thalidomide

A mild sedative, it was on the market for a few years in the 1950s before being withdrawn. During early pregnancy the formation of limbs was adversely affected, resulting in congenital deformity. Several victims' associations exist.

The drug is now being researched for possible uses in fighting AIDS, where it seems to reduce weight loss.

Despite the bad rep of this drug due to its unfortunate teratogenic effects on foetuses (principally being deformed limbs), there has been some research into therapeutic uses.

Sadly, thalidomide was originally given in some areas to treat morning sickness.

Thalidomide has been approved for use in Leprosy and is being investigated for use for immunological disorders, AIDS and some cancers (including hepatomas and gliomas). It is contraindicated in pregnancy, unsurprisingly.

Side effects of thalidomide are a skin rash, somnolence and constipation.

more information:
http://cerhr.niehs.nih.gov/genpub/topics/thalidomide2.html
http://www.nlm.nih.gov/pubs/cbm/thalidomide.html

I imagine that Thalidomide had no effect on pregnant rats and their offspring. So, we had no way of knowing what would happen in humans. Turns out it's bad fetuses. No one intended the pregnant mothers in the case of thalidomide to be guinea pigs; no one knew the deformaties would happen. How could anyone have known? You wouldn't believe how hard it is to talk pregnant women into new drug testing. This, and other cases, has caused the FDA to swing to the side of extreme caution.

This caution results in the delay or denial of useful drugs to the US population. We have swung so far in the direction of protecting corporations and the FDA that we now have less effective drugs than most other countrires.

Case in point: There is a new treatment available in Canada which is much more effective than what we have here in the US in holding HIV and Hepatitus C at bay. It will likely be years before US Citizens have access to these medications.

I realize some of you will be saying "What does she mean - "protecting corporations and the FDA"? Well, while it seems that new drug approval is delayed here in order to protect consumers (and, indeed, this is probably 50% true), the other side of the story is that the FDA and the pharmaceutical companies do not want to be sued by the .004% of the population that might have a negative reaction to a drug that could save that other 99.996% of the population. The sad part is that the one person who sues can cause a medicine to be removed permanently from the market. Our litigative nature is harming us!

There must be a balance between protection and progress. I hope we find it some day.

Thalidomide is a chiral compound. Tests on mice indicated that one enantiomer is theraputic, the other teratogenic. Unfortunately, a process in the human body racemizes the compound, meaning that, even if you're given a pure dose of the ``safe'' version, you'll end up with the teratogen in your system. Further tests using rabbits showed that both forms of the compound had both effects--teratogenic and theraputic.

It was first synthesised in 1953 and was widely prescribed for morning sickness from 1957 to 1962, but not in the USA, because the Food and Drug Administration had refused to approve it.

In 1992 the FDA urged drug manufacturers to evaluate racemates and enantiomers for new drugs. Patent protection means that if one enantiomer is protected, another might not be, so companies will try to see if they can market a racemate or an enantiomer of an existing product.

In new cancer research, Thalidomide was used as an angiogenesis (formation of new blood vessels) inhibitor to slow or even stop the growth of cancerous tumors. This new phase of cancer research was begun by Dr. Judah Folkman who originally started work as a surgeon. Most cancer research at the time, and even up until just a few years ago, focused on the genetics of the cancer cells themselves - perhaps to find the mechanism by which they spread and thus find a reliable way to keep them from spreading further. Dr. Folkman, being a surgeon and having removed numerous tumors, noticed that the tumors were always riddled with blood vessels and seemed to have a constant supply of fresh blood. Through research he discovered that without these vessels constantly pumping in freshly oxygenated blood, the cancer cells would lay dormant and would not grow any further.

Dr. Folkman also discovered that cancer cells release a molecule that stimulates the formation of new blood vessels so that the cell can gain its much needed blood supply. Essentially the cancer cells would modify the body to make it better suit their growth. Logically, he then searched for a way to inhibit the growth of these new capillaries and thus stop the food supply to the cancerous cells.

