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)

Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents. Numerous truncated alteplase or saruplase molecules have been constructed by deletion and domain substitution or hybrids made of the two molecules without gaining in thrombolytic potency. Recombinant staphylokinase and plasminogen activator from bat saliva have some interesting properties and are being investigated. Thrombus-targeted thrombolytic drugs were constructed using monoclonal antibodies against fibrin fragments or against epitopes of activated platelets. Fibrin-specific thrombolytic drugs require the concomitant use of a potent antithrombotic drug to prevent reocclusion. Whether hirudin or synthetic thrombin inhibitors are superior to heparin and whether novel antiplatelet agents, including monoclonal antibodies to platelet receptors and disintegrins, are more effective than aspirin is under clinical investigation. The place of stable analogues of prostacyclin during thrombolytic treatment is still unsettled.
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PMID:Advances in thrombolytic therapy. 139 Mar 21

Three thrombolytic agents are frequently used in the United States for treating patients with acute myocardial infarction: streptokinase, alteplase (tissue plasminogen activator [t-PA]), and anistreplase (anisoylated plasminogen-streptokinase activator complex [APSAC]). A fourth agent, urokinase, is occasionally used but clinical experience is considerably more limited with this agent. Streptokinase, alteplase, and anistreplase differ in a number of pharmacologic properties, which include half-life, enzymatic efficiency, and induction of platelet aggregation; these differences may be clinically important. For example, anistreplase and alteplase have high affinity for fibrin and bind to intravascular thrombi after intravenous administration, which may result in higher clot specificity. Anistreplase has the longest half-life of the 3 agents and, therefore, can be administered conveniently and quickly. Alteplase has a shorter half-life and heparin is generally a necessary adjunctive agent. These differences can be clinically significant in various settings and application of such theoretical advantages is just beginning.
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PMID:Importance of the pharmacological profile of thrombolytic agents in clinical practice. 174 49

Despite enormous advances made in understanding of the biochemistry of fibrinolytic agents and their extensive clinical use in acute myocardial infarction a number of unresolved issues remain. There is an intriguing divergence of left ventricular response and reduction of mortality in patients with acute myocardial infarction treated with thrombolytic drugs. It is also difficult to explain why patients treated late have a reduced mortality after thrombolytic treatment. Uncertainty prevails on the validity of thrombolysis in patients with a low and very high risk of mortality. Resistance of coronary occlusion to any thrombolytic is another unexplained fact. Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. It is being explored whether prolonged intravenous maintenance infusions are more effective if replaced by a bolus injection, accelerated infusion or the combined intravenous administration of thrombolytic agents.
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PMID:Unresolved issues in the thrombolytic treatment of myocardial infarction. 178 46

The characteristics and efficacy of alteplase in treating acute myocardial infarction (AMI) are described, and the role of the pharmacist with respect to thrombolytic therapy is discussed. Most patients with AMI have an acute thrombotic occlusion in the coronary artery supplying the infarcted tissue. Subsequent mortality from AMI can be reduced if patients receive thrombolytic therapy within 4 to 24 hours after the onset of symptoms. Tissue-type plasminogen activator produced by recombinant DNA techniques (alteplase) is purported to be indistinguishable from the endogenous protein. When given intravenously, alteplase has a rapid onset of action and a half-life of three to nine minutes, producing plasma concentrations of plasminogen activator 1000 times greater than those seen under normal physiologic conditions. Because alteplase has an affinity for fibrin and is, therefore, clot specific, its use does not induce the systemic plasminogen activation seen with streptokinase or urokinase therapy. The major adverse effect of alteplase therapy is bleeding. Comparative studies have shown reperfusion rates of 66% to 75% with alteplase and of 36% to 76% with streptokinase. Alteplase has generally been more effective than streptokinase in initiating reperfusion. Alteplase may be used for treatment of reocclusion after initial treatment with either alteplase or streptokinase. Because alteplase costs approximately 30 times more than streptokinase, informed medical decision making is imperative. It is suggested that pharmacists develop protocols, monitor thrombolytic therapy in their institutions, stay informed about current research, regularly report their findings to medical colleagues, and provide information and education to physicians, nurses, and patients. The rational use of thrombolytic agents requires consideration of the attendant clinical and economic consequences.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Risks versus benefits: the alteplase experience. 251 14

