Thalidomide, past and present

Thalidomide 1 see a Lot more in Link

Thalidomide is widely regarded as the worst drug disaster in history for its role in causing thousands of congenital malformations. This post attempts to provide a brief overview of how the tragedy came about and outlines how the same drug has now made a comeback in the treatment of cancer and leprosy.

Thalidomide was developed in West Germany in 1954 by a pharmaceutical company that was attempting to produce low-cost antibiotics. The drug displayed no antibiotic properties but was found to act as a sedative. It was labelled non-toxic as extremely high doses were given to rats, mice, guinea pigs, rabbits, cats and dogs with no apparent side effects. No further testing was done before the drug was released commercially in 1957. Sold in 46 countries worldwide, thalidomide quickly became a best-selling medication and in many places it was nearly as popular as aspirin.

Lauded as a completely safe alternative to barbiturate sleeping tablets, thalidomide was used in the treatment of anxiety, insomnia and seizure disorders. Patients reported that the drug had a calming and sleep inducing effect. After it was found to have antiemetic properties it was commonly prescribed for women suffering from morning sickness in the first trimester of pregnancy.

Concerns arose when doctors began to report that some patients who had been taking the drug were developing signs of nerve damage known as peripheral neuritis. Even more alarming was the unusually high rate of babies being born with malformations. In particular, phocomelia – a rare congenital condition in which the limbs are stunted or missing – appeared at a level never previously seen. By 1961 thalidomide had been banned and withdrawn from the international market after use of the drug was linked to the incidence of these severe birth defects.

Between 1957 and 1961 an estimated 40 000 people developed peripheral neuritis and 12 000 infants were born with malformations. In addition to missing or shortened limbs, deformities included blindness, brain damage and the absence of internal organs. More than half of these children died within their first year while the survivors suffered lasting disability. The thalidomide tragedy resulted in improved drug testing procedures and many survivors have received compensation awarded through high profile lawsuits.

Given the effects of the tragedy, it it surprising to note that thalidomide is still used today as the result of a serendipitous discovery made after the drug was banned. In 1964 the Israeli doctor Jacob Sheskin was caring for a patient with erythema nodosum leprosum, a painful dermatological complication of leprosy. After finding an old bottle of thalidomide in a cupboard he gave it to the patient to help him sleep because the man was dying and in a lot of pain. To his surprise the man slept soundly and awoke feeling better the following morning. New clinical trials supported this discovery and thalidomide revolutionised the treatment of leprosy by improving the management of erythema nodosum leprosum.

Thalidomide has also been approved for the treatment of some types of cancer and is particularly effective for multiple myeloma after attempts at standard therapies such as chemotherapy have proven unsuccessful. Research has shown that the drug inhibits the growth of new blood vessels from pre-existing ones (a process known as angiogenesis). Tumours are unable to grow without a steady blood supply; thalidomide prevents the proliferation of malignant cells by reducing the angiogenesis of surrounding blood vessels.

It has been proposed that the drug’s effect on neural tissue and blood vessel development is the mechanism for the birth defects seen in the late 1950s and early 1960s. Although it is now known that pharmaceuticals can cross the placenta, at that time it was thought to be a barrier that protected the foetus from the harmful substances the mother was exposed to. Angiogenesis of the placenta is crucial for foetal development and the transfer of oxygen, nutrients and wastes. The first trimester of pregnancy is a critical period for the development of basic body structures and organ systems and it appears that a restriction in vascular growth resulting from the drug seriously impacted this process.

Sadly there is a second generation of thalidomide victims in the babies born to Brazilian women taking the drug for the treatment of leprosy. Researchers are currently working to develop a safe analogue of thalidomide that can be administered to leprosy and cancer patients without the risk of causing birth defects.

Image credit

Derer, M. (1998). Thalidomide [Image]. Retrieved from https://www.flickr.com/photos/duckwalk/9636420141

References 

Goldman, D. A. (2001). Thalidomide use: past history and current implications for practice. Nursing Oncology forum, 28(3), 471-477.

Silverman, W. A. (2002). The schizophrenic career of a “monster drug”. Pediatrics, 110(1), 404-406.

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