国产人尿激酶原的药效学、药理学和毒理学研究

Investigation of Pharmacodynamics,Pharmacology,and Toxicology of Domestic Human Prourokinase

通过对重组人尿激酶原(rhRhpro-UK)不同剂量(8万IU/kg和16万IU/kg)对家兔纤溶功能的影响并与尿激酶(UK)(8万IU/kg)比较实验显示,rhpro-UK和UK都能明显缩短兔优球蛋白溶解时间,rhpro-UK对纤溶参数影响比UK小.rhpro-UK对体外血栓的溶解作用随剂量增加而增加,与同剂量UK比较有显著差别.rhpro-UK和UK对猪冠脉血栓都有明显的溶栓作用,对猪的纤溶指标纤维蛋白原(FG)、纤溶酶原(PLG)和α2抗纤溶酶(α2-AP)无明显影响.rhpro-UK对出血时间、凝血时间、单位时间内出血量均明显低于UK.表明rhpro-UK的副作用明显低于UK.rhpro-UK对小鼠、大鼠、犬和豚鼠回肠的一般药理学实验表明,rhpro-UK对受试动物的一般行为、状态及中枢神经系统、心血管系统、呼吸系统、消化系统等均无明显影响.仅发现犬实验中手术创面有渗血现象,对全身血液有类似肝素化状态.rhpro-UK的毒理实验表明,rhpro-UK的半数致死量为97.5mg/kg;Beagle犬接受2,8,28mg/kgrhpro-UK后,除8mg和28mg组有一过性牙龈充血,凝血时间明显延长,Tchol,TP和Alb含量有升高趋势外,未观察到明显毒性反应,病理学检查也未观察到药物造成直接的脏器损伤,2mg/kg组未观察到任何毒副反应.特殊毒性实验表明,rhpro-UK没有致突变和致畸作用.

The comparison of the effect of fibrinolytic activity of recombinant human prourokinase（rhpro-UK） and urokinase（UK） with rabbits indicated rhpro-UK and UK all decreased resolution time of globular proteins,and the affect of rhpro-UK on parameter of fibrinolysis of rabbits was less than UK.The solution of thrombin of rhpro-UK in vitro was increased with dosage of rhpro-UK,and when rhpro-UK was compared with isodose UK,the difference is significant.Both rhpro-UK and UK all was marked solution of thrombin from Chinese piglets,and it were not evident effect on fibrinogen,plasminogen,and a2-antiplasmin of the piglets.The affect of rhpro-UK on bleeding time,clotting time,bleeding amount of unit time was less than UK.It indicated that the side effect of rhpro-UK was distinguished less than UK.The investigation of pharmacology of ileums of mice,rats,dogs,and guinea pigs indicated that rhpro-UK was not marked affect on behavior,state,central nervous system,cardiovascular system,respiratory system,and digestive system of the tested animals.But tested dogs were bleeding at location of operation,and the blood of the animal was heparinized.The studis of toxicology of rhpro-UK indicated that rhpro-UK was median lethal dose of 97.5 mg/kg in mice.When The Beagle dogs was administed rhpro-UK of 2,8,28 mg/kg,the toxic reaction was not observed,except for temporal hyperemia of gum,extend of clotting time,increasing of total cholerythrin,total proteins,albumin of the dogs,the direct damage of organs for the medicine was not observed in examination of pathology in the dosages of 8 and 28 mg/kg,any toxic reaction was not observed in dosage of 2 mg/kg.The special toxic experiments proved that rhpro-UK was not of mutagenesis and teratogenesis.