中国药物警戒 ›› 2023, Vol. 20 ›› Issue (7): 775-782.
DOI: 10.19803/j.1672-8629.20220512

• 基础与临床研究 • 上一篇    下一篇

金匮肾气丸临床前安全性评价研究

左泽平1, 田颖颖2, 徐意1, 姜克武3, 杨硕1, 杨海润1, 张志聪1, 曹欣垚1, 吴笑如1#, 王志斌1,2*   

  1. 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
  • 收稿日期:2022-08-30 出版日期:2023-07-15 发布日期:2023-07-14
  • 通讯作者: *王志斌,男,教授·博导,中药药理与毒理。E-mail: wangzhibin4804@126.com。#为共同通信作者。
  • 作者简介:左泽平,女,硕士,主管药师,中药生物活性测定与毒理。
  • 基金资助:
    国家重点研发计划（2019YFC1711400）

Preclinical safety evaluation of Jinkui Shenqi pills

ZUO Zeping1, TIAN Yingying2, XU Yi1, JIANG Kewu3, YANG Shuo1, YANG Hairun1, ZHANG Zhicong1, CAO Xinyao1, WU Xiaoru1#, WANG Zhibin1,2,*   

  1. 1Pharmaceutical Factory, Beijing Tongrentang Science & Technology Development Co., LTD., Beijing 100079, China;
    2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China;
    3Pharmaron (Beijing) Biotechnology Co., LTD., Beijing 102206, China
  • Received:2022-08-30 Online:2023-07-15 Published:2023-07-14

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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。

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

Abstract: 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 long-term administration. It is safe at the therapeutic doses.

Key words: Jinkui Shenqi pill, mice, rats, toxicity, single administration, repeated administration, safety

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