21 mg for six weeks,
while light smokers (10 or fewer cigarettes a day) start at 14 mg. After
six weeks, consumers are to lower their dose for two weeks, with heavy
smokers lowering th eir dose a second time.

Skin irritation or redness may occur where the patch is placed on the
skin. Users should stop using the product if the skin irritation
persists or if they have irregular heartbeat, palpitations, or other
symptoms of nicotine overdose, such as nausea, vomiting, dizziness, and
weakness.

People who have significant heart disease or take certain prescription
drugs for depression or asthma should seek their doctor's advice before
using either patch.

The Nicotrol Transdermal System is marketed by McNeil Consumer Products
Co. of Fort Washington, Pa., for Pharmacia Upjohn Inc. of Kalamazoo,
Mich. The NicoDerm CQ is marketed by SmithKline Beecham Consumer
Healthcare of Pittsburgh for ALZA Corporation of Palo Alto, Calif.

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

AIDS Drug Approved in 119 Days

The first in a new class of AIDS drugs--non-nucleoside reverse
transcriptase inhibitors--was approved by FDA in only 119 days.

Viramune (nevirapine) was approved by the agency June 21 for use--in
combination with other AIDS drugs--to treat adult HIV patients whose
health has deteriorated. The drug interferes with HIV replication in a
way similar to the older AIDS drugs AZT (zidovudine, marketed as
Retrovir), ddC (zalcitabine, marketed as Hivid), ddI (didanosine,
marketed as Videx), and d4T (stavudine, marketed as Zerit).

Viramune must be used in combination with at least one of these other
AIDS drugs. Studies showed that AZT and ddI, combined with Viramune,
were more effective than AZT and ddI alone in improving health
indicators like CD4 cell counts (an indicator of immune system strength)
and the amount of HIV detected in the bloodstream. When Viramune was
used alone, the virus quickly became resistant to treatment.

Viramune's most significant side effect is a rash. According to the
drug's labeling, treatment should be discontinued if patients develop a
severe rash or a rash with fever, blistering, oral lesions, swelling,
muscle or joint aches, general weakness, or conjunctivitis (inflammation
in the eyes). To decrease the incidence of rash, patients take a
200-milligram dose of the drug once daily for two weeks, and then start
on a 400-mg dose.

The drug manufacturer, Boehringer Ingelheim Pharmaceuticals Inc., of
Ridgefield, Conn., is conducting studies of Viramune's safety and
effectiveness in children with HIV.

(See also "Living with Aids: New Treatments Give Hope," in the
January-February 1992 FDA Consumer.)

First Urine Test for HIV

The first HIV test that uses urine samples has been licensed by FDA.
Previous HIV tests use either blood or oral fluid samples.

The manufacturer, Calypte Biomedical Corporation of Berkeley, Calif.,
will market the new test as the Calypte HIV-1 Urine EIA. It will also be
marketed by Seradyn Inc. of Indianapolis as the Seradyn Sentinel HIV-1
Urine EIA.

The new test uses an enzyme-linked immunosorbent assay (ELISA) method to
detect the presence of antibodies to HIV-1, the virus that causes the
vast majority of U.S. AIDS cases. While it is licensed to screen for
HIV-1 infection, it may also be useful for medical purposes when the
collection of blood samples is impractical. It is not licensed for blood
donor screening, which requires more accurate ELISA blood tests.

Only doctors may order the test, and certified medical laboratories will
analyze samples. Any initially reactive sample will be retested twice.
If even one retest is reactive, the test will be considered positive,
although this positive finding does not always indicate HIV infection.
For confirmation of a positive urine test, the person must be tested
with a more accurate blood test.

In clinical studies, 298 patients were diagnosed with AIDS and tested
with both the urine test and a licensed ELISA blood test. The urine test
was positive in initial screening 99.3 percent of the time. In patients
infected with HIV-1 but without symptoms, the urine test would be
expected to miss 1 or 2 people in every 100.

In other studies in people without HIV-1 antibodies in their blood, the
urine test gave a false positive result in 1 or 2 in 100 people,
compared to 1 in 1,000 with an ELISA blood test.

Before being screened with the new urine test, a person will receive a
patient information sheet outlining the test's limitations. This is in
addition to the usual information on HIV and AIDS already provided
before any HIV testing. After reading the sheet, the person will initial
a statement confirming they received the pretest counseling, peel off
the sample label, and apply it to the urine collection cup.

New Drug for AIDS-Related Eye Infection

A new drug is available for treating cytomegalovirus (CMV) retinitis, a
potentially severe eye infection that can lead to blindness.

While other therapies must be given daily, the new intravenous
treatment, Vistide (cidofovir), is administered once a week for the
first two weeks and then once every two weeks.

FDA based its June 26 approval on two studies in a total of 148
patients. One study showed that the retinitis progressed more slowly in
patients treated immediately with Vistide than in patients with delayed
treatment. The second study showed the drug was effective in patients
with relapsing CMV retinitis who had received other therapy previously.

Vistide's most significant side effect is potential kidney damage, which
can be reduced with the drug Benemid (probenecid) and by hydrating the
body to increase its water content. Other side effects included
decreased white blood cells, weakness, nausea, diarrhea, and decreased
pressure in the eye.

Some studies have shown that the drug may cause cancer in rats, but such
cancers have not been seen in human studies.

Vistide is manufactured by Gilead Sciences Inc., of Foster City, Calif.

