Pharmacogenetics
is the science and study of drugs and their administration in relationship to
genetics.It deals with genetic
predisposition to drug reactions, effectiveness of drug treatments on
individuals depending on genetic predisposition, and with prediction of disease
susceptibility based on genetic profile.With
advancements in scientific technology, Pharmacogenetics is becoming increasingly
important both in administration of medication and the treatment of disease. Back to top
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History
Genetic sensitivity to certain substances has been
long-recognized.For example, the
susceptibility to alcohol by certain ethnic groups was observed well over a
hundred years ago, even if the observers weren't aware that genetic inheritance
was the reason.The actual
science of Pharmacogenetics began in earnest in the 1950s, however, in an effort
to isolate genetic differences in metabolizing drugs. Before technology allowed the isolation of various genes, the subject was
based on ethnic variation, and variation in drug response was based on studies
of ethnic populations.These
studies were first carried out mainly by chance or just because investigators
were curious about how one race compared to another in response to a drug.Eventually, the collected data showed that this should be a standard part
of any drug development process.
The first pharmacogenetic trait to be observed as such was a
"taste blindness" to a chemical called phenylthiourea (PTU).Individuals with a certain gene profile could not taste the chemical,
while others could.It was the first chemical insensitivity shown to be
hereditary, and incidence widely varied within ethnic population groups, leading
scientists to an early understanding that there were racial definitions for
genetic differences.More
importantly, it was also an early indication that one could not assume
percentages of genetic differences would be the same from race to race.
Since the 1950s, there has been a rush of new technologies
combined with a new genetic approach so that variations could be isolated on a
person-to-person level.
One broad application of Pharmacogenetics is to oncology (the
study and treatment of cancers).One
early example of Pharmacogenetics in oncology appeared back in 1988, when The
Journal of Clinical Investigation reported on the case of a 40-year-old woman
being treated for breast cancer.The
woman almost died from what was then regarded as a standard dose of a
chemotherapy agent.It was then
discovered she possessed a genetic defect which made it difficult for her to
metabolize such agents.An
understanding of the Pharmacogenetics behind the drug response led to an entirely
new approach to treatment, and today, it is widely understood the reactions to
cancer treatments can vary widely from patient to patient.
The technology now exists to test for many genetic
differences, called polymorphisms, which show how individuals will
metabolize medications. Back to top
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Drug Metabolism
The discovery of differences in drug metabolism is leading
to a whole new way of patient evaluation prior to medication.For example, a drug called warfarin, a blood-thinning agent used to
combat blood clotting, can have a drastically negative reaction on poor
metabolizers of the drug -- and it is now estimated that one percent of the U.S.
population falls into this category.Genetic
testing will discover how a patient will metabolize warfarin, and due to the
potential adverse reactions, lack of such testing on a potential patient can be
fatal.
Another example, one which is obtaining more and more
attention at present, is testing for variations in a category of enzymes known
as P450.This group is responsible
for the metabolizing of one-fourth of all prescription drugs, and variations in
these enzymes can make enormous differences in patient reactions to various
medications.The enzyme variations
have genetic causes, and can be found by genetic evaluation.
Administration of certain drugs in the absence of genetic
testing for P450 variations has produced a number of adverse drug reactions,
some of them fatalities.In 2000, a
nine-year-old boy diagnosed with attention-deficit-disorder,
obsessive-compulsive disorder, and Tourette's disorder and treated with a number
of different drugs including Eli Lilly's controversial anti-depressant Prozac,
died from cardiac arrest.An
autopsy revealed concentrations of medication several times higher than expected
based on overdose qualifications, and the medical examiner's report indicated
death caused by fluoxetine toxicity (fluoxetine is the chemical name of Prozac).Further genetic testing of autopsy tissue revealed the presence of a gene
defect in regards to an enzyme in the P450 group known as CYP2D6 which causes a
poor metabolism of fluoxetine.Had
genetic testing been in place, the boy's death would have been prevented.Since that time, there have been two lawsuits against Eli
Lilly and Company regarding their lack of information on the danger of this same
genetic defect from families of victims.
Since adverse reactions to many drugs can now be predicted
by genetic testing, doctorsneed to
integrate genetic testing for adverse drug reaction into their normal evaluation
process for treatments or risk malpractice suits.Patients who are conscious of their safety also need to demand
these tests. Back to top
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Other Impacts of
Pharmacogenetics
In addition to preventing adverse drug reactions,
Pharmacogenetics is also evolving into use in the drug-development process.One goal of Pharmacogenetics is "new drug targets", meaning
defects or potential illnesses revealed by genetic analysis that can be targeted
by new drugs.This would also
include predispositions to certain illnesses shown by genetic analysis
potentially prevented by new drugs.
