Re: One Person's Cure ??? - Another's Poison (2nd attempt to send to Suzy)

April 16, 2002

Hi Suzy and Dawn,

Something is weird with those messages you sent Dawn. I was unable to

view them at work (there was a big black box where the text should

have been) but when I came home I was able to view them perfectly

(except for that annoying advert laying over the top of the

first paragraph). So it must have something to do with how mine and

suzy's systems are set up to receive the way your messages were sent.

> Hi Suzy,

>

> Again, in your response to me saying the page is blank, the

document really

> is there on my side!!! Must be a phantom document!!! I've copied

and

> pasted it here in a different text version. Hopefully this will

come

> through OK... Let me know if it doesn't.

>

> Dawn

>

> One person's cure can be somebody else's poison. To find out which

drug is

> right for you, reports Schmidt, doctors may soon turn to

genetic

> testing

> AFTER much suffering, a deeply troubled young woman drags herself

to her

> doctor for help. The doctor diagnoses severe depression and says

> reassuringly, " Now we'll just test your DNA to see what meds will

work best

> for you, " as he reaches over and plucks a hair from her head. " When

we get

> the results this afternoon, I'll call in a prescription and you'll

soon be

> feeling better. " For the first time in a long time, she smiles

hopefully.

> Such a scenario may not be far off. According to many

pharmaceuticals and

> biotech companies, patients could soon be taking drugs tailored to

their

> genetic makeup, saving time and bundles of money now wasted on

ineffective

> treatments, as well as minimising debilitating side effects. Today

doctors

> would tell this young woman to try a medication-say, Prozac-and

then wait

> four to six weeks to find out whether she is one of the lucky 40

per cent

> the drug helps. It might take another six months and four different

drugs

> before she finds the best treatment for her depression. A quick

genetic test

> to replace this torturous trial-and-error would mean " a big

improvement in

> the way patients get treated " and lower healthcare costs for

society at

> large, says Cohen, a geneticist at a Paris-based genomics

company

> called Genset.

> That's the promise of pharmacogenomics, an emerging science that

aims to

> describe at the genetic level precisely why some people respond

well to

> certain drugs and others don't. Such information will be used to

create

> diagnostic tests to help select the right drugs for each patient.

In some

> cases, this gene-based approach may even save lives by identifying

people

> who are likely to develop a fatal reaction to a drug.

> Pharmacogenomics will be part of " the next revolution in medicine, "

says

> Francis , director of the National Human Genome Research

Institute

> near Washington DC. Doctors will soon routinely test patients to

ensure that

> the drugs they take really are the best for them, he predicts.

> But consumers aren't the only ones who stand to benefit

from " personalised

> medicine " . Pharmacogenomics should also boost corporate profits:

biotech

> companies expect to sell genetic test kits, and drugs companies

hope to

> increase the number of medications that survive clinical trials and

make it

> to market. " If we could identify who will strongly benefit [from a

drug], we

> could promote it to a defined segment of the population; that

should also

> make it easier to show it's safe and effective, " says Spear,

director

> of pharmacogenetics at Abbott Laboratories in North Chicago. In

fact, drugs

> companies have already begun collecting DNA samples from people who

take

> part in their clinical trials. One day they hope to find a genetic

pattern

> that will distinguish people who might be helped by a drug from

those the

> drug might harm.

> The prospect of developing customised medicines drew corporate

researchers

> to New York for a conference on pharmacogenomics last month and the

topic

> was recently the subject of a special issue of Nature Biotechnology

(vol 16,

> supplement). But people like Haseltine, head of Human

Genome

> Sciences in Rockville, land, wonder whether such enthusiasm may

send

> drugs companies heading off down the wrong path, spurred on in part

by

> exuberance over new technologies for rapidly cataloguing and

comparing the

> minute genetic variations of large numbers of people.

> Haseltine fears that the focus may shift from finding the right

drugs to

> treat individuals to pinpointing the people who are " genetically

right " for

> the drugs pharmaceuticals companies want to sell. Such screening

might leave

> a significant portion of the population medically out of

luck. " That's not

> where we want to go, " he says. " We still want new drugs that treat

as many

> people as possible. "

> Genset's Cohen disagrees. " Humans are polymorphic and diseases are

also, " he

> says. " Pharmaceuticals companies dream of a drug that treats

everyone, but

> life is such that this is not possible. "

> Skilled physicians have always understood that individual patients

respond

> to drugs differently. And many factors contribute to this broad

variability.

> Age, gender, health status and whether the person is taking other

drugs all

> dictate whether a drug will work and what its side effects might

be. But

> it's now clear that genes have a considerable influence over how

someone

> reacts to a drug. Individuals inherit specific versions of enzymes

that

> affect how they metabolise, absorb and excrete drugs. So far,

researchers

> have identified several dozen enzymes that vary in their activity

throughout

> the population and that probably dictate people's response to drugs-

which

> may be good, bad or sometimes deadly.

> Adverse drug reactions caused more than 100 000 deaths in the US in

1994,

> according to a recent article in The Journal of the American

Medical

> Association (vol 279, p 1200). Perhaps more frightening is that

these

> reactions often occur in patients receiving a standard dose of a

particular

> drug. As an example, doctors in the 1950s would administer a drug

called

> succinylcholine to induce muscle relaxation in patients before

surgery. More

> than a few patients, however, never woke up from anaesthesia-the

compound

> paralysed their breathing muscles and they simply suffocated.

Doctors

> discovered that these unfortunate patients had inherited a mutant

form of

> the enzyme that clears succinylcholine from their system.

> The drugs don't work

> And that's not the only time genes have been implicated in a toxic

drug

> response. As early as the 1940s doctors noticed that a good number

of

> tuberculosis patients treated with the antibacterial drug isoniazid

would

> feel pain, tingling and weakness in their limbs. These patients

were

> unusually slow to clear the drug from their bodies-isoniazid must

be rapidly

> converted to a nontoxic form by an enzyme called N-

acetyltransferase. The

> " slow acetylator " phenotype isn't exactly rare-40 to 60 per cent of

> Caucasians have a less active form of the enzyme than " rapid

acetylators. "

> Again, this difference in drug response, it was later discovered,

is due to

> differences in the gene encoding the enzyme.