(See also "Living with Aids: New Treatments Give Hope," in the
January-February 1992 FDA Consumer.)

FDA Warns Against Using a Mexican Skin Cream

Consumers should not use a Mexican facial skin cream because it can
cause mercury poisoning, FDA warned last July. The product was taken off
the market in July, but consumers may still have some bought previously.
Anyone using the product, Crema de Belleza--Manning, should stop at
once, contact their local health authority, and see a doctor for a
medical evaluation.

The cream, labeled in Spanish for reducing facial oil and removing
pimples and blackheads, was sold mainly in Mexico, but also in Arizona,
California, New Mexico, and Texas--mainly in Hispanic communities. The
manufacturer is Laboratories Vide Natural SA de CV., Tampico,
Tamaulipas, Mexico.

The label lists the ingredient calomel, which is mercurous chloride, a
salt of mercury. Because of the toxicity of mercury compounds and
because mercury is readily absorbed through the skin, FDA restricts its
use in cosmetics. Mercury may be used only as a preservative in eye-area
cosmetics at concentrations not exceeding 65 parts per million when
there is no safe and effective nonmercurial preservative available for
such use.

At the time of the warning, the national Centers for Disease Control and
Prevention had identified about 200 users of the cream in the four U.S.
border states. CDC testing showed elevated mercury levels in more than
80 people who had used the product. At least three people were diagnosed
with mercury poisoning. Product samples were found to contain 6 percent
to 10 percent mercury by weight. Chronic exposure to mercury salts can
cause nervousness, irritability, tremors, weakness, fatigue, memory
loss, changes in hearing or vision or taste, nausea, vomiting, diarrhea,
kidney damage, and death.

The cream was sold in semi-opaque plastic bottles marked as containing
160 milliliters. The bottles, about 6 inches high, have beige plastic
caps and red and blue labels. If undisturbed, the contents separate into
an upper layer of clear liquid and a lower layer of white solids.

Both U.S. and Mexican authorities removed the product from the two
markets.

Free Backgrounder on Protease Inhibitors

A free new backgrounder on proper use of protease inhibitors, a new
class of drugs used to treat HIV, is available from FDA.

The new backgrounder provides information about appropriate dosing, the
similarities and differences of each approved protease inhibitor,
storage, potential drug interactions, and treatment options. A fairly
technical document, the backgrounder will be of most use to doctors and
other health professionals.

A free copy of "The Protease Inhibitors--Backgrounder" may be ordered
from FDA's Office of AIDS and Special Health Issues by calling (301)
443-0104, by facsimile transmission at [phone], or by E-mailing
[e-mail].

Foods in Menu Claims Must Meet FDA Rule

Restaurants that include dishes with claims like "low fat" or "heart
healthy" on the menu must be able to demonstrate that there is a
reasonable basis for believing that the food is qualified to bear this
claim, according to standards recently set by FDA.

The July 30 final rule for the standards allows restaurant owners
considerable flexibility in establishing this reasonable basis and in
presenting the information to consumers. However, owners must be
prepared to show officials that their menu claims are consistent with
the claim definitions established under the Nutrition Labeling and
Education Act of 1990.

Unlike processed foods, restaurant menu selections don't have to supply
complete nutrition information. Also, menu items bearing a claim can be
shown to meet the rule by more economical means than the strict
standards of laboratory analyses required for processed foods. For
example, a restaurant could show that an item was designed to meet the
requirements for the claim because it was prepared using a recipe from a
recognized health professional association or dietary group, or that the
nutritional values for the dish were calculated using a reliable
nutrition database.

Furthermore, nutrition information can be provided to the consumer by
any reasonable means. It does not have to be presented in the "Nutrition
Facts" format seen on packaged food labels, nor does it have to appear
on the menu. For example, information on the fat content of all menu
items that bear fat claims could be compiled in a notebook available to
consumers upon request.

FDA estimates that the rule's flexibility, limited scope, and compliance
date of May 1997 should minimize its economic impact on the restaurant
industry.

The new menu rules are identical to the standards that have been in
effect since May 1994 for nutrient content claims on placards and signs
in large and medium-sized restaurants, and since May 1995 for such
claims in smaller restaurants.

FDA Eases Way for Limited-Market Devices

Medical devices used to treat diseases affecting fewer than 4,000 people
annually now will be easier and less costly to bring to market,
according to a recent FDA policy change.

This change is in addition to FDA's orphan drug program. (See "Orphan
Products: New Hope for People with Rare Disorders" in the June 1994 FDA
Consumer.)

The agency announced in a final rule that it will approve rare-disease
devices for marketing as long as manufacturers show:

 * The device will not expose the patient to any significant or
   unreasonable risk.

 * The probable benefits outweigh the probable risks.

 * No comparable treatment is available.

 * The company would not be able to bring the product to market otherwise.

Makers of new medical devices usually must show that products are
effective, a requirement that involves controlled clinical studies. The
expense of such studies has been a disincentive to medical device
firms--most of which are small--to develop products for rare conditions
that have a limited market.

Manufacturers of rare-disease devices still may be required to do
clinical studies to establish safety but will not have to establish
effectiveness.

To ensure patient protection, such devices may be used only in medical
facilities with local institutional review boards that have approved the
device for a specific rare disorder. Also, FDA's approval of such a
device is valid for 18 months but can be extended in 18-month increments
as long as the criteria for a rare-disease device are met.

