重组组织型纤溶酶原激活剂联合尿激酶治疗急性脑梗死的临床观察

目的观察低剂量重组组织型纤溶酶原激活剂(rt-PA)联合尿激酶静脉溶栓治疗急性脑梗死的远期疗效和安全性。方法选择急性脑梗死患者161例,分为4组:联合溶栓组44例,给予静脉rt-PA尿激酶;rt-PA组37例,尿激酶组32例,对照组48例。观察治疗前及治疗后90 d美国国立卫生研究所卒中量表(NIHSS)评分,同时观察再梗死率、脑出血率及病死率。结果与治疗前比较,4组治疗后90 d NIHSS评分差异均有统计学意义(P<0.01)。3个溶栓组与对照组在90 d有效率及疗效满意率差异均有统计学意义(P<0.01);3个溶栓组90 d有效率及疗效满意率差异无统计学意义(P>0.05)。联合溶栓组与rt-PA组和尿激酶组脑出血率比较差异均有统计学意义(2.3%υs 18.9%υs 18.7%,P<0.05)。结论 rt-PA联合尿激酶治疗急性脑梗死远期疗效和单用rt-PA、单用尿激酶相当,但脑出血率降低,因此该治疗方法是安全有效的,值得推广应用。     

低剂量重组组织型纤溶酶原激活剂与尿激酶联合溶栓治疗急性脑梗死

目的观察联合应用重组组织型纤溶酶原激活剂（rt—PA）和尿激酶治疗急性脑梗死的有效性和安全性。方法选择发病〈6h的急性脑梗死患者81例,分为联合溶栓组（20例）、单用rt—PA组（22例）、单用尿激酶组（18例）及对照组（21例）。联合溶栓组静脉给予rt—PA20mg,尿激酶30万-50万IU;单用rt—PA组静脉给予rt—PA0．9mg／kg;单用尿激酶组静脉给予尿激酶1万～2万IU／kg（体质量超过75kg者按75kg给药）,最大剂量150万IU;未溶栓病例为对照组。主要疗效指标是观察治疗前与发病后4周的神经功能缺损评分（NIHSS）变化,以溶栓后出血转化、24h内再梗死及死亡等作为安全指标。结果联合溶栓组、单用rt—PA组、单用尿激酶组及对照组的观察结果为：①NIHSS评分治疗前分别为18．1±3．6、17．9±3．6、18．0±3．4、17．3±4．0,治疗后分别为9．1±5．6、8．8±5．5、9．6±5．2、14．1±4．6,符组治疗前、后比较,差异均有统计学意义（P〈0．01）,3个溶栓组与对照组比较差异均有统计学意义（P〈0．01）;3个溶栓组比较,差异无统计学意义。②4组治疗后总有效率分别为85．0％（17／20）、86．4％（19／22）、83．3％（15／18）和42．9％（9／21）,与对照组比较差异有统计学意义（P〈0．05）;各溶栓组间比较,差异无统计学意义（P〉0．05）。③联合溶栓组溶栓后24h内再发脑梗死1例,出血转化1例;单用rt—PA组出血转化3例;单用尿激酶组再梗死1例,出血转化有2例,其中死亡1例。对照组再梗死1例,死亡1例。结论与单用rt—PA和单用尿激酶比较,联合低剂量rt-PA和尿激酶溶栓治疗急性脑梗死同样安全、有效,相对rt—PA价格便宜,值得推广应用。     

Safety of thrombolytic therapy with urokinase or recombinant tissue plasminogen activator for peripheral arterial occlusion: a comprehensive compilation of published work.

PURPOSE: To report a comprehensive literature review focused on comparing the risk of complications with urokinase versus recombinant tissue plasminogen activator (rtPA) for thrombolytic treatment of peripheral arterial occlusions. METHODS: The English-language literature between 1985 and 2002 was searched for studies that used tissue-derived urokinase or rtPA in the treatment of peripheral arterial occlusions. Forty-eight studies (22 urokinase, 22 rtPA, and 4 that included both treatments) were identified, encompassing 2226 urokinase-treated patients and 1927 rtPA-treated patients. The safety of each thrombolytic agent was assessed based on the incidence of major hemorrhage, intracerebral hemorrhage, major limb amputation, transfusions, and mortality. RESULTS: The review revealed a wide range of study protocols, patient conditions, ages of occlusions, dosages/delivery methods of lytic agents, and criteria for reporting complications. The incidence of major hemorrhage varied widely, but the overall rate was lower among urokinase-treated patients (6.2%) than for patients treated with rtPA (8.4%, p=0.007). The overall incidence of intracerebral hemorrhage was also significantly lower for urokinase (0.4% versus 1.1% for rtPA, p=0.020). The major amputation rate was similar for both treatments (urokinase 7.9%, rtPA 7.2%), but the mortality rate was significantly lower for urokinase (3.0% versus 5.6% for rtPA, p<0.001). The need for transfusions was less frequent with urokinase (11.1% versus 16.1%, p=0.002). CONCLUSIONS: These results from a large body of published literature suggest that urokinase may be associated with a lower incidence of complications than rtPA in the treatment of peripheral arterial occlusions.     

Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells

Binding of urokinase (uPA) to its receptor (uPAR; CD87) focuses proteolytic activity on the cell surface and this system is of importance in malignant matrix degradation and tumour invasion. By immunocytochemistry and flow cytometry, we found that primary myeloma cells and myeloma cell lines expressed uPA and uPAR. Soluble uPA was present in cell line supernatants and lysates in low concentrations. In cell lines, uPA and uPAR were located both on the cell surface and intracellularly, but the expression of both proteins was low. Higher levels of uPAR was detected on the cell surface of primary myeloma cells. When primary myeloma cells were gated by CD45 expression, stronger expression was found on immature CD45+ cells than on mature CD45-/dim cells. Finally, both myeloma cell lines and primary cells were able to cleave a uPA-specific substrate showing that the uPA system is functionally active. We conclude that myeloma cells are able to produce uPA and uPAR. This opens up a possible role of the uPA system in myeloma cell invasion and in the proteolytic digestion of bone matrix.     

Outcome of different reperfusion strategies in patients with former contraindications to thrombolytic therapy: A comparison of primary angioplasty and tissue plasminogen activator

High-risk patients have been excluded from most thrombolytic trials because of concern over hemorrhagic complications or lack of efficacy. However, based on several recent studies suggesting that patients with relative thrombolytic contraindications may also benefit from reperfusion, recommendations have been made to broadly expand the eligibility criteria for thrombolytic therapy, despite higher absolute complication rates. Primary percutaneous transluminal coronary angioplasty (PTCA) may be an attractive alternative for patients presenting at appropriately equipped hospitals who would otherwise remain at high risk after thrombolytic therapy. In the Primary Angioplasty in Myocardial Infarction (PAMI) trial, 395 patients with acute myocardial infarction were randomized to tissue plasminogen activator (t-PA) or primary PTCA. Conditions were present In 151 patients (38%) which formerly would have contraindicated thrombolytic therapy (age >70 yr, symptom duration >4 hr, or prior bypass surgery). In-hospitality was 4.3-fold higher in patients with former thrombolytic contraindications compared to lytic-eligible patients (8.6% vs. 2.0%, P = .002). Lytic-eligible patients treated with t-PA and PTCA had similar in-hospital mortality (1.7% vs. 2.4%, P = NS). In contrast, both in-hospital (2.9% vs. 13.2%, P = .025) and 6-mo mortality (2.9% vs. 15.7%, P = .009) were significantly reduced in patients with former thrombolytic contraindications treated by primary PTCA compared to t-PA. By logistic regression analysis, treatment by PTCA rather than t-PA was the strongest predictor of survival in patients with former thrombolytic contraindications. We conclude that patients with conditions formerly contraindicating thrombolytic therapy constitute a high-risk group with significant morbidity and mortality after lytic reperfusion. Our data suggest that patients with former contraindications to thrombolytic therapy may benefit by preferential management with primary PTCA without antecedent thrombolysis. © 1996 Wiley-Liss, Inc.     

Thrombolytic therapy in canine pulmonary embolism. Comparative effects of urokinase and recombinant tissue plasminogen activator

We compared thrombolytic and pulmonary hemodynamic effects of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) in canine micropulmonary thromboembolism. Dogs were embolized with radioactive autologous blood clot to increase mean pulmonary artery pressure (from 13 to 34 mm Hg, p less than 0.005) and decrease cardiac output (2.5 to 1.6 L min, p less than 0.005). Four groups of six dogs were treated. We employed two doses of UK, 30,000 U/kg (UK30) and 60,000 U/kg (UK60), and two doses of rtPA, 1 mg/kg (rtPA1) and 2 mg/kg (rtPA2). Drugs were infused over 15 min. Rate and extent of pulmonary thrombolysis were assessed by continuously counting over both lung fields with a gamma camera. Compared with treatment with UK, both rtPA regimes significantly increased thrombolysis. Mean total pulmonary thrombolysis was 14 and 23% with UK30 and UK60, respectively, and 35 and 43% with rtPA1 and rtPA2. Corresponding to the increased thrombolysis, pulmonary hemodynamics improved most with rtPA. From 90 min to 3 h, pulmonary artery pressure was significantly lower with both rtPA regimes than with either UK regime. These results indicate, at least in the model employed, that compared with treatment with UK, pulmonary thrombolysis and corresponding hemodynamic improvement are greatest with rtPA.     