Through years of research and with a team of experienced scientists, Dr. Folkman isolated the molecules from some substances that would stop angiogenesis in the right environment. Most of these compounds proved too weak however and the search continued. Through a stroke of luck, one of the scientists working with Dr. Folkman thought to look through existing pharmaceuticals to see if any of them had the side effect that they desired. He stumbled directly onto Thalidomide. Its angiogenesis-inhibiting properties caused the deformity in the children who had been exposed to it in the womb. The drug had stopped the growth of new blood vessels, thus causing loss of limbs and poor circulation.

As stated previously, Thalidomide was not found to be effective enough in clinical trials to be used extensively, but it was one of the building blocks of this new research which could very well be crucial in the fight against cancer. A new drug, called Endostatin, has been produced and has been found to significantly slow the growth of cancer in many individuals.

The research continues, and the documentary this was taken from can be seen at the PBS website.

http://www.pbs.org/wgbh/nova/cancer/

The structure of thalidomide is as follows :-

      
     
     /\     O
    /  \    ||      O
   /    \   /\      \\___
  /  /\  \ /  \     /    NH
 |  /  \  |    \   /      \
 | |    | |     N--        C=O
 |  \  /  |    /   \      /
  \  \/  / \  /     \____/
   \    /   \/
    \  /    ||
     \/     O
     
      

This shows a 6-membered benzene ring fused to a 5 membered nitrogen containing ring, which is then joined to another 6 membered nitrogen containing ring.

Contrary to what FDA tells the US congress when it is defending (or lobbying to expand) its bureaucratic turf the agency did not actively reject thalidomide, rather the agency simply failed to approve it on its normal schedule.

If FDA had followed its normal procedures it would have approved thalidomide for sale in the US. The exact details of the reasons for that delay are certainly not the one's quoted by FDA or the their reviewer.

After the fact (and after having been given the Distinguished Federal Civil Service Award by JFK the reviewer (Francis Kelsey MD) began to claim that she had been concerned about reproductive safety, however she did not document these concerns prior to the onset of deformed births in Europe.

FDA was given widely expanded regulatory power as a direct result of this accidental coup. One direct result is that almost certainly more US citizens die annually from delayed (as compared with the rest of the industrialized world) introduction of new drugs than are benefited by protection of potentially dangerous drugs. Some analyses of the long-term effects of US drug policy can be read in the following URLs.

http://w3.ag.uiuc.edu:8001/Liberty/Tales/Thalidomide.Html
http://www.isil.org/resources/lit/death-regulation.html
http://www.self-gov.org/ruwart/q0106.html

Consider the following scenarios:

Latex is widely recognized as a material which causes allergic reactions in a significant fraction of users. Latex, however is still the material of choice in many context in device design for the simple reason that it has decades of track record. As with drugs, FDA guidelines require highly expensive testing for the use of any new material in any given application.

Additionally, FDA's requirements for new methods virtually never gets less stringent. This directly results in a system that existing designs will be favored (even if they are clearly inferior) in an economic environment whose rules are mostly determined by FDA.

Today in the US there are 3 condoms (to my knowledge) on the market which are made of a material other than latex. By FDA rules none of these are permitted to make any label claim regarding pregnancy or STD transmission until completing a highly expensive battery of testing. It probably costs no more to manufacture a urethane condom than one made of latex, yet these retail at double or more the price of the latex variety. Further, non-latex condoms are not affected by ozone or oil-based lubricants (which cause immediate failure of latex condoms).

One clear group of economic winners here are the manufacturers who have invested in the manufacture of latex condoms. Releasing new condom designs to the market is inexpensive as long as they are of latex construction.

HIV/AIDS therapies are a far more striking (and costly) example. In addition to the discussions in the URLs cited above consider:

The US is (for the present and foreseeable future) the central wheel of new drug and medical device development. Therefor it is principally US concerns which are engaging in research in drug therapies for HIV. The FDA rules substantially prevent US citizens from using more effective drugs with lower levels of toxic effects.

Additionally the developers expect to be paid US - scaled prices for the products they develop. Thus FDA's policies are both substantially escalating the costs of new therapies, and slowing their delivery to patients, and this effect is global.

None of the above is intended to suggest that there are easy answers both our laws and our manner of doing medical research are highly complex and are not quick to change. Also, many of FDA's scientists and researchers are absolutely top people.

The legacy of thalidomide on the US regulation of medical technology however, is not an entirely healthy one.