thalidomide

Last week we had news that a drug trial in France led to one fit, young healthy man dying and has left another five volunteers with serious brain damage. A new drug which acted on cannabis receptors and was hoped to act as a pain killer was being trialled on 90 young men.

In 2006 the TGN1412 trial at Northwick Park Hospital in London led to severe multiple organ dysfunction in 5 healthy volunteers. It was given at supposed sub-clinical doses, some 500 times lower than the dose found safe in animals. It is hard to predict how drugs will work in humans. We can and must do trials on tissue samples, animal testing is still necessary but all new drugs are ‘unknown’.

The thalidomide scandal was the worst drug scandal. In the UK alone 2000 babies were born limbless. This recent drug tragedy in France is particularly poignant because  ‘Attacking The Devil’ the thalidomide story a film about the disaster was released on Friday.

Thalidomide was developed by a German drug company 50 years ago. It was found to have a number of benefits particularly for nausea and sickness and was marketed as being especially beneficial for pregnancy sickness. At that time it was thought that drugs did not cross the placental barrier and were not passed to the foetus. Thousands of pregnant women took the drug which caused phocomelia – a condition in which limb development fails.

Estimates of the number affected range from 10,000 to 20,000. There are varying degrees of severity; in the most severe hands and feet are directly attached to shoulders or hips with no intervening limb. The number of limbs affected also varies. Victims are of normal intelligence. Most have adapted by learning to write and draw with a foot for example but now aged around 50 they are suffering from arthritis from over use of their remaining limbs

Optical isomerism

Thalidomide has one chiral atom and so exists as two enantiomers. The S enantiomer is tetragenic [causes birth defects]  but the R isomer was an effective sedative and anti sickness tablet. However conversion between the two occurs in a patient’s body. One theory is that S thalidomide fits neatly into the major groove of DNA at purine sites and has an effect on genes controlling the development of blood vessels particularly limbs and also eyes and ears. Another theory is that S thalidomide binds to the protein cereblon which is important in limb formation.

Sickness in pregnancy occurs in the early stages, the first 12 weeks of pregnancy. This is when development of the foetus occurs, by 12 weeks the organs in a foetus are virtually fully formed and it mainly just grows in size for the remainder of the pregnancy. Thalidomide therefore had devastating consequences as it was marketed for early pregnancy symptoms. The Thalidomide disaster led to much more stringent drug testing and general rule that drugs should not be given to pregnant women especially in the early stage of pregnancy.

Interestingly Thalidomide’s effect of suppressing blood vessel growth means it is now being used as treatment for cancers and auto-immune condition, so some good may finally come out of this tragedy.

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