In the past decade, thrombolytic therapy has become standard treatment of acute myocardial infarction. When the importance of thrombosis in the pathogenesis of acute infarction was fully recognised, several plasminogen activators were developed, streptokinase, urokinase, recombinant tissue-type plasminogen activator (t-PA, alteplase), anistreplase and saruplase (prourokinase). Thrombolytic agents are plasminogen activators which possess as a common characteristic the ability to activate plasminogen to plasmin, and result in fibrinolysis and varying degrees of depletion of circulating fibrinogen, factor V and factor VIII. A lot of animal experiments provided the basis for the rationale that recanalisation and reperfusion early in the course of myocardial infarction would limit myocardial necrosis, improve left ventricular function, and improve patient outcome. Native tissue plasminogen activator is normally secreted by vascular endothelium and the most important property of the drug is its relative fibrin specificity. Fibrin strikingly increases the rate of conversion of plasminogen to plasmin by t-PA. The isolation of the complementary DNA coding for t-PA, its insertion into the genome of Chinese hamster ovary cells, and its expression in suspension cultures of these cells have facilitated the large-scale production of t-PA, making it available as a drug for the treatment of acute myocardial infarction. A variety of dosage schemes have been used for alteplase, the standard schedule has been 100 mg given over 3 hours. Higher doses and faster administration (accelerated, front-loaded) are associated with higher patency rates. Alteplase has generally but not always been shown to have higher reocclusion rates than the non-fibrin-specific plasminogen activators. Reocclusion has been shown to be associated with adverse clinical outcome. Therefore, the rate of reocclusion is considered an important measure in evaluating thrombolytic regimens. The combination of alteplase with either urokinase or streptokinase has resulted in early patency rates comparable to alteplase alone, and low rates of reocclusion. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality significantly in patients with ST elevation treated within the first 6 to 12 hours of acute myocardial infarction. As compared to an overall reduction of mortality with thrombolytic treatment, neither the GISSI-2/international trial nor the Third International Study of Infarct Survival (ISIS-3) trial of more than 60,000 patients found a difference in associated mortality between the use of streptokinase and the use of t-PA, or between the use of these agents and that of anistreplase. The addition of subcutaneous heparin to the regimens did not significantly reduce mortality as compared with no use of heparin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[t-PA in thrombolytic therapy of acute myocardial infarct]. 784 90

Alteplase is the product of recombinant DNA technology and is chemically identical to endogenous tissue-type plasminogen activator: Plasminogen is converted to plasmin by alteplase, and fibrinolysis of blood thrombi is subsequently stimulated. Alteplase is now firmly established as a treatment of choice in the management of acute myocardial infarction. The efficacy of intravenous alteplase in the treatment of pulmonary thromboembolism has also been established and appears to be similar to that of streptokinase and urokinase in this indication and in arterial thrombotic occlusion. However, its use in this latter indication and in other vascular disorders has not been as extensively documented. Although trials demonstrating the efficacy of intravenous alteplase in patients with deep vein thrombosis and intra-arterial alteplase in patients with arterial thrombotic occlusion exist, reliable data on the efficacy of the fibrinolytic in ischaemic stroke and intracranial haemorrhage are scarce. Little clinical benefit is apparent in patients with unstable angina, although careful use may be warranted in those with definite pretreatment coronary thrombi. Of concern, there is a suggestion that general use of alteplase in patients with unstable angina may be associated with increased incidence of myocardial infarction. The incidence of major haemorrhage associated with alteplase therapy increases with increasing dose and appears to be similar to that seen with other fibrinolytic agents. Thus, further well-designed studies of the use of alteplase in ischaemic stroke and cerebral haemorrhage are required. However, a small subset of patients with unstable angina and definite pretreatment coronary thrombi may benefit from alteplase therapy. Further, preliminary data suggest efficacy in the therapy of deep vein thrombosis and arterial thrombotic occlusion, and alteplase has a proven place in the fibrinolytic treatment of pulmonary thromboembolism.
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PMID:Alteplase. A reappraisal of its pharmacology and therapeutic use in vascular disorders other than acute myocardial infarction. 852 60

In a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We investigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogen activator (PA) and is accelerated by ultrasonic irradiation. Lysis of compacted crosslinked human plasma clots was measured after addition of nine different PAs to the surrounding plasma and the effect of 3 MHz ultrasound on the speed of lysis was assessed. Fibrin-specific PAs showed bell-shaped dose-response curves of varying width and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodus rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold range). However, in terms of speed of lysis, these three PAs exceeded tPA only slightly. Reteplase and single-chain urokinase were comparable to tPA, whereas two-chain urokinase, anistreplase, and streptokinase were inferior to tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the outer plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot. In conclusion, PAs with improved fibrin-specificity induce rapid lysis of plasminogen-poor compacted plasma clots in much wider concentration ranges than tPA. This offers a possibility of using single-or double-bolus administration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-opening of the occluded arteries since they are only moderately superior to tPA in terms of maximal speed of lysis. Application of high-frequency ultrasound as an adjunct to thrombolytic therapy may increase the treatment efficiency, particularly in conjunction with fibrin-specific PAs.
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PMID:Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro. 1023 48

