鸟氨酸杂质的小鼠急性毒性和细胞毒性考察
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摘要
目的:研究鸟氨酸杂质3-氨基-2-哌啶酮盐酸盐的急性毒性和细胞毒性。方法:预实验确定用药剂量,小鼠静脉注射给药,采用Bliss法计算其半数致死量(LD_(50))。根据LD_(50)的结果设高、中、低3个剂量组和溶媒对照组,给药后连续观察14d,记录动物反应,并进行血液生化检查,解剖后肉眼观察主要脏器变化并进行组织形态检查。应用成纤维细胞(L929)观察3-氨基-2-哌啶酮盐酸盐的细胞毒性。结果:3-氨基-2-哌啶酮盐酸盐尾静脉一次给药对小鼠的LD_(50)为802.18 mg·kg~(-1)(95%置信区间758.49~848.08 mg·kg~(-1));高、中、低3个剂量组(660,330,170 mg·kg~(-1))在观察期内一般毒性、体质量、血液生化指标、脏器的肉眼观察及组织形态检查与溶媒对照组比较,均无明显差异。对成纤维细胞(L929)有一定的细胞毒作用。小鼠体内NOAEL值为660mg·kg~(-1)。结论:3-氨基-2-哌啶酮盐酸盐对小鼠和成纤维细胞(L929)有一定的毒性作用,本研究为氨基酸注射液质量标准中鸟氨酸杂质限度的制定提供了依据。
Objective: To study the acute toxicity in mice and cytotoxicity of the impuritiy( 3-amino-2-piperidinone hydrochloride)in ornithine. Methods: The mice were given the impurity by intravenous injection. The acute toxicity was observed and LD50 in mice was calculated by Bliss method. According to the result of LD50,the mice were given the impurity respectively at high,medium and low dose. The changes of general condition and body weight were recorded,and the blood biochemical indices and histomorphology of organs and tissues were observed after 14 days. The cytotoxicity was measured on fibroblasts( L929) cells. Results: The LD50 and 95% confidence limit of the impurity( intragastric administration) was 758. 49-848. 08 mg·kg~(-1). All the detected indices of the three groups( 660,330 and 170 mg·kg~(-1)) including general condition,weight change,biochemical indices,organ morphological and histological change were all within the normal ranges. The impurity significantly decreased the viability of L929 cells. The NOAEL value was 660 mg·kg~(-1) in mice. Conclusion: The impurity has certain toxicity to mice and cells. The data can provide experimental basis for the quality standard establishment for ornithine and the safety improvement in clinic use.
Objective: To study the acute toxicity in mice and cytotoxicity of the impuritiy( 3-amino-2-piperidinone hydrochloride)in ornithine. Methods: The mice were given the impurity by intravenous injection. The acute toxicity was observed and LD50 in mice was calculated by Bliss method. According to the result of LD50,the mice were given the impurity respectively at high,medium and low dose. The changes of general condition and body weight were recorded,and the blood biochemical indices and histomorphology of organs and tissues were observed after 14 days. The cytotoxicity was measured on fibroblasts( L929) cells. Results: The LD50 and 95% confidence limit of the impurity( intragastric administration) was 758. 49-848. 08 mg·kg~(-1). All the detected indices of the three groups( 660,330 and 170 mg·kg~(-1)) including general condition,weight change,biochemical indices,organ morphological and histological change were all within the normal ranges. The impurity significantly decreased the viability of L929 cells. The NOAEL value was 660 mg·kg~(-1) in mice. Conclusion: The impurity has certain toxicity to mice and cells. The data can provide experimental basis for the quality standard establishment for ornithine and the safety improvement in clinic use.
引文
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4 中华人民共和国食品药品监督管理局.化学药物杂质研究技术指导原则[S].2005
5 何伍,王海学.浅谈药物杂质限度的制订方法[J].中国医药工业杂志,2009,40(10):787-790
6 胡向青,郝福,李志刚,等.药物中杂质及有害物质控制限度的研究进展[J].现代药物与临床,2014,29(9):953-964
7 张爱华,孙志伟.毒理学基础[M].北京:科学出版社,2008:60-65
8 王建茹,王国辉,张立新,等.复方敏维糖浆的急性毒性和长期毒性研究[J].中国药师,2016,19(8):1578-1580