Thalidomide

Thalidomide (C₁₃H₁₀N₂O₄; phthalimido-glutarimide; one of a number of systematic names is 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione) is a sedative[?] and hypnotic drug that was sold during the 1950s and 1960s as a sleeping aid[?] and to pregnant women as an antiemetic to combat morning sickness and other symptoms. Thalidomide is most widely known for the large number of severe birth defects discovered in the babies of women who had taken the drug during the 1960s.

The drug was synthesized at Chemie Grünenthal in West Germany in 1953. It was marketed from October 1, 1957 mainly in Germany and Britain and was available in around fifty countries, although not in the USA, under at least forty different names (such as Talimol, Kevadon, Nibrol, Sedimide, Quietoplex etc).

It was later (1960-61) found to be teratogenic in fetal development, most visibly as a cause of amelia or phocomelia as the drug is a angiogenesis inhibitor - interfering with blood vessel development, especially if taken during the first 25 to 50 days of pregnancy. Around 15,000 fetuses were damaged by Thalidomide.

Thalidomide is racemic; one isomer is effective against morning sickness, and the other is teratogenic.

The drug is most toxic if taken orally and is a mild carcinogen. Other symptoms can include peripheral neuritis[?], numbness, paresthesias in the extremities, peripheral neuropathy, mental confusion, unsteadiness, hypotension, and absent reflexes. Excessive dosages can lead to pulmonary oedema, atelectasis or aspiration pneumonia, and refractory hypotension.

Thalidomide was banned for its intended use but it has been found to be effective elsewhere and is currently (2001) undergoing clinical trials with the name Thalomid(R): as an antineoplastic agent, in the treatment of leprosy symtoms (ENL, erythema nodosum leprosum), in HIV related symptoms by reducing inflammation (blocking Tumor Necrosis Factor[?] (TNF)), for advanced multiple myeloma, prostate cancer, and glioblastoma, and Crohn's disease.

The Thalidomide Tragedy Thalidomide had passed safety tests performed on animals, primarily because the proper tests - particulary those involving pregnant animals - had not been correctly administered. These tests were either conducted inadequately, or the results were faked. In fact, later tests demonstrated that administering thalidomide to pregnant rats reduces the number in the litter by 50%, and giving it to rabbits produces characteristic deformities in the offspring. If such basic testing had ever been done, thalidomide would never have been approved to be sold anywhere. Some opponents of animal testing still incorrectly cite thalidomide as an example of the ineffectiveness of such testing.

In 1960, Chemie Grünenthal decided to expand into the United States, and applied to the Food and Drug Administration for approval to sell the drug. This approval was not expected to be controversial, and the case was given to the agency's newest reviewer, Frances Oldham Kelsey[?]. Kelsey had previously done animal toxicity research (including effects in pregnancy), and refused to clear thalidomide for sale until she obtained better documentation of its effects, especially in light of some unusual neurolical side effects being reported in Britain. In fact, the testing had not been done adequately, and satisfactory documentation was not forthcoming.

Though the US marketer (William S. Merrell Company[?]) was increasing pressure to have it cleared for sale, Kelsey held out for more toxicity data before coming to a decision. The decision was pre-empted by births throughout the world giving evidence of thalidomide's effect on the embryo, and the manufacturers quickly withdrew their application. Kelsey's delay probably prevented thousands of deformities in the US, and made her a national hero.

In August 1962, Frances Kelsey was awarded the President's award for distinguished Federal Civilian Service (the highest civilian award in the US) by President John F. Kennedy.

Seven members of Chemie Grünenthal were put on trial for various falsification of records and attempt to cover-up the effects of thalidomide. The case lasted over two years, before the prosecutor decided (December 1970) not to continue, as in April 1970, Chemie Grünenthal had made an out-of-court agreement to pay 100 million Marks into a trust fund for the 2,866 known victims in Germany.

In Britain, the drug was manufactured by Distillers, an alcoholic drinks company that wanted to branch out into the profitable pharmaceutical market. They marketed thalidomide under the tradename 'Distaval'; it was widely used, with the same disastrous effects seen elsewhere. By the early 1970s, pressure was growing from the parents of affected children for compensation: since they were not legally obliged to do so, Distillers refused, claiming their duty to stockholders in the company. Matters came to a head as public opinion hardened against Distillers; around 1973, small posters began to appear nationwide - professionally printed, from an unknown source - urging a boycott of Distillers' products, and listing the alcoholic drinks made by them. In the face of a barrage of bad publicity, and signs of an emerging boycott, Distillers capitulated, setting up a large fund for the needs of the affected children.