Friends , this is a good article from the NY Times :
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October 12, 1999
Too Much of a Good Thing? Doctor
Challenges Drug Manual
By DENISE GRADY
W hen doctors need information about what dose of medicine to
prescribe, they usually consult a fat navy blue book called
the
Physicians' Desk Reference -- P.D.R. for short -- which is an
extensive
compilation of data about drugs from their manufacturers.
But the doses recommended in the P.D.R. may be too high for many
people and may cause adverse reactions, ranging from dizziness and
nausea all the way to death, according to an article published last
month
in the journal Postgraduate Medicine. For many drugs -- including
Viagra, Prozac and some medicines used to treat high blood pressure,
allergies, insomnia and high cholesterol -- smaller doses would work
just
as well as the standard ones, with far less risk of bad reactions,
said the
author of the article, Dr. Jay S. Cohen, an associate professor of
psychiatry at the University of California at San Diego.
"Side effects drive a lot of people
out of treatment that they need,"
Dr. Cohen said, noting that
people with chronic conditions
like high blood pressure,
headaches and depression often
give up trying to treat their
illnesses when they find that the
cure is worse than the disease.
But if doctors were to
individualize dosages for each
patient, more people might take
their medicine.
Dr. Cohen said he became
aware of the problem because he
encountered many patients who
suffered from side effects even
though they had taken what were
supposedly the correct doses of
medicine. When Dr. Cohen
consulted medical journals and
textbooks, he discovered studies
showing that many patients were
helped by smaller than usual
amounts of medication. And
many of his own patients did
better with reduced doses.
He said his findings helped
explain a study published last
year by other researchers, who reported that drug reactions in
hospitals
were among the nation's leading causes of death, killing more than
100,000 Americans a year. The deaths that the team studied were not
due to medication errors by doctors or patients; they occurred in
people
taking doses thought to be correct.
But Dr. Cohen thinks many of the patients died because they were
taking
too much medicine: the "correct" doses were too strong for them.
People
vary greatly in their sensitivity to drugs, he said, and one
person's remedy
may be another's overdose. Although weight, age and sex help
determine
how a dose of medicine will affect someone, it is also possible for
two
people who are identical in those traits to react quite differently
to the
same dose of the same drug. Dosing guidelines from drug companies
may
be right for most people, but too high for "large subsets of
patients," Dr.
Cohen said.
Dosing guidelines generally tend to be too high because they are
based
on studies conducted in limited numbers of patients by drug
companies
when they are seeking approval for new products, Dr. Cohen said. For
those studies to run efficiently, doses need to be high enough to
show as
quickly as possible that the drug works. But later, after the drug
is
approved, far more people take it, sometimes along with other drugs,
and individual differences begin to show up. That information does
not
always make it into the P.D.R., Dr. Cohen said.
Dr. Peter Honig, deputy director of the office of postmarketing risk
assessment at the Food and Drug Administration, said, "We learn a
lot
about a drug after it's been approved. I think we would agree with
that. I
think he makes some good points. Individualized dosing is the way to
go.
But it's not well taught in medical school."
Dr. David Bates, an associate professor of medicine at the Harvard
Medical School, called Dr. Cohen's idea an interesting hypothesis.
"In the elderly, it's clear that you want to start with lower
doses," said Dr.
Bates, who has written about adverse reactions for medical journals.
"In
them in particular it's quite clear that you get in trouble if you
use a 'one
size fits all' dosing, which doctors have tended to do. It may well
be for
younger people, too, that there's considerable variability in the
way drugs
are broken down."
Doctors are taught to "start low, go slow," Dr. Bates said, when
prescribing medicines for people over 60 or 65, but that the advice
may
apply to younger patients as well.
Dr. Raymond Woosley, chairman of the department of pharmacology at
Georgetown University in Washington, called Dr. Cohen's article "an
outstanding paper, and a very important message."
Dr. Woosley named several drugs with recommended doses that he
considered too high, including Viagra and the over-the-counter
allergy
medicine Chlortrimeton. In addition, he said, the AIDS drug AZT was
first marketed at doses that turned out to be far too high and that
had to
be reduced.
Dr. Cohen said doctors might identify some people at risk for
reactions
by asking patients whether they had ever had an adverse reaction to
a
drug and whether they considered themselves unusually sensitive to
medications or prone to side effects. Having a strong reaction to a
little
bit of alcohol or caffeine may also be a clue that a patient will be
very
sensitive to medicines, he said.
Drugs that have caused trouble in the past should be avoided, he
said,
and people who seem very sensitive to medicines can be started on
low
doses, which can be gradually increased if necessary. Some pills,
but not
capsules, can be cut to fine-tune doses.
But Dr. Woosley said that in his experience a bad reaction to one
medicine could not be used to predict how a patient would fare with
others.
Dr. Cohen cautioned that patients should not begin tinkering with
doses
of prescription drugs on their own. He said they needed to work with
doctors to adjust the doses safely. With some drugs, doses cannot be
changed: for example, antibiotics, antivirals and other medications
used to
treat infections must be taken full strength, according to the
directions on
the label. And in emergencies, he said, it is always safest to stick
with the
recommended doses.
A spokesman for Medical Economics Inc., publisher of the P.D.R.,
said
that the information in the book was supplied by drug manufacturers
and
approved by the Food and Drug Administration.
Dr. Carl Peck, a former director of the Center for Drug Evaluation
and
Research at the Federal drug agency, said, "One dose fits all is a
marketing myth, but it's the holy grail that every drug company
tries to
achieve."
While at the drug agency, Dr. Peck conducted a study that showed
that
some drugs did come to market from 1980 to 1993 with dosing advice
that had to be lowered. But, he said, that is less likely to occur
today
because during the last decade drug manufacturers have begun to
study
ranges of doses in the trials done before drugs are approved.
Some newer drugs, like cholesterol lowering agents and a nose spray
for
allergies, come with labeling that gives a recommended dose range
and
advises doctors to try to find the lowest effective dose. Dr. Peck
is now
director of the center for drug development science at the
Georgetown
University Medical Center.
"The whole issue of getting the dose right has become an important
focus
for the F.D.A.," Dr. Peck said, "and I think the F.D.A. and the drug
companies are making a good-faith effort to do better these days."
Copyright 1999 The New York Times Company
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