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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。
AIM: To investigate the long-term toxicity of recombinant human prourokinase (rhpro-UK) to rhesus monkeys. Methods: The healthy rhesus monkeys were randomly divided into low, medium and high dose groups (3, 10 and 30 mg · kg-1) and blank control group according to their body weight. Each group consisted of 6 males and half males. iv administration, qd, continuous 14d, after the last administration sacrificed half of the animals for pathological anatomy, the other half after stopping the drug to observe the 7d. Observed symptoms and test indicators include: ① general symptoms. ② ECG. ③ clotting time (CT) and other hematological indicators. ④ thrombin time (TT) and other blood biochemical indicators. ⑤ urine test. ⑥ antibody assay. ⑦ bone marrow examination. ⑧ pathological examination. Results: Compared with d0 or blank control group, the CT, TT, aPTT and PT of the blood samples collected after d14 administration were significantly prolonged, and the levels of plasma fibrin The original content (Fig) decreased obviously, and there was a dose-effect relationship. d21 blood samples collected, the above indicators returned to normal. Histopathological examination of d14 and d21 revealed that some animals in each group showed hepatic and renal congestion and mild cellular edema, which may be caused by the latent infection of animals rather than by drugs. In the d14 high and middle dose groups, some animals showed large or focal alveoli or focal hemorrhage, intimal hyperplasia or necrosis at the injection site, hemorrhage of soft tissue, phlebitis and perivascular inflammation. The lung tissue in d21 administration group was basically normal, the bleeding in the injection site and Inflammation basically disappeared. CONCLUSION: rhpro-UK has certain pharmacological and toxicological effects on the hematological system of the monkey. The main effects of rhpro-UK are CT, TT, aPTT, prolonged PT and reduced Fig content. However, these toxic effects are reversible. The safe dose of rhpro-UK to monkeys was 3 mg · kg -1.