From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,sci.med.pharmacy
Subject: Re: FDA approves Thalidomide
Date: 20 Jul 1998 08:25:25 GMT

In <1998071919253100.PAA16255@ladder03.news.aol.com> davblade11@aol.com
(DAVBLADE11) writes:

>Thalidomide was banned worldwide in the 1960s after causing 12,000 babies
>to be born with no limbs or flipperlike arms and legs, serious facial
>deformities and defective organs. The sedative and morning-sickness pill
>had been sold in 48 countries -- but not in the United States, because an
>FDA scientist uncovered early signs of toxicity and blocked approval.


Comment:

    Boy, what a stilted version of the truth.  Francis Kelsey, a female
physician who was assigned the new drug application for thalidomide at
the FDA in early 1960, didn't like the neuropathy reported in
thalidomide users, but she didn't uncover it-- it was part of the
application and well known.  And it wouldn't have been fatal for the
approval.  The fact is that the FDA sat on the thalidomide application
through most of 1960 because Kelsey's husband, a pharmacologist, didn't
like the pharm kinetic studies for the drug and thought they should be
repeated.  If they had been before the European disaster stuff came in,
the US should surely have approved the drug.  We missed because of foot
dragging, and had no inkling of the teratogenicity of the compound.

   But it's easy to make a company foot-drag.  You don't need a woman
(or a man) with an advanced degree. to do it.  You just make a rule: no
drug approved in the US until Europeans and other animals have used it
for at least 2 years.  That would cost less than the FDA, and serve the
exact same function. Of course, it would lead to embarrassing questions
about tradeoffs that nobody really is prepared to think about.  So we
do it this way, but we pretend we don't.  And we spend a lot of money
doing it, so we can lie to ourselves.


>The FDA approved thalidomide Thursday to alleviate an agonizing
>leprosy-related inflammation. Leprosy is rare in the United States, and
>only about 50 patients a year are diagnosed in the country with this
>erythema nodosum leprosum, or ENL.


    The stuff has been used in Brazil for this, for 30 years.  Right on
the job, FDA.



>To get the drug, doctors, pharmacists and patients must follow strict
>rules.
>
>Every American prescribed thalidomide will be enrolled in a
>government-monitored registry. Manufacturer Celgene Corp. will allow
>prescriptions to be dispensed only by doctors and pharmacists that the
>New Jersey company trains about thalidomide's dangers. Women must undergo
>repeated pregnancy tests, and men and women must sign statements
>acknowledging they were instructed to use effective birth control.


    It makes no more sense to handle thalidomide differently than
Accutane (just as potent a teratogen) is handled now.  The difference
is in the name.  Great science, FDA.  They're going to make men watch
this stuff also?  When there is NO (repeat) NO evidence that men taking
the drug ever caused any fetal abnormalities in partners?  What's the
point of precautions against something that NEVER was EVER documented
to happen, and yet had plenty of chance to, if it was possible?
Suppose we treated HIV infection like that?  Wups, politics.  You don't
want to go there.




>The FDA acknowledges many more Americans will use thalidomide than just
>leprosy patients. It is legal for U.S. doctors to prescribe drugs in any
>way they see fit,

    Except Celgene won't let them have it.  Nice end-run around the law
there, FDA.   If you don't like the law, see if you can get congress to
change it.  Don't try it yourselves.



                                           Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,sci.med.pharmacy
Subject: Re: FDA approves Thalidomide
Date: 21 Jul 1998 04:14:05 GMT

In <6ovgtd$mef$1@basement.replay.com> nobody@REPLAY.COM (Anonymous)
writes:


>Steven B. Harris (sbharris@ix.netcom.com) wrote:
>
>>But it's easy to make a company foot-drag.  You don't need a woman
>>(or a man) with an advanced degree. to do it.  You just make a rule:
>>no drug approved in the US until Europeans and other animals have used
>>it for at least 2 years.  That would cost less than the FDA, and serve
>>the exact same function. Of course, it would lead to embarrassing
>>questions about tradeoffs that nobody really is prepared to think
>>about.  So we do it this way, but we pretend we don't.  And we spend a
>>lot of money doing it, so we can lie to ourselves.
>
>As a practical matter, isn't this pretty much how things are done now?
> Except the period is generally a bit longer than 2 years.