Saruplase is a relatively new fibrinolytic drug. Dose finding studies indicated that 70-80 mg saruplase given intravenously results in a high perfusion rate. With a 20 mg bolus followed by a 60 mg infusion over 1 h, a rapid and complete restoration of blood flow can be achieved in a fairly high number of patients. This dose regimen was used in subsequent studies comparing saruplase with other thrombolytic agents. The PRIMI (Pro-urokinase In Myocardial Infarction) study compared saruplase with streptokinase. Early patency rate at 60 min (TIMI grade 2 and 3 flow) was significantly higher with saruplase (71.8%) than with streptokinase (48.0%). In the SESAM (Study in Europe with Saruplase and Alteplase in Myocardial Infarction) study comparing saruplase with alteplase, at 60 min patency rate was 79.9% versus 75.3%, respectively, and at 90 min the rate was 79.9% versus 81.4%, respectively. In the LIMITS (Liquemin in Myocardial Infarction during Thrombolysis with Saruplase) study a heparin bolus of 5000 IU was shown to have an important impact on patency rate. Both heparin and acetylsalicylic acid are recommended as adjunctive therapy before fibrinolysis with saruplase. The reocclusion rates within 24-40 h were between 0.9% and 2.4% in the saruplase studies. There is some variation in estimating whether patency rates are higher with anterior or with inferior infarctions. Saruplase appears to be equally effective in the treatment of infarction in both locations.
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PMID:Clinical profile of saruplase: angiographic findings. 1034 35

Several lines of research towards improvement of thrombolytic agents are being explored, including the construction of mutants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, and plasminogen activators from animal or bacterial origin. Some of these new thrombolytic agents have shown promise in animal models of venous or arterial thrombosis; only those which are being investigated in clinical studies are briefly discussed. Monteplase is a modified tissue type-plasminogen activator (t-PA) constructed by substituting only one amino acid in the epidermal growth factor domain (Cys84-->Ser) and expressed in baby Syrian hamster kidney cells. It has a prolonged half-life of more than 20 min, as compared to 4 min for native t-PA. TNK-t-PA differs from t-PA by 3 mutations. This mutant has increased thrombolytic potency, slower clearance and enhanced resistance to the inhibitor PAI-1. Reteplase is a non-glycosylated deletion mutant of wild-type human t-PA which contains only kringle 2 and the protease domain but lacks its kringle 1 and the finger and growth factor domains. The structural changes in reteplase translate into a decreased fibrin binding, a lower affinity to endothelial and liver cells resulting in an extended half-life. Lanoteplase is a deletion mutant of t-PA with a half-life that is circa 10 times greater than alteplase, making it suitable for single bolus injection. YM866 is another mutant of t-PA in which the aminoacids 92 to 173 of kringle 1 were deleted and arginine275 replaced by glutamic acid which confers a longer half-life to the mutant. Recombinant glycosylated prourokinase has a greater stability than recombinant unglycosylated pro-urokinase, is rapid acting and safe in the clinical doses used. Staphylokinase (SAK) is produced by Staphylococcus aureus. It induces efficient and rapid recanalization, also after bolus injection, but is immunogenic. There are only a few large scale clinical trials published directly comparing fibrin-selective thrombolytic drugs. In patients with acute myocardial infarction, reteplase, administered in bolus injections, is associated with a similar mortality and bleeding rate as front loaded t-PA. Bolus TNK-t-PA has a similar incidence of cerebral bleeding as front loaded t-PA and is associated with the same survival rate after acute myocardial infarction in a large mortality trial.
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PMID:Newer thrombolytic agents. 1057 30

Thrombolytic drugs, streptokinase and urokinase, were initially used in pulmonary embolism. More recently, new drugs like alteplase, reteplase, lanoteplase and saruplase have been a breakthrough in the treatment of acute myocardial infarction. Their efficacy has been demonstrated when treatment is initiated before the 6th hour of infarction onset. A 50% reduction of death rate is expected, if treatment starts within the 1st hour. Alteplase and reteplase are the most efficient thrombolytics despite a higher risk of cerebral bleeding. In pulmonary embolism with clinical signs of severity, thrombolysis is clearly indicated. In deep vein thrombosis of the lower limbs, therapeutic thrombolysis is still controversial. Some acute ischemic strokes (before the 3rd hour) could be treated with alteplase if there is no absolute or relative contraindication for thrombolysis. In prosthetic heart valve thrombosis, thrombolysis may be used if surgical treatment is contraindicated but the risk of bleeding and embolism should be taken into account.
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PMID:[Indications for thrombolytics]. 1058 97


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