重组人尿激酶原对恒河猴的长期毒性研究

Study of long term toxicity of recombinant human pro-urokinase in rhesus monkeys

目的:研究重组人尿激酶原(rhpro-UK)对恒河猴的长期毒性。方法:健康恒河猴分别按体质量随机分为低、中、高剂量组(3,10和30mg·kg-1)和空白对照组,每组6只,雌雄各半。iv给药,qd,连续14d,末次给药后处死一半动物做病理解剖,另一半停药后继续观察7d。观察症状和检测指标包括:①一般症状。②心电图。③凝血时间(CT)等血液学指标。④凝血酶时间(TT)等血液生化指标。⑤尿液检查。⑥抗体测定。⑦骨髓检查。⑧病理检查。结果:d14给药后采集的血样中,与d0或空白对照组相比,给药组的CT、TT、部分凝血活酶时间(aPTT)、凝血酶原时间(PT)明显延长、血浆纤维蛋白原含量(Fig)明显降低,且存在量效关系。d21采集的血样中,上述指标恢复正常。d14及d21病理组织学检查发现每组均有部分动物出现肝、肾淤血,轻度细胞水肿,可能系动物的隐性感染而非药物所致。d14高、中剂量组可见部分动物肺泡大片或灶性出血,注射部位静脉内膜增生或坏死、软组织出血、静脉炎及血管周围炎,d21给药组肺组织基本正常,注射部位皮肤的出血和炎症反应基本消失。结论:rhpro-UK对猴血液系统有一定的药理毒理作用,主要表现为使猴CT,TT,aPTT,PT时间延长,Fig含量降低,但这些毒性作用均是可逆的。rhpro-UK对猴的安全剂量为3mg·kg-1。

Objective:To study long term toxicity of recombinant pro-urokinase (rhpro-UK) in rhesus monkey.Methods:24 rhesus monkeys were randomly equally divided to receive once daily dose of 0,3,10,or 30mg·kg-1 of rhpro-UK given by intravenous injection for 14 consecutive days. For pathological examination, half of the animals were killed at the end of medication and the rest were killed after another 7 days of recovery. Hematological parameters, urinalysis values,ECG, specific antibodies, bone marrow, and pathological profile of organs were measured. Results: In comparison with control group on day 14 or the same group on dO,the CT (clotting time) ,TT (thrombin time) ,aPTT (activated partial thromboplastin time) ,and PT (prothrombin time) in rhpro-UK groups were significantly prolonged and the Fig (concentration of fibrinogen) was significantly decreased,and dose-effect relationship was observed. These parameters returned to normal on day 21. Histopathological examination showed that there were hepatic and renal blood stasis and mild cell edema of some animals in each group. Perhaps these were induced by silent infection in animals. Hemorrhage in alveolar sheet or focal bleeding and that hyperplasia or necrosis of venous intima,soft tissue bleeding, phlebitis and perivas culitis in injection site were observed in 30 and 10mg·kg-1 groups on day 14 but no such reactions were observed on day 21. Conclusion: rhpro-UK possesses some pharmacological and toxicological effects on blood system in rhesus monkeys, the effects include significant prolongation of CT,TT,aPTT, and PT and decrease in Fig but are reversible. The safety dosage of rhpro-UK for rhesus monkeys is3mg·kg-1.