替芬泰大鼠胚胎-胎仔发育毒性研究  

Studies on embryos-fetus developmental toxicity of Tyrophentide

作　　者：温和 刘妍[1] 高绪聪[1] 申秀萍[1] 黄正明 梁光益 WEN He;LIU Yan;GAO Xucong;SHEN Xiuping;HUANG Zhengming;LIANG Guangyi(Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co. Ltd, Tianjin 300193, China)

机构地区：[1]天津药物研究院新药评价有限公司,天津300193

出　　处：《药物评价研究》2018年第5期810-815,共6页Drug Evaluation Research

摘　　要：目的对妊娠动物从胚胎着床至硬腭闭合期ig给予替芬泰,评价其对妊娠动物、胚胎及胎仔发育的影响。方法将交配成功后的SD大鼠于妊娠6~15 d连续ig给予替芬泰,剂量为50、175和620 mg/kg,溶媒对照组给予0.5%羧甲基纤维素钠溶液。试验期间定期记录孕鼠体质量及24 h摄食量,于妊娠21 d解剖孕鼠进行大体检查,称量子宫质量,计数黄体数,植入数,吸收胎、死胎和活胎数。胎仔经称质量、性别鉴定、顶臀长和尾长测定及外观检查后,各留取50%胎仔制作标本进行骨骼和内脏的检查。结果给药期间,与溶媒对照组比较,替芬泰175(个别天数)和620 mg/kg剂量组孕鼠24 h摄食量明显减少、体质量明显降低及体质量增长明显缓慢(P<0.05、0.01);3个剂量的受试物对孕鼠的生育能力无影响;620mg/kg剂量组胎仔体质量偏低;在胎仔外观、内脏和骨骼检查中,给药组和溶媒对照组均出现一些发育异常,其中与溶媒对照组比较,620 mg/kg剂量组胎仔体质量显著降低、波状肋发生率明显增加(P<0.05、0.01),其他指标均差异不显著。结论本试验条件下,ig给予175和620 mg/kg剂量的替芬泰,妊娠大鼠出现一定的系统毒性,50 mg/kg(临床拟用剂量的30倍)为妊娠大鼠的无毒性反应剂量;ig给予620 mg/kg替芬泰,对胚胎发育有一定毒性,175 mg/kg剂量为大鼠胚胎发育的无毒性反应剂量。Objective To evaluate the effects on the pregnant female, and development of the embryo and fetus consequent to expose Tyrophentide to the female from implantation to closure of the hard palate. Methods Three dose of Tyrophentide（50, 175, or 620 mg/kg） were administered by ig method to mated SD female rats over days 6 – 15 of gestation. Control animals received 0.5% CMC-Na solution by gavage. Body weight and food consumption data in dams were collected during the study. On day 21 of gestation, the dams were euthanized and examined grossly. The uterus was removed and weighed. The numbers of corpora lutea, implantations, absorbed fetuses, dead fetuses, and live fetuses were counted. After the fetuses subsequently weighed, sexed, measured crown-rump length, and examined for external, approximately one half of the fetuses respectively in each litter were examined visceral and skeletal abnormalities. Results During the administration period, compared with dissolvent control group, there were significant decreased in maternal food consumption, mean body weight, and body weight gain in the 175 and 620 mg/kg groups（P 〈 0.05 and 0.01）. There was no reproductive toxicity noted in dams in all groups. Compared with dissolvent control group, at the 620 mg/kg dose, there were significant changes seen including a decreased fetal body weight and an increased incidence of wavy ribs. Conclusion Under the experimental conditions, by gavaging to Tyrophentide, the nontoxic reaction dose was 50 mg/kg（30 times the dose for clinical use） in dams based on a general toxicity at 175 and 620 mg/kg dose. The Nontoxic reaction dose for embryo-fetal development was 175 mg/kg based on teratogenicity and embryofeto-toxicity at 620 mg/kg dose.

关 键 词：替芬泰 胚胎-胎仔发育毒性 大鼠 

分 类 号：R962.2[医药卫生—药理学]