Thalidomide phocomelia

The spectrum of malformations was also notable for its breadth. In addition to phocomelia, thalidomide babies suffered from spinal cord defects, cleft lip or palate, absent or abnormal external ears, and heart, renal, gastrointestinal or urogenital malformations (D Arcy 1994 See also US HHS 1997 ). Before the epidemic was finished, over 12000 infants were born with deformities attributable to thalidomide (Sherman 1968 see also Szeinberg 1968 see also Flaherty 1984 ). In 1971, 62 of the estimated 430 British children injured by... 

Lenalidomide was approved recently for the indication of myelodysplastic syndrome where the 5q deletion is present. Since lenalidomide is an analog of thalidomide, all the same precautions must be taken to prevent phocomelia. The time to maximum lenalidomide concentrations occurs 0.5 to 4 hours after the dose. The terminal half-life ranges from 3 to 9 hours. Approximately 65% of lenalidomide is eliminated unchanged in the urine, with clearance exceeding the glomerular filtration rate. To date, no pharmacokinetic studies have been done in patients with renal dysfunction. Lenalidomide is used in the treatment of myelodysplastic syndrome and multiple myeloma. Other side effects are neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary embolus. 

Thalidomide Developed as a sedative in the early 1960s but found to cause a rare birth defect, phocomelia. In 1962 legislation was passed that new drugs must undergo sufficient animal and human testing prior to approval for use by the US FDA. 

Case-control studies start with patients that had the event of interest, often an adverse event (such as phocomelia), and compare the previous events (such as medications used) in the patients lives to those in a group of control patients who did not have the event of interest. These studies are especially useful to generate ideas about causes of uncommon events. The example of thalidomide-induced phocomelia is a classic example of the use of this epidemiological approach. 

The second catastrophe that influenced the development of medicines regulation far more than any event in history was the thalidomide disaster. Thalidomide was a sedative and hypnotic that first went on sale in Western Germany in 1956. Between 1958 and 1960 it was introduced in 46 different countries worldwide resulting in an estimated 10,000 babies being born with phocomelia and other... 

Thalidomide was not evaluated as it needs a specific MAS in our FETAX setup, but the Xenopus laevis embryo has been shown to be sensitive to the teratogenic activity of thalidomide, phocomelia being observed after metamorphosis (17). 

Thalidomide Phocomelia (shortened bones of tiie limbs)... 

Thalidomide First Phocomelia (shortened or absent long bones of the limbs) and many internal malformations... 

This is a sedative drug with low adult toxicity, which proved to be a very potent human teratogen, causing phocomelia (shortening of the limbs) and other defects when taken between the third and eighth week. In some cases, only a few doses were taken, but on the critical days (e.g., days 24-27 for phocomelia of arms). It is not readily reproducible in laboratory animals (e.g., rats). Mechanism is unknown, but a metabolite suspected, possibly produced by cytochrome P-450. A number of metabolites are produced and some chemical breakdown occurs. Phthalylglutamic acid metabolite is teratogenic in mice. Thalidomide may acylate nucleic acids and polyamines. The S-enantiomer is more embryotoxic than the R-enantiomer. 

Specifically, thalidomide produced a characteristic stunting of limb bud tissue, apparently due to interference with normal vascularization. The result was the development of a relatively unique syndrome known as phocomelia. At least 10,000 children, most of them German, were born with flippers instead of arms or legs. Unfortunately, some thalidomide babies are still being born in South America where the drug continues to be manufactured and many people are unaware of its proper uses (it is used fairly extensively for treating certain skin lesions in leprosy patients). 

Phocomelia The syndrome of having shortened arms and legs due to an adverse effect on the embryo such as caused by thalidomide. 

Taussig HB. A study of the German outbreak of phocomelia The thalidomide syndrome. JAMA 1962 180 110 14. 

The principles of teratology have been articulated by Wilson (104). The first principle is that teratogens act with specificity. A teratogen produces a specific abnormality or constellation of abnormalities. For example thalidomide produces phocomelia/ and valproic acid produces neural tube defects. This specificity also applies to species because drug effects may be seen in one species and not in another. The best example is cortisol which produces cleft palate in mice but not in humans. 

It was withdrawn from the [West] German market in November and from the British market in December 1961. By that time reports had also come from other coimtries. A case-control study showed that of 46 cases of phocomelia 41 mothers had taken thalidomide and of 300 mothers with normal babies none had taken thalidomide between the fourth and ninth week of pregnancy. 

Drugs known to be teratogenic include cytotoxics, warfarin, alcohol, lithium, methotrexate, phenytoin, valproate, ACE inhibitors and isotretinoin. Selective interference can produce characteristic anatomical abnormalities, and the phocomelia (flipper-Uke) limb defect was one factor that caused thalidomide to be so readily recognised. (For an account of thalidomide see p. 81.)... 

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