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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