Regulation of plasminogen activator inhibitor-1 secretion by urokinase and tissue plasminogen activator in rat epithelioid-type smooth muscle cells

Tissue plasminogen activator (tPA) and urokinase (uPA) are targets of plasminogen activator inhibitor-1 (PAI-1) inhibition. We have previously shown that both proteases can also induce PAI-1 secretion in rat smooth muscle cells (SMCs). We now report that both proteases appear to use very similar cellular mechanisms for signal transduction. They induced PAI-1 secretion using a pathway(s) involving protein kinase C (PKC). They also activated the Raf/Mek/mitogen-activated protein kinase (MAPK) pathway, which lies downstream of PKC activation. Activation of protein kinase A (PKA), however, lowered PAI-1 secretion induced by uPA and tPA, as a result of an inhibition of the PKC pathway and inhibition of Raf, Mek and MAPK phosphorylations. Src and syk family non-receptor tyrosine kinases (TK) were also involved in PAI-1 induction. The mechanisms of interaction of these tyrosine kinases with other pathways appeared to be quite different: src appeared to act within the PKC and PKA pathways, while syk operated independently of these pathways. Furthermore, whereas src inhibition resulted in inhibition of Raf/Mek/Erk phosphorylations, syk inhibition could only inhibit Mek and Erk phosphorylations but not the phosphorylation of Raf. These multiple pathways utilized by uPA and tPA to modulate PAI-1 secretion might be involved in determining the proteolytic or antiproteolytic potential of the SMCs under different pathophysiological conditions.     

尿激酶与组织型纤溶酶原激活剂静脉溶栓治疗急性心肌梗塞的对比研究

为比较尿激酶（UK）及组织型纤溶酶原激活剂（t-PA）静脉溶栓辅以阿司匹林及肝素对急性心肌梗塞的效果及其副作用。对急性心肌梗塞患者发病6h内者，42例给予静脉UK15例静脉内t-PA溶栓辅以静脉肝素及阿司匹林治疗。结果表明，t-PA组、UK组临床血管再通率分别为86．7％与57．1％（P＜0．05），前者消化道与呼吸道出血并发症为13．3％，而后者为0（P＜0．05）。本研究提示静脉t-PA溶栓血管再通率显著高于静脉UK，但出血合并症的发生t-PA组显著高于UK组。     

小剂量重组织型纤溶酶原激活剂与尿激酶、重组链激酶溶栓治疗急性心肌梗死的临床对比分析

目的观察小剂量重组织型纤溶酶原激活剂（rt—PA）、尿激酶（UK）和重组链激酶（r—sK）治疗急性心肌梗死的疗效和安全性。方法114例急性心肌梗死患者随机分为rt—PA组38例，UK组37例，r—SK组39例。分别应用纤溶酶原激活剂50mg、尿激酶150万U、链激酶150万U静脉输入。结果rt—PA组、UK组、r—sK组临床血管再通率分别为84．21％、51．35％、69．23％，三者之间疗效比较P〈0．05。3组溶栓后不良反应、5周病死率比较P〉0．05，差异无显著性。结论rt—PA治疗急性心肌梗死的疗效明显优于UK和r—SK，而r—SK的疗效优于UK。溶栓后不良反应、5周病死率比较差异无显著性。     

Intrapleural low-molecular-weight urokinase or tissue plasminogen activator versus single-chain urokinase in tetracycline-induced pleural loculation in rabbits

The authors compared the ability of a single dose of the proenzyme single-chain urokinase (scuPA), low-molecular-weight urokinase, tissue plasminogen activator (tPA), or a mutant site-inactive scuPA to resolve intrapleural loculations at 72 to 96 hours after tetracycline-induced pleural injury in rabbits. Both scuPA and tPA reversed loculations at 96 hours after injury P < or = .001, whereas low-molecular-weight urokinase and the scuPA mutant were ineffective. scuPA and tPA generated inhibitor complexes, induced fibrinolytic activity, and quenched plasminogen activator-1 activity in pleural fluids. The authors conclude that scuPA reverses loculations as effectively as tPA at clinically applied intrapleural doses, whereas low-molecular-weight urokinase was ineffective.     

uPA纤溶途径与肝纤维化

细胞外基质(extracellular matrix,ECM)过度沉积是肝纤维化的特征性表现,纤溶系统尤其是尿激酶型纤溶酶原激活剂(urokinase- plasminogen activator,uPA)所介导的纤溶途径与肝纤维化关系密切,其主要成分包括纤溶酶原、纤溶酶、纤溶酶原激活剂及其抑制剂．uPA纤溶途径位于ECM降解酶系的顶端,肝纤维化时通过uPA-纤溶酶-基质金属蛋白酶(matrix metalloproteinases,MMPs)-ECM级联机制下调ECM降解,促进ECM在肝内沉积,而且可能在肝星状细胞(hepatic stellate cell,HSC)增殖、迁移以及肝细胞再生等过程中起到重要作用．     

Differences in the reactivities of human urokinase and the porcine tissue plasminogen activator.

