Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Three available thrombolytic agents, streptokinase, alteplase, and anistreplase, have been shown to have similar effects on preservation of left ventricular function and mortality reduction after acute myocardial infarction (AMI). The agents are, however, quite different with respect to their safety profiles. Clinical trials to date suggest that alteplase (tissue plasminogen activator) or anistreplase administration is associated with a high incidence of cerebral hemorrhage. In contrast, streptokinase is associated with a low rate of cerebral hemorrhage. Streptokinase and anistreplase are associated with a higher risk of allergic reaction when compared with alteplase. Hypotension is also more common with streptokinase and anistreplase, but occurs significantly with alteplase as well. Alteplase is associated with a lower reinfarction rate when compared with streptokinase and anistreplase. The Third International Study of Infarct Survival (ISIS-3), a direct comparison of 3 thrombolytic agents (streptokinase, anistreplase, and duteplase), may provide some insight regarding the safety of these agents. Because these agents have been shown to be equally effective, selection of an appropriate agent for an individual patient may depend more on assessment of the likelihood of an adverse event or other factors, such as cost or convenience of administration, rather than assessment of the probability of greater benefit with a particular agent.
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PMID:Comparative safety of thrombolytic agents. 174 50

The demonstration in animals that recombinant tissue-type plasminogen activator produces prolonged thrombolysis after its clearance from the circulation has prompted a few pilot studies of bolus administration in patients. Alteplase (bolus dose of 70 mg) resulted in the highest recanalization rate in our previous pilot study comparing bolus doses of 50, 60 and 70 mg of alteplase in patients with acute myocardial infarction. The aim of the present trial was to assess the efficacy and safety of the same bolus dose in a larger number of patients. A further objective was to study the angiographic reocclusion rate at 12 to 24 hours in patients who had a recanalized infarct-related coronary artery at 90 minutes and were randomized at that time to a bolus dose or an infusion for 3 hours of 30 mg of alteplase. Sixty patients with acute myocardial infarction and angiographically documented total occlusion of the infarct-related coronary artery before thrombolysis were treated within 5 hours of onset of symptoms with an intravenous 70-mg bolus dose of alteplase (or 80 mg if body weight was greater than or equal to 90 kg). Each patient received 5,000 IU of heparin intraarterially and 100 mg of aspirin by mouth before administration of alteplase. Coronary angiography was repeated 60 and 90 minutes after alteplase administration. The recanalization rate of the infarct-related coronary artery was 55% (95% confidence interval, 43 to 66%) at 60 minutes and 48% (95% confidence interval, 37 to 60%) at 90 minutes. Pretreatment levels of lipoprotein (a) were not significantly related to recanalization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coronary recanalization rate after intravenous bolus of alteplase in acute myocardial infarction. 182 74

In 1987 the Second International Standard for tissue plasminogen activator (t-PA) was established by the World Health Organization following an international collaborative study. At that time, the Center for Biologics Evaluation and Research (CBER) decided to establish a national reference t-PA to be used in lot release potency testing of Alteplase, a licensed t-PA biological or of other t-PAs in development. A candidate recombinant t-PA (rt-PA) preparation was donated by Genentech, Inc. (South San Francisco, California) for this purpose and a collaborative study was launched to calibrate this material against the 2nd I.S. Four laboratories (including the Center for Biologics Evaluation and Research (CBER) and three manufacturers) participated in the study to establish the potency of the rt-PA preparation using a clot lysis assay. The results indicate that the potency of the U.S. reference for t-PA is 2900 international units (IU) per vial.
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PMID:A collaborative study to establish a U.S. reference for tissue plasminogen activator (t-PA). 195 4

Alteplase (recombinant tissue-type plasminogen activator (rt-PA)) was infused within four hours of onset of symptoms in 286 patients with acute myocardial infarction. Delayed coronary angiography was performed 72 hours after admission with coronary angioplasty if indicated. Electrocardiographic monitoring was continuous during the first hour of treatment. The sum of the ST segment elevations (sigma ST) was calculated on electrocardiograms recorded at entry and an hour later. ST elevations resolved rapidly within one hour of treatment in 189 patients and persisted in 97 patients. Rapid resolution of ST elevation correlated with angiographic coronary patency as determined by coronary angiography 72 hours after admission. The patients with rapid resolution of sigma ST had significantly smaller infarcts and a better clinical outcome than the patients with persistent ST elevation. sigma ST values at entry and one hour after treatment had no additional independent predictive value. Rapid resolution of ST elevations in patients undergoing thrombolysis with alteplase was associated with a significantly smaller release of creatine kinase, better preservation of left ventricular function, lower morbidity, and less short and long term mortality. Rapid resolution of sigma ST elevation is an efficient indicator of clinical outcome in groups of patients with acute myocardial infarction undergoing thrombolysis with alteplase.
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PMID:Rapid resolution of ST elevation and prediction of clinical outcome in patients undergoing thrombolysis with alteplase (recombinant tissue-type plasminogen activator): results of the Israeli Study of Early Intervention in Myocardial Infarction. 212 Nov 99

An overview of eight randomized controlled trials of tissue-type plasminogen activator (Alteplase or Duteplase) and 10 of anisoylated plasminogen streptokinase activator complex (Anistreplase) showed that the odds of early death were reduced by 29% by tissue-type plasminogen activator and 46% by anisoylated plasminogen streptokinase activator complex, with overlapping 95% confidence intervals. Although the beneficial effects of both agents are consistent and are strengthened when all the trials are considered together, the available data do not permit comparisons of the relative efficacy of these two agents with each other or with streptokinase.
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PMID:Effects of tissue-type plasminogen activator and anisoylated plasminogen streptokinase activator complex on mortality in acute myocardial infarction. 214 38

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

The turnover of tissue plasminogen activator (tPA) was studied in rabbits using a double-label technique which allowed the comparison of various tPA derivatives with a standard tPA in individual animals. Purified recombinant tPA (Alteplase) was labelled with 125I and used as a standard for each experiment. Various tPA preparations which lacked specific carbohydrate structures were labelled with 131I (in separate experiments) and injected along with the 125I-tPA standard into rabbits. The clearance of standard tPA was biphasic with an average T 1/2 alpha and T 1/2 beta of 0.85 min and 12 min respectively. Type II tPA which lacks a portion of carbohydrate associated with Type I tPA as well as desialated tPA demonstrated a longer T 1/2 beta than standard tPA.
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PMID:Turnover of tPA in rabbits: influence of carbohydrate moieties. 313 90

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


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