Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant.
Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.
Higdon
G L
GL
Toxicology Research Laboratories, Eli Lilly and Co., Greenfield, Indiana 46140.
McKinley
E R
ER
Markham
J K
JK
D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001549:Benzamides / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D015394:Molecular Structure; D011817:Rabbits; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains
D000927:Anticonvulsants; D001549:Benzamides; C055323:ameltolide