重组葡激酶溶栓作用的实验研究

目的　研究重组葡激酶对体内外血栓的溶解作用。方法　采用体外纤维蛋白溶解法,家兔体内纤维蛋白溶解试验,胶原蛋白 肾上腺素诱发小鼠体内脑血栓形成模型及静脉结扎形成大鼠下腔静脉血栓模型。结果　重组葡激酶体外给药对纤维蛋白具有显著溶解作用,使家兔血浆优球蛋白溶解时间明显缩短,给药后０－５至２ｈ间血浆鱼精蛋白试验均呈阳性反应,但对血浆纤维蛋白原含量无显著影响;可显著降低脑血栓小鼠死亡率,缩短偏瘫动物的恢复时间;对结扎形成的大鼠下腔静脉血栓湿重有明显降低,给药后血栓所占血管面积明显减少。结论　重组葡激酶具有极显著溶解体内外血栓的作用,等剂量条件下,作用优于尿激酶。     

重组葡激酶对实验性猫冠状动脉血栓的影响

目的　研究重组葡激酶对实验性冠状动脉血栓的溶栓作用。方法　采用实验性猫冠状动脉血栓形成模型。结果　重组葡激酶显著降低猫冠脉血栓切面与冠脉管腔比值 ,减少心肌缺血范围 ,给药后对心电图也有一定程度的改善。结论　重组葡激酶具有极显著溶解猫冠状动脉血栓的作用     

重组葡激酶溶栓作用的研究

目的　研究重组葡激酶的溶栓作用。方法　通过测定家兔血浆优球蛋白溶解时间 (ELT)、纤维蛋白原降解产物(FDP)的含量及纤维蛋白原 (Fg)的含量 ,以观察重组葡激酶对家兔纤维溶解活性的影响。采用家兔动静脉旁路血栓形成法、家兔肺栓塞法及大鼠体外血栓形成法模型 ,以观察重组葡激酶的溶栓作用。结果　重组葡激酶 (6 2 5 0U·kg-1,1 2 5万U·kg-1)可明显缩短ELT ,增加FDP含量 ,对Fg含量无明显影响 ;重组葡激酶 (8333U·kg-1,2 5万U·kg-1,7 5万U·kg-1)在 3种血栓形成模型上 ,均有溶栓作用。结论　重组葡激酶具有明显的溶栓作用。     

海洋假单胞菌碱性蛋白酶对实验性家兔股动脉血栓的溶解作用

目的研究海洋假单胞茵碱性蛋白酶(MPAP)对体内血栓的溶解作用及对凝血功能的影响。方法建立家兔股动脉血栓模型，股动脉造影观察用药后股动脉血栓的溶解情况，通过测定PT，TT，KPTT及Fbg含量，评估MPAP对家免凝血和纤溶功能的影响。结果结果显示，MPAP能明显促进家免股动脉血栓再通，用药后，TT，PT，KPTT显著延长，Fbg含量降低。结论MPAP对实验性家兔股动脉血栓有一定的溶解作用，并且有明显的抗凝功能。     

重组葡激酶在健康受试者的耐受性

目的 评价健康受试者对重组葡激酶（血栓溶解药）的安全性和耐受性.方法 27例健康受试者静脉滴注重组葡激酶（2.5,5,10,15 mg）.结果 用药前后,所有受试者用药前后血压、心率及呼吸无异常变化,与溶栓有关的血液学参数、血尿常规、肝肾功能及血糖均无显著性变化.有10例（37.0%）发生轻微过敏反应;9例（33.3%）发生轻微出血;6例仅有牙龈少量渗血;1例发现尿中红细胞;1例出现静脉穿刺部位小瘀斑;在15 mg剂量组中,1例同时具有上述3种出血表现.结论 在2.5～15 mg内,健康受试者均能较好地耐受重组葡萄酶,但有少数出现轻度药物不良反应.     

