UNIPROT:P00750 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To localize the binding region of porcine tissue-type plasminogen activator (EC 3.4.21.31) (t-plasminogen activator) to heparin, functionally active A and B chains (molecular mass of each 33 kDa) were separated from the two-chain t-plasminogen activator after mild reduction and alkylation. The A chain bound to fibrin-Sepharose, but not to heparin-Sepharose. In contrast, the B chain showed amidase activity toward HD-Ile-Pro-Arg-p-nitroanilide (S-2288) and a high affinity for heparin-Sepharose, but no affinity for fibrin-Sepharose. Plasminogen activator activity of the B chain was stimulated by heparin (about 3-fold), but not by fibrin. On the other hand, the elastase digestion fragments of plasminogen, kringle 1-3 and kringle 4, had no affinity for a heparin-Sepharose column, whereas the other fragment, Val442-plasminogen, efficiently bound to the column and was eluted with 1.6 M KSCN-containing buffer. The stimulatory effect of fibrin on two-chain t-plasminogen activator-catalyzed Val442-plasminogen activation was clearly diminished by heparin. These results suggest that heparin can form a complex with both t-plasminogen activator and plasminogen molecules through their catalytic regions located in each B chain, and that the heparin connection between t-plasminogen activator and plasminogen may improve the plasminogen activation kinetics by making a situation in which t-plasminogen activator is easily approachable to plasminogen.
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PMID:Localization of the binding sites of porcine tissue-type plasminogen activator and plasminogen to heparin. 312 Jul 75

Alteplase is a human tissue plasminogen activator (t-PA) produced by recombinant DNA technology. It is a relatively fibrin-specific thrombolytic agent, used primarily to lyse coronary artery clots. It has proven effective in the treatment of acute myocardial infarction (AMI). Despite continuous reevaluation of pharmacokinetic parameters for t-PA, limited distribution and clearance data mandate administration of t-PA as a continuous infusion. Tissue plasminogen activator is eliminated primarily by hepatic metabolism with an elimination half-life of five to ten minutes. Plasma levels show great interindividual variation but correlate with infusion rate and decrease in fibrinogen level. The current recommended dose is 100 mg administered as a 10-mg iv bolus followed by a continuous infusion over three hours. However, 40-150 mg has been used in clinical trials. The compound has undergone extensive testing, comparing it with placebo and streptokinase (SK), and combining it with angioplasty and coronary artery bypass surgery. Tissue plasminogen activator is effective at opening clotted coronary arteries in approximately 70 percent of AMI patients and has been shown to be approximately twice as effective as SK in one U.S. trial. Although there is considerable evidence of efficacy with t-PA, data evaluating the influence of t-PA on mortality are limited, but suggest a reduction to five percent. Currently, thrombolytic therapy is indicated for patients experiencing a transmural AMI with onset of symptoms within three to six hours before presenting to the emergency room. Active internal bleeding or conditions predisposing to serious hemorrhage are contraindications to thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alteplase: a tissue plasminogen activator for acute myocardial infarction. 312 86

Alteplase (recombinant tissue-type plasminogen activator) stimulates the fibrinolysis of blood clots by converting plasminogen to plasmin. The efficacy of intravenous alteplase in the early treatment of patients with acute myocardial infarction has been unequivocally proven, and recent results from the GUSTO trial indicate a significant advantage in 30-day survival for alteplase in an accelerated dosage regimen (< or = 100mg infused over 90 minutes rather than 3 hours) over streptokinase. The advantage of the accelerated alteplase dosage regimen seems to be maintained for at least 1 year. The role of heparin as adjunctive therapy to thrombolysis remains to be fully defined but heparin administration appears to be more important in conjunction with alteplase than with streptokinase. Ideally, patients should receive alteplase as soon as possible after the onset of symptoms of acute myocardial infarction and, while therapy is most beneficial when administered early, survival is improved when the drug is administered up to 12 hours after symptom onset. The accelerated regimen of alteplase used in the GUSTO trial demonstrated a survival advantage in patients < or = 75 as well as those > 75 years of age which was at least as great as that seen with streptokinase. Similarly, alteplase reduces mortality in patients with both anterior and inferior infarctions; however, those with anterior wall infarctions show an improved outcome over those with inferior infarcts. On the basis of pharmacoeconomic analysis of GUSTO data, the accelerated alteplase regimen cost an estimated additional $US32,678 per year of life saved compared with a conventional streptokinase regimen. Cumulative 1-year costs were greater in patients who received the accelerated alteplase regimen but survival was significantly greater than in patients who received streptokinase. No difference in quality of life was evident in patients who received either treatment. The incidence of major haemorrhage associated with alteplase therapy appears to be similar to that seen with other fibrinolytic agents, increasing with increasing dose; however, the risk of stroke, particularly haemorrhagic stroke, is higher with alteplase than with streptokinase. Thus, alteplase has become firmly established as a first-line option in the management of acute myocardial infarction. On the basis of accumulated evidence, the greatest risk reduction with alteplase therapy may be in certain high risk groups, such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset.
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PMID:Alteplase. A reappraisal of its pharmacological properties and therapeutic use in acute myocardial infarction. 758 83

