雷诺嗪对大鼠的长期毒性试验  

Long-term toxicity of ranolazine in rats

作　　者：周一平[1] 李亚军[1] 陈四艳[1] 张同辉[1] 杨旻昊[1] 余启枝[1] 何映[1] 

机构地区：[1]湖北省医药工业研究院有限公司湖北省药物安全性评价中心,武汉430061

出　　处：《中国新药杂志》2007年第3期200-203,共4页Chinese Journal of New Drugs

基　　金：湖北省科技厅重点项目(2004AA301B01)

摘　　要：目的:考察反复给予雷诺嗪{N-(2,6二甲基苯基)-2-4-[2-羟基-3-(2-甲氧苯氧基)丙基]-1-哌嗪乙酰胺}对大鼠产生的毒性反应。方法:SD大鼠随机分为雷诺嗪高、中、低剂量(400,150和50 mg.kg-1.d-1)组和溶媒对照(0.5%羧甲基纤维素钠)组,每组32只大鼠,雌雄各半。各组均灌胃给予等体积的药物或溶媒(20 mL.kg-1),每周给药7 d,连续给药4周。停药后每组留12只动物(雌雄各半)再饲喂2周进行恢复性观察。观察动物一般状况、体重、进食量、饮水量、血液学、血液生化学、脏器重量系数及组织病理学改变。结果:雷诺嗪400 mg.kg-1组大鼠给药初期出现活动减少、呆滞和抽搐,体重增加值低于对照组,饮水量、丙氨酸氨基转换酶(ALT)、尿素氮(BUN)、总胆固醇(T-Cho)及肝、肾系数高于对照组。雷诺嗪50和150 mg.kg-1组各项指标与对照组比较均无统计学差异。恢复期各剂量的各项指标与对照组比较均无统计学差异。结论:雷诺嗪150 mg.kg-1为安全剂量,400 mg.kg-1有短时神经系统毒性并对动物生长,肝、肾功能和脂代谢产生可逆性影响。Objective： To assess the long-term toxicity of ranolazine （N-（ 2,6-dimethylphenyl）- 2- { 4- [ 2-hydroxy-3- （2-methoxyphenoxy） propyl ] piperazinyl t acetamide ） in rats. Methods ： 128 SD rats were randomly medicated orally with ranolazine （400, 150 or 50 mg·kg^-1, n = 32 each） or 0.5% CMC- Na（20 mL· kg^- 1, n = 32） daily 4 weeks. 20 rats in each group were sacrificed after the last dosing and the rest of 12 rats in each group were sacrificed after 2-weeks recovery. The changes of physical status （body weight, growth rate and appetite）, blood parameters of hematology and biochemistry and pathologic profiles were measured. Results： The rats receiving 400 mg·kg^-1 showed significant worsening of nervous functions, such as reduced activity, languishment and twitch, and the slow growth rate and higher levels of ALT, BUN, total cholesterol and kidney and hepatic weight indexes, compared with the CMC-Na-treated rats. No significant differences of the physical conditions, blood outcomes and pathohistological profiles were found in the rats dosing 50 and 150 mg· kg^-1 of ranolazine from the rats supplemented with CMC-Na. At the end of the 2-week recovery, the rats in each group were back normal in the physical conditions, blood outcomes and pathohistological profiles. Conclusion： The rats receiving ranolazine 150 mg· kg^-1 or below showed safe profiles and 400 mg· kg ^-1 experienced a reversible toxicity on the growth rate, liver and kidney functions, and lipid metabolism.

关 键 词：雷诺嗪 长期毒性试验 安全性评价 大鼠 

分 类 号：R965.3[医药卫生—药理学] R972.3[医药卫生—药学]