光化学法诱导大鼠冠状动脉血栓模型的建立和应用

目的建立光化学法诱导大鼠冠状动脉血栓致心肌梗死模型。方法大鼠分为激光和化学单独刺激组、联合刺激组和重组葡激酶处理组,通过注射光敏剂四氯四碘荧光素二钠(虎红)后激光照射冠状动脉形成血栓致心肌梗死动物模型,比较各组血管栓塞程度以及心电图Ⅱ导联ST段高度变化选择出最佳模型。并用该模型评价重组葡激酶溶栓作用效果。结果相对于单独刺激组,联合刺激组心脏激光照射处均出现明显损伤病灶。HE染色心肌细胞肿胀,排列紊乱,动静脉内均见血栓。心电图出现不同程度心律失常,ST段抬高。其中注射40 mg.kg-1虎红后照射15 min心律失常出现时间较早,心电图ST段抬高幅度高、维持时间长,而且死亡率低,为本研究中最佳光化学法冠状动脉血栓模型。重组葡激酶处理组能够部分溶解动静脉血管内血栓,减小血栓面积(P<0.01),抑制ST段抬高(P<0.05～0.01)。结论该文建立了最佳光化学法诱导大鼠冠状动脉血栓模型,适于溶栓药物研发评价。     

重组葡激酶静脉溶栓疗法在老年急性心肌梗死治疗中的临床应用价值分析

目的探讨对老年急性心肌梗死患者实施重组葡激酶静脉溶栓治疗的临床价值。方法选取老年急性心肌梗死患者53例,随即分为两组。其中,对照组26例,给予重组组织型纤溶酶原激活物静脉溶栓治疗;观察组27例,给予重组葡激酶静脉溶栓治疗。对两组患者的治疗效果及并发症情况进行比较。结果观察组患者血管再通情况明显优于对照组,并发出血情况明显低于对照组,两组比较差异具有统计学意义（P〈0.05）。结论重组葡激酶用于治疗老年急性心肌梗死安全可靠,效果明显,值得临床推广。     

施爱克

[通用名称]recombinant staphylokinase for injection（r-Sak）,注射用重组葡激酶 　　[性状]为白色疏松体,溶解后为澄明液体. 　　[药理作用]本品具有溶栓作用.其溶栓机制为：与血浆中纤溶酶原形成复合物,激活纤溶系统,促使纤溶酶原转化为纤溶酶,特异性地降解纤维蛋白,使血栓溶解.     

纳豆激酶对实验动物溶栓作用的研究

目的观察纳豆激酶在体内溶解血栓的作用。方法利用30%FeCl3制造大鼠颈动脉血栓模型,随机分为5组,包括血栓对照组,低剂量纳豆激酶组,高剂量纳豆激酶组,蚓激酶对照组和生理盐水对照组。利用花生油喂食的方法构建高脂血症动物模型,分成4组进行试验,包括普通饲料对照组,添加花生油对照组,同时添加低剂量纳豆激酶和同时添加高剂量纳豆激酶组。结果血栓复制40 min后,纳豆激酶组与单纯血栓组相比,股动脉血压显著下降。此外,纳豆激酶组与单纯血栓组比较,经纳豆激酶处理的动物其血栓的湿质量、干质量降低。在高脂血症动物模型中,添加纳豆激酶组表现出总胆固醇(TC)和高密度脂蛋白胆固醇(HDL-C)明显降低,而且这种趋势随着纳豆激酶量的增高更加显著。结论纳豆激酶在体内具有明显的溶栓效果,并且有一定的预防和降低血脂的作用。     

国产重组葡激酶对兔股动脉血栓溶栓疗效的对照研究

目的观察同等剂量国产重组葡激酶(r-SAK)、重组链激酶(r-SK)和尿激酶(UK)对兔股动脉血栓的溶栓疗效。方法新西兰兔20只,随机分为对照组、r-SAK组、UK组和r-SK组。用球囊损伤法制作兔右股动脉血栓形成模型。球囊损伤后2h分别经耳缘静脉匀速输注各溶栓药物,持续30min:①对照组:生理盐水10ml;②r-SAK组:r-SAK3.0万U/kg;③UK组:UK3.0万U/kg;④r-SK组:r-SK3.0万U/kg。溶栓后持续监测兔股动脉压力以判断血管开通状况。结果球囊损伤后120min各实验组右股动脉脉压均降为0或低于左侧脉压的10%;对照组输注生理盐水后右股动脉压力无显著变化,r-SAK组溶栓后右股动脉脉压均显著增加至大于左侧脉压的50%,而UK和r-SK组溶栓后右侧股动脉压力较溶栓前均无显著变化;溶栓后5h,r-SAK组所有再通血管的脉压均下降至左侧脉压的50%以下。结论同等剂量的国产r-SAK溶栓疗效优于UK和r-SK。     

Thrombolytic efficacy of native recombinant staphylokinase on femoral artery thrombus of rabbits

