Embryotoxic effects of thalidomide derivatives in the non-human primate callithrix jacchus. IV. Teratogenicity of micrograms/kg doses of the EM12 enantiomers.
The dose-response of the teratogenic potency of the thalidomide (Thd) derivative EM12 was evaluated in the common marmoset (Callithrix jacchus). The smallest daily dose found to be effective was 30 micrograms EM12/kg body wt. This is the lowest dose of a Thd derivative ever reported to induce severe skeletal abnormalities. Ten micrograms EM12/kg body wt may be considered the no-observed-adverse-effect-level (NOAEL) under the experimental conditions chosen. The teratogenic potencies of the two EM12 enantiomers were tested at 100 micrograms/kg body wt, the dose which just induces an almost 100% effect in the case of the racemate. The S(-)-EM12 was found to induce typical severe limb abnormalities such as amelia, phocomelia, and radius aplasia, and none of the exposed fetuses were devoid of skeletal defects. In contrast, only few and minor skeletal defects were observed after application of the R(+) enantiomer. Although a pronounced teratogenic potency of the R(+)-EM12 can now largely be excluded, these low-dose studies are not sufficient to completely rule out any teratogenic potential of this enantiomer, since racemisation to small amounts of the S(-) form may occur in vivo. Further studies with Thd derivatives which are unable to racemise are necessary to prove the assumed complete ineffectiveness of the R(+) enantiomers.
Heger
W
W
Institut für Toxikologie und Embryopharmakologie, Universitätsklinikum Rudolf Virchow, Freie Universität Berlin, Germany.
Schmahl
H J
HJ
Klug
S
S
Felies
A
A
Nau
H
H
Merker
H J
HJ
Neubert
D
D
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D013237:Stereoisomerism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000633:toxicity
C001079:2-(2,6-dioxopiperidin-3-yl)phthalimidine; D013792:Thalidomide