Teratogenicity thalidomide-induced

One enantiomer of penicillamine (D-) exhibits antiarthritic properties but foe other is highly toxic (Figure 8.3). The teratogenic effects of thalidomide were induced by one enantiomer, foe other exhibited foe beneficial effects against morning sickness. 

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

Although the concept of drug-induced teratogenicity was well established at the time thalidomide was being developed, questions remain today as to whether the effects on embryo-fetal development would have been detected using the standard testing methods. 

There is clear evidence from many different sources that the metabolism of compounds may be involved in their teratogenic effects, as will be seen in the final chapter in the discussion of thalidomide and diphenylhydantoin teratogenicity. The embryo and fetus of some species clearly have metabolic activity toward foreign compounds, which may be inducible by other foreign compounds. 

Pregnancy (A). Limb malformations induced by the hypnotic thalidomide (Contergan) first focused attention on the potential of drugs to cause malformations (teratogenicity). Drug effects on the unborn fall into two basic categories ... 

The two enantiomers of thalidomide, R and S, undergo fast chiral interconversion at physiological pH (16). The apparent clearance rates in adults are 10 1/hour for R-thahdomide and 211/hour for 5-thalidomide however, each has a half-life of about 5 hours, impljdng different volumes of distribution (70 hters for the R-enantiomer and 150 hters for the 5-enantiomer). Because of rapid interconversion, administration of R-thahdomide alone as a hjrpnotic would not avoid the teratogenic affects of 5-thalidomide. Thalidomide does not induce its own metabohsm. Its plasma protein binding is low. 

The drug thalidomide serves to illustrate the first of these points with respect to hypnotic potency, the (S)-(—), (ii)-(+) and (i S)-( ) racemate of thalidomide are all equally active, as tested by prolonging of sleep induced by phenobarbitol. (5)-(-)-Thalidomide, but not (/f)-(+)-thali-domide, is transformed in vivo to L-A -phthaloylglutamine and L-Af-phthaloylglutamic acid, products that are both embryotoxic and teratogenic in SWS mice and Natal rats. The d isomers of these products, formed by the drug, are not. ... 

At best, it floats about in the body doing nothing. At worst, it interacts with a totally different receptor and results in an undesired side-effect. Herein lies the explanation for the thalidomide tragedy. One of the enantiomers was an excellent sedative. The other reacted elsewhere in the body as a poison and was teratogenic (induced abnormalities in human embryos). If the two enantiomers had been separated, then the tragedy would not have occurred. 

Have adverse toxicological effects e.g. ethambutolantituberculosis, while enantiomer may induce blindness (also, by reputation, thalidomide (/ -sedative, i -teratogenic) but see qualification in text and references cited therein)... 

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