Another use of Pharmacogenetics is testing for reaction to
environmental toxins.This is
especially useful today, when many areas have high carcinogenic (cancer-causing)
agents.A person tested for
susceptibility (or immunity) to such agents could determine the safest place for
them to live a long, normal life. Back to top
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Impact on
Health Care
Since millions of people the world over depend on managed
health care, these corporations are beginning studies on incorporation of
genetic testing into normal medical treatment.Since genetic testing is relatively new, cost will play a factor in
managed health care corporations' adaptation of it.Yet ignorance or avoidance of genetic testing or inclusion of
it as part of covered treatment will cost managed health care many more millions
in lawsuits than inclusion of it. Back to top
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As with any science,
plays a factor.Money, unfortunately, is the primary motivation for corporate survival,
and new drugs can make lots of money.The
scientific community, the FDA, and like approval agencies elsewhere in the world
must demand proof that a certain genetic defect exists before allowing a
drug to treat the malady that the defect purportedly causes.
Abuses of genetic analysis can lead to whole segments of
the population being misdiagnosed and having "treatment" forced upon
them that may not be required.This
can also lead to stigmas and other social and individual problems. Back to top
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Conclusion
The ramifications of Pharmacogenetics are manifold, but
probably the most important breakthrough is the ability to screen potential
recipients of medication for potential adverse reactions.As with any technology, it must be adapted applied before it will
work.It will likely involve
patient demand that both doctors and managed health care organizations quickly
come on board with Pharmacogenetics. Back to top
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Anti-Depressants and ADHD Treatments:
The Serious Danger of Poor Metabolism
In late 2002, a lawsuit was filed in the U.S. District
Court in Georgia on behalf of William H. Shell, widower of LaVerne M. Shell,
against Eli Lilly and Company, developers and marketers of Prozac
anti-depressant medication.Mrs.
Shell had shot herself to death at the age of 63, 11 days after starting on a
prescription of Prozac to treat migraine headaches.
What happened to Mrs. Shell could also happen to you, so it
is very important that you understand this information. Back to top
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CYP2D6
An Enzyme You Need to Know About
An enzyme is a chemical in the body that breaks down food,
liquids, drugs, or anything else ingested, through a process called metabolism.There are many different types of enzymes, but there is only one enzyme
that primarily makes it possible to break down more than a quarter of all
prescription drugs, including virtually all anti-depressants and ADHD
treatments.This enzyme is called CYP2D6. Back to top
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The First Danger
According to current statistics, roughly 10% of the
population has a poorly functioning version of this enzyme.That means that any drug that uses this metabolism “pathway” will not
be metabolized.It will simply build up in the body, making a person very
sick or even killing them.Because
of the resulting high concentration, it can also raise side-effects markedly,
making violence and suicide very real possibilities.
This is what happened to LaVerne Shell.Her doctor failed to diagnose her as a “poor metabolizer” of drugs
such as Prozac, and so issued her the wrong dosage.The result was her suicide.But
the doctor was not to blame in this case, as the drug’s manufacturer, Eli
Lilly and Company, had failed to publish any information on this danger.
Before you begin taking any anti-depressant or ADHD
treatment, or before you allow such a drug to be given to your child, insist that
you or your child are tested for a properly-functioning CYP2D6 enzyme.
We’ll warn you ahead of time that your doctor may not be
aware of this problem.Many are
not.In fact, we suggest that you
take this article to your doctor, and advise him or her to check the
Physician’s Desk Reference for the drug they are prescribing -- they will find
the details there.If your
doctor still insists that this isn’t a problem and that the test isn’t
needed, we suggest you find another doctor.Or, advise the doctor that in the case of a drug-related problem he or
she could be successfully sued for malpractice.
But the danger doesn’t stop there, and you will want to
be fully informed before you proceed further. Back to top
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The Second Danger
Although still largely unknown, the above information on
the CYP2D6 enzyme is now being published (following several lawsuits) by the
manufacturers.
But there is further danger that has yet to be made broadly
available.And for good reason:If warned with this information, most people wouldn’t take these drugs
at all.
According the Physician’s Desk Reference, the bible for
dispensing medications by doctors, any drug which uses the CYP2D6“pathway” will actually inhibit it and will turn a person who
is a “normal metabolizer” into a “poor metabolizer” while they are
taking the drug.
If this sounds wild or incredible, that’s because it is.
This means that one of these drugs, administered to a
“normal metabolizer” will, after a period of time, cause the person to be
come a “poor metabolizer”.The
drug -- or any other drug in this category given simultaneously or
shortly thereafter -- will then begin to build up in the system, as it would in
someone who is natively a “poor metabolizer,” putting the person at the very
same risk. Back to top
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Don’t Put Yourself in Danger
Before taking any anti-depressant or ADHD treatment, or
before having such administered to a child or relative:
1.Fully
investigate the drug and the disorder it seeks to “cure.”There are many alternative treatments out there which require no
drugs, let along dangerous drugs.
2.If you are considering an anti-depressant or drug to treat ADHD, make
sure you have yourself or the potential recipient of the drug tested for a
poorly-functioning CYP2D6 enzyme.
3.Following #2, if you decide to have the drug administered, remember that,
due to the fact these drugs inhibit the CYP2D6 pathway, toxic buildup is
inevitable.Watch
side-effects very
carefully, and report any abnormalities to your doctor immediately.
Eli Lilly loses
Prozac suit due to CYP2D6 enzyme. Click here
