Teratogenic effects of Thalidomide

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 critical phase for teratogenic effects of thalidomide is from the 27th to the 40th day after conception or from the 37th to the 54th day after the first day of the last menstrual period (155). In 12 of 86 cases the date of conception was fairly well known and the narrowest... 

Teratogenic effects of thalidomide are well described in several animal models. Pregnant cats have tolerated doses of 500 mg kg day of thalidomide... 

Human CRBN encodes a 442-amino acid protein that had been reported to interact with DDBl in a proteomic analysis [13]. However, the functional relevance of this interaction was unclear at that time. DDBl is a component of E3 ubiquitin ligase complexes [ 14]. Molecular biological and biochemical studies ultimately showed that thalidomide binds to CRBN and inhibits the associated ubiq-uitin ligase activity. From extensive experimentation with zebrafish and chicks, Handa and coworkers demonstrated that these interactions are responsible for the teratogenic effects of thalidomide. 

The macaque embryofetal development study design has been shown to be appropriate for detecting the teratogenic effects of the small molecular weight drugs thalidomide and isotretinoin [35,36]. For large molecular weight biopharmaceuticals that do not cross the placenta the standard macaque... 

Aside from teratogenicity, the main adverse effects of thalidomide include somnolence, dizziness, fatigue, tremor, rash, constipation, and edema. Although these adverse effects are generally mild and reversible, more severe adverse effects, such as peripheral neuropathy, deep vein thrombosis, and neutropenia, have occasionahy been reported. 

Thalidomide has significant teratogenic effects in humans, and it also affects the central and peripheral nervous systems through unknown mechanisms. Evidence of a toxic arene oxide metabolite is unsubstantiated. Thalidomide likely inhibits neutrophil chemotaxis and monocyte phagocytosis, inhibits free radical formation, and alters the ratio of helper and suppressor T-cells. Reduced formation of tissue necrosis factor-a may be at least partially responsible for the antiinflammatory effects of thalidomide. 

The glutarimide best known to the lay public, thalidomide (40), owes its reputation not to efficacy, but to the wholly unanticipated and tragic teratogenic effects elicited by this compound. It might be noted that the very efficacy and lack of the usual barbiturate side effects shown by this drug led to its prescription as a hypnotic for expectant mothers. Condensation of the phthalimide of glutamic acid (39) with ammonia at elevated... 

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