Gene/Protein Disease Symptom Drug Enzyme Compound
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 16,800 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 The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents.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

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 data reviewed above show that the ideal thrombolytic or thrombolytic plus anticoagulant regimen does not exist. Nor is it clear to me that one regimen is unequivocally better than another in regards to clinical outcome. Publication of the full results of the ISIS-3 study and completion of the TAPS study, the GUSTO study, the TIMI-4 study plus others only now in the planning phases, should help. This review will not stay current very long. These data do, however, give some guides to certain circumstances in which one regimen might be preferred over others. If economics is a compelling issue, as it may be in public hospitals on a fixed budget or in the developing world, streptokinase may be the best choice. For early application of thrombolytic therapy, such as at the site of infarct occurrence and in automotive and aerial ambulances, anistreplase may be preferred because of its ease of administration. Previous administration of streptokinase or anistreplase (within the period of 48 h to 6 months after prior use) militate against their use as does a recent streptococcal infection. Heightened concerns about bleeding risk, except intracranially, in the absence of absolute contraindication of fibrinolytic therapy, e.g. remote gastrointestinal hemorrhage or the expected imminent need for an invasive procedure, may lead to preference for alteplase over streptokinase or anistreplase. On the other hand, heightened concerns about intracranial hemorrhage may lead to preference for streptokinase over alteplase or anistreplase. Alteplase may be preferred over non-fibrin-selective agents in the treatment of patients when administration is begun more than three hours after the presumed onset of infarction. These considerations notwithstanding, it is crucial that debates over the best choice of a regimen must not be allowed to prolong the time before administration of an effective thrombolytic agent to a patient with evolving Q-wave infarction who is a good candidate for this therapy. This review may also become dated in the not-too-distant future because of expected further advances in thrombolytic regimen. Application of new antithrombotic regimens was noted above. Future thrombolytic and antithrombotic regimens may be "cocktails" of one or more thrombolytic agents plus more powerful antithrombotic and antiplatelet agents. New generations of thrombolytic agents may replace the current first and second generation agents now used. Combination thrombolytic and anti-fibrin antibody agents and mutant tissue-type plasminogen activators with lower affinity for plasminogen activator inhibitor and longer half-lives are being developed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Considerations affecting selection of thrombolytic agents. 180 63

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 this article we report on the development, introduction, and maintenance of a policy to promote rational use of thrombolytic drugs by hospital doctors. The work was undertaken within the framework of the voluntarily operated Riverside East drugs guide (formulary) management system (FMS). The policy was introduced in October 1988 and revised in November 1989 to coincide with the launch of the new, expensive thrombolytic drugs, alteplase (rt-PA, Actilyse) in 1988 and antistreplase (APSAC, Eminase) in 1989. Streptokinase was recommended as the first-line drug for patients who had not received it within the last 6 months. The policy was communicated to all staff in meetings and a drugs guide bulletin and reinforced by ward pharmacists. Results over a 15 month period show voluntary compliance by prescribers with the recommended policy. One hundred and seventy-four patients (22% cardiac admissions) presented with acute myocardial infarction. Of these 43 (25%) received streptokinase, the first-line recommended drug, 7 received alteplase and none received anistreplase. The savings in drug expenditure from using streptokinase rather than alteplase or anistreplase for the 15-month period of investigation were over pounds 27,000. This work represents an example of the effectiveness of the Riverside East FMS model in influencing prescribing behaviour.
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PMID:Medical audit and formulary management: a policy for rational use of thrombolytic drugs. 190 56

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

399 out of 474 inpatients with unstable angina were monitored for 48 h and 97 of these were found to be refractory to conventional antianginal treatments and entered a randomised double-blind study. With the initial protocol heparin infusion or bolus were compared with aspirin; with a modified protocol, heparin infusion, the best of these three treatments, was compared with alteplase. Patients were monitored for 3 days after starting treatment and then observed clinically for 4 more days. On the first days of treatment heparin infusