Higdon G L, McKinley E R, Markham J K
Toxicology Research Laboratories, Eli Lilly and Co., Greenfield, Indiana 46140.
Teratology. 1991 Jul;44(1):37-44. doi: 10.1002/tera.1420440107.
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.
阿美托利德是一种新型抗惊厥药，在动物模型中已显示出对控制癫痫发作有效。在两个物种中评估了阿美托利德的发育毒性。自然交配的大鼠和兔子分别在妊娠第6至17天和第6至18天通过灌胃每日给药一次。大鼠给予0、10、25或50mg/kg的剂量；兔子给予0、25、50或100mg/kg的剂量。在妊娠第20天对大鼠进行剖腹手术，在妊娠第28天对兔子进行剖腹手术。在大鼠中，25mg/kg和50mg/kg剂量水平出现母体毒性，表现为体重增加受抑。50mg/kg剂量水平时胎儿体重降低。胎儿活力和形态未受影响。大鼠成体毒性和发育毒性的未观察到影响水平（NOEL）分别为10mg/kg和25mg/kg。在兔子中，50mg/kg和100mg/kg剂量水平出现母体毒性，表现为体重净损失。100mg/kg剂量水平时胎儿活力和体重降低。在50mg/kg剂量水平（伴有严重母体毒性）时，一只胎儿的右前爪出现指骨缩短，在100mg/kg剂量水平时，来自不同窝的两只胎儿的后爪出现指骨缩短。在100mg/kg剂量水平时，来自四窝的九只胎儿的前爪出现指骨骨化不全。阿美托利德在兔子中具有弱致畸性。兔子成体毒性和发育毒性的NOEL为25mg/kg。