Comment:
   Yessss, that was my point.  Wasn't I making that clear?  The period
varies, but the point is that the FDA is a lot more expensive than a
mandated waiting period, and yet it doesn't DO much more than provide
window dressing for the real information-getter on drugs, which comes
from actual clinical use of the drug on a population first (somebody
else's) before it's used on *us*, the important people.  You have to
pay for mice and rats and their housing, but wogs pay for themselves.
It's a hell of a deal, if we'd just quit wasting money pretending
that's not what we're buying.

   Of course, the "wogs" will have their revenge.  Many countries do
not pay their share of pharmaceutical development costs.  Canada, for
example, has one tenth the US population, but hardly produces one tenth
of the new drugs we do, yet they use them all.  And the Swiss are well
ahead of *us*.  Some countries basically steal information, and call
that the advantages of socialism.  Well, it always was one of the
advantages of socialism-- it's great for catching up, since you can
avoid mistakes and apply what have been found to be good answers to
problems, uniformly right from the start.  But it's not exactly fair.
It sort of reminds me of the guys riding just behind the lead bicyclist
or skater in the olympics, using the guy in the lead for a wind break.
They're not as hot as they possibly think they are-- but they do look
pretty good to the uninformed.   Some countries do use drugs (which
they did not develop) early, and end up partially paying for their
information thievery, by putting themselves at risk and providing
information to everybody else.  And other countries, like Canada, don't
follow any courageous or self-reliant strategy of any kind.  In this
department, they just suck.

                                       Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,sci.med.pharmacy
Subject: Re: FDA approves Thalidomide
Date: 21 Jul 1998 05:03:58 GMT

In <35B3EE60.251@pop.pitt.edu> "J.T. Robicheau" <jtrst4@pop.pitt.edu>
writes:

>Steven B. Harris wrote:
>
>>You just make a rule: no drug approved in the US until Europeans and
>>other animals have used it for at least 2 years.  That would cost less
>>than the FDA, and serve the exact same function..
>
>
>animal studies did not uncover the teratogenicity of this drug,
>which why human subjects were allowed to use it.....



   Wrong.  As careful a search as can be done historically shows that
NO animal teratogenicity studies were ever done on the drug before it
was released.  As incredible as that is to believe, that's the way
things were in the late 1950's.  They hadn't yet had the example of
thalidomide, remember.

   Later, they went back and did some studies, and found that
thalidomide doesn't cause birth defects in rats, and thus got started
the myth that rat studies had been done, and that's how the disaster
happened.  Wrong.  And the drug DOES cause defects in rabbits, guinea
pigs, monkeys (primates in general), and a number of other species.  So
it's not like Mother Nature was out to get us.  We just ^%$#ed up.  The
FDA saved the US by not allowing us to *&^% up as fast as the rest of
the world did.  We pay for that by not being allowed to doing things
right in pharmacology as fast as the rest of the world.  The FDA's
infamous multiyear ban on beta blockers in the US cost us tens of
thousands of lives, at miniumum.  Their foot dragging on folate has
resulted in the same number of really horrid birth defects-- ones that
must make parents want to trade for thalidomide.  Babies paralyzed from
the waist down.  Babies with brains hanging out.  You name it.  The FDA
had good reason to think this was happening to women with low folate
intakes as early as 1984.  It took till 1998 for them to stop blocking
addition of folate to flour by the USDA.

                                             Steve Harris, M.D.