> In the past few years, researchers have also found that variations

in

> certain genes can determine whether a drug treats a disease

effectively. For

> example, a cholesterol-lowering drug called pravastatin won't help

people

> with high blood cholesterol if they have a common gene variant for

an enzyme

> called cholesteryl transfer protein (CETP). And several studies

suggest that

> the version of the ApoE gene that is associated with a high risk of

> developing Alzheimer's disease in old age goes hand in hand with a

poor

> response to an Alzheimer's drug called tacrine.

> This is where pharmacogenomics might be able to help. Right now,

doctors can

> run tests to determine whether a patient is likely to react badly

to a

> handful of drugs. However, these tests usually measure a phenotype-

such as

> the amount of enzyme activity in a person's blood-rather than which

form of

> a gene a person has. For instance, doctors can use an enzyme test

developed

> by researchers at the Mayo Medical School in Minnesota to determine

which

> dose of 6-mercaptopurine to give children with leukaemia. About 1

in 300

> Caucasian children have severe-often fatal-reactions to this

chemotherapy

> because the enzymes they need to metabolise and detoxify the drug

are

> defective. So physicians around the world send blood samples to a

lab-the

> Mayo Clinic analyses nearly 1000 a year-to determine whether it's

best to

> give a child a full dose or as little as one-fifteenth of the

normal

> prescription.

> Such tests for phenotype are fine for identifying people who may

have bad

> reaction to a drug because they lack certain enzymes. But

identifying people

> whose cholesterol can't be lowered by pravastatin treatment, for

example, is

> not so simple. Although toxic reactions often involve defects in

single

> genes, good or bad treatment responses are likely to be determined

by

> multiple genes, says Roses, head of worldwide genetics

research for

> the British-based drugs giant Glaxo Wellcome. And the more genes

involved,

> the more possible combinations will need to be tested before the

best

> treatment can be prescribed. That's why researchers are turning to

the power

> of pharmacogenomics to look directly at the variations in the genes

> themselves. By comparing the genetic profiles of people who respond

well

> with those who have a bad reaction to a drug, scientists should be

able to

> identify the genes involved, and which versions lead to the best

outcome.

> Recent advances in rapid gene sequencing and the statistical

comparison of

> data collected from large populations are now making such studies

possible.

> With laboratories all over the world churning out massive amounts

of human

> DNA sequence, researchers can now focus on finding the hot spots in

human

> chromosomes that vary in sequence from person to person and then

look to see

> whether these are related to differences in drug response. The US

Human

> Genome Project-part of the international effort to sequence all 3

billion

> base pairs of DNA in the human genome-aims to discover and map 50

000 to 100

> 000 of these hot spots, called SNPs (single nucleotide

polymorphisms,

> pronounced " snips " ).

> To chart these tiny differences in an individual's DNA, many

researchers are

> turning to a new tool called a SNP chip, a tiny microarray studded

with

> genetic variations commonly found in human chromosomes (see " Speed

freaks " ,

> p 46). A technician prepares a solution containing a patient's DNA.

When

> this sample is washed over the chip, gene fragments that match the

SNP

> sequences bind to the chip and fluoresce. A computer then analyses

the

> resulting pattern, determining which variations are present in the

patient's

> genes. Researchers then tally the variations present in two

different groups

> of people-say, people who have a good or a poor response to a drug.

With the

> help of sophisticated new statistical techniques that can

simultaneously

> compare thousands of SNPs from thousands of patients, scientists

look for

> associations between particular SNPs and different responses to

drugs. By

> mapping out the location of these SNPs, researchers can generate a

trail

> that will lead them to the genes involved in drug response.

> Abbott Laboratories and Genset have teamed up to do just that.

Genset has

> put together a rough SNP map of the human genome and Abbott has

collected

> DNA samples from people in clinical trials for zileuton, its asthma

drug.

> Genset is now analysing these DNA samples and looking for

differences that

> may reveal which genes control a person's response to zileuton, a

drug that

> can damage the liver in 3 per cent of patients. Their study may

eventually

> lead to a simple test to filter out patients who might not respond

well to

> the drug.

> Tailored therapies

> Soon SNP chips may be available for use in clinics, an advance that

would

> mark the real beginning of " personalised medicine " based on gene

screening.

> Affymetrix, a biotech company in Santa Clara, California, has

developed a

> chip to detect 12 different variants of two genes that encode the

cytochrome

> P450 enzymes. This family of enzymes is involved in the metabolism

of at

> least 20 per cent of all commonly prescribed drugs, including the

> antidepressant Prozac, the painkiller codeine, and high-blood-

pressure

> medications such as captopril. In the near future, clinics may use

the chip

> to determine the correct drug dose to give a patient, says

Lipshutz,

> vice-president of corporate development at Affymetrix.

> Before they can even think about matching the right drugs with the

right

> patients, though, drugs companies will have to find out during

clinical

> trials who will be compatible with a product and who will not. Many

> companies, such as Glaxo Wellcome and Abbott, have begun collecting

DNA

> samples from people taking part in their clinical trials. But

Glaxo, for

> one, is holding onto the DNA until a SNP map of the entire human

genome

> becomes available. Then they will look for a recognisable overall

pattern in

> the people who respond well or badly to each of their products.

> Theoretically, doctors would not even have to understand how or why

patients

> respond to certain drugs, says Glaxo's Roses. They'd just identify

the good

> responders and give them the drugs that DNA tests indicate should

work best.

> Haseltine, for one, is sceptical of Roses's suggestion that

physicians might

> prescribe drugs, based on gene testing, without understanding why a

patient

> might respond well or poorly to the treatment. These new DNA

diagnostic

> tests are not yet fully understood or even 100 per cent accurate,

he notes.

> A patient whose treatment doesn't work-or worse, makes him sick-

might sue.

