目的 研究昂丹斯琼杂质的急性毒性和细胞毒性.方法 预实验确定用药剂量,正式实验120只动物随机分组(雌雄各半,每组20只),给药后连续观察14 d,记录动物反应及死亡情况.应用成纤维细胞(L929)、狗肾细胞(MDCK)及人脐静脉内皮细胞(HUVEC)观察化合物的细胞毒性.结果 昂丹斯琼杂质1灌胃给药对小鼠的LD50及95%置信限为1798.8±178.2 mg·kg-1,解剖未见明显内脏损伤.昂丹斯琼杂质2静脉注射给药对小鼠的LD50及95%置信限为49.63±7.63 mg·kg-1,静注后出现呼吸急促、抽搐等现象,解剖未见明显内脏损伤.昂丹斯琼杂质3 2000 mg·kg-1灌胃给予小鼠,每天1次,连续给药3天,动物全部存活且无明显中毒表现,解剖未发现明显内脏损伤.昂丹斯琼杂质1,2,3均对成纤维细胞(L929)有一定的细胞毒作用(P <0.05).昂丹斯琼杂质3显著促进人脐静脉内皮细胞的增殖(P <0.05).结论 昂丹斯琼杂质1和杂质2对小鼠和细胞具有一定毒性,昂丹斯琼杂质3毒性低.本研究为制定昂丹斯琼质量标准提供实验依据,提高临床使用安全.%Objective To study the acute toxicity in mice and cytotoxicities of the impurities of Ondansetron. Methods pre-experiment to determine the initial dose, the mice were grouped randomly (half male and half female, 20 mice per group) in the formal experiment. The animal reactions and death were recorded for 14 days. The cytotoxicities on fibroblasts(L929), canine kidney cells(MDCK) and human umbilical vein endothelial cells(HUVEC) were measured. Results The LD50 and 95% confidence limit of the impurity 1 of Ondansetron(intragastric administration) was 1798.8 + 178.2 mg·kg-1, no apparent damage was discovered in the anatomy of the viscera. The LD50 and 95% confidence limit of the impurity 2 of Ondansetron injected intravenously in mice was 49.63+7.63 mg·kg-1, shortness of breath and convulsions were shown after intravenous injection and gradually ease, no apparent damage was shown in the anatomy of the viscera. The impurity 3 of Ondansetron was adminstrated intragastriclly to mice 2 000 mg·kg-1 daily for 3 days, all mice was survived and no toxicity reactions were shown during the observed period. The purity 1,2, and 3 all significantly decreased the viability of L929 cells (P <0.05). The impurity 3 of Ondansetron significantly promoted the proliferation of HUVEC(P <0.05). Conclusion The impurity 1 and 2 of Ondansetron had certain toxicity to mice and cells. The toxicity of the impurity 3 of Ondansetron is low. The data can provide the experimental basis to establish the quality standards of Ondansetron, and improve the safety of clinic use.
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