It has previously been shown, that large differences exist between the effects of 6-aminohexanoic acid or alpha1-antitrypsin on fibrinolysis caused by a porcine tissue plasminogen activator or by human urokinase, while insignificant differences exist between the effects of a number of natural protease inhibitors on fibrinolysis caused by the two types of plasminogen activator. The present study shows that changes in substrate composition (pH, ionic strength fibrinogen concentration, plasminogen concentration) may influence to different degrees the fibrinolytic activities of human urokinase and the porcine tissue plasminogen activator. It is suggested, that this finding is partly related to marked differences in affinity for fibrin of the two activators.     

Optimal dosage regimens of tissue-type plasminogen activator

The optimal therapeutic regimen for t-PA in humans remains to be determined. The ideal dosage regimen for t-PA should achieve effective thrombolysis as quickly as possible with minimum fibrinogenolysis to minimize bleeding. Our findings in rabbits suggest that the present regimens in humans might be improved by using frequent rapid infusions rather than the more prolonged infusions. Clearly, the results of our animal studies will have to be confirmed in man before firm recommendations can be made.     

Controversies about tissue plasminogen activator: Extending the window of therapy

The management of stroke has undergone significant development over the past 15 years. Perhaps the single most important landmark has been the approval by the Food and Drug Administration of intravenous (IV) tissue plasminogen activator (t-PA) for the treatment of ischemic stroke. However, the approval of this drug has not met with unanimous support by the medical community and, at present, only a minority of stroke patients receive t-PA. Although this is partly due to the fact that many patients do not meet criteria for treatment with IV t-PA, others simply do not arrive at medical facilities sufficiently early to be safely managed using thrombolysis. The appropriate use of IV t-PA in the treatment of ischemic stroke requires proper selection of patients and strict adherence to clinical protocols of treatment. The ideal stroke patient for treatment with IV t-PA is one who suffers occlusion of a small artery that leads to a disabling deficit.     

肝硬化患者血浆中尿激酶型纤溶酶激活物的检测及其意义

目的 探讨肝硬化患者血浆尿激酶型纤溶酶激活物(uPA)、尿激酶型纤溶酶激活物受体(uPAR)、纤溶酶原激活物抑制剂-1(PAI-1)的变化及其意义。 方法 确诊的72例乙型肝炎后肝硬化患者,Child-pugh分级A级23例(A组),B级29例(B组),C级20例(C组)。6例健康志愿献血者为正常对照组。酶联免疫吸附实验测定血浆uPA、uPAR、PAI-1的变化。并同时检测血透明质酸(HA)、Ⅳ型胶原(C Ⅳ)、Ⅲ型前胶原(PC Ⅲ)、血浆白蛋白、胆红素、凝血酶原时间及其活动度改变。 结果 随着肝硬化的进展,血浆uPA、uPAR、PAI-1逐渐增加,HA、PC Ⅲ也明显增加。Child C组患者血浆uPA、uPAR、PAI-1水平(μg/L)分别为1.88±0.64、4.82±2.02和52.60±16.87,A组分别为1.36±0.43、3.03±1.48和24.09±7.14,B组分别为1.79±0.62、4.80±2.22和41.40±17.52,C组与A、B组比较,t值为2.81～7.38,P值均<0.01。A组血浆uPA与PC Ⅲ呈负相关(r=-0.4785,P<0.05);C组PAI-1与HA呈正相关(r=0.5447,P<0.01)。 结论 肝硬化晚期,虽然血浆uPA、PAI-1增加,但总的效应表现为uPA相对不足,肝基质纤维降解受抑制,血浆uPA、PAI-1与肝硬化发展密切相关。     

Inhibition of the plasminogen activator urokinase by alpha-tocopherol

alpha-Tocopherol (vitamin E) inhibited the activity of urokinase on fibrin plates and on the amidolytic substrate S-2444 in a concentration- and time-dependent manner. Inhibition was not removed by dialysis. In the presence of dilutions of plasma, protein-containing fractions of gel-filtered plasma, or bovine serum albumin, the inhibition of urokinase by alpha-tocopherol was abolished. Urokinase activity was not inhibited by phytol, menadione or hydroquinone.