重组人尿激酶原药效学研究

Pharmalogical Effects of Recombinant Human Prourokinase

利用人血浆及其产生的血栓凝块 ,在试管中模拟纤溶酶原激活剂在体内引起血栓溶解的过程及麻醉开胸犬电刺激冠脉左旋支引起的冠脉血栓形成模型评价重组人尿激酶原的溶栓活性 ,并与尿激酶进行比较 .InVitro实验结果表明 :2 4 0IU /mL是 prouk血纤维蛋白专一的最大浓度 ,低浓度的重组prouk比天然 prouk具有更高的溶栓能力 ,这可能与其非糖基化结构有关 .当重组prouk浓度小于 1μg/mL时 ,它在血浆中几乎不降解任何纤维蛋白原 .犬静脉给予重组人尿激酶原 9× 10 4 、4 .5× 10 4 、2 .2 5× 10 4 IU·kg- 1 对冠脉血栓产生显著的溶栓效果 ,栓塞冠脉血管很快出现再通 ,残存血栓较溶剂对照分别减少了 6 9.2 %、5 7.0 %、4 3.1% ;心肌梗死范围明显缩小 ;与等剂量尿激酶溶栓作用相似 .血浆优球蛋白溶解时间明显缩短 ;溶栓不伴有明显的血浆纤维蛋白原降解 ,而尿激酶溶栓的同时 ,纤维蛋白原明显降低 .除高剂量组个别动物外 ,对伤口出血量增加出血时间无明显影响 .

I labeled clots prepared from human plasma were utilized in vitro to mimic the in vivo process of thrombolysis induced by plasminogen activation.The model of coronary thrombosis, which was created by electric stimulation of the left coronary artery in the anesthetic thoracotomic dogs, evaluated the thrombolytic activity of prouk. The two chain urokinase used regularly in clinic was used as a control. The in vitro experimental results indicated that the concentration of 240 IU/ml of prouk was the maximum clot selective dosage. The thrombolysis by rhprouk of low conentration was faster than that of natural prouk. This was presumably due to the lack of glycosylation in recombinant prouk. When the concentration of recombinant prouk was less than 1 ug/ml, no fibrinogen loss occurred, confirming the stability of recombinant prouk in a plasma milieu. Recombinant prouk administered i.v. to dogs at doses of 9×10 4, 4.5×10 4 and 2.25×10 4 IU/kg produced obvious effects on coronary thrombolysis, and the coronary artery demonstrated that reperfusion occurred (60±25), (71±51) and (93±39) minutes respectively after initiation of treatment. The residual thrombi decreased by 69.2%, 57% and 43.1% respectively as compared to the control. The areas of myocardial infarction decreased by 30.2% and the time of eugloleulin lyses also reduced after a 60 min intravenous infusion of recombinant prouk (2.25×10 4～9.0×10 4 IU/kg). Fibrinogen levels fell to only 18% from baseline at 2 ug/ml of prouk concentration. In contrast, the thrombolysis induced by two chain UK was accompanied with dramatic fibrinogen degradation. All the subjects showed that there was no significant influence on bleeding time, except individuals administered by high doses of recombinant prouk.