From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com>
Newsgroups: sci.med,sci.med.pharmacy
Subject: Re: Thalidomide Urban Mythology (was Re: Safe Minds and Mercury Policy 
	Project Statement on "Mercury concentrations and metabolism in 
	infants receiving vaccines containing mercury: a descriptive study"
Date: Sat, 30 Nov 2002 17:12:27 -0700
Message-ID: <asblbq$atu$1@slb1.atl.mindspring.net>

john" <john@nospam.com> wrote in message
news:asah89$gsu$1@helle.btinternet.com...
> FOR IMMEDIATE RELEASE
> http://www.ewire-news.com/wires/5D606D56-3ACE-4A0B-AA90AC497F2C5D56.htm
>
> Safe Minds and Mercury Policy Project Statement on "Mercury concentrations
> and metabolism in infants receiving vaccines containing mercury: a
> descriptive study"
>
>
> Washington, DC, Nov. 29 -/E-Wire/-- According to Safe Minds and Mercury
> Policy Project, few, if any, definitive conclusions can be drawn from this
> latest thimerosal study.

[snip]

>            3. The reference point that they use to establish safety levels
> for thimerosal is methylmercury, a different compound than the
> ethylmerucry in thimerosal. Simply because a compound is similar does
> not mean it is as safe.
> 
> A good example is thalidomide, a sedative drug that was prescribed to
> pregnant women from 1957 into the early 60's. It was present in at least
> 46 countries under different brand names. When taken during the first
> trimester of pregnancy, Thalidomide prevented the proper growth of the
> foetus, resulting in horrific birth defects in thousands of children
> around the world. The reason is the Thalidomide molecule is chiral, with
> left and right-handed versions. The drug that was marketed was a 50/50
> mixture. One of the molecules was a sedative, whereas the other was
> found later to cause foetal abnormalities.
> 
> The tragedy could have been avoided had the physiological properties of
> the individual thalidomide [molecules] been tested prior to
> commercialization. Molecules that look almost exactly alike can behave
> very differently.  The FDA is very rigid about testing the precise
> molecule being approved.


Comment by Steve Harris, M.D.:

The above is complete nonsense, an example of an urban myth which has gotten
out of hand, and now is spreading like the story of the scuba diver found in
the burned-out forest.

First of all, there is NO evidence so far that one chiral version of thalido
mide causes birth defects and the other doesn't, although many years ago
this was hypothesized to be the case. In fact, it's a theory that cannot be
tested, because real thalidomide converts between one enantiomer and the
other so fast in the body, that whenever you give one, the other appears (is
made from it). No matter if you give the right or left-handed molecule (R or
S), or a 50:50 mix, they will interconvert and you'll end up with a body
concentration of about 2:1 of R vs. S, simply because S is excreted faster
from the body.

Now, there are derivatives or analogs of thalidomide (EM12) that don't do
this spontaneous interconversion, and they do show differences between
chiral molecules on embryos. But this has nothing to do with thalidomide
itself, which as noted, is always present in the body in both forms, no
matter which form (enantiomer or mirror-image or "chiral" molecule) is
administered.

The statement above that "the drug that was marketed was a 50/50 mixture" is
true. The statement "One of the molecules was a sedative, whereas the other
was found later to cause foetal abnormalities" is false. No such study was
done, or can be done with thalidomide, even in principle.

The statement: "The tragedy could have been avoided had the physiological
properties of the individual thalidomide [molecules] been tested prior to
commercialization." is also nonsense, for obvious reasons. Such testing
could not have been carried out even had anyone tried, since (again!) one
molecule converts to the other rapidly in the body.

The reason for the thalidomide tragedy is simple: no teratogenic testing of
the compound was done on animals. It's another urban myth that thalidomide
was tested in the wrong animals-- actually it wasn't tested at all. (It is
true that the effects of thalidomide vary drastically between species, and
primates are much more sensitive to the embroytoxic effects. However, these
effects are seen in many species, at high enough doses.) In any case, animal
testing standards were very different in the late 1950's than they are today
(in part because of thalidomide). Thalidomide historically was held up
briefly in the approval process by F.O. Kelsey, MD at the FDA because it
hadn't been as well tested pharmacokinetically as she wanted, and because
the FDA didn't like the neuropathy it could produce. However, the drug would
no doubt have passed the FDA, and it was only luck and red tape which held
up its FDA approval, for less than a year, till fetal abnormality reports
came in from Europe in 1960. Kelsey was to say later that she'd had concerns
about thalidomide's embryotoxicity, but that was in retrospect-- there is
ZERO documentation to support that. And in fact no such scrutiny was part of
the FDA's evaluation of ANY drugs in 1959 or 1960.