> " I don't think any pharmaceuticals company would do it because of

> liability. "

> And in the end, many pharmaceuticals companies may be more

concerned with

> profit margins than with public health. Indeed, if the goal were

truly to

> reduce adverse drug reactions, many simple tests could be developed

now,

> says Nebert, a human geneticist at the University of

Cincinnati. For

> example, a genotype test could be developed to detect slow

acetylators

> because the genes and their variations are known. Says Nebert, " You

could

> pick up 95 per cent of slow acetylators with just a couple of DNA

tests. "

> And it would truly save lives, he says. If a slow acetylator

receives

> procainamide, a drug commonly used after a heart attack, the

patient has a

> 60 per cent chance of developing a liver disease which could kill

him.

> At the same time, finding out such information about people's

genotypes

> opens a Pandora's box of other ethical issues. Epidemiological

studies

> suggest that slow acetylators are more susceptible to some

environmental

> insults. So a person known to be a slow acetylator may have trouble

getting

> health insurance. One study found that among post-menopausal women

who

> smoked cigarettes, slow acetylators were four times as likely to

develop

> breast cancer as rapid acetylators.

> There's always a danger that genetic information will be misused.

But " the

> fight should be against the misuse, not the science " , argues Cohen.

Whether

> society deals with the potential ethical consequences or avoids

them,

> researchers will continue to plug away at identifying and

sequencing drug

> response genes, and developing clinical tests. Pharmacogenomics may

not meet

> all the promises being made, says Weinshilboum of the Mayo

Clinic.

> " But I see this as the most exciting time in the history of

medicine as far

> as helping to explain disease and treat it. "

>

> The body's response to drug treatment for disease

>

> What made us all different

> Drugs can be harmful. And sometimes one ethnic group is affected

more than

> others. During the Second World War, for example, African-American

soldiers

> given the antimalarial drug primaquine developed a severe form of

anaemia.

> The soldiers who became ill had a deficiency in an enzyme called

> glucose-6-phosphate dehydrogenase (G6PD) due to a genetic variation

that

> occurs in about 10 per cent of Africans, and very rarely in

Caucasians.

> Such ethnic variation in reaction to drugs is not uncommon. Of the

45 or so

> genes that are involved in drug metabolism, 37 show ethnic

differences, says

> Werner Kalow, a pharmacologist at the University of Toronto in

Canada.

> How do such differences arise? The answer may lie in the

environment, say

> Nebert of the University of Cincinnati and of

the

> National Institutes of Health near Washington DC. Take the

cytochrome P450

> family of enzymes, for example. These enzymes evolved some 400

million years

> ago to protect plant-eating animals from being poisoned. As plants

evolved

> more powerful toxins to defend themselves, animals evolved better

enzymes

> for detoxifying them.

> After dozens of generations, certain gene variants for these

metabolic

> enzymes become prevalent in some human populations because of their

diet. A

> population that's dined on mostly goat meat and milk for 6000 years

is

> likely to evolve different forms of drug-metabolising enzymes than

one that

> has subsisted on tropical fruits and plants, says Nebert. Thanks to

genetic

> differences in P450, for example, 6 to 10 per cent of Whites, 5 per

cent of

> Blacks, and less than 1 per cent of Asians are poor drug

metabolisers.

> Other environmental factors can also play a role. G6PD deficiency

probably

> became more common in Africans because it confers some protection

against

> malaria.

>

> Further reading:

> • Further reading Variations on a theme: Cataloguing human DNA

sequence

> variation by Francis and others, Science, vol 278, p 1580

(1997)

> • Polymorphisms in drug-metabolizing enzymes: What is their

clinical

> relevance and why do they exist? by Nebert, The American

Journal of

> Human Genetics, vol 60, p 265 (1997)

> Schmidt

> F. Schmidt is a freelance journalist based in Washington DC

>

> ----Original Message Follows----

> From: " suzy nakauchi " <suzynakauchi@h...>

> Reply-SSRI medications@y...

> SSRI medications@y...

> Subject: Re: One Person's " Cure " ??? - Another's

Poison

> Date: Tue, 16 Apr 2002 23:38:10 +0000

>

> << message3.txt >>

>

> _________________________________________________________________

> Chat with friends online, try MSN Messenger:

http://messenger.msn.com

April 16, 2002

Hi Suzy and Dawn,

Something is weird with those messages you sent Dawn. I was unable to

view them at work (there was a big black box where the text should

have been) but when I came home I was able to view them perfectly

(except for that annoying advert laying over the top of the

first paragraph). So it must have something to do with how mine and

suzy's systems are set up to receive the way your messages were sent.

> Hi Suzy,

>

> Again, in your response to me saying the page is blank, the

document really

> is there on my side!!! Must be a phantom document!!! I've copied

and

> pasted it here in a different text version. Hopefully this will

come

> through OK... Let me know if it doesn't.

>

> Dawn

>

> One person's cure can be somebody else's poison. To find out which

drug is

> right for you, reports Schmidt, doctors may soon turn to

genetic

> testing

> AFTER much suffering, a deeply troubled young woman drags herself

to her

> doctor for help. The doctor diagnoses severe depression and says

> reassuringly, " Now we'll just test your DNA to see what meds will

work best

> for you, " as he reaches over and plucks a hair from her head. " When

we get

> the results this afternoon, I'll call in a prescription and you'll

soon be

> feeling better. " For the first time in a long time, she smiles

hopefully.

> Such a scenario may not be far off. According to many

pharmaceuticals and

> biotech companies, patients could soon be taking drugs tailored to

their

> genetic makeup, saving time and bundles of money now wasted on

ineffective

> treatments, as well as minimising debilitating side effects. Today

doctors

> would tell this young woman to try a medication-say, Prozac-and

then wait

> four to six weeks to find out whether she is one of the lucky 40

per cent

> the drug helps. It might take another six months and four different

drugs

> before she finds the best treatment for her depression. A quick

genetic test

> to replace this torturous trial-and-error would mean " a big

improvement in

> the way patients get treated " and lower healthcare costs for

society at

> large, says Cohen, a geneticist at a Paris-based genomics

company

> called Genset.

> That's the promise of pharmacogenomics, an emerging science that

aims to

> describe at the genetic level precisely why some people respond

well to

> certain drugs and others don't. Such information will be used to

create

> diagnostic tests to help select the right drugs for each patient.

