Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine monoclonal antiplatelet antibodies MA-TSPI-1 (directed against human thrombospondin) and MA-PMI-2, MA-PMI-1, and MA-LIBS-1 (directed against ligand-induced binding sites [LIBS] on human platelet glycoprotein IIb/IIIa) were conjugated with recombinant single-chain urokinase-type plasminogen activator (rscu-PA) using the cross-linking reagent N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The conjugates (rscu-PA/MA-TSPI-1, rscu-PA/MA-PMI-2, rscu-PA/MA-PMI-1, and rscu-PA/MA-LIBS-1), purified by immunoadsorption and gel filtration, were obtained with recoveries of 34% to 45%, with an average stoichiometry of 1.6 to 1.8 IgG molecules per rscu-PA molecule, and with unaltered specific activities and affinities. Preincubation of human platelet-rich plasma with rscu-PA/MA-PMI-2, rscu-PA/MA-PMI-1, or unconjugated rscu-PA resulted in partial inhibition of ADP-induced aggregation; 25% inhibition was obtained with 63 micrograms/mL rscu-PA and with 6 micrograms u-PA/mL rscu-PA/MA-PMI-2 or 1.2 micrograms u-PA/mL rscu-PA/MA-PMI-1. In an in vitro system composed of a 125I-fibrin-labeled platelet-rich human plasma clot immersed in normal human plasma, the conjugates had threefold to greater than 15-fold less fibrinolytic potency than unconjugated rscu-PA. The thrombolytic potency of rscu-PA/MA-PMI-1 and rscu-PA/MA-LIBS-1 was compared with that of rscu-PA and that of a control conjugate rscu-PA/MA-1C8 in a pulmonary embolism model in the hamster, using clots prepared from platelet-poor or platelet-rich human plasma. Lysis was measured 30 minutes after the end of a 60-minute intravenous infusion of the thrombolytic agents. rscu-PA, rscu-PA/MA-PMI-1, rscu-PA/MA-LIBS-1, as well as rscu-PA/MA-1C8 had comparable thrombolytic potencies (percent lysis per dose administered) towards platelet-poor human plasma clots. In contrast, the thrombolytic potency of rscu-PA/MA-PMI-1 and of rscu-PA/MA-LIBS-1 towards platelet-rich clots was 2.3- to 3-fold higher than that of rscu-PA (P less than .005) and fivefold to sevenfold higher than that of the control conjugate (P less than .01).
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PMID:Effect of chemical conjugation of recombinant single-chain urokinase-type plasminogen activator with monoclonal antiplatelet antibodies on platelet aggregation and on plasma clot lysis in vitro and in vivo. 183 Oct 57

Systemic lysis may protect against the platelet activation and ongoing thrombosis associated with coronary thrombolysis. To address this hypothesis, we compared urokinase and tissue-type plasminogen activator (t-PA) given intravenously in a chronic, canine model of coronary thrombosis. T-PA 10 micrograms/kg per min induced reperfusion in 55 +/- 7 min but complete reocclusion occurred in 9/10 animals. Reocclusion was prevented by combining t-PA with 7E3, an antibody to the platelet glycoprotein IIb/IIIa which abolished ex vivo platelet aggregation. A similar time to reperfusion was seen with urokinase 750-1,000 U/kg per min. In contrast to t-PA, complete reocclusion occurred in only 1/20 cases (P less than 0.001 vs. t-PA), despite evidence of continued platelet activation in vivo and platelet aggregation ex vivo. Furthermore, this did not reflect a difference in the clearance of the two plasminogen activators. However, plasma fibrinogen was undetectable after urokinase in contrast with t-PA. Furthermore, in animals treated with prourokinase 20 micrograms/kg per min, reocclusion (4/7) correlated with the degree of systemic lysis. To determine whether platelet activation modified the response to urokinase, it was combined with 7E3. 7E3 0.8 mg/kg reduced the time to reperfusion with t-PA (30 +/- 5, n = 6; P = 0.025), but not with urokinase (56 +/- 8 vs. 62 +/- 6, P = ns). Systemic lysis protects against the propensity of continued thrombosis during coronary thrombolysis to delay reperfusion and induce reocclusion. This may modify the requirement for adjunctive antiplatelet therapy.
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PMID:Systemic lysis protects against the effects of platelet activation during coronary thrombolysis. 193 47