The new FDA rule--called the Humanitarian Device Exemption--was mandated
by the 1990 Safe Medical Devices Act, which requires the agency to
exempt manufacturers of products that benefit fewer than 4,000 people
from effectiveness requirements of medical device law. FDA published the
rule in the June 27, 1996, Federal Register.

Data Requested on Safety of Laxative Ingredients

After recent animal studies indicated a possible link between cancer and
two ingredients in over-the-counter laxatives, FDA asked manufacturers
for more data to establish the safety of the two ingredients and three
similar ones.

In a letter dated May 21, 1996, FDA informed the firms it plans to
reclassify the five ingredients--phenolphthalein, bisacodyl, senna,
aloe, and cascara sagrada--from category I (safe and effective) to
category III (more data needed).

Studies by the National Toxicology Program (NTP) provided new evidence
that phenolphthalein (chemically related to bisacodyl) may cause cancer
in rodents and that senna (chemically related to aloe and cascara
sagrada) may cause gene or chromosome irregularities. FDA has no adverse
reports or other information linking use of the ingredients with cancer
in humans.

To determine whether the new evidence may translate into a risk for
humans, FDA's Carcinogenicity Assessment Committee met twice with
manufacturers and NTP representatives. Finding available safety
information to be inadequate for a clear assessment, the agency
requested the additional data.

Products containing the five ingredients may be marketed until FDA
publishes a final regulation.

Psyllium, castor oil, docusate sodium, and 20 other ingredients are
still considered safe and effective components of laxative products.

Reforms to Speed New Animal Drugs to Market

Recent FDA reforms promise to shorten the time needed for development of
new animal drugs and significantly cut the agency's review time for such
products.

The reforms, announced May 10, include:

 * encouraging sponsors to meet with FDA reviewers early in a drug's
   development to encourage a common understanding of data needed and
   the most efficient way to get data

 * reviewing submissions in phases

 * reviewing technical submissions directly, so sponsors can deal with
   individual FDA reviewers, instead of dealing through an FDA project
   manager.

In addition, FDA will propose rules providing clear, up-to-date guidance
on all crucial phases of animal drug development and production
processes.

Free New Reprints and Spanish-English Brochure

Two new FDA Consumer reprints and a new brochure--Spanish on one side,
English on the other--are available free from FDA.

The publications and their numbers are:

 * Taking the Fat Out of Food (FDA) 96-2305

 * Fighting Fleas and Ticks (FDA) 96-6051

 * Cuide la Seguridad de su BebΘ: Coma los Quesos Duros En Vez de los
   Blandos Durante el Embarazo; Keep Your Baby Safe: Eat Hard Cheeses
   Instead of Soft Cheeses During Pregnancy (FDA) 96-2304S.

To order single copies, write to FDA, HFE-88, Rockville, MD 20857. To
order 2 to 100 copies, 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.

Cocoa butter substitutes made from safflower or sunflower oil, proposed
for use in frostings, candy coatings, and sweet toppings, are generally
recognized as safe, according to a final FDA rule. The agency based its
ruling in part on a comparison of the new substitutes with an existing
cocoa butter substitute made from palm oil. (FR July 10)

The effective date for certain portions of the regulation requiring
medical device manufacturers to report adverse events has been
temporarily delayed. The delay will allow FDA to evaluate new issues on
the 1995 rule concerning industry burdens and to determine if
requirements should be revised. (FR July 31)

The first recognized case of group O HIV infection has been reported in
the United States, according to the national Centers for Disease Control
and Prevention. CDC described the case as a woman who recently came from
West Central Africa, where group O HIV is found almost exclusively,
accounting for about 6 percent of AIDS cases there. Despite clinical
findings consistent with HIV infection, the patient's blood tested
negative or inconclusive for HIV over a two-year period. FDA has asked
manufacturers of HIV screening tests to develop modified tests that
could reliably detect the new strain. Several tests sensitive to group O
are in development. For more information about group O HIV, call CDC's
National AIDS Hotline, (1-800) 342-2437. (Morbidity and Mortality Weekly
Report, July 5)

Reducing pathogenic microorganisms such as Salmonella in poultry and
meat products is the subject of new requirements established in a final
rule by the Food Safety and Inspection Service of the Agriculture
Department. Under the rule, food establishments must use written
sanitation standard operating procedures, slaughterhouses must conduct
regular microbial testing and establish reduction standards for
Salmonella, and all meat and poultry establishments must implement a
system of preventive controls to improve product safety. (FR July 25)

Child-resistant packaging has saved hundreds of lives since it was
mandated for oral prescription drugs in 1974, according to an article in
the Journal of the American Medical Association. Researcher Gregory
Rodgers, Ph.D., found that an average of 24 fewer children's deaths from
accidental overdose occurred annually from 1974 through 1992. (JAMA,
June 4)

Bed-wetting, or primary nocturnal enuresis, can continue until age 18,
and studies have indicated it can cause low self-esteem, attention
deficit, or behavioral problems. Parents of bed-wetting children now can
call a National Kidney Foundation hot line at (1-800) 622-9010 to
receive free information and a referral to a local physician who treats
the condition.

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


Investigators' Reports

Companies, Employees Answer To Corrupt Milk Practices

by Paula Kurtzweil

A busy grapevine that kept alive a rumor of an illegal dairy practice
wound its way into unexpected territory: FDA. The agency investigated
and discovered that the rumor was indeed true.

