华蟾素注射液心脏毒性评价  

Cardiotoxicity assessment of cinobufotalin injection

作　　者：李旻 黄黎华 邵姝鸣 崔甜甜 黄明姝 汪溪洁 李华 马璟 LI Min;HUANG Li-hua;SHAO Shu-ming;CUI Tian-tian;HUANG Ming-shu;WANG Xi-jie;LI Hua;MA Jing(China State Institutes of Pharmaceutical Industry,Shanghai InnoStar Bio-Tech Co.,Ltd.,Shanghai 201203,China)

机构地区：[1]中国医药工业研究总院上海益诺思生物技术股份有限公司,上海201203

出　　处：《中国新药杂志》2020年第13期1485-1494,共10页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项资助项目(2018ZX09201017-008)。

摘　　要：目的:华蟾素注射液作为一种传统中药注射剂,已在临床使用40多年,已有临床报道显示其可能诱导心血管不良反应。故而本实验的目的为评价华蟾素注射液心脏毒性。方法:本实验为通过SpragueDawley(SD)大鼠连续2周静脉注射给予华蟾素注射液,探索华蟾素注射液对心脏的毒性作用。本实验初次设3个组,包括溶剂对照组(0 g·kg^-1,0.9%氯化钠注射液)和华蟾素注射液组(剂量分别为1和5 g·kg^-1),给药容量为10 mL·kg^-1。实验每组10只动物,雌雄各半。补充设计SD大鼠连续1周静脉注射给予华蟾素注射液。设2个组,包括溶剂对照组(0 g·kg-1,0.9%氯化钠注射液)和华蟾素注射液组(剂量为10g·kg^-1),给药容量为20 mL·kg^-1。实验每组10只动物,雌雄各半。实验期间评估以下指标:死亡或濒死、临床征状、心肌损伤指标[心肌钙蛋白I(cardiac troponin I,cTn-I)、肌酸磷化脢-同功脢MB(creatine kinaseisoenzymes MB,CK-MB)、天冬氨酸转氨酶(aspartate transaminase,AST)、乳酸脱氢酶(lactate dehydrogenase,LDH)、C反应蛋白(C-reactive protein,CRP)]、大体解剖、脏器重量以及组织病理学检查。结果:实验期间,各剂量组动物均未见死亡或濒死。1,5和10 g·kg^-1组雌雄动物临床征状、脏器重量、心肌损伤指标(CK-MB,AST,LDH,CRP)大体解剖以及组织病理学检查均未见与受试物相关的改变异常。与溶剂对照组相比,仅5和10 g·kg^-1组cTn-I出现与受试物相关的异常改变,cTn-I在给药后1.5和/或3 h升高,且至24 h已经基本恢复。结论:本实验结果证实了华蟾素注射液具有心脏毒性,其次为临床上监测华蟾素注射液的心脏毒性提供了可参考的监测时间点和监测生物标志物。Objective:Cinobufotalin injection,successfully used as a traditional Chinese medicine preparationfor forty years,may induce cardiovascular adverse reactions according to clinical reports.The aim of the study wasto evaluate its cardiotoxicityin vivo.Methods:To assess the cardiotoxicity,cinobufotalin injection was administeredto Sprague-Dawley (SD) rats via intravenous infusion for two weeks.Three groups of SD rats,each consisting of 5 males and 5 females,were administered with cinobufotalin injection at doses of 0,1 and 5 g·kg^-1.The dosage volumewas 10 mL·kg^-1.An additional experiment was designed as that Sprague-Dawley (SD) rats were administered bycinobufotalin injection via intravenous infusion for one weeks.Two groups of SD rats,each consisting of 5 malesand 5 females,were administered with cinobufotalin injection at 0 and 10 g·kg^-1.The dose volume was 20mL·kg^-1.The following parameters and endpoints were assessed during experiment:morbidity and mortality,clinical observations,indicators of myocardial injury[cardiac troponin I (cTn-I),creatine kinase isoenzymes MB(CK-MB),aspartate transaminase (AST),lactate dehydrogenase (LDH),C-reactive protein (CRP)],organweights,gross and microscopic pathology.Results:During the study,all animals survived to the day of theirscheduled sacrifice.No test article-related changes in clinical observation,organ weight,indicators of myocardialinjury (CK-MB,AST,LDH,and CRP),macroscopic and microscopic findings were noted in males and females at1,5 and 10 g·kg^-1group.As compared to the vehicle group,the cinobufotalin injection-related changes were onlyobserved in cTn-I at 5 and 10 g·kg^-1group.cTn-I increased at 1.5 and/or 3 hours after administration,and almostrecovered after 24 hours.Conclusions:The results confirmed the cardiotoxicity of cinobufotalin injection,whichmight shed light on the appropriate monitoring time points and parameters of cardiotoxicity induced by cinobufotalininjection.

关 键 词：蟾蜍二烯内酯 心脏毒性 心肌钙蛋白I 华蟾素注射液 

分 类 号：R99[医药卫生—毒理学]