Thalidomide, teratogenesis

Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis -Xenopus (EETAX) ... 

Although, in the 1950s nonclinical safety testing was limited to rodents, with appropriate testing, malformations could be produced in that species and resorptions were a known indicator of possible teratogenesis. The separation of response in rats and rabbits with thalidomide formed the basis for reproductive toxicology guidelines used today. 

The adverse effect profile of thalidomide is extensive. The most important toxicity is teratogenesis. Because of this effect, thalidomide prescription and use is closely regulated by the manufacturer. Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis. Thrombosis is sufficiently frequent, particularly in the hematologic malignancy population, that most patients are placed on some type of anticoagulant when thalidomide treatment is initiated. 

The mechanism underlying thalidomide teratogenesis has been the subject of considerable research. Thalidomide exists as two isomers, one intriguing finding is that there is a difference in the toxicity of the two isomers of thalidomide, with only the S- enantiomer being teratogenic and not the R+ enantiomer (Fig. 7.74). 

Hansen, J., and Harris, C. A novel hypothesis for thalidomide-induced limb teratogenesis Redox mis-regulation of the NF-kB pathway. Antioxid. Redox Signal. 6,1-14, 2004. 

GORDON, G.B., SPIELBERG, S.P., BLAKE, D.A. and BALASEIBRAMANIAN, V. (1981) Thalidomide teratogenesis Evidence for a toxic arene oxide metabolite. Proc. Natn. Acad. Sci. USA, 78,2545. 

A final remarkable feature of teratogenesis is the dramatic species- and strain-dependent variability in susceptibility for some xenobiotics. For example, some strains of mice are sensitive to phenytoin teratogenicity, while other strains are resistant. In the case of thalidomide, primates (including humans) and rabbits are sensitive, while all rodent (mice and rats) strains tested are resistant. These differences must be considered in the design and interpretation of data from animal studies when directed towards an evaluation of human risk. 

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