Peculiarities and Possible Mode of Actions of Thalidomide

Evaluation of the developmental toxicity of lenalidomide in rabbits

“…In view of differences in the developmental effects of thalidomide in various species and the fact that exposure to thalidomide produces limb malformations in rabbit fetuses, among other findings, the NZW rabbit is traditionally considered to be an appropriate model for evaluating the developmental toxicity of thalidomide in humans (Fratta et al, 1965;Schardein, 1985). As summarized by Neubert and Neubert, previously published studies of effects of thalidomide in pregnant rabbits showed a high rate of limb malformation, with 440% of fetuses affected by dosages of 50-500 mg/kg/day (Neubert and Neubert, 1997). In the current study, conducted in conformance with ICH (United States Food and Drug Administration, 1994) and FDA guidelines (United States Food and Drug Administration, 1987), and in which NZW rabbits were given thalidomide at a dosage of 180 mg/kg/day or lenalidomide at a range of dosages from 3-20 mg/kg/day, the incidence of limb malformations in the thalidomide-exposed group was much higher than that observed in these other studies of thalidomide.…”

“…Speciesselective teratogenicity of thalidomide is well established, and many animal species do not respond similarly to humans in which thalidomide produces limb defects (Schardein, 1985;Shepard, 1989;Neubert and Neubert, 1997). Rabbits are among the species that do show limb defects similar to those observed in humans (Somers, 1962;Nudleman and Travill, 1971;Schardein, 1985;Neubert and Neubert, 1997), and studies of thalidomide in rabbits have shown that it causes multiple endpoints of developmental toxicity, including congenital malformations, postimplantation losses, abortions, reduced fetal body weights, and decreased postnatal survival of pups (Hay, 1964;Fratta et al, 1965;Nudleman and Travill, 1971;Teo et al, 2004). However, most of these studies were conducted using rabbit strains with small or no historic databases, relatively few animals, and were academic in nature, i.e., designed to identify the mechanism of action by which limb malformations were induced.…”

Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients

“…On the basis of the AUC values determined in the present study (Table 1), rabbits would be expected to be intermediate between humans and mice in their responsiveness to thalidomide, and there is a single report of daily high doses of thalidomide (200 mg/kg/day) achieving a 55% reduction in tumor volume of V2 carcinomas in rabbits (29). The teratogenicity of thalidomide in rabbits at high doses and in humans at low doses, as well as the resistance of rodents to teratogenicity (14), may also be related to the AUC and exposure to the parent drug (Table 1). Thalidomide modulates the biosynthesis of a number of cytokines that are essential to the growth and survival of multiple myeloma cells, suggesting that its primary mechanism of action in multiple myeloma patients involves down-regulation of cytokine synthesis (30,31).…”

“…The difficulties in determining thalidomide's teratogenic properties during its initial development were perhaps because of the widely disparate interspecies sensitivities to the action of thalidomide. Rodents appear resistant to the teratogenicity of thalidomide, whereas rabbits and humans were highly susceptible (14). It has been suggested that the antiangiogenic and teratogenic effects are caused by stable metabolites, and species specific differences in thalidomide metabolism form the basis for the interspecies differences in the action of thalidomide (15).…”

Sea urchin embryos exposed to thalidomide during early cleavage exhibit abnormal morphogenesis later in development

“…Thalidomide, marketed as Contergan in Germany, gained wide popularity in Europe, Australia, Canada, and Japan, where it is was prescribed as a sedative and sleep aid. Clinical testing in adults indicated that the drug had a very low level of acute toxicity when overdosed (Daemmrich, 2002;Lenz, 1985Lenz, , 1988Neubert and Neubert, 1997). At that time (the late 1950s and early 1960s), extensive reproductive testing was not standard protocol for new drug development and the drug was assumed to be safe for use by pregnant women (Daemmrich, 2002;Neubert and Neubert, 1997;Warkany, 1988).…”