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Thalidomide

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* THALIDOMIDE * By: KAUSHIK DOWARAH * The thalidomide disaster is one of the darkest episodes in pharmaceutical research history. The drug was marketed as a mild sleeping pill safe even for pregnant women. However, it caused thousands of babies worldwide to be born with malformed limbs. The damage was revealed in 1962. Before then, every new drug was seen as beneficial. Now there was suspicion and rigorous testing. * SYNTHESIS AND EARLY USE * Thalidomide was developed in the 1950s by the West German pharmaceutical company Chemie Grünenthal GmbH to expand the company’s product range beyond antibiotics. It was an anticonvulsive drug, but instead it made users sleepy and relaxed. It seemed a perfect example of newly fashionable tranquilisers. The drug also reduced morning sickness, so it became popular with pregnant women. * First suspicions and the disaster * By 1960 doctors were concerned about possible side effects. Some patients had nerve damage in their limbs after long-term use. In the United States, the Food and Drug Administration (FDA)’s drug examiner Frances Oldham Kelsey did not approve the drug for use. * There was an increase in births of thalidomide-impaired children in Germany and elsewhere. However, no link with thalidomide was made until 1961. The drug was only taken off the market after the German Widukind Lenz and the Australian William McBride independently suggested the link. Over 10,000 children were born with thalidomide-related disabilities worldwide. Well-known people in the UK affected by thalidomide include actor and writer Mat Fraser. * AFTERMATH * Research into thalidomide’s effects on leprosy resulted in a 1967 World Health Organisation (WHO) clinical trial. Positive results saw thalidomide used against leprosy in many developing countries. It is also used successfully to control some AIDS-related conditions, and its effects on various cancers are under investigation. * The renewed use of thalidomide remains controversial. The positive effects are undeniable. However, there is a risk of new thalidomide births, particularly in countries where controls may not be efficient. Black-market trade of unlicensed thalidomide by people with leprosy may increase the risks. * Thalidomide today * Thalidomide is now used as a treatment for leprosy and bone cancer. Its use is heavily regulated, however, to prevent a repeat of the problems it caused in the last century. * This medication is used to treat or prevent certain skin conditions related to Hansen's disease, once known as leprosy (erythema nodosum leprosum). Thalidomide is also used to treat a certain type of cancer (multiple myeloma). It works in Hansen's disease by reducing swelling and redness (inflammation). It also reduces the formation of blood vessels that feed tumors. * MECHANISM OF ACTION * The precise mechanism of action for thalidomide is unknown, but possible mechanisms include anti-angiogenic and oxidative stress-inducing effects. It increases lymphocyte count, costimulates T cells and modulates natural killer cell cytotoxicity. * Thalidomide binds to and inactivates the protein cereblon, which is important in limb formation and for the proliferative capacity of myeloma cells. This was confirmed in studies that reduced the production of cereblon in developing chick and zebrafish embryos using genetic techniques. * SIDE EFFECTS * Drowsiness, dizziness, lightheadedness, constipation, weakness, and dry skin may occur. Thalidomide may cause possibly severe nerve damage, which may be permanent. This may occur during treatment or after treatment has stopped. Any of the following symptoms can occur: numbness/tingling/pain/burning in the feet or hands, muscle weakness/cramps, feeling of tightness in the feet. *

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