With technological advances in equipment and increased experience of operators, the success rates of percutaneous transluminal coronary angioplasty (PTCA) now exceed 90%. However, acute periprocural occlusion continues to complicate approximately 6% of all procedures, and many of these occlusions are due to intracoronary (IC) thrombus. Patients at highest risk for this complication include those with acute ischemic syndromes or with angiographically apparent thrombus. These individuals may be candidates for the use of prolonged heparin infusions prior to dilatation, intracoronary thrombolytic therapy, or monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor. All patients undergoing PTCA should receive adequate antiplatelet therapy, including aspirin, and heparin with dosing monitored by activated clotting times (ACT). In addition, some recommend the use of ionic contrast material. When IC thrombus accumulates following intervention, initial therapy should include IC nitroglycerin followed by a combination of redilatation and IC urokinase infusion. Prolonged balloon inflations may be useful, particularly with the use of autoperfusion catheters. Platelet glycoprotein IIb/IIIa receptor antagonists may prove to be beneficial in this situation as well. If the patient's clinical status deteriorates in spite of these measures, emergency coronary artery bypass graft surgery may be required.
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PMID:Management of intracoronary thrombosis complicating percutaneous transluminal coronary angioplasty. 881 33

Thrombolysis of arterial occlusions has limitations, e.g. it requires extensive time for thrombolysis, occlusions may be resistant to lysis, and the rate of reocclusions may be high. c7E3 Fab inhibits platelet aggregation by binding to the GPIIb/IIIa receptor on platelets. Experimentally, this monoclonal antibody has been shown to decrease, the time required for lysis, and to prevent reocclusion. This is the first report on the adjunctive use of c7E3 Fab in peripheral arterial occlusions in humans. Three patients with occlusion of the iliac or femoropopliteal artery were treated with c7E3 Fab (bolus injection of 0.25 mg/kg KG + i.v.-application 12 micrograms/min for 12 h). In addition, the patients received urokinase (100,000 IU bolus + 100,000 IU/h). Heparin (5,000 IU bolus + 1,000 IU/h) and acetylsalicylate (100 mg/day/p.o.). Occlusion length ranged between 6-40 cm. Therapy was successful in all patients. During the follow-up period (4-6 months) no reocclusion occurred. There were no serious side effects like major bleeding or thrombocytopenia. We conclude that the applied doses appear safe. Even the time required for thrombolysis was short, a conclusion in respect of a significant reduction of the time required for lysis can be drawn only after further controlled studies.
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PMID:[The adjuvant use of the monoclonal antibody c7E3 Fab in peripheral arterial thrombolysis]. 915 99

The effect of fibrinolytic agents on platelet adhesion onto insolubilized collagen type I was evaluated. Normal human whole blood samples were incubated with agents and perfused over collagen-coated surfaces in a parallel-plate flow chamber. Platelet adhesion and aggregation were analyzed by video microscopy and image processing. When blood was perfused at 1500/s, both streptokinase and urokinase, each at 500 U/ml, caused a significantly less normalized platelet deposition, compared with controls. At 480/s, platelet deposition was not different between controls and test samples. Inhibition of platelet deposition at high flow rates was partly due to inhibition of platelet adhesion. Both ristocetin- and ADP-induced platelet aggregation were inhibited in test samples. The agents caused proteolytic degradation of plasma fibrinogen, but no degradation of platelet glycoproteins Ib and IIb-IIIa (GPIb and GPIIb-IIIa) and of plasma von Willebrand factor in test samples prior to perfusion. Post-perfusion von Willebrand factor degradation was not found. Plasmin may cause functional changes to plasma proteins and/or platelet receptors, altering their adhesive properties under flow. At high shear, fibrinogen degradation products may interfere with GPIIb-IIIa binding to insolubilized von Willebrand factor, leading to decreased platelet adhesion. Inhibition of platelet adhesion by thrombolytic agents could help maintain vessel patency after recanalization in stenosed arteries. Publishers.
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PMID:Fibrinolytic agents inhibit platelet adhesion onto collagen type I-coated surfaces at high blood flow conditions. 966 3

