冠心宁注射液对大鼠重复给药毒性试验研究

Experimental study on chronic toxicity of Guanxinning Injection in rats

目的研究SD大鼠连续iv冠心宁注射液13周的毒性反应。方法 120只大鼠随机分为4组:溶媒对照组和冠心宁注射液高、中、低剂量(3.40、1.70、0.85 g/kg)组,雌雄各半。连续iv给药13周,每周检测1次体质量和摄食量,每天观察动物药后外观体征变化,分别于给药结束和停药4周时进行脏器相对质量(脏脑比)、血液学指标、血液生化学指标、组织病理学检查。结果冠心宁注射液3.40、1.70 g/kg每次药后即刻出现呼吸急促、步态不稳、俯卧不动、眼球突出等征状,随给药时间的延长,上述症状逐渐减轻,恢复时间逐渐缩短;0.85 g/kg剂量组动物未出现明显的异常反应。冠心宁注射液3.40 g/kg剂量下2只雄性动物给药约4周时死亡,0.85、1.70 g/kg剂量组均未出现动物死亡。与溶媒对照组比较,0.85、1.70 g/kg剂量组动物血液学、血液生化学、脏器相对质量、组织病理学检查均未见明显异常;冠心宁注射液3.40 g/kg剂量下给药13周后可导致大鼠血液中尿素氮(BUN)水平明显升高、肾脏相对质量明显增加;停药4周后,上述各项指标均恢复正常,其余检测指标未见明显异常。结论重复大剂量iv冠心宁注射液对大鼠有肾脏毒性,重复iv给予0.85 g/kg无毒性反应,是临床等效剂量的12倍。

Objective To observe the repeat administration toxicity of Guanxinning Injection in rats. Methods Totally 120 rats（males and females） were randomly divided into vehicle control group and three Guanxinning Injection groups with different dosages（3.40, 1.70, and 0.85 g/kg）. Rats were administered with Guanxinning Injection by consecutive intravenous injection for 13 weeks. Besides the general conditions were observed, the related indexes were detected, such as body weight, the routine control of blood, hepatic function, renal function, the metabolism condition of lipids, the glycometabolism indexes, and histopathology analysis were determined at 13 weeks of treatments and 4 weeks after the withdrawal, respectively. Results Rats in the Guanxinning Injection group at 3.40, 1.70 g/kg apperance shortness of breath, unsteady gait, lying motionless, and other symptoms. There was no obvious abnormal reaction in the 0.85 g/kg dose group. There were two male rats in the Guanxinning Injection group at 3.40 g/kg died at about week 4 of treatments, and there was no death in the 0.85 and 1.70 g/kg dose groups. Compared with vehicle control group, the related indexes of blood, blood biochemistry, organ relative quality, and histopathological showed no obvious abnormalities in Guanxinning Injection 0.85 and 1.70 g/kg group. The levels of urea nitrogen（BUN） and the relative weight of kidney in Guanxinning Injection 3.40 g/kg group were significantly higher than those in vehicle control group at 13 weeks. The change of these parameters regained to normal at 4 weeks after withdrawal and the rest of the detection index showed no obvious abnormality in 3.40 g/kg dase group. Conclusion Intravenous administration of Guanxinning Injection for 13 weeks at high dose could induce reversible damage to kidney.