Embryotoxic effects of thalidomide-derivatives in the non-human primate Callithrix jacchus. I. Effects of 3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (EM12) on skeletal development.
The response of pregnant marmosets (Callithrix jacchus) to the thalidomide derivative EM 12 was evaluated. EM 12 was selected for these studies because it is more active than thalidomide and is much more stable for hydrolysis. Skeletal gross structural abnormalities were observed when EM 12 was given to marmosets for 3-7 days during the period between days 49 and 60 post ovulation. Using the treatment schedule finally adapted in our laboratory, i.e. treatment during days 51-57 post ovulation, doses of 5 (or 10) mg EM 12/kg body wt induced the typical limb abnormalities known from man with an 80-100% certainty. In some animals we could observe the typical pattern of abnormalities even with doses as low as 1 mg EM 12/kg body wt. Abnormalities of the skeleton induced during this sensitive period are described. None of these (except some bifurcations of ribs) were seen in any of the ten litters (23 fetuses) serving as controls during the period of the study.
Merker
H J
HJ
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Heger
W
W
Sames
K
K
Stürje
H
H
Neubert
D
D
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D005147:Facial Bones / Q000002:abnormalities; D005260:Female; D005865:Gestational Age; D017880:Limb Deformities, Congenital; D008297:Male; D011247:Pregnancy; D012886:Skull / Q000002:abnormalities; D013045:Species Specificity; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000633:toxicity
C001079:2-(2,6-dioxopiperidin-3-yl)phthalimidine; D013792:Thalidomide