As a result, earlier this year, two Arkansas companies and four
individuals were sentenced to fines totaling more than $300,000 for
allowing milk contaminated with drug residues and a cancer-causing toxin
to enter interstate commerce. Two of the convicted people also were
sentenced to jail. All four are now on probation or under supervised
release.

A fifth man pleaded guilty July 16 to a related charge of accessory
after the fact, a misdemeanor. At press time in September, his
sentencing hearing had not been set.

Their scheme came to light after a milk hauler questioned a Tennessee
state milk inspector about a milk cooperative's practice of transporting
contaminated bulk milk to a cheese curd manufacturer after milk
processing plants had rejected the milk. The milk hauler had learned
about the practice from fellow milk haulers, according to former FDA
compliance officer Ray McCullough. The milk hauler wanted to know why
this particular milk cooperative was allowed to ship contaminated milk
when he had to dump his.

The milk that went to the cheese curd manufacturer contained residues of
the antibiotics penicillin and tetracycline and of sulfa compounds, all
of which can be used to treat diseases in cows. However, it is illegal
to allow milk contaminated with these drugs into the food supply because
the drugs can cause allergic and other adverse reactions in some people.
The drugs also may interfere with the effectiveness of human medications
and may contribute to the development of drug-resistant bacteria. In
addition, one sulfa drug, sulfamethazine, is a potential carcinogen.

The milk also contained aflatoxin, which is produced by certain species
of mold and may cause liver cancer. The mold can grow on grains used in
animal feed, causing the toxin to form. The toxin can then pass into the
milk of animals eating the feed.

Those sentenced last March for participating in the scheme were:

 * Associated Milk Producers Inc. (AMPI) Mid-South Division, of Little
   Rock, Ark. This company, a milk cooperative, is a division of one of
   the largest milk-producing associations in the United States,
   according to McCullough. Each division is made up of dairy farmers
   who sell their raw milk to milk processing plants. AMPI collects the
   milk and transports it to processing plants for the farmers.

 * Hills Valley Foods Inc., of Batesville, Ark. This company made cheese
   curd, an intermediary substance in cheese production, and sold it to
   a Missouri cheese company.

 * Jerry Moore, manager of AMPI's Mid-South Division

 * John Wilbanks, president of Hills Valley Foods

 * Darrell Williams, laboratory supervisor for AMPI's Mid-South Division

 * Larry Miller, dispatcher and administrative assistant for AMPI's
   Mid-South Division.

In addition, Jerry Griggs, milk movement coordinator for AMPI's Southern
Region office, in Arlington, Texas, pleaded guilty in the U.S. District
Court for the Eastern District of Arkansas.

FDA got involved in the case when the Tennessee Department of
Agriculture reported the milk hauler's allegations to the agency in fall
1990.

Typically, milk haulers collect raw milk from farms and take it to
processing plants via bulk tanker trucks. Each tanker holds about 20
metric tons (45,000 pounds) of milk, worth about $8,000, and milk from
one to as many as nine farms can be put into one tanker, depending on
the amount of milk from each farmer, McCullough said.

Before haulers unload the milk, the processing plant screens each
truckload for chemical contaminants, bacteria, and other quality
factors. If the milk tests positive for drug residues or aflatoxin, it
must be dumped.

According to the milk hauler's allegations, this was the point at which
AMPI truck drivers shipped milk that tested positive for illegal drug
residues or aflatoxin to Hills Valley Foods rather than dump it.

FDA began to investigate the allegations in October 1990. McCullough,
along with other FDA investigators, interviewed a number of employees
with Hills Valley Foods and AMPI, including laboratory personnel,
dispatchers, and milk truck drivers. The investigators reviewed recorded
test results of milk samples, milk deliveries, and routing information.
With this information, they compiled a computerized database. They then
used the database to cross-reference positive drug residue and aflatoxin
test results with delivery dates and other pertinent information. The
cross-references enabled them to show that contaminated milk was shipped
to Hills Valley Foods, where it was made into cheese curds and then
shipped to the Missouri cheese maker.

As a result of these findings, the U.S. Attorney's Office undertook a
grand jury investigation in June 1993, subpoenaing about 50 witnesses,
including AMPI and Hills Valley employees who had refused earlier to
cooperate with FDA investigators.

The grand jury charged that:

 * AMPI Mid-South Division had an agreement with Hills Valley Foods in
   which AMPI sold rejected contaminated milk to Hills Valley. According
   to FDA investigators, Hills Valley bought the contaminated milk at a
   favorable price.

 * The scheme involved hundreds of thousands of pounds of contaminated
   milk sold on about 30 occasions between about December 1987 and about
   April 1993.

 * Employees often changed positive test results for antibiotics and
   aflatoxins to negative results. This finding, according to FDA's
   McCullough, was borne out by U.S. Postal Service forensics laboratory
   testing that enabled investigators to decipher erased original
   entries.

 * Employees Moore and Williams instructed truck drivers to call ahead
   to Hills Valley to inform personnel that a "hot," or contaminated,
   load of milk was on its way. This preannouncement signaled Hills
   Valley personnel that they would have to add an extra dose of starter
   culture (called "hot shot" by both parties) to prevent the drugs in
   the milk from inhibiting the bacterial culture needed to make cheese.

 * AMPI identified farmers whose milk had contaminated each truckload,
   and Moore and Williams would arrange for direct pickup of that
   farmer's milk for delivery to Hills Valley.