> Molecules that look almost exactly alike can behave very differently.  The
FDA is very rigid about testing the precise molecule being approved.<

Or mix of molecules. Indeed they are, but this has nothing to do with
thalidomide at all.

Those who want a reference for the rapid interconversion of thalidomide
enantiomers in the body are referred below. There is plenty of other stuff
on medline to support it.

And lastly, don't believe anything you see on the net posted by john at
"whale". He lies when he says "hello."

SBH


Eur J Clin Pharmacol  2001 Aug;57(5):365-76
Clinical pharmacology of thalidomide.

Eriksson T, Bjorkman S, Hoglund P.

Hospital Pharmacy, University Hospital, Lund, Sweden.
tommy.eriksson@apoteket.se

BACKGROUND: Thalidomide has a chiral centre, and the racemate of (R)- and
(S)-thalidomide was introduced as a sedative drug in the late 1950s. In
1961, it was withdrawn due to teratogenicity and neuropathy. There is now
a growing clinical interest in thalidomide due to its unique
anti-inflammatory and immunomodulatory effects. OBJECTIVE: To critically
review pharmacokinetic studies and briefly review pharmacodynamic effects
and studies of thalidomide in consideration of its chemical and
stereochemical properties and metabolism.  METHODS: Literature search and
computer simulations of pharmacokinetics.  RESULTS: Rational use of
thalidomide is problematic due to lack of basic knowledge of its
mechanism of action, effects of the separate enantiomers and metabolites
and dose- and concentration-effect relationships. Due to its inhibition
of tumour necrosis factor-alpha and angiogenesis, racemic thalidomide has
been tested with good effect in a variety of skin and mucous membrane
disorders, Crohn's disease, graft-versus-host disease, complications to
human immunodeficiency virus and, recently, in multiple myeloma. Adverse
reactions are often related to the sedative effects. Irreversible toxic
peripheral neuropathy and foetal malformations are serious complications
that can be prevented.  The results of several published pharmacokinetic
studies can be questioned due to poor methodology and the use of
non-stereospecific assays. The enantiomers of thalidomide undergo
spontaneous hydrolysis and fast chiral interconversion at physiological
pH. The oral bioavailability of thalidomide has not been unequivocally
determined, but available data suggest that it is high.  Absorption is
slow, with a time to maximum plasma concentration of at least 2 h, and
may also be dose-dependent; however, that of the separate enantiomers may
be faster due to higher aqueous solubility. Estimation of the volume of
distribution is complicated by probable hydrolysis and chiral inversion
also in peripheral compartments. A value of around 11/kg is however
plausible. Plasma protein binding is low with little difference between
the enantiomers. Elimination of thalidomide is mainly by pH-dependent
spontaneous hydrolysis in all body fluids with an apparent mean clearance
of 10 l/h for the (R)- and 21 l/h for the (S)-enantiomer in adult
subjects. Blood concentrations of the (R)-enantiomer are consequently
higher than those of the (S)-enantiomer at pseudoequilibrium.  The mean
elimination half-life of both enantiomers is 5 h. One hydroxylated
metabolite has been found in low concentrations in the blood. Since both
enzymatic metabolism and renal excretion play minor roles in the
elimination of thalidomide, the risk of drug interactions seems to be
low. CONCLUSIONS:  The interest in and use of thalidomide is increasing
due to its potential as an immunomodulating and antiangiogenic agent. The
inter-individual variability in distribution and elimination is low.
Apart from this, its use is complicated by the lack of knowledge of dose-
or concentration-effect relationships, possible dose-dependent oral
absorption and of course by its well-known serious adverse effects.

Publication Types:
Review
Review, Tutorial

PMID: 11599654 [PubMed - indexed for MEDLINE]