Ban Y, Konishi R, Kawana K, Nakatsuka T, Fujii T, Manson J M
Development Research Laboratories, Banyu Pharmaceutical Co., Ltd. Saitama, Japan.
Arch Toxicol. 1994;69(1):65-71. doi: 10.1007/s002040050139.
L-691,121 is a class III antiarrhythmic agent which blocks potassium currents, leading to prolongation of cardiac potential and prevention of cardiac arrhythmia. In a developmental toxicity study in rats, there was a dose-dependent decrease in embryonic/fetal survival, and death of the entire litter was seen at an oral dose of 0.8 mg/kg per day. The critical period for embryolethality was determined as gestational days (GD) 10-13. In a study where females received 1 mg/kg on a critical day (GD 10 or 12) and were killed at 24-h intervals, a high embryonic mortality was seen at 72 h (GD 10 treatment) or 48 h (GD 12 treatment) after dosing. The surviving embryos had morphological abnormalities such as enlarged cardiac tube and pericardium, generalized edema, and hematoma. In order to investigate a possible mechanism for the embryolethality, GD 11 embryos were dissected from females at 4 h after dosing of 1 mg/kg and incubated for 5 h in vitro. The embryonic heart rates were decreased for the first 2 h after incubation but tended to recover to control levels thereafter. When GD 11 embryos were incubated for 4 h with the drug, there were decreases in the heart rates during the entire observation period. In a washout study where the embryos were transferred to drug-free medium after 1-h exposure, decreased heart rates recovered to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)
L-691,121是一种III类抗心律失常药物，它可阻断钾电流，导致心脏电位延长并预防心律失常。在一项大鼠发育毒性研究中，胚胎/胎儿存活率呈剂量依赖性下降，口服剂量为每天0.8毫克/千克时可见整窝死亡。胚胎致死的关键时期确定为妊娠第10至13天。在一项研究中，雌性大鼠在关键日（妊娠第10天或12天）接受1毫克/千克药物，每隔24小时处死一批，给药后72小时（妊娠第10天给药）或48小时（妊娠第12天给药）出现高胚胎死亡率。存活的胚胎有形态异常，如心脏管和心包增大、全身性水肿和血肿。为了研究胚胎致死的可能机制，在给1毫克/千克药物后4小时从雌性大鼠中取出妊娠第11天的胚胎，在体外培养5小时。培养后的前2小时胚胎心率下降，但此后趋于恢复到对照水平。当妊娠第11天的胚胎与药物一起培养4小时时，在整个观察期内心率下降。在一项洗脱研究中，胚胎暴露1小时后转移到无药培养基中，下降的心率恢复到对照水平。（摘要截短于250字）