In June 1995, a grand jury for the U.S. District Court for the Eastern
District of Arkansas indicted the two companies and four individuals on
charges related to the distribution of contaminated milk. In November
1995, Moore, AMPI's division manager, signed a plea agreement,
acknowledging guilt to a one-count felony conspiracy charge and agreeing
to cooperate in the grand jury's investigation. He was sentenced Feb.
29, 1996, to five months in prison, five-months' home detention, and
three years of supervised release and was fined $20,000.

Five other parties pleaded guilty to misdemeanor offenses throughout
1995 and 1996 and were sentenced in March 1996 as follows:

 * AMPI Mid-South Division--fined $200,000.

 * Hills Valley Foods--fined $88,000 and placed on two years' probation.

 * John Wilbanks of Hills Valley Foods--sentenced to 30 days in the
   county jail, five-months' home detention, and seven months of other
   supervised release; fined $20,000.

 * Darrell Williams of AMPI--one year of probation; fined $2,500.

 * Larry Miller of AMPI--one year of probation; fined $5,000.

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


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Cream Doesn't Pay

A Wyndmere, N.D., husband and wife learned that "cream doesn't pay"--at
least not if a cheaper fat is used in place of the real thing. The
couple were sentenced to probation, fines and community service for
selling soybean oil labeled as "farm cream."

Clayton Rawhouser, 46, was sentenced Feb. 6, 1996, to two years'
supervised probation, plus two and a half months in jail (which he
served while awaiting sentencing), and 50 hours of community service. He
also was ordered to pay a $75 special assessment. Janice Rawhouser, 45,
was sentenced Nov. 28, 1995, to six months' unsupervised probation,
fined $250, and ordered to pay a $50 assessment.

A grand jury in the U.S. District Court for the District of North Dakota
had indicted the couple on 48 counts of mail fraud, obstruction of
justice, and shipping adulterated and misbranded farm cream across state
lines. Both Rawhousers pleaded guilty to lying to a U.S. Customs agent
and introducing misbranded or adulterated food into interstate commerce.

The North Dakota Department of Agriculture notified FDA's resident post
in Fargo about a problem the state's assistant dairy commissioner, Tom
Haak, discovered during a routine inspection of Wyndmere Creamery on
Jan. 26, 1994. Haak had found bills of lading showing that since Jan. 1,
the creamery had imported more than 563 metric tons (1.25 million
pounds) of raw cream from Mexico. This violates the federal Milk
Importation Act, which prohibits importing milk and cream from Mexico
because these products do not meet American health standards. The
inspector returned two days later with a state-issued embargo for all
cream and butter products at the dairy.

On Feb. 1, Haak returned to Wyndmere Creamery with Howard Burmeister, an
investigator with FDA's Fargo resident post, to obtain product samples
and copies of records. Clayton allowed them to take samples, but would
not give them access to any records and ordered them off the premises.
The next day, Burmeister and a county deputy sheriff arrived at the
dairy with a subpoena from the state of North Dakota ordering the
surrender of all pertinent records.

"No records were found in the search," said Jess Talty, special agent
with FDA's Office of Criminal Investigations in Chicago, "and neither
was Clayton. He had taken off, and Janice said she burned the records
Jan. 31."

In response to a request from the Rawhousers' attorney, the North Dakota
Department of Agriculture offered to settle with Wyndmere Creamery if
the creamery gave the department information about the illegal
importation of Mexican cream and paid for disposing of the finished
product in North Dakota and in Chicago, where it had been sold to Danish
Maid Butter Co. between Oct. 27, 1993, and Jan. 31, 1994. The dairy
rejected the offer.

"The burning question was how FDA and U.S. Customs could have allowed 26
semi-truckloads of Mexican cream to be smuggled across the border,"
Talty said. "The answer was 'we didn't, and it wasn't': There never was
any imported Mexican cream."

FDA Special Agents Daniel Piovosi and Greg Aspinwall learned this when
they went back to the creamery on Feb. 23 to interview Janice Rawhouser
and dairy employees. According to Talty, Rawhouser said the creamery had
never used Mexican cream. Instead, she said, they used cream from
smaller nearby farms.

"She said she wouldn't tell anyone where they got the cream because they
didn't want their employees to find out and start their own business,"
Talty said. "As we talked to the employees, though, we got the
impression that it was almost impossible for the dairy to process the
amount of cream the Rawhousers were bringing in and shipping out in such
a short period of time."

In reviewing phone and trucking records and talking to employees, the
investigators found the creamery had had many transactions with
Honeymead Soybean Oil Co., in Mankato, Minn. Talty and U.S. Customs
Special Agent Anthony Onstad interviewed officials at Honeymead on March
9 and learned that Clayton Rawhouser had set up contracts to buy 116
metric tons (257,460 pounds) of soybeans in November 1993, 261 metric
tons (579,360 pounds) in December 1993, 315 metric tons (700,280 pounds)
in January 1994, and 394 metric tons (875,000 pounds) each in February,
March and April 1994.

Meanwhile, laboratory results of samples taken during the Feb. 1
inspection at Wyndmere and from Danish Maid on Feb. 3 showed the "farm
cream" in fact was mostly soybean oil with some food coloring added to
make the product look like cream.

On Feb. 22, 1995, FDA's Office of Criminal Investigations (OCI) turned
the information over to the Department of Justice, which presented the
case to the grand jury Sept. 8, 1995.

OCI special agents arrested Janice Rawhouser Sept. 9 but continued to
look for Clayton Rawhouser, who officials believe fled the state around
March 1994.

