2-(α-羟基戊基)苯甲酸钾反复给药对大鼠的毒性研究

Experimental Study on Repeated Dose Toxicity of dl-PHPB by Intravenous Injection in Rats

目的观察Ⅰ类抗脑缺血新药2-(α-羟基戊基)苯甲酸钾[potassium 2-(1-hydroxypentyl)-benzoate,dl-PHPB]反复给药对大鼠的毒性反应。方法SD大鼠,雌、雄各半,根据给药剂量分为10,30,90 mg/kg组及溶剂对照组,尾静脉反复给药30 d,停药后恢复期观察21 d。检测指标包括动物一般状况、体重、进食量、血液常规、血液生化、尿10项和病理组织学检查等。结果 SD大鼠连续静脉注射dl-PHPB 30 d,可剂量依赖性地引起肝脏重轻度增加、血清球蛋白升高、凝血酶时间(TT)延长。30,90 mg/kg剂量组尿潜血阳性及90 mg/kg剂量组尿蛋白升高。这些改变停药后均可恢复。在90 mg/kg剂量、药物质量浓度为45 g/L时,可见明显的血管刺激性,恢复期结束时血管病变仍然存在,但已开始修复。结论SD大鼠静脉注射dl-PHPB 30 d,其无毒反应剂量为30 mg/kg(相当于药效剂量的10倍);90 mg/kg(相当于药效剂量的30倍)时可见轻度毒性反应,主要为可逆性的肝脏、肾脏损伤及血管刺激性。上述研究结果为dl-PHPB的临床安全合理应用提供了参考。

Objective To observe the repeated dose toxicity of potassium 2- （1- hydroxypentyl）- benzoate（dl- PHPB） in rats. Methods SD rats, half male and half female, were divided into the doses of 10, 30, 90 mg/kg groups and the solvent control group according to doses. Repeated doses were administrated by caudal vein injection for 30 d. After drug withdrawal, the recovery period was observed for 21 d. The detected indexes included the general condition, body weight, food-intake, blood routine, blood biochemistry, urine 10 items and histopathology examination. Results Repeatedly intravenous injection of dl- PHPB for 30 d in SD rats could dose-dependently cause slight increase of the liver weight, elevation of serum globulins and extension of the thrombin time（TT）. Urinary occult blood in the doses of 30, 90 mg/kg groups and urine protein in the dose of 90 mg/kg group were increased. These changes were recovered after drug withdrawal. In the dose of 90 mg/kg and the drug concentration of 45 g/L, the vascular irritation was obvious. At the end of recovery period, angiopathy still existed, but began to repair. Conclusion In repeatedly intravenous injection of dl- PHPB for 30 d in rats, the non-toxic reaction dose is 30mg/kg （equivalent to 10 times of efficacy dose）,the dose of 90 mg/kg（equivalent to 30 times of efficacy dose） causes mild toxic reaction, mainly reversible liver and renal lesions and vascular irritation. These research results may provide reference for safe and rational application of dl- PHPB in clinic.