重组巴曲酶对猴长期毒性观察

Long-term toxic effect of recombinant batroxobin on Macaca mulatta

目的:观察重组巴曲酶(rBAT)连续iv30 d对猴的长期毒性。方法:健康恒河猴按体质量随机分为低、中、高剂量组(1.5、5.0和15.0 kU/kg)和溶剂对照组(n=6,雌雄各半)。连续30 d静注给药。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15 d。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)血浆纤维蛋白原含量(Fib)等血液生化指标;(5)尿液检查;(6)骨髓检查;(7)病理检查;(8)抗体检测。结果:d15及d30给药后30 min采集的血样中,与d0或与溶剂对照组相比,低、中、高剂量组的Fib明显减少,且有剂量依赖性,但d15及d30给药后24h及d45采集的血样中上述指标恢复正常。病理组织学检查发现d30及d45各剂量组均有部分动物肝肾淤血,细胞轻度水肿,可能是动物隐性感染;d30注射部位皮肤出现局部炎症反应,d45炎症反应基本消失。其余观察指标未见明显异常。d15到d45均可检测到抗rBAT非中和抗体。结论:rBAT对猴血液系统有一定的药理毒理作用,主要表现为使猴低、中、高剂量组Fib呈剂量依赖性降低。rBAT对猴药理毒理作用靶器官为血液系统,其作用均是可逆的。rBAT对猴的安全剂量为1.5 kU/kg。临床使用时应密切注意rBAT对血液系统的影响。

Objective：To study the long-term （iv for 30 days） toxic effect of recombinant batroxobin （rBAT） on Macaca rnulatta. Methods： Twenty-four Macaca mulatta （12 male and 12 female） were randomly divided into 4 groups according to their body weights （n= 6） ： rBAT treatment groups （1.5, 5.0, 15.0 kU/kg of rBAT once daily for 30 consecutive days through iv injection） and acetate buffer treatment group （as control）. Half of the animals in each group were sacrificed at the end of medication and the rest were sacrificed after another 15 days＇ recovery. The general symptoms, the hematological, chemical parameters, urinalysis values, ECG results, bone marrow findings, pathologic changes and the antibody detection were observed or performed in all groups. Results： On d15 and d30, the blood samples of each group were collected at 30 min and 24 h after iv injection. Compared with control group or with dO data of each corresponding group, the fibrinogen （Fib） was significantly decreased 30 min after iv injection of rBAT, and the decrease was in a dose-dependent manner. Fib returned to the normal level 24 h after iv injection. Histopathological examination showed congestion and slight edema of liver and kidney cells in each group, probably due to latent infection of the animals. On d30, there was local inflammatory reaction in the injection sites of some animals in each group, but none was found on d45. Non-neutralizing antibodies to rBAT were continuously detected from d15 to d45. Conclusion.. rBAT has pharmacological and toxicological effects on hematology system of Macaca mulatta. It can dose-dependently decrease Fib. The target organ of rBAT is the hematology system and the effect of rBAT is reversible. The safety dose of rBAT for Macaca mulatta is 1.5 kU/kg. Attention should be given when rBAT is used clinically.