Talty located an address for Rawhouser in Pharr, Texas, and notified
OCI's Austin, Texas, office. On Sept. 12, 1995, Special Agent Ray
Strucker, along with an agent from U.S. Customs and a U.S. marshal, went
to the address, which turned out to be a storage facility.

"The owner wouldn't give them any information, so they went back to the
Customs Office to get a summons to serve him with," Talty said. "Then
they went back to the warehouse and, lo and behold, who should come
driving up right in front of the place but Clayton."

Clayton Rawhouser was arrested in Pharr on Sept. 12 and held in jail
until his sentencing.

--Marian Segal


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Food Analyst in Prison for Falsifying Data

For falsifying data from tests on food samples salvaged from a warehouse
fire, a Massachusetts consultant received a two-year prison sentence, a
$10,000 fine, and three years of supervised release.

George T. Michael, 51, of Dedham, Mass., pleaded guilty to one count of
wire fraud related to the scheme and one count of making false
statements to secure a bank loan at his March 12 sentencing.

Michael's scheme began following a December 1991 fire in the Americold
facility, a 100-acre underground storage cave in Kansas City, Kan. The
facility housed millions of pounds of food products owned by various
clients. Damage estimates from the fire ranged as high as $1 billion.
Insurers paid off food owners' claims; then, to recoup some of the
losses, they hired salvagers to determine what food could be resold.

In early 1992, a salvage company, M.F. Bank and Co. Inc., hired Michael
to oversee chemical analyses of more than $2 million worth of food. The
company wanted Michael to verify if the products had been contaminated
with toxic substances from the fire. The tests would determine whether
the food had to be destroyed or could be released to the public.

Michael subcontracted with Minnesota Valley Testing Laboratories (MVTL)
in New Ulm, Minn., to perform the analyses. The food was supposed to be
tested for benzene, toluene, styrene, xylene, and polychlorinated
biphenyls (PCBs). Contamination from any of these chemicals would render
the food unsuitable for human consumption.

The Kansas Department of Health and Environment (KDHE) oversaw the fate
of the warehouse food, basing its decisions on submitted test results.
On Oct. 6, 1992, the department called Greg Dixon, an investigator in
FDA's Kansas City district office to discuss sample data. KDHE officials
reported that Michael had submitted a laboratory report on MVTL
letterhead that read "none detected" for various contaminants, yet no
levels of sensitivity for the tests were listed, as is common practice.

"This made us and KDHE suspicious of the accuracy of Michael's data,"
Dixon says.

FDA's Kansas City district then asked the agency's Minnesota district
office to investigate the Minnesota laboratory. After interviewing the
analyzing chemist at MVTL, Minnesota district investigators concluded
that because not all the tests indicated on Michael's lab report had
been done, Michael must have falsified results.

On Nov. 23, 1992, FDA's Minnesota district office completed its
investigation of the testing laboratory, which included interviews and
reviews of records. The investigation confirmed that Michael had
submitted false test results to KDHE. Officials determined neither the
laboratory nor the salvage company that hired Michael was involved in
Michael's scheme.

In September 1995, the U.S. District Court for the District of
Massachusetts charged Michael with the two criminal counts. The court
charged a wire fraud violation because Michael transmitted the false
results over a facsimile machine. The other count was for obtaining a
loan in 1988 from a Massachusetts savings and loan by providing false
statements.

--John Henkel


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Alcohol-Free Mouthwash with Twist of Bacteria

A chemical company recalling contaminated mouthwash called on the
specialized services of a water company to help get the mouthwash maker
out of hot water.

Hydrox Chemical Co., of Elgin, Ill., hired Culligan Water Co. following
an FDA investigation that faulted Hydrox for failing to maintain its
purified water system. Unmaintained for almost a year, the system
apparently introduced the bacterium Pseudomonas cepacia into hundreds of
thousands of gallons of Fresh Moment Alcohol Free Mouthwash produced by
Hydrox between August 1995 and February 1996. The mouthwash was
distributed to hospitals across the country and caused infection in 12
hospitalized patients on ventilators.

While rarely harmful to healthy people, Pseudomonas cepacia can be
dangerous to people with depressed immune systems.

Laboratory analyses identified the bacteria in samples of the mouthwash.
The company voluntarily began recalling the mouthwash in February, and
by August, all of it had been recalled.

FDA became aware of the contamination last Feb. 2, when a epidemiologist
with Froedtert Lutheran Memorial Hospital in Milwaukee contacted the
agency. He reported that since Dec. 20, 1995, 12 hospital patients--all
on ventilators--developed Pseudomonas cepacia infections. The hospital
laboratory identified the bacterium in patients' sputum and in bottles
of Hydrox's Fresh Moment mouthwash, which was distributed to patients. A
doctor caring for the ventilator patients became suspicious after
noticing that a number of patients developed rashes around their mouths,
where their face masks rested. Health-care workers had used the
mouthwash to swab patients' throats.

All the patients recovered from the infection following antibiotic
treatment.

FDA traced the manufacture of the mouthwash to Hydrox, which also makes
other cosmetics, over-the-counter drugs, and veterinary products.
Theodore Thorsen, an investigator with FDA's Chicago district office,
inspected the company's facility Feb. 2. He collected samples of the
company's mouthwash, as well as other company products, such as body
lotions, baby shampoo, and milk of magnesia antacid and laxative. FDA's
Midwest Laboratory for Microbiological Investigations analyzed the
samples and identified Pseudomonas cepacia in the mouthwash. The other
products tested negative for bacterial contamination.

