金匮肾气丸临床前安全性评价研究  

Preclinical safety evaluation of Jinkui Shenqi pills

作　　者：左泽平 田颖颖 徐意 姜克武 杨硕 杨海润 张志聪 曹欣垚 吴笑如 王志斌 ZUO Zeping;TIAN Yingying;XU Yi;JIANG Kewu;YANG Shuo;YANG Hairun;ZHANG Zhicong;CAO Xinyao;WU Xiaoru;WANG Zhibin(Pharmaceutical Factory,Beijing Tongrentang Science&Technology Development Co.,LTD.,Beijing 100079,China;School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China;Pharmaron(Beijing)Biotechnology Co.,LTD.,Beijing 102206,China)

机构地区：[1]北京同仁堂科技发展股份有限公司制药厂,北京100079 [2]北京中医药大学中药学院,北京100029 [3]康龙化成(北京)生物技术有限公司,北京102206

出　　处：《中国药物警戒》2023年第7期775-782,共8页Chinese Journal of Pharmacovigilance

基　　金：国家重点研发计划(2019YFC1711400)。

摘　　要：目的研究经典名方金匮肾气丸单次给药毒性和26周重复给药毒性反应,为其临床安全应用提供参考。方法以最高配制浓度和最大可给药剂量灌胃ICR小鼠(11.2 g·kg^(-1)BW,相当于临床人用剂量的102倍),观察给药后14 d动物毒性反应;SD大鼠随机分为平行对照组和金匮肾气丸高、中、低剂量组(5.6、2.8、1.4 g·kg^(-1)BW,分别相当于临床人用剂量51、25.5、12.75倍),连续灌胃26周,检测给药13周、26周,以及在4周恢复期动物体重和摄食量的变化,采用血液分析仪检测血液学和凝血指标等变化,采用全自动生化分析仪检测相关生化指标的变化,并通过组织病理学检查,来评价药物的潜在毒性反应、毒性的可逆性,以及可能的继发和/或延迟效应。结果金匮肾气丸单次给药毒性试验给药后和14 d观察期小鼠未出现动物死亡和异常症状,最大给药量(MFD)为11.2 g·kg^(-1)BW(相当于临床人用剂量的102倍);金匮肾气丸大鼠连续灌胃26周,SD大鼠一般状态、血常规及血生化未出现与药物相关的严重不良反应,病理检查未见与药物毒性相关的主要脏器组织形态学改变,停药后未见药物延迟性毒性反应,无不良反应剂量(NOAEL)为5.6 g·kg^(-1)BW·d-1(为临床人用剂量的51倍)。结论金匮肾气丸最大给药量未见急性毒性反应,长期给药未出现潜在/继发/延迟性毒性反应,在治疗剂量范围内安全性高。Objective To investigate the toxicity of Jinkui Shenqi pills after single administration and after 26 weeks of repeated administration so as to provide reference for safe clinical use.Methods ICR mice were given intragastrically the highest concentration and maximum dose of Jinkui Shenqi pills before the animal toxicity was observed 14 days after administration(11.2 g·kg^(-1) BW,which was 102 times the clinical human dose).SD rats were randomly divided into the control group and Jinkui Shenqi pill high-dose,medium-dose and low-dose groups(5.6 g·kg^(-1) BW,2.8 g·kg^(-1) BW,1.4 g·kg^(-1) BW,which were 51 times,25.5 times,12.75 times the clinical human dose,respectively),gavaged twice a day for 26 weeks.Thirteen weeks and 26 weeks into administration and during the four weeks of recovery,the body weight,food intake,hematology and coagulation indexes of the rats were detected by a blood analyzer,and the related biochemical indexes by an automatic biochemical analyzer.Histopathological examination was conducted to evaluate the potential toxicity,reversibility of toxicity,and possible secondary and/or delayed effects of the drug.Results After single-dose toxicity test and during the 14 days of observation,there was no abnormality or death among the rats.The maximum dose of administration(MFD)was 11.2 g·kg^(-1) BW,which was equivalent to 102 times the clinical human dose.Twenty-six weeks of continuous intragastric administration of Jinkui Shenqi pills did not cause any serious adverse reactions among the SD rats.No histopathological changes related to drug toxicity were observed in major organs of the rats.There was no delayed drug toxicity after drug withdrawal.The NOAEL was 5.6 g·kg^(-1) BW·d^(-1),which was 51 times the clinical human dose.Conclusion Jinkui Shenqi pills cause neither acute toxic reactions nor potential/secondary/delayed toxic reaction after longterm administration.It is safe at the therapeutic doses.

关 键 词：金匮肾气丸 小鼠 大鼠 毒性 单次给药 重复给药 安全性 

分 类 号：R961[医药卫生—药理学] R994[医药卫生—药学]