单硝酸异山梨酯盐酸伊伐布雷定复方对Beagle犬的长期毒性研究  

Experimental Study on the Long-term Toxicity of Isosorbide Mononitrate and Ivabradine Hydrochloride Compound in Beagle Dogs

作　　者：胡晓乐 李会恩 李斌 王恩力 冯中 赵涛 

机构地区：[1]山东省临沂市中医院,山东临沂273400 [2]鲁南制药集团股份有限公司新药安评中心,山东临沂273400 [3]鲁南制药集团国家手性制药工程技术研究中心,山东临沂273400

出　　处：《中国药物警戒》2015年第2期65-68,共4页Chinese Journal of Pharmacovigilance

基　　金：国家科技支撑计划(2014BAI16B01)

摘　　要：目的观察Beagle犬连续30天口服单硝酸异山梨酯盐酸伊伐布雷定复方(ISMN-I)所产生的毒性反应,为临床剂量的拟定提供依据。方法 Beagle犬32只,雌雄各半,分为4组:空白对照组,复方低、中、高(30、75、180 mg·kg-1)剂量组,每组8只动物。每日给药1次,连续给药30天,停药观察14天。实验期间,每日进行一般状态观察,每周测定1次体质量及摄食量,于给药前、给药末期及停药恢复期末,各组动物分别进行眼科、体温、尿液、血压、心电图(Ⅱ导联)、血液学指标、血液生化学检测,给药期及恢复期结束剖检并进行病理组织学检查。结果 ISMN-I复方高剂量组、中剂量组给药末期可使舒张压(DBP)出现降低,且高剂量组、中剂量组均可导致Beagle犬在给药期间出现呕吐、振颤、抽搐、无力等反应,低剂量组个别犬偶尔出现一次性的呕吐反应。结论本试验条件下,单硝酸异山梨酯盐酸伊伐布雷定复方对Beagle犬无不良反应剂量(NOAEL)为30 mg·kg-1。Objective To observe the toxicity of isosorbide mononitrate and ivabradine hydrochloride compound （ISMN-I） in beagle dogs, and to provide safety evidences for clinical experiment. Methods 32 healthy beagle dogs, half male and half female, were randomly disvided into control, low-, mid-, and high-dose （30, 75, and 180 mg·kg^-1） groups, 8 dogs in each group. The beagle dogs were administered for 30 days, and observed for 14 days after the last administration. During the experiment, the general conditions of animals were observed daily. Body weight and food consumption were weighed weekly. The related indexes including ophthalmology, body temperature, urinary routine, blood pressure, electrocardiogram, hematological and blood biochemical indexes were detected at different time points such as before administration, the end of administration and the end of recovery period, then the dogs were dissected and histopathologic examination was carried out. Results Compared with control group, the blood pressure of DBP in high-dose group and mid-dose group declined obviously at the end of administration. Dogs in high-dose group and mid-dose group vomited, shaked, convulsed obviously during the administration, individual dogs in low-dose group vomited occasionally. Conclusion In this study, the no observed adverse effect level （NOAEL） is 30 mg·kg^-1 in beagle dogs for 30 days by oral administration.

关 键 词：长期毒性研究 BEAGLE犬 单硝酸异山梨酯(ISMN) 盐酸伊伐布雷定 

分 类 号：R992[医药卫生—毒理学] R972.4[医药卫生—药学]