In some

> cases, this gene-based approach may even save lives by identifying

people

> who are likely to develop a fatal reaction to a drug.

> Pharmacogenomics will be part of " the next revolution in medicine, "

says

> Francis , director of the National Human Genome Research

Institute

> near Washington DC. Doctors will soon routinely test patients to

ensure that

> the drugs they take really are the best for them, he predicts.

> But consumers aren't the only ones who stand to benefit

from " personalised

> medicine " . Pharmacogenomics should also boost corporate profits:

biotech

> companies expect to sell genetic test kits, and drugs companies

hope to

> increase the number of medications that survive clinical trials and

make it

> to market. " If we could identify who will strongly benefit [from a

drug], we

> could promote it to a defined segment of the population; that

should also

> make it easier to show it's safe and effective, " says Spear,

director

> of pharmacogenetics at Abbott Laboratories in North Chicago. In

fact, drugs

> companies have already begun collecting DNA samples from people who

take

> part in their clinical trials. One day they hope to find a genetic

pattern

> that will distinguish people who might be helped by a drug from

those the

> drug might harm.

> The prospect of developing customised medicines drew corporate

researchers

> to New York for a conference on pharmacogenomics last month and the

topic

> was recently the subject of a special issue of Nature Biotechnology

(vol 16,

> supplement). But people like Haseltine, head of Human

Genome

> Sciences in Rockville, land, wonder whether such enthusiasm may

send

> drugs companies heading off down the wrong path, spurred on in part

by

> exuberance over new technologies for rapidly cataloguing and

comparing the

> minute genetic variations of large numbers of people.

> Haseltine fears that the focus may shift from finding the right

drugs to

> treat individuals to pinpointing the people who are " genetically

right " for

> the drugs pharmaceuticals companies want to sell. Such screening

might leave

> a significant portion of the population medically out of

luck. " That's not

> where we want to go, " he says. " We still want new drugs that treat

as many

> people as possible. "

> Genset's Cohen disagrees. " Humans are polymorphic and diseases are

also, " he

> says. " Pharmaceuticals companies dream of a drug that treats

everyone, but

> life is such that this is not possible. "

> Skilled physicians have always understood that individual patients

respond

> to drugs differently. And many factors contribute to this broad

variability.

> Age, gender, health status and whether the person is taking other

drugs all

> dictate whether a drug will work and what its side effects might

be. But

> it's now clear that genes have a considerable influence over how

someone

> reacts to a drug. Individuals inherit specific versions of enzymes

that

> affect how they metabolise, absorb and excrete drugs. So far,

researchers

> have identified several dozen enzymes that vary in their activity

throughout

> the population and that probably dictate people's response to drugs-

which

> may be good, bad or sometimes deadly.

> Adverse drug reactions caused more than 100 000 deaths in the US in

1994,

> according to a recent article in The Journal of the American

Medical

> Association (vol 279, p 1200). Perhaps more frightening is that

these

> reactions often occur in patients receiving a standard dose of a

particular

> drug. As an example, doctors in the 1950s would administer a drug

called

> succinylcholine to induce muscle relaxation in patients before

surgery. More

> than a few patients, however, never woke up from anaesthesia-the

compound

> paralysed their breathing muscles and they simply suffocated.

Doctors

> discovered that these unfortunate patients had inherited a mutant

form of

> the enzyme that clears succinylcholine from their system.

> The drugs don't work

> And that's not the only time genes have been implicated in a toxic

drug

> response. As early as the 1940s doctors noticed that a good number

of

> tuberculosis patients treated with the antibacterial drug isoniazid

would

> feel pain, tingling and weakness in their limbs. These patients

were

> unusually slow to clear the drug from their bodies-isoniazid must

be rapidly

> converted to a nontoxic form by an enzyme called N-

acetyltransferase. The

> " slow acetylator " phenotype isn't exactly rare-40 to 60 per cent of

> Caucasians have a less active form of the enzyme than " rapid

acetylators. "

> Again, this difference in drug response, it was later discovered,

is due to

> differences in the gene encoding the enzyme.

> In the past few years, researchers have also found that variations

in

> certain genes can determine whether a drug treats a disease

effectively. For

> example, a cholesterol-lowering drug called pravastatin won't help

people

> with high blood cholesterol if they have a common gene variant for

an enzyme

> called cholesteryl transfer protein (CETP). And several studies

suggest that

> the version of the ApoE gene that is associated with a high risk of

> developing Alzheimer's disease in old age goes hand in hand with a

poor

> response to an Alzheimer's drug called tacrine.

> This is where pharmacogenomics might be able to help. Right now,

doctors can

> run tests to determine whether a patient is likely to react badly

to a

> handful of drugs. However, these tests usually measure a phenotype-

such as

> the amount of enzyme activity in a person's blood-rather than which

form of

> a gene a person has. For instance, doctors can use an enzyme test

developed

> by researchers at the Mayo Medical School in Minnesota to determine

which

> dose of 6-mercaptopurine to give children with leukaemia. About 1

in 300

> Caucasian children have severe-often fatal-reactions to this

chemotherapy

> because the enzymes they need to metabolise and detoxify the drug

are

> defective. So physicians around the world send blood samples to a

lab-the

> Mayo Clinic analyses nearly 1000 a year-to determine whether it's

best to

> give a child a full dose or as little as one-fifteenth of the

normal

> prescription.

> Such tests for phenotype are fine for identifying people who may

have bad

> reaction to a drug because they lack certain enzymes. But

identifying people

> whose cholesterol can't be lowered by pravastatin treatment, for

example, is

> not so simple. Although toxic reactions often involve defects in

single

> genes, good or bad treatment responses are likely to be determined

by

> multiple genes, says Roses, head of worldwide genetics

research for

> the British-based drugs giant Glaxo Wellcome. And the more genes

involved,

> the more possible combinations will need to be tested before the

best

> treatment can be prescribed. That's why researchers are turning to

the power

> of pharmacogenomics to look directly at the variations in the genes

> themselves. By comparing the genetic profiles of people who respond

well

> with those who have a bad reaction to a drug, scientists should be

able to

> identify the genes involved, and which versions lead to the best

outcome.

