中国药物警戒 ›› 2021, Vol. 18 ›› Issue (1): 24-29.
DOI: 10.19803/j.1672-8629.2021.01.05

• 复方与联合用药安全性评价专栏(第一辑) • 上一篇    下一篇

Beagle犬灌胃厄多司坦盐酸氨溴索混合物的急性和亚慢性毒性研究

王姝廷1, 李慧2, 王江雪2, 张紫璇2, 牟文波2, 郭新苗2, 叶向锋2, 靳洪涛1,2,*   

  1. 1中国医学科学院北京协和医学院药物研究所新药安全评价研究中心,北京 100050;
    2北京协和建昊医药技术开发有限责任公司,北京 100176
  • 收稿日期:2020-09-18 修回日期:2021-01-18 出版日期:2021-01-15 发布日期:2021-01-18
  • 通讯作者: *靳洪涛,男,博士,研究员·硕导,药物毒害因素识别及有效防控。E-mail:jinhongtao@imm.ac.cn
  • 作者简介:王姝廷,男,在读硕士,药物肝脏毒害因素识别及有效防控。
  • 基金资助:
    十三五重大新药创制专项(2018ZX09201017-5; 2018ZX09711001-002-001):吸入毒性和儿童用药等特色创新药物安全性评价关键技术研究; 新技术新方法在药物毒性中的应用; 中国医学科学院医学与健康科技创新工程项目( 2017-I2M-1-011 ):肺功能保护产品研发

Acute and Subchronic Toxicity of Erdosten Ambroxol Hydrochloride Mixture by Gavage in Beagle Dogs

WANG Shuting1, LI Hui2, WANG Jiangxue2, ZHANG Zixuan2, MU Wenbo2, GUO Xinmiao2, YE Xiangfeng2, JIN Hongtao1,2,*   

  1. 1New Drug Safety Evaluation Center,Institute of Materia Medica,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100050,China;
    2China Beijing Union-Genius Pharmaceutical Technology Co.,Ltd.,Beijing 100176,China
  • Received:2020-09-18 Revised:2021-01-18 Online:2021-01-15 Published:2021-01-18

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摘要： 目的 观察Beagle犬给予厄多司坦盐酸氨溴索混合物后出现的急性和亚慢性毒性反应,为临床安全用药剂量的设计和毒副反应监测提供参考。方法 选用Beagle犬进行急性和13周亚慢性毒性试验。急性试验中,设置厄多司坦盐酸氨溴索混合物剂量组(5.04 g/kg)、厄多司坦组(4.80 g/kg)、盐酸氨溴索组(0.24 g/kg)和空白对照组,采用最大给药量法进行测定。亚慢性毒性试验设置厄多司坦盐酸氨溴索混合物高(180 mg/kg)、中(60 mg/kg)、低(20mg/kg)3个剂量组,另设厄多司坦(171.4 mg/kg)、盐酸氨溴索(8.6 mg/kg)和空白对照3组。13周连续给药,对动物临床症状、各种生化指标和大体组织病理学进行检查。结果 急性毒性试验结果表明,厄多司坦盐酸氨溴索混合物高剂量(5.04 g/kg)单次给药情况下,动物的主要毒性反应为俯卧、精神萎靡、震颤、少动、乏力,第2 d基本恢复正常,药后毒性反应与厄多司坦组和盐酸氨溴索组动物相似。亚慢性毒性试验表明,给药结束及恢复期结束时,厄多司坦盐酸氨溴索混合物高剂量(180 mg/kg)组和厄多司坦组的肌酐轻微升高,其他未见异常。结论 Beagle犬单次灌胃厄多司坦盐酸氨溴索最大给药量为5.04 g/kg,与厄多司坦(4.80 g/kg)和盐酸氨溴索(0.24 g/kg)组相比,混合物组药后毒性反应未见增加。Beagle犬口服厄多司坦盐酸氨溴索混合物高、中、低剂量组13周反复给药的结果显示,未见毒性反应剂量为中剂量(60 mg/kg)组,本研究可为厄多司坦盐酸氨溴索混合物临床应用提供参考数据。

关键词: Beagle犬, 厄多司坦, 盐酸氨溴索, 灌胃, 急性毒性, 亚慢性毒性

Abstract: Objective To observe the acute and subchronic toxicity after oral administration of erdostatin hydrochloride ambroxol mixture in Beagle dogs,and to provide reference for clinical safe dose design and toxicity monitoring.Methods Beagle dogs were selected for acute and 13-week subchronic toxicity tests.During the acute experiment,dogs were divided into erdostine hydrochloride ambromine mixture dose group (5.04 g/kg),erdostine hydrochloride group (4.80 g/kg),ambroxol hydrochloride group (0.24 g/kg) and blank control group using the maximum dose method.In the subchronic toxicity test,dogs were assigned to the high dose group (180 mg/kg),medium dose group (60mg/kg) and low dose group (20 mg/kg) of erdostine hydrochloride ambroxol mixture,while erdostine hydrochloride (171.4 mg/kg) group,ambroxol hydrochloride (8.6 mg/kg) group and blank control were also set up.The drug was given for thirteen consecutive weeks before the general condition,biochemical indexes and histopathology of the animals were examined.Results The results of acute toxicity tests showed that the main toxic reactions of animals were proneness,lethargy,tremor,inactivity and fatigue at a single dose (5.04 g/kg) of erdostatin hydrochloride ambroxol mixture,but these animals basically returned to normal on the second day,and the post-drug toxicity was similar to that of erdostine group and ambroxol hydrochloride group.The subchronic toxicity tests showed that at the end of administration and recovery,the levels of creatinine slightly increased in high dose group of erdostine hydrochloride ambroxol mixture and erdostine group,but no abnormality was found in the other groups.Conclusion The maximum dose of erdostatin hydrochloride ambroxol mixture was 5.04 g/kg in beagle dogs.Compared with erdosten (4.80 g/kg) and ambroxol hydrochloride (0.24 g/kg),the toxicity of the mixture group did not increase.The results of 13-week repeated administration of erdosten ambroxol hydrochloride mixture in beagle dogs showed that the middle dose (60 mg/kg)group had no observed adverse toxic reactions.This study may provide reference for clinical application of erdosten ambroxol hydrochloride mixture.

Key words: beagle dogs, erdostatin, ambroxol, oral, acute toxicity, subchronic toxicity

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