AIM: To investigate the thrombolytic efficacy, ideal dosage and administration of native recombinant staphylokinase (r-SAK). METHODS: Forty New Zealand rabbits were randomly assigned into the control, r-SAK low-dose, medial-dose, high dose, single bolus, allied therapy, recombinant streptokinase (r-SK) and urokinase (UK) groups. The right femoral artery thrombosis models were made by balloon injury, and 120 min after the injury, the thrombolytic agents were infused through the rabbits' parallel-ear vein. RESULTS: (1) 2 h after balloon injury, the pulse pressures of the right femoral arteries reduced to 0 or less than 10% of that of left femoral arteries in all groups; (2) after thrombolytic therapy, the pulse pressures in some of the femoral arteries markedly enhanced to more than 50% of that of left femoral arteries; (3) the reopening rates in the r-SAK medial and high dose groups were significantly higher than that of the control. The reopening rate of the same dose native r-SAK was significant higher than that of UK and r-SK; (4) the patency score of the right femoral arteries tended to be better in the r-SAK medial and high-dose groups than that of the low-dose group, and the time to reopening in the allied therapy group tended to be shorter. CONCLUSION: (1) r-SAK has a definite thrombolytic effect on the femoral artery thrombus of rabbits; (2) single bolus is an effective manner of r-SAK therapy, and r-SAK allied therapy with heparin may shorten the time to recanalization; (3) the efficacy of the same dose native r-SAK was superior to that of r-SK and UK.     

The usefulness of systemic administration of recombinant human tissue-type plasminogen activator in femoral arterial thrombolysis of rabbits

The thrombolytic effect of locally or systemically administered recombinant human tissue-type plasminogen activator (rt-PA) was investigated in comparison with the effect of tissue culture urokinase (TCUK), using a model of femoral artery thrombosis in rabbits. An 125I-labeled fibrinogen thrombus was formed in the femoral artery following injury of the intima by diluted sulfuric acid, and thrombolytic activity was evaluated one hour after the end of infusion of the agents. Local infusion of rt-PA (500-10,000 IU/kg) and TCUK (10,000 IU/kg) induced a marked thrombolysis. When rt-PA and TCUK were injected systemically in a high dose (200,000 IU/kg), rt-PA but not TCUK had a significant thrombolytic activity. In these cases, rt-PA was not accompanied by systemic activation of the fibrinolytic system, as evaluated by unaltered levels of alpha 2-antiplasmin in the plasma, while TCUK led to a substantial decrease in the alpha 2-antiplasmin level. These results suggest that systemically administered rt-PA but not TCUK induce a significant thrombolysis without systemic activation of the fibrinolytic system in cases of peripheral artery thrombosis.     

New derivative of staphylokinase SAK-RGD-K2-Hirul exerts thrombolytic effects in the arterial thrombosis model in rats

SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul are recombinant proteins that are derivatives of r-SAK (recombinant staphylokinase). They are characterized by their fibrin-specific plasminogen activation properties and their antithrombin and antiplatelet activities. The difference between these proteins is the presence of the antithrombotic fragment (hirudin or hirulog) in the C-terminal portion of the r-SAK. The aim of the present study was to examine the thrombolytic potentials of SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul in an electrically induced carotid artery thrombosis model in rats and to compare the potentials to that of r-SAK. We determined that a bolus injection of SAK-RGD-K2-Hirul was more effective than one of r-SAK in the improvement and maintenance of carotid patency and in arterial thrombus weight reduction; however, it had the same potency as SAK-RGD-K2-Hir. The bleeding time, prothrombin time and activated partial thromboplastin time were significantly prolonged in the animals that were treated with either dose (1.5 or 3.0 mg/kg) of SAK-RGD-K2-Hir or SAK-RGD-K2-Hirul, whereas no changes were observed in the plasma fibrinogen concentration or the α2 plasmin inhibitor level. r-SAK alone did not change the bleeding time or coagulation parameters. In conclusion, our findings demonstrate the thrombolytic activity of intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hirul in rats. Although this protein compares favorably with r-SAK, we were unable to show the presence of any beneficial effects of SAK-RGD-K2-Hirul over those of SAK-RGD-K2-Hir. Furthermore, our results suggest that high doses of SAK-RGD-K2-Hirul bear the risk of bleeding.     

Prevention of thrombosis and rethrombosis and enhancement of the thrombolytic actions of recombinant tissue-type plasminogen activator in the canine heart by DMP728, a glycoprotein IIb/IIIa antagonist.