> Recent advances in rapid gene sequencing and the statistical

comparison of

> data collected from large populations are now making such studies

possible.

> With laboratories all over the world churning out massive amounts

of human

> DNA sequence, researchers can now focus on finding the hot spots in

human

> chromosomes that vary in sequence from person to person and then

look to see

> whether these are related to differences in drug response. The US

Human

> Genome Project-part of the international effort to sequence all 3

billion

> base pairs of DNA in the human genome-aims to discover and map 50

000 to 100

> 000 of these hot spots, called SNPs (single nucleotide

polymorphisms,

> pronounced " snips " ).

> To chart these tiny differences in an individual's DNA, many

researchers are

> turning to a new tool called a SNP chip, a tiny microarray studded

with

> genetic variations commonly found in human chromosomes (see " Speed

freaks " ,

> p 46). A technician prepares a solution containing a patient's DNA.

When

> this sample is washed over the chip, gene fragments that match the

SNP

> sequences bind to the chip and fluoresce. A computer then analyses

the

> resulting pattern, determining which variations are present in the

patient's

> genes. Researchers then tally the variations present in two

different groups

> of people-say, people who have a good or a poor response to a drug.

With the

> help of sophisticated new statistical techniques that can

simultaneously

> compare thousands of SNPs from thousands of patients, scientists

look for

> associations between particular SNPs and different responses to

drugs. By

> mapping out the location of these SNPs, researchers can generate a

trail

> that will lead them to the genes involved in drug response.

> Abbott Laboratories and Genset have teamed up to do just that.

Genset has

> put together a rough SNP map of the human genome and Abbott has

collected

> DNA samples from people in clinical trials for zileuton, its asthma

drug.

> Genset is now analysing these DNA samples and looking for

differences that

> may reveal which genes control a person's response to zileuton, a

drug that

> can damage the liver in 3 per cent of patients. Their study may

eventually

> lead to a simple test to filter out patients who might not respond

well to

> the drug.

> Tailored therapies

> Soon SNP chips may be available for use in clinics, an advance that

would

> mark the real beginning of " personalised medicine " based on gene

screening.

> Affymetrix, a biotech company in Santa Clara, California, has

developed a

> chip to detect 12 different variants of two genes that encode the

cytochrome

> P450 enzymes. This family of enzymes is involved in the metabolism

of at

> least 20 per cent of all commonly prescribed drugs, including the

> antidepressant Prozac, the painkiller codeine, and high-blood-

pressure

> medications such as captopril. In the near future, clinics may use

the chip

> to determine the correct drug dose to give a patient, says

Lipshutz,

> vice-president of corporate development at Affymetrix.

> Before they can even think about matching the right drugs with the

right

> patients, though, drugs companies will have to find out during

clinical

> trials who will be compatible with a product and who will not. Many

> companies, such as Glaxo Wellcome and Abbott, have begun collecting

DNA

> samples from people taking part in their clinical trials. But

Glaxo, for

> one, is holding onto the DNA until a SNP map of the entire human

genome

> becomes available. Then they will look for a recognisable overall

pattern in

> the people who respond well or badly to each of their products.

> Theoretically, doctors would not even have to understand how or why

patients

> respond to certain drugs, says Glaxo's Roses. They'd just identify

the good

> responders and give them the drugs that DNA tests indicate should

work best.

> Haseltine, for one, is sceptical of Roses's suggestion that

physicians might

> prescribe drugs, based on gene testing, without understanding why a

patient

> might respond well or poorly to the treatment. These new DNA

diagnostic

> tests are not yet fully understood or even 100 per cent accurate,

he notes.

> A patient whose treatment doesn't work-or worse, makes him sick-

might sue.

> " I don't think any pharmaceuticals company would do it because of

> liability. "

> And in the end, many pharmaceuticals companies may be more

concerned with

> profit margins than with public health. Indeed, if the goal were

truly to

> reduce adverse drug reactions, many simple tests could be developed

now,

> says Nebert, a human geneticist at the University of

Cincinnati. For

> example, a genotype test could be developed to detect slow

acetylators

> because the genes and their variations are known. Says Nebert, " You

could

> pick up 95 per cent of slow acetylators with just a couple of DNA

tests. "

> And it would truly save lives, he says. If a slow acetylator

receives

> procainamide, a drug commonly used after a heart attack, the

patient has a

> 60 per cent chance of developing a liver disease which could kill

him.

> At the same time, finding out such information about people's

genotypes

> opens a Pandora's box of other ethical issues. Epidemiological

studies

> suggest that slow acetylators are more susceptible to some

environmental

> insults. So a person known to be a slow acetylator may have trouble

getting

> health insurance. One study found that among post-menopausal women

who

> smoked cigarettes, slow acetylators were four times as likely to

develop

> breast cancer as rapid acetylators.

> There's always a danger that genetic information will be misused.

But " the

> fight should be against the misuse, not the science " , argues Cohen.

Whether

> society deals with the potential ethical consequences or avoids

them,

> researchers will continue to plug away at identifying and

sequencing drug

> response genes, and developing clinical tests. Pharmacogenomics may

not meet

> all the promises being made, says Weinshilboum of the Mayo

Clinic.

> " But I see this as the most exciting time in the history of

medicine as far

> as helping to explain disease and treat it. "

>

> The body's response to drug treatment for disease

>

> What made us all different

> Drugs can be harmful. And sometimes one ethnic group is affected

more than

> others. During the Second World War, for example, African-American

soldiers

> given the antimalarial drug primaquine developed a severe form of

anaemia.

> The soldiers who became ill had a deficiency in an enzyme called

> glucose-6-phosphate dehydrogenase (G6PD) due to a genetic variation

that

> occurs in about 10 per cent of Africans, and very rarely in

Caucasians.

> Such ethnic variation in reaction to drugs is not uncommon. Of the

45 or so

> genes that are involved in drug metabolism, 37 show ethnic

differences, says

> Werner Kalow, a pharmacologist at the University of Toronto in

Canada.

