Developmental toxicity study in rats treated with the anticonvulsant, ralitoline.
The developmental toxicity of the anticonvulsant compound, ralitoline, was investigated in Sprague-Dawley rats administered oral doses of 0, 15, 60, 120, 180, or 240 mg/kg on days 6 through 15 of gestation. An untreated control group and a vehicle control group pair-fed to the high dose group were included. Maternal and fetal parameters were evaluated on day 21 of gestation. Fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal death occurred at 180 and 240 mg/kg. Dose-dependent decreases in body weight, food consumption, and water consumption were observed at 60 mg/kg and above. Body weight gain during treatment was similar in the pair-fed and 240 mg/kg groups. Dose-related CNS signs (hypoactivity, ataxia, prostration, and/or convulsions) were observed at 60 mg/kg and above. Decreased numbers of live fetuses and increased postimplantation loss were observed in a dose-related manner at 120, 180, and 240 mg/kg while no changes occurred in pair-fed controls. Fetal body weights and placental weights were decreased in pair-fed controls and in the 120, 180, and 240 mg/kg groups. The percent fetuses per litter, and the percent litters with external/visceral malformations, were significantly increased at 120, 180, and 240 mg/kg compared with vehicle and pair-fed controls. Dose-related increases in cardiovascular malformations, specifically of the aortic arch (interrupted, stenotic, extra vessel), were apparent at 120 mg/kg and above. The incidence of skeletal variations was increased at 120 mg/kg and above.(ABSTRACT TRUNCATED AT 250 WORDS)
Dostal
L A
LA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Anderson
J A
JA
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D000927:Anticonvulsants / Q000633:toxicity*; D001013:Aorta, Thoracic / Q000002:abnormalities*; D001259:Ataxia / Q000139:chemically induced; D001842:Bone and Bones / Q000002:abnormalities; D004305:Dose-Response Relationship, Drug; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D005327:Fetal Resorption / Q000139:chemically induced; D007928:Lethal Dose 50; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced; D013844:Thiazoles / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
D000927:Anticonvulsants; D013844:Thiazoles; C054894:Ralitoline