Antithrombotic therapy is a basic part in the treatment of acute as well as chronic coronary syndromes. The rationale is an enhanced platelet activity with predomination of procoagulatory mechanisms in coronary artery disease. The current status of antiplatelet drugs, anticoagulation, and chronic thrombolysis used in the treatment of chronic coronary syndromes is discussed. It is concluded that low-dose aspirin is the current drug of choice for long term oral treatment in patients with stable chronic coronary artery disease. In contrast, oral anticoagulation with coumadin should be considered in patients with higher risk for atrial or ventricular thrombosis. The impact of long-term intermittent urokinase therapy in patients with end-stage coronary artery disease and refractory angina pectoris leads to a marked improvement of clinical symptoms. Oral blockade of platelet membrane glycoprotein IIb/IIIa receptor and clinical trials regarding antiischemic effects of low-molecular weight heparins in chronic coronary syndromes are expected for the future.
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PMID:[Antithrombotic therapy in chronic coronary syndromes--value of thrombocyte aggregation inhibition, anticoagulation and chronic thrombolysis]. 982 73

Thrombolysis is well established in the treatment of acute myocardial infarction. However, clinical application of thrombolytic agents has limitations with respect to efficacy and specificity. To achieve highly effective and at the same time clot-selective plasminogen activation urokinase was coupled to a bispecific antibody consisting of the monovalent Fab' from the antifibrin monoclonal antibody 59D8 and the monovalent Fab' from the anti-glycoprotein GPIIb/IIIa monoclonal antibody 7E3. The bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) was synthesized and characterized. Assays with either immobilized platelets, GPIIb/IIIa or fibrin showed an increase in plasminogen activation compared to uncoupled urokinase by 10-fold, 58-fold and 13-fold, respectivley (p < 0.0001 each). In vitro clot lysis was performed on platelet-rich and fibrin-rich clots and revealed an up to 5-fold higher potency of BAAUC compared to uncoupled urokinase (p < 0.0001). In vitro platelet aggregation was effectively inhibited by the hybrid molecule, whereas urokinase had no effect. BAAUC and two monospecific urokinase-conjugates, UK-59D8-IgG and UK-7E3-(Fab')2 were compared with each other with regard to similar tests. In vitro clot assays with platelet-rich and platelet-poor clots were performed. BAAUC achieved a significantly higher plasminogen activation compared to each of the monospecific conjugates (p < 0.05, respectively). We conclude that BAAUC, a bispecific plasminogen activator with antifibrin and antiplatelet properties has the potency to lyse both fibrin-rich and platelet-rich thrombi with high efficacy and to effectively inhibit platelet aggregation.
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PMID:A bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) induces enhanced clot lysis and inhibits platelet aggregation. 1045 63

The interaction of fibrinolytic components with platelets or coagulation factors after endothelial injury, was investigated in mouse deficient in tissue type plasminogen activator (tPA -/-), or urokinase (uPA -/-) and in their wild type control (tPA +/+, uPA +/+). A thrombus was induced in the murine carotid artery using the photochemical reaction. Blood flow was continuously monitored and the time needed before the vessel became completely obstructed was within 11 min in all types of mice. When GR144053, a platelet glycoprotein IIb/IIIa antagonist, or argatroban, a thrombin inhibitor, was applied, the time required to occlusion was prolonged in a dose-dependent manner in all types of mice. However, when GR144053 was injected in tPA -/- mice, the most significant changes were observed: that is the estimated ED50 was 14.8 times higher than the one in tPA +/+ mice. On the other hand, when argatroban was injected in tPA -/- mice, the estimated ED50 was not changed. Platelet aggregation, haemostasis tests and bleeding times were not significantly different among the different types of mice. In conclusion, the antithrombotic effect of platelet inhibition by a GPIIb/IIIa antagonist, is severely affected by the absence or presence of tPA-production. Thus, the lack of tPA significantly reduces the antithrombotic efficacy.
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PMID:Lack of tPA significantly affects antithrombotic therapy by a GPIIb/IIIa antagonist, but not by a thrombin inhibitor in mice. 1078 Mar 25