Thorsen continued to inspect and monitor the company's activities
through February and March. His inspections identified six problems:

 * The purified water system had not been properly cleaned and tested
 since May 1995. Hydrox's president, Kapana Ramanandan, told FDA
 officials the company skipped the scheduled maintenance because it
 couldn't afford it. The company filed for bankruptcy in March 1995,
 under Chapter 11 of the Federal Bankruptcy Act.

 * The reverse osmosis membranes of the water system had not been
   changed for more than a year, although this should be done every four
   months, according to the company's written procedure, to prevent
   microbial buildup. The company again cited financial difficulties as
   the reason.

 * Employees failed to perform adequate microbial challenge
   tests--specifically of Pseudomonas cepacia, which can flourish in the
   presence of the antibacterial agent the company added to its Fresh
   Moment mouthwash.

 * Employees did not use the appropriate hose clamps on equipment.
   Thorsen noted that the clamps used "appeared to be basic hose clamps
   that are used in the automotive trade" and were rusty, dirty and
   discolored.

 * Employees left doors open during production, allowing airborne dust
   from outside to enter the manufacturing area.

By Feb. 23, Hydrox had taken steps to correct problems, according to a
Feb. 13 letter Hydrox president Ramanandan sent to FDA's Chicago
district office and a conference he had with FDA officials on Feb. 23.
Chief among his actions was to contact Hydrox's mouthwash
customers--hospitals, medical device repackers, and clinics--and request
that they return mouthwash made between July 1, 1995, and Feb. 2, 1996.
The company relied on product coding and invoices to identify customers
that had received contaminated lots.

By testing mouthwash in reserve, the company traced the point at which
contamination began to the end of August. The company decided to extend
the cutoff point to July 1 as a precaution.

Ramanandan also said the company had:

 * contracted with the Culligan Water Co. for $30,000 to reengineer,
   validate and maintain Hydrox's water purification system

 * sanitized the entire water system with hydrogen peroxide

 * changed the reverse osmosis membranes

 * rewrote the standard of operation for the purified deionized water system

 * replaced hoses and clamps with new sanitary connectors.

Ramanandan also said the company would train employees on the need to
keep doors closed during production.

On April 4, 1996, FDA issued company president Ramanandan a warning
letter because of "concern over this matter," wrote Raymond Mlecko,
FDA's Chicago district director. He cited the company's manufacture of
other products with water from the same system used to make mouthwash
and the company's refusal to perform routine equipment maintenance when
scheduled. Mlecko warned the company that failure to correct problems
could result in enforcement action, such as a seizure or injunction.

The company responded in a May 9 letter reiterating the corrective
measures it had taken. FDA's Thorsen continues to monitor the company.

According to Kathy Haas, recall coordinator for FDA's Chicago district
office, the company had recalled all of the affected products by Aug. 1.
The company destroyed the mouthwash at a landfill, she said.

--Paula Kurtzweil


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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.

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SEIZURE ACTIONS

Food/Contamination, Spoilage, Insanitary Handling


PRODUCT: Alcobaca Portugal broad beans and fava beans, canned,
at Milford, Ill. (C.D. Ill.); Civil No. 92-2195.

CHARGED 6-30-92: While held for sale after shipment in interstate
commerce at the Fremont Company, in Milford, Ill., the articles were
adulterated in that they consisted of insects and insect-damaged
beans--402(a)(3). The articles were also adulterated in that they were
prepared and packed under insanitary conditions whereby they might have
become contaminated with filth--402(a)(4).

DISPOSITION: A default decree of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 66443; S. No. 92-610-596; S.J. No.
1)


PRODUCT: Flounder fillets, frozen, at Newport News, Va. (E.D. Va.);
Civil No. 4:95CV00125.

CHARGED 9-6-95: While held for sale after shipment in interstate
commerce at Top Quality Seafood, Inc., in Newport News, Va., the
articles were adulterated in that they consisted of decomposed
fish--402(a)(3).

DISPOSITION: A consent decree of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 67104; S. No. 95-733-868; S.J. No.
2)


PRODUCT: Fresh plate fish, frozen, at Columbus, Ohio (S.D. Ohio); Civil
No. C2-89-125.

CHARGED 2-13-89: While held for sale after shipment in interstate
commerce at Interstate Cold Storage, Inc., in Columbus, Ohio, the
articles were adulterated in that Smooth Oreo Dory was substituted for
Orange Roughy--402(b)(2). The articles were misbranded in that they were
offered for sale under the name of another food, and labeling failed to
bear the common name of the food--403(b) and 403(i). The articles were
also misbranded in that their labeling was false because the food was
labeled as Orange Roughy when it was Smooth Oreo Dory--403(a)(1).

DISPOSITION: The articles were donated to a charitable organization.
(F.D.C. No. 65619; S. No. 89-547-961; S.J. No. 3)


PRODUCT: Raisins, at Selma, Calif. (E.D. Calif.); Civil No.
CV-F-94-5689-GEB-SSH.

CHARGED 7-5-94: While held for sale after shipment in interstate
commerce at American Raisin Packers, Inc., in Selma, Calif., the
articles were adulterated in that they consisted of insects, insect
fragments, insect cast skins, and feather barbules--402(a)(3). The
articles were misbranded in that they were manufactured from two or more
ingredients, and their label failed to bear the common name of each
ingredient--402(i)(2).

