大鼠90天重复灌胃三乌胶丸毒性研究

Study on toxicity of Sanwujiao pill after 90 days repeated intragastric administration in rats

目的探讨SD大鼠90d重复灌胃三乌胶丸的毒性情况。方法选择检疫和体重合格的SFP级SD大鼠80只,雌雄各半,体重176.8~223.5g,按性别体重随机分为4组,即空白对照组、低剂量组(三乌胶丸6.251g生药/kg)、中剂量组(三乌胶丸12.458g生药/kg)、高剂量组(三乌胶丸24.915g生药/kg),各20只,雌雄各半。按15mL/kg体积灌胃给药,1次/d,连续给药90d,停药后恢复观察4周。按计划于给药末期及恢复末期分别解剖40只SD大鼠进行体重、摄食量测定,动物步态检测;尿常规、血液学、血液生化、凝血及电解质检查、眼科检查、骨髓检查;脏器系数测定,组织病理学检查。结果所有大鼠均按计划实施安乐死,无大鼠意外死亡。①试验期间,大鼠一般状况、体重、血液学和凝血、血液生化和电解质、眼科检查和组织病理学检查均未见与三乌胶丸相关的异常改变;②三乌胶丸能引起大鼠尿常规异常、脏器系数增大,并存在一定剂量相关性,但均无毒理学意义;③三乌胶丸能引起大鼠步态变化。结论本试验条件下,SD大鼠经口灌胃给予三乌胶丸90d对大鼠一般状况、体重、血液学和凝血、血液生化和电解质、脏器等均无明显影响,但高剂量能引起大鼠部分步态指标的改变,提示长期临床应用时需重点关注感觉神经反应的变化。三乌胶丸的无毒副反应水平(NOAEL)的剂量为12.458g生药/kg,约相当于成人临床使用剂量的25倍(按成人公斤体重计算)和46倍(按体表面积计算)。

Objective To investigate the toxicity of repeated intragastric administration of Sanwujiao pill for 90 days in SD rats.Methods Eighty SFP SD rats,half male and half female,weighing 176.8~223.5g,were selected and randomly divided into four groups according to their sex and weight,namely blank control group,low-dose group(6.251g crude drug/kg of Sanwujiao pill),middle-dose group(12.458g crude drug/kg of Sanwujiao pill)and highdose group(24.915g crude drug/kg of Sanwujiao pill).15mL/kg was given orally once a day for 90 days,and the observation was resumed for 28 days after stopping the drug.According to the plan,40 SD rats were dissected at the end of administration and recovery,and the weight,food intake and gait of SD rats were measured.Urine routine,hematology,blood biochemistry,coagulation and electrolyte examination,ophthalmology examination,bone marrow smear,determination of organ coefficient and histopathological examination of SD rats were measured.Results All SD rats were euthanized as planned,and no animals died unexpectedly.①During the experiment,there were no abnormal changes in general condition,weight,hematology and coagulation,blood biochemistry and electrolyte,ophthalmology examination and histopathological examination of rats.②Sanwujiao pill could cause abnormal urine routine and increase organ coefficient in rats,and there was a certain dose correlation,but it had no toxicological significance.③Sanwujiao pill could cause gait changes in rats.Conclusion Under the experimental conditions,oral administration of Sanwujiao pill to SD rats for 90 days has no obvious effect on the general condition,weight,hematology,coagulation,blood biochemistry,electrolytes and organs of rats,but high dose Sanwujiao pill can change some gait indexes of rats.The long-term clinical application should focus on the changes of sensory nerve response.The NOAEL of Sanwujiao pill is 12.458g crude drug/kg,which is about 25 times of the clinical dose(calculated by kg body weight)and 46 times(calculated by body surface area).