To define the interaction of fibrinolytic components with platelets or coagulation factors on thrombus formation, we investigated mouse deficient in tissue plasminogen activator (tPA -/-) or urokinase plasminogen activator (uPA -/-) and in their wild-type control (tPA +/+, uPA +/+). A thrombus was induced in the murine carotid artery using photochemical reaction. Blood flow was monitored and the time needed before the vessel became completely obstructed was within 12 min in all types of mice. When DX-9065a, a selective factor Xa inhibitor, or GR144053, a platelet glycoprotein (GP) complex IIb/IIIa antagonist was applied, the time required to occlusion was prolonged in a dose-dependent manner in all types of mice. When a factor Xa inhibitor was injected in tPA -/- mice, the estimated ED50 was not changed. However, when GR144053 was injected in tPA -/- mice, the most significant changes were observed: the estimated ED51 was 19.6 times higher than the one in tPA +/+ mice. Platelet aggregation, hemostasis tests, and bleeding times were not significantly different among the different types of mice. In conclusion, the antithrombotic effect of platelet inhibition by a GPIIb/IIIa antagonist, is severely affected by the absence or presence of tPA production. On the contrary, the inhibition of factor Xa shows a stable antithrombotic effect with or without tPA. Thus the lack of tPA, but not of uPA, significantly affects antithrombotic efficacy.
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PMID:tPA, but not uPA, significantly affects antithrombotic therapy by a glycoprotein IIb/IIIa antagonist, but not by a factor Xa inhibitor. 1111 78

A meta-analysis by the Cochrane Stroke Group (CSG) showed that thrombolytic therapy increased deaths as well as symptomatic and fatal intracranial hemorrhage within the first seven to 10 days and at final follow-up, although these risks are offset by a reduction in disability in survivors, so that there is overall a significant net reduction in the proportion of patients dead or dependent. Trials testing intravenous (i.v.) tPA suggest that it may be associated with less hazard and more benefit. A recent trial demonstrated that intra-arterial pro-urokinase improved long-term outcome in patients with M 1 or M 2 occlusion within 6 hours of onset. Trials of the third generation of thrombolytic agents are ongoing in patients with acute ischemic stroke. The latest CSG's meta-analysis showed that immediate anticoagulant therapy in patients with acute ischemic stroke was not associated with net short or long-term benefit because there was no evidence that anticoagulant therapy reduced deaths or non-fatal stroke during treatment or patients dead or dependent at the end of follow-up. However, an i.v. low-molecular-weight heparinoid showed a trend toward improving long-term outcome in subgroup of patients with atherothrombotic stroke. The thrombin inhibitor argatroban was proven to be comparable to the thromboxane A2 synthetase inhibitor ozagrel in the effect on the outcome at one month in patients with atherothrombotic stroke within 48 hours of onset in Japan, and a trial of the agent is ongoing in patients with ischemic stroke within 12 hours of onset in the United States. Two large trials of aspirin in patients with ischemic stroke within 48 hours of onset indicated that aspirin had a modest effect on reducing patients dead or dependent at the end of follow-up. An international trial of abciximab, a monoclonal antibody directed against platelet glycoprotein IIb/IIIa, is ongoing in patients with ischemic stroke within 6 hours of onset.
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PMID:[Strategy for circulatory disturbance]. 1223 94


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