1. We studied DMP728, a non-peptide glycoprotein (GP) IIb/IIIa receptor antagonist, for prevention of coronary artery thrombosis or rethrombosis in a chronic canine model subjected to arterial injury. 2. In protocol I, DMP728 (1.0 mg kg-1, i.v., n = 8) or saline (n = 8) was administered and a 150 microA anodal current was applied to the intimal surface of the left circumflex coronary artery (LCX). Dogs were monitored for 6 h and again on each of 5 subsequent days. 3. Ex vivo platelet aggregation was inhibited but returned to baseline 1 day after drug administration. Thrombus weight was reduced (saline, 20.7 +/- 5.0 mg; DMP728 1.7 +/- 0.4 mg; P < 0.05), as was infarct size [saline, 27.5 +/- 4.3; DMP728, 1.6 +/- 0.7 (per cent left ventricle); P < 0.05]. All control animals died by day 3, while all but one of the treated dogs survived the entire protocol (P < 0.05). 4. In protocol II, an LCX thrombus was induced and thrombolytic therapy was initiated 30 min later. DMP728 (1.0 mg kg-1, i.v., n = 8) or saline (n = 8) was administered 5 min after recombinant tissue-type plasminogen activator infusion had begun. The incidence of reocclusion was reduced by DMP728 (saline, 4/8; DMP728, 1/8). One day after thrombolysis, 7/8 DMP728-treated animals were alive compared with 1/8 in the control group (P = 0.01). 5. DMP728 inhibited ex vivo platelet aggregation, prevented primary and secondary occlusive thrombus formation, reduced thrombus weight and infarct size and increased survival in a chronic canine model of coronary artery thrombus formation.(ABSTRACT TRUNCATED AT 250 WORDS)     

重组葡激酶对中国实验小型猪冠脉血栓作用的研究

目的:观察重组葡激酶(r-SaK)对中国实验小型猪冠状动脉血栓、心肌缺血、心肌梗塞的影响.方法:直接电刺激中国实验小型猪冠状动脉造成动脉内膜损伤,逐渐形成冠脉内血栓.运用冠状动脉病理切片、显微成像、多媒体图象分析、心外膜电图、心肌组织化学染色、血清生化酶学检查、血液流变学等多种试验手段,研究了r-SaK静脉给药对冠脉血栓的溶栓作用.结果:r-SaK对冠脉血栓有显著的溶栓作用,与对照组比较,r-SaK两个剂量组均能明 显缩小冠脉血栓横切面积(P<0.01),减轻心肌缺血程度和范围(P<0.01),缩小梗塞区(P<0.01),降低CPK活性和血液粘度(P<0.05),抑制血小板粘附、血小板聚集及纤维蛋白原的形成(P<0.05).结论:r-SaK对冠状动脉血栓具有明显的溶栓作用,并可对抗心肌缺血、心肌梗塞等病理反应.     

Antithrombotic effect of a novel tissue plasminogen activator from the venom of Gloydius brevicaudus viper

OBJECTIVE To investigate the thrombolytic and antiplatelet effects of a novel plasminogen activator from the venom of Gloydius brevicaudus viper(GBV-PA)in vitro and in vivo.METHODS Thrombolytic experiments were performed in rabbit models of ear vein thrombosis and carotid artery thrombosis,and in dog model of acute cerebral infarction.Inhibition of thrombus formation was evaluated in rat inferior vena cava thrombosis model and ferric chloride-induced arterial thrombosis.In vitro,we assayed the antithrombotic effect of GBV-PA on rabbit blood clots,euglobulin lysis time(ELT)of rabbit plasma,and on ADP-induced platelet aggregation.RESULTS GBV-PA intravenous administ ration significantly reduced vascular recanalization times of rabbit ear veins thrombosis and thrombus weight of rabbit carotid artery thrombosis.The arterial recanalization rates were dose-and time-dependently improved after administration of GBV-PA in canine acute cerebral infarction model.Thrombus length and weight was significantly reduced by GBV-PA both in rat inferior vena cava and ferric chloride-induced arterial thrombosis models.Thrombus formation of blood of rabbits they were administrated with GBV-PA was also inhibited.GBV-PA radically reduced plasma ELT of rabbit′s blood clots.ADP-induced platelet aggregation was inhibited by GBV-PA in a dose-dependent manner with a half-maximal inhibitory concentration of 19.9μg·mL-1.CONCLUSION This study demonstrates that GBV-PA is a thrombolytic and antiplatelet agent.It has significant antithrombotic effects on various in vitro and in vivo experimental models of thrombosis.The mechanisms that underline its antithrombotic effects were related to GBV-PA′s capabilities of increasing fibrinolytic activities and inhibition of platelet aggregation.