DISPOSITION: A consent decree ordered the articles destroyed. (F.D.C.
No. 66984; S. No. 94-705-349; S.J. No. 4)


PRODUCT: Shrimp, frozen, at Tampa, Fla. (M.D. Fla.); Civil No.
95-1877-Civ-T-23(A).

CHARGED 11-14-94: While held for sale after shipment in interstate
commerce at Seaboard Cold Storage, in Tampa, Fla., the articles were
adulterated in that they consisted of decomposed shrimp--402(a)(3).

DISPOSITION: A consent decree of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 67111; S. No. 95-713-265; S.J. No.
5)



Drugs/Human Use

PRODUCT: Broncho saline, sterile, at Evansville, Ind. (S.D. Ind.); Civil
No. EV-91-83.

CHARGED 6-18-91: While held for sale after shipment in interstate
commerce at Blairex Laboratories, Inc., in Evansville, Ind., the
articles were adulterated in that they were unapproved new
drugs--505(a). The articles were misbranded in that they were
represented to be a drug, sodium chloride inhalation solution, which is
recognized by the U.S. Pharmacopeia, but they were not packaged and
labeled in single-dose containers as required by the U.S.
Pharmacopeia--502(g).

DISPOSITION: A consent decree of condemnation ordered the articles
destroyed. (F.D.C. No. 66083; S. No. 91-555-243/244; S.J. No. 6)



Medical Devices

PRODUCT: Thor of Genesis I, vibrational sound instrument, at South
Euclid, Ohio (N.D. Ohio); Civil No. 1:93CV1724.

CHARGED 8-17-93: While held for sale after shipment in interstate
commerce at the Window of Mind Bookstore in South Euclid, Ohio, the
article was adulterated in that it was a class III device without an
application for premarket approval--501(f)(1)(B). The article was
misbranded in that its labeling was false and other information
regarding the article was not provided as required--502(a) and (o).

DISPOSITION: The article was destroyed. (F.D.C. No. 66704; S. No.
93-670-674; S.J. No. 7)




INJUNCTION ACTIONS

DEFENDANTS: Big E Industries, Rio Arriba Minerals, Inc., Action Trading
Company, Inc., and Harvey L. Earles, at Oklahoma City, Okla. (W.D.
Okla.); Civil No. Civ-89-957-W.

CHARGED 5-31-89: The defendants introduced and delivered into interstate
commerce adulterated industrial grade/inedible oils and blended feeding
fat--301(a). The industrial grade/inedible oils were adulterated in that
statements warning of their inferior quality were removed--301(k). The
defendants also adulterated blended feeding fat, which is used as an
ingredient in animal feeds, in that it was unfit for food and its
inferior quality was concealed--402(a)(3) and 402(b)(3).

DISPOSITION: The parties were ordered by the court to enter into an
agreement calling for written standard operating procedures. The company
subsequently was found to be in compliance with the court's order. (Inj.
No. 1207; S. No. 89-527-364/367; S.J. No. 8)



DEFENDANT: Frank Gasper, at Tulare, Calif. (E.D. Calif.); Civil No.
96-5443-REC DLB.

CHARGED 4-29-96: The defendant introduced or caused to be introduced
into interstate commerce adulterated calves for slaughter for use as
food--301(a). The calves were adulterated in that they contained unsafe
new animal drugs--402(a)(2)(D). The calves were also adulterated in that
they were held under insanitary conditions whereby they might have been
rendered injurious to health--402(a)(4).

DISPOSITION: A consent decree of permanent injunction was filed. The
defendant later was found to be in compliance with the decree. (Inj. No.
1392; S. No. 95-753-841; S.J. No. 9)



MISCELLANEOUS ACTIONS

ACTION: Henley v. FDA, at Mineola, N.Y. (2d Cir.); Civil No. CV 93-5389.

CHARGED 11-26-93: Plaintiff-appellant requested that FDA require oral
contraceptive manufacturers to include in the labeling of their product
the following warning statement: "Estrogen has been shown to cause
cancer in animals." FDA denied the petition and a subsequent petition
for reconsideration. The district court granted a summary judgment in
favor of the defendant and denied the plaintiff's cross-motion for
summary judgment.

DISPOSITION: Plaintiff appealed. The appellate court affirmed the
district court's ruling. Plaintiff did not file a petition for
certiorari. (Misc. No. 1016; S.J. No. 10)



ACTION: Public Citizen, Inc. v. DHHS, et al., at Washington, D.C.
(D.D.C.); Civil No. 1:94CV02338.

CHARGED 10-28-94: Plaintiff charged that FDA had unreasonably delayed
publishing regulations under the Safe Medical Devices Act of 1990.

DISPOSITION: While in litigation, three of the four regulations the
plaintiff was suing over were published--510(k) summary/statement, civil
money penalties, and medical device reporting. Plaintiff lost on the
remaining claim relating to postmarket surveillance. Plaintiff was
awarded a settlement under the Equal Access to Justice Act. (Misc. No.
1075; S.J. No. 11)


------------------------------------------------------------------------
Correction:
S.J. No. 5 in the April 1996 FDA Consumer Summaries of Court Actions
stated (in the Disposition) that Duramed Pharmaceutical entered into a
consent decree of permanent injunction. The consent decree was
subsequently dissolved by the U.S. District Court for the District of
Maryland on Jan. 2, 1996.

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

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

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