Streptokinase and alteplase are established therapies in acute myocardial infarction. Reteplase is a new thrombolytic agent that can be given as a double bolus. This trial was designed to determine whether the effect of reteplase on survival was at least equivalent (within 1% of fatality rate) to that of a standard streptokinase regimen. Patients from 208 centres in nine countries (n = 6010) with symptoms and electrocardiographic criteria consistent with acute myocardial infarction were randomised to receive double-blind either streptokinase 1.5 MU intravenously over 60 min or reteplase two boluses of 10 MU given 30 min apart. Treatment could be started up to 12 h from onset of symptoms. All patients received intravenous heparin for at least 24 h. The primary endpoint was 35-day outcome. There were 270 deaths (9.02%) in the reteplase and 285 deaths (9.53%) in the streptokinase group, a non-significant difference (95% CI -1.98% to 0.96%). Among patients who received treatment (98.8%) there were 263 deaths (8.90%) in the reteplase compared with 279 deaths (9.43%) in the streptokinase group (a difference of -0.53%). Because the upper limit of the 90% CI for this difference is 0.71%, this result shows that reteplase is at least as effective as streptokinase. In-hospital stroke rates were 1.23% for reteplase and 1.00% for streptokinase. Bleeding events were similar in the two treatment groups (0.7% reteplase, 1.0% streptokinase). The incidence of recurrent myocardial infarction was similar, but there were significantly fewer cases of atrial fibrillation, asystole, cardiac shock, heart failure, and hypotension in the reteplase group. We conclude that reteplase is an effective drug in the treatment of acute myocardial infarction. It is clinically safe, its administration is simple, and it will be a useful addition to the range of thrombolytic agents available.
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PMID:Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. International Joint Efficacy Comparison of Thrombolytics. 1111 34

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

The Bolus Alteplase Pulmonary Embolism (BAPE) Group and a consortium of French investigators utilized essentially the same investigational protocol to test reduced dose bolus alteplase vs full dose 100 mg/2 h alteplase in the treatment of pulmonary embolism (PE). The principal hypothesis was that reduced dose bolus alteplase (n = 96) would result in fewer bleeding complications than full dose 100 mg of 2 h alteplase (n = 44) administered as a continuous infusion to hemodynamically stable patients with PE. To provide data on bolus alteplase's safety profile in a larger sample size than would have been feasible in either trial alone, we present an overview of the BAPE and French trials. There were no differences between the reduced dose bolus and full dose 2 h rt-PA groups with respect to bleeding complications. Therefore, the principal hypothesis of these two randomized controlled trials could not be confirmed. Efficacy was similar in the two treatment groups. Interpretation of the results will vary because the increased convenience and cost savings from using a reduced dose of bolus alteplase may be offset by a higher mortality rate. However, a trial that compared the mortality rates of the two treatment regimens would have required more than 800 patients.
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PMID:Two trials of reduced bolus alteplase in the treatment of pulmonary embolism. An overview. 808 47

The purpose of this prospectively conducted study was to determine the prevalence of transient myocardial ischemia, evaluated from 24 h continuous ECG monitoring and exercise test, 6 months after inclusion in the Anglo Scandinavian Study of Early Thrombolysis (the ASSET trial, a randomised, placebo controlled study of alteplase for survival in patients with suspected acute myocardial infarction (AMI)), and to relate these findings to development of cardiac events. Of the 58 consecutively studied patients ischemic responses were found in 13 (45%) of 29 patients initially treated with placebo, and in 21 (72%) of 29 alteplase treated patients (P = 0.03). After another 6 months, i.e. 12 months after the acute event, two patients were dead, two had non-fatal reinfarctions and three had coronary artery by-pass surgery in the group with ischemic response; no events were recorded in patients without ischemia (P < 0.05). Alteplase treated patients more often had late myocardial ischemia, and cardiac events were found in patients with ischemia. Since the ASSET trial has demonstrated significantly higher short- and long-term survival rate in the alteplase treated group, it was indicated (1) that alteplase treated patients were better positioned for sustaining subsequent ischemia and thus cardiac events due to preservation of viable myocardial tissue, and (2) that late ischemia in the setting of initial alteplase treatment may convey other information than ischemia occurring in placebo treated patients.
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PMID:The prevalence of myocardial ischemia six months after thrombolytic treatment of acute coronary episodes. A subset of a placebo controlled, randomised trial, the ASSET Study. 810 12

Patients with a patent coronary artery after reperfusion therapy show an increased rate of evolution of QRS changes and of resolution of S-T changes as compared to patients with a persistent occlusion. Dynamic vectorcardiography permits multi-lead monitoring of changes in QRS complex and S-T segment over time. We monitored 150 patients randomized to alteplase or streptokinase for 24 h after admission. Alteplase was associated with significantly more rapid evolution of electrocardiographic changes but also with an increased occurrence of recurrent S-T changes. This may indicate a higher rate of early reperfusion with alteplase but due to recurrent ischemia, an electrocardiographic catch-up is seen with similar extent of myocardial damage observed after 24 h of monitoring.
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PMID:Early electrocardiographic changes in acute myocardial infarction treated by streptokinase or alteplase: a randomized study with dynamic, multi-lead, electrocardiographic monitoring. 840 57

We describe an autopsy case of severe intracranial hemorrhage which occurred during the infusion of tissue plasminogen activator (t-PA) for acute myocardial infarction. A 75-year-old man was admitted with substernal chest pain of 3-h duration and electrocardiographic changes consistent with an acute inferior myocardial infarction. Physical examination was unremarkable, except for an initial blood pressure reading of 160/96 mmHg. The patient received 3,000 IU intravenous heparin followed by a 2.4 x 10(6) IU bolus dose of tissue plasminogen activator (t-PA) (Alteplase). This was followed by a drip infusion of 21.6 x 10(6) IU of t-PA over 1 h (total dose 41 mg). Thirty minutes after the infusion of t-PA was initiated, the patient suddenly lost consciousness and began to have violent convulsions, followed by cardiac arrest. Autopsy revealed massive hemorrhage in the bilateral cerebrum and brain stem. To our knowledge, this is the first case of sudden death during t-PA infusion therapy.
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PMID:An autopsy case of intracranial hemorrhage during tissue plasminogen activator infusion. 840 27

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

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