> How do such differences arise? The answer may lie in the

environment, say

> Nebert of the University of Cincinnati and of

the

> National Institutes of Health near Washington DC. Take the

cytochrome P450

> family of enzymes, for example. These enzymes evolved some 400

million years

> ago to protect plant-eating animals from being poisoned. As plants

evolved

> more powerful toxins to defend themselves, animals evolved better

enzymes

> for detoxifying them.

> After dozens of generations, certain gene variants for these

metabolic

> enzymes become prevalent in some human populations because of their

diet. A

> population that's dined on mostly goat meat and milk for 6000 years

is

> likely to evolve different forms of drug-metabolising enzymes than

one that

> has subsisted on tropical fruits and plants, says Nebert. Thanks to

genetic

> differences in P450, for example, 6 to 10 per cent of Whites, 5 per

cent of

> Blacks, and less than 1 per cent of Asians are poor drug

metabolisers.

> Other environmental factors can also play a role. G6PD deficiency

probably

> became more common in Africans because it confers some protection

against

> malaria.

>

> Further reading:

> • Further reading Variations on a theme: Cataloguing human DNA

sequence

> variation by Francis and others, Science, vol 278, p 1580

(1997)

> • Polymorphisms in drug-metabolizing enzymes: What is their

clinical

> relevance and why do they exist? by Nebert, The American

Journal of

> Human Genetics, vol 60, p 265 (1997)

> Schmidt

> F. Schmidt is a freelance journalist based in Washington DC

>

> ----Original Message Follows----

> From: " suzy nakauchi " <suzynakauchi@h...>

> Reply-SSRI medications@y...

> SSRI medications@y...

> Subject: Re: One Person's " Cure " ??? - Another's

Poison

> Date: Tue, 16 Apr 2002 23:38:10 +0000

>

> << message3.txt >>

>

> _________________________________________________________________

> Chat with friends online, try MSN Messenger:

http://messenger.msn.com

April 17, 2002

Dear Dawn,

Thank you for reposting this article. I agree with everything except

the last paragraph's statement that less than 1% Asians are poor

metabolizers. Of course, you knew I would.

Love,

Suzy

>From: " DAWN RIDER " <israelswarrior@...>

>Reply-SSRI medications

>SSRI medications

>Subject: One Person's " Cure " ??? - Another's Poison (2nd

>attempt to send to Suzy)

>Date: Tue, 16 Apr 2002 19:33:52 -0600

>

>Hi Suzy,

>

>Again, in your response to me saying the page is blank, the document really

>is there on my side!!! Must be a phantom document!!! I've copied and

>pasted it here in a different text version. Hopefully this will come

>through OK... Let me know if it doesn't.

>

>Dawn

>

>One person's cure can be somebody else's poison. To find out which drug is

>right for you, reports Schmidt, doctors may soon turn to genetic

>testing

>AFTER much suffering, a deeply troubled young woman drags herself to her

>doctor for help. The doctor diagnoses severe depression and says

>reassuringly, " Now we'll just test your DNA to see what meds will work best

>for you, " as he reaches over and plucks a hair from her head. " When we get

>the results this afternoon, I'll call in a prescription and you'll soon be

>feeling better. " For the first time in a long time, she smiles hopefully.

>Such a scenario may not be far off. According to many pharmaceuticals and

>biotech companies, patients could soon be taking drugs tailored to their

>genetic makeup, saving time and bundles of money now wasted on ineffective

>treatments, as well as minimising debilitating side effects. Today doctors

>would tell this young woman to try a medication-say, Prozac-and then wait

>four to six weeks to find out whether she is one of the lucky 40 per cent

>the drug helps. It might take another six months and four different drugs

>before she finds the best treatment for her depression. A quick genetic

>test

>to replace this torturous trial-and-error would mean " a big improvement in

>the way patients get treated " and lower healthcare costs for society at

>large, says Cohen, a geneticist at a Paris-based genomics company

>called Genset.

>That's the promise of pharmacogenomics, an emerging science that aims to

>describe at the genetic level precisely why some people respond well to

>certain drugs and others don't. Such information will be used to create

>diagnostic tests to help select the right drugs for each patient. In some

>cases, this gene-based approach may even save lives by identifying people

>who are likely to develop a fatal reaction to a drug.

>Pharmacogenomics will be part of " the next revolution in medicine, " says

>Francis , director of the National Human Genome Research Institute

>near Washington DC. Doctors will soon routinely test patients to ensure

>that

>the drugs they take really are the best for them, he predicts.

>But consumers aren't the only ones who stand to benefit from " personalised

>medicine " . Pharmacogenomics should also boost corporate profits: biotech

>companies expect to sell genetic test kits, and drugs companies hope to

>increase the number of medications that survive clinical trials and make it

>to market. " If we could identify who will strongly benefit [from a drug],

>we

>could promote it to a defined segment of the population; that should also

>make it easier to show it's safe and effective, " says Spear, director

>of pharmacogenetics at Abbott Laboratories in North Chicago. In fact, drugs

>companies have already begun collecting DNA samples from people who take

>part in their clinical trials. One day they hope to find a genetic pattern

>that will distinguish people who might be helped by a drug from those the

>drug might harm.

>The prospect of developing customised medicines drew corporate researchers

>to New York for a conference on pharmacogenomics last month and the topic

>was recently the subject of a special issue of Nature Biotechnology (vol

>16,

>supplement). But people like Haseltine, head of Human Genome

>Sciences in Rockville, land, wonder whether such enthusiasm may send

>drugs companies heading off down the wrong path, spurred on in part by

>exuberance over new technologies for rapidly cataloguing and comparing the

>minute genetic variations of large numbers of people.

>Haseltine fears that the focus may shift from finding the right drugs to

>treat individuals to pinpointing the people who are " genetically right " for

>the drugs pharmaceuticals companies want to sell. Such screening might

>leave

>a significant portion of the population medically out of luck. " That's not

>where we want to go, " he says. " We still want new drugs that treat as many

>people as possible. "

>Genset's Cohen disagrees. " Humans are polymorphic and diseases are also, "

>he

>says. " Pharmaceuticals companies dream of a drug that treats everyone, but

>life is such that this is not possible. "

>Skilled physicians have always understood that individual patients respond

>to drugs differently. And many factors contribute to this broad

>variability.

>Age, gender, health status and whether the person is taking other drugs all

>dictate whether a drug will work and what its side effects might be. But

>it's now clear that genes have a considerable influence over how someone

>reacts to a drug. Individuals inherit specific versions of enzymes that

>affect how they metabolise, absorb and excrete drugs. So far, researchers

>have identified several dozen enzymes that vary in their activity

>throughout

>the population and that probably dictate people's response to drugs-which

>may be good, bad or sometimes deadly.

>Adverse drug reactions caused more than 100 000 deaths in the US in 1994,

>according to a recent article in The Journal of the American Medical

>Association (vol 279, p 1200). Perhaps more frightening is that these

>reactions often occur in patients receiving a standard dose of a particular

>drug. As an example, doctors in the 1950s would administer a drug called

>succinylcholine to induce muscle relaxation in patients before surgery.

>More

>than a few patients, however, never woke up from anaesthesia-the compound

>paralysed their breathing muscles and they simply suffocated. Doctors

>discovered that these unfortunate patients had inherited a mutant form of

>the enzyme that clears succinylcholine from their system.

>The drugs don't work

>And that's not the only time genes have been implicated in a toxic drug

>response. As early as the 1940s doctors noticed that a good number of

>tuberculosis patients treated with the antibacterial drug isoniazid would

>feel pain, tingling and weakness in their limbs. These patients were

>unusually slow to clear the drug from their bodies-isoniazid must be

>rapidly

>converted to a nontoxic form by an enzyme called N-acetyltransferase. The

> " slow acetylator " phenotype isn't exactly rare-40 to 60 per cent of

>Caucasians have a less active form of the enzyme than " rapid acetylators. "

>Again, this difference in drug response, it was later discovered, is due to

>differences in the gene encoding the enzyme.

>In the past few years, researchers have also found that variations in

>certain genes can determine whether a drug treats a disease effectively.

>For

>example, a cholesterol-lowering drug called pravastatin won't help people

>with high blood cholesterol if they have a common gene variant for an

>enzyme

>called cholesteryl transfer protein (CETP). And several studies suggest

>that

>the version of the ApoE gene that is associated with a high risk of

>developing Alzheimer's disease in old age goes hand in hand with a poor

>response to an Alzheimer's drug called tacrine.

>This is where pharmacogenomics might be able to help. Right now, doctors

>can

>run tests to determine whether a patient is likely to react badly to a

>handful of drugs. However, these tests usually measure a phenotype-such as

>the amount of enzyme activity in a person's blood-rather than which form of

>a gene a person has. For instance, doctors can use an enzyme test developed

>by researchers at the Mayo Medical School in Minnesota to determine which

>dose of 6-mercaptopurine to give children with leukaemia. About 1 in 300

>Caucasian children have severe-often fatal-reactions to this chemotherapy

>because the enzymes they need to metabolise and detoxify the drug are

>defective. So physicians around the world send blood samples to a lab-the

>Mayo Clinic analyses nearly 1000 a year-to determine whether it's best to

>give a child a full dose or as little as one-fifteenth of the normal

>prescription.

>Such tests for phenotype are fine for identifying people who may have bad

>reaction to a drug because they lack certain enzymes. But identifying

>people

>whose cholesterol can't be lowered by pravastatin treatment, for example,

>is

>not so simple. Although toxic reactions often involve defects in single

>genes, good or bad treatment responses are likely to be determined by

>multiple genes, says Roses, head of worldwide genetics research for

>the British-based drugs giant Glaxo Wellcome. And the more genes involved,

>the more possible combinations will need to be tested before the best

>treatment can be prescribed. That's why researchers are turning to the

>power

>of pharmacogenomics to look directly at the variations in the genes

>themselves. By comparing the genetic profiles of people who respond well

>with those who have a bad reaction to a drug, scientists should be able to

>identify the genes involved, and which versions lead to the best outcome.

>Recent advances in rapid gene sequencing and the statistical comparison of

>data collected from large populations are now making such studies possible.

>With laboratories all over the world churning out massive amounts of human

>DNA sequence, researchers can now focus on finding the hot spots in human

>chromosomes that vary in sequence from person to person and then look to

>see

>whether these are related to differences in drug response. The US Human

>Genome Project-part of the international effort to sequence all 3 billion

>base pairs of DNA in the human genome-aims to discover and map 50 000 to

>100

>000 of these hot spots, called SNPs (single nucleotide polymorphisms,

>pronounced " snips " ).

>To chart these tiny differences in an individual's DNA, many researchers

>are

>turning to a new tool called a SNP chip, a tiny microarray studded with

>genetic variations commonly found in human chromosomes (see " Speed freaks " ,

>p 46). A technician prepares a solution containing a patient's DNA. When

>this sample is washed over the chip, gene fragments that match the SNP

>sequences bind to the chip and fluoresce. A computer then analyses the

>resulting pattern, determining which variations are present in the

>patient's

>genes. Researchers then tally the variations present in two different

>groups

>of people-say, people who have a good or a poor response to a drug. With

>the

>help of sophisticated new statistical techniques that can simultaneously

>compare thousands of SNPs from thousands of patients, scientists look for

>associations between particular SNPs and different responses to drugs. By

>mapping out the location of these SNPs, researchers can generate a trail

>that will lead them to the genes involved in drug response.

>Abbott Laboratories and Genset have teamed up to do just that. Genset has

>put together a rough SNP map of the human genome and Abbott has collected

>DNA samples from people in clinical trials for zileuton, its asthma drug.

>Genset is now analysing these DNA samples and looking for differences that

>may reveal which genes control a person's response to zileuton, a drug that

>can damage the liver in 3 per cent of patients. Their study may eventually

>lead to a simple test to filter out patients who might not respond well to

>the drug.

>Tailored therapies

>Soon SNP chips may be available for use in clinics, an advance that would

>mark the real beginning of " personalised medicine " based on gene screening.

>Affymetrix, a biotech company in Santa Clara, California, has developed a

>chip to detect 12 different variants of two genes that encode the

>cytochrome

>P450 enzymes. This family of enzymes is involved in the metabolism of at

>least 20 per cent of all commonly prescribed drugs, including the

>antidepressant Prozac, the painkiller codeine, and high-blood-pressure

>medications such as captopril. In the near future, clinics may use the chip

>to determine the correct drug dose to give a patient, says Lipshutz,

>vice-president of corporate development at Affymetrix.

>Before they can even think about matching the right drugs with the right

>patients, though, drugs companies will have to find out during clinical

>trials who will be compatible with a product and who will not. Many

>companies, such as Glaxo Wellcome and Abbott, have begun collecting DNA

>samples from people taking part in their clinical trials. But Glaxo, for

>one, is holding onto the DNA until a SNP map of the entire human genome

>becomes available. Then they will look for a recognisable overall pattern

>in

>the people who respond well or badly to each of their products.

>Theoretically, doctors would not even have to understand how or why

>patients

>respond to certain drugs, says Glaxo's Roses. They'd just identify the good

>responders and give them the drugs that DNA tests indicate should work

>best.

>Haseltine, for one, is sceptical of Roses's suggestion that physicians

>might

>prescribe drugs, based on gene testing, without understanding why a patient

>might respond well or poorly to the treatment. These new DNA diagnostic

>tests are not yet fully understood or even 100 per cent accurate, he notes.

>A patient whose treatment doesn't work-or worse, makes him sick-might sue.

> " I don't think any pharmaceuticals company would do it because of

>liability. "

>And in the end, many pharmaceuticals companies may be more concerned with

>profit margins than with public health. Indeed, if the goal were truly to

>reduce adverse drug reactions, many simple tests could be developed now,

>says Nebert, a human geneticist at the University of Cincinnati. For

>example, a genotype test could be developed to detect slow acetylators

>because the genes and their variations are known. Says Nebert, " You could

>pick up 95 per cent of slow acetylators with just a couple of DNA tests. "

>And it would truly save lives, he says. If a slow acetylator receives

>procainamide, a drug commonly used after a heart attack, the patient has a

>60 per cent chance of developing a liver disease which could kill him.

>At the same time, finding out such information about people's genotypes

>opens a Pandora's box of other ethical issues. Epidemiological studies

>suggest that slow acetylators are more susceptible to some environmental

>insults. So a person known to be a slow acetylator may have trouble getting

>health insurance. One study found that among post-menopausal women who

>smoked cigarettes, slow acetylators were four times as likely to develop

>breast cancer as rapid acetylators.

>There's always a danger that genetic information will be misused. But " the

>fight should be against the misuse, not the science " , argues Cohen. Whether

>society deals with the potential ethical consequences or avoids them,

>researchers will continue to plug away at identifying and sequencing drug

>response genes, and developing clinical tests. Pharmacogenomics may not

>meet

>all the promises being made, says Weinshilboum of the Mayo Clinic.

> " But I see this as the most exciting time in the history of medicine as far

>as helping to explain disease and treat it. "

>

>The body's response to drug treatment for disease

>

>What made us all different

>Drugs can be harmful. And sometimes one ethnic group is affected more than

>others. During the Second World War, for example, African-American soldiers

>given the antimalarial drug primaquine developed a severe form of anaemia.

>The soldiers who became ill had a deficiency in an enzyme called

>glucose-6-phosphate dehydrogenase (G6PD) due to a genetic variation that

>occurs in about 10 per cent of Africans, and very rarely in Caucasians.

>Such ethnic variation in reaction to drugs is not uncommon. Of the 45 or so

>genes that are involved in drug metabolism, 37 show ethnic differences,

>says

>Werner Kalow, a pharmacologist at the University of Toronto in Canada.

>How do such differences arise? The answer may lie in the environment, say

> Nebert of the University of Cincinnati and of the

>National Institutes of Health near Washington DC. Take the cytochrome P450

>family of enzymes, for example. These enzymes evolved some 400 million

>years

>ago to protect plant-eating animals from being poisoned. As plants evolved

>more powerful toxins to defend themselves, animals evolved better enzymes

>for detoxifying them.

>After dozens of generations, certain gene variants for these metabolic

>enzymes become prevalent in some human populations because of their diet. A

>population that's dined on mostly goat meat and milk for 6000 years is

>likely to evolve different forms of drug-metabolising enzymes than one that

>has subsisted on tropical fruits and plants, says Nebert. Thanks to genetic

>differences in P450, for example, 6 to 10 per cent of Whites, 5 per cent of

>Blacks, and less than 1 per cent of Asians are poor drug metabolisers.

>Other environmental factors can also play a role. G6PD deficiency probably

>became more common in Africans because it confers some protection against

>malaria.

>

>Further reading:

>• Further reading Variations on a theme: Cataloguing human DNA sequence

>variation by Francis and others, Science, vol 278, p 1580 (1997)

>• Polymorphisms in drug-metabolizing enzymes: What is their clinical

>relevance and why do they exist? by Nebert, The American Journal of

>Human Genetics, vol 60, p 265 (1997)

> Schmidt

> F. Schmidt is a freelance journalist based in Washington DC

>

>----Original Message Follows----

>From: " suzy nakauchi " <suzynakauchi@...>

>Reply-SSRI medications

>SSRI medications

>Subject: Re: One Person's " Cure " ??? - Another's Poison

>Date: Tue, 16 Apr 2002 23:38:10 +0000

>

><< message3.txt >>

>

>_________________________________________________________________

>Chat with friends online, try MSN Messenger: http://messenger.msn.com

_________________________________________________________________

Send and receive Hotmail on your mobile device: http://mobile.msn.com

Another blank.

Is it just me?

Suzy

>From: " DAWN RIDER " <israelswarrior@...>

>Reply-SSRI medications

>prozactruth , SSRI medications

>Subject: One Person's " Cure " ??? - Another's Poison

>Date: Tue, 16 Apr 2002 03:47:14 -0600

>

_________________________________________________________________

Chat with friends online, try MSN Messenger: http://messenger.msn.com

April 17, 2002