Teratogenic effects of nitroimidazopyridazine on the CNS in fetal Wistar (WU) rats.
Teratogenic effects caused by a new nitroimidazopyridazine were examined in Wistar (WU) rats after repeated oral administration of 0, 2.5, 10, and 40 mg/kg, given on days 6-17 post coitum (p.c.) (Day of mating = Day 0) in a regular study on embryo-fetal development according to ICH S5A. At day 20 p.c., fetuses were removed and carefully examined under a dissecting microscope for external, visceral and skeletal malformations. The exposure to the high dose of the test compound during the organogenesis and early histogenesis periods of prenatal development induced prominent CNS malformations (exencephaly, neural tube defects (NTD)) associated with external malformations (hyperflexion of the forelimbs). To support the data from this study additional histological evaluation of the brains was performed with the following results: disorganization of the cerebral cortex associated with ectopic subcommissural organs. Additionally, an in vitro test (whole embryo culture, WEC) showed alterations of the developing neural tube after the incubation of rat embryos with the test compound on gestation days 9.5-11.5. Our data demonstrated that nitroimidazopyridazine caused NTDs and limb malformations during organogenesis. Based on these data the further development of the test compound was stopped.
Institute for Pathology and Toxicology, ALTANA Pharma AG, Friedrich-Ebert-Damm 101, 22047, Hamburg, Germany. Thomas.woehrmann@altanapharma.com
Thomas
T
Woehrmann
Jutta
J
Volland
Klaus
K
Tuch
Gerd
G
Bode
Ulrich
U
Hübel
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001921:Brain / Q000002:abnormalities*; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D005552:Forelimb / Q000002:abnormalities*; D018811:Maternal Exposure; D009924:Organ Culture Techniques; D011247:Pregnancy; D011724:Pyridazines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity*
D011724:Pyridazines; D013723:Teratogens