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Lethal Drug Sensitivities:
Test Could Tailor Drugs for Individuals

Updated 4:59 PM ET June 5, 2000

Doctors accused her of being a hypochondriac:
The woman suffered dizziness and a racing heartbeat from each
antidepressant she tried, even though she was taking doses normally
far too low to cause side effects.

The desperate woman finally saw Dr. Raymond Woosley, who scanned
her DNA with a special "gene chip" and discovered she actually has a
genetic quirk that makes her super-sensitive to certain medicines.

She's lucky: Some people die while taking some of the world's most
popular drugs - from antibiotics to heartburn remedies - all because
no one knew their genes made them uniquely susceptible to devastating
side effects.

That's about to change. A new science called "pharmacogenomics"
aims to curb the problem by replacing today's one-dose-fits-all culture
with simple tests to help doctors customize prescriptions, picking the
safest, most effective drug for each patient's DNA.

Already, Woosley and colleagues are testing the new technology at
Georgetown University Medical Center.

Just swab the inside of a patient's cheek for a DNA sample, and
run it over a tiny glass gene chip the size of a postage stamp.

The chip detects an errant enzyme system called p450 [paraoxonase]
that affects how safely people metabolize dozens of popular medicines.

[Paraoxonase is the enzyme that is responsible for the detoxification
of organophosphate pesticides and some 50 other common prescription
and over-the-counter drugs.  Please see  the page: Dr. Furlong's Research:
Sensitivity to Organophosphates Due to Enzyme Paraoxonase (PON1)

P450 testing is so successful that Woosley just launched an international
registry, closely watched by the Food and Drug Administration, to
investigate other gene variations that make some people collapse
with a lethal irregular heartbeat after taking any of 50 common drugs.

And some companies are poised to begin offering, possibly within
the next year, the first direct-to-consumer pharmacogenomic testing.
The idea: Instead of waiting for gene chips to reach your doctor's office,
just send a cheek swab to a gene-testing laboratory to see if you're at
risk from certain drugs, explains Josh Baker, president of PPGx Inc.,
one company hoping to offer consumer testing. Then give the test
results to your doctor.

"It's very clear this concept works," says Woosley, a clinical
pharmacologist and heart specialist. New research to pinpoint
who's at risk "is some of the most exciting stuff I've ever seen."

Even the best medicines don't help everyone. Drugs are sold after
they prove an effect on the average disease sufferer, not every individual.
So there's little way to know who's wasting time on treatment that will
fail, and who will suffer side effects.
Some 2 million Americans are
hospitalized annually for side effects, and 100,000 die.

Pharmacogenomics aims to improve that.

This is not your standard gene test. It doesn't reveal disease-causing
gene mutations.
Instead, tests hunt subtle genetic variations called polymorphisms that can determine reactions to medications.

Take p450, the best-known family of drug-processing enzymes. An
estimated 7 percent of Americans lack certain p450 enzymes, allowing
some drugs to climb to toxic levels in their bodies. Other people's
p450 enzymes work too fast, clearing a drug out of the bloodstream
too fast for it to fight disease.

P450 isn't the only concern. Leukemia specialists are starting to test
patients for another enzyme deficiency that makes the standard dose
of a children's leukemia therapy called mercaptopurine far too high
for their bodies.

Also, 50 common drugs [and organophosphate pesticides]
occasionally cause a lethal irregular heartbeat.

Patients' hearts first exhibit a rhythm change called "long QT interval"
before going into the arrhythmia with the unwieldy name "torsades
de points."

Some genes can spur this problem by making drugs 10 times more
potent at blocking heart relaxation channels, Woosley said.

His lab just launched an international effort to research survivors and
create gene chips to test patients for the risk before they take a new drug.
Doctors, or torsades survivors, can check to

Gene chips will take several more years to hit the market. But PPGx
and other labs today can find gene-drug interactions through standard,
cheap gene-test methods - they already provide p450 and other enzyme
tests for drug manufacturers. Consumers very soon will demand such
tests, too, Baker predicts.

"If they shouldn't take a drug, they should know. I know I would
want to know."

~~~EDITOR'S NOTE - Lauran Neergaard covers health and medical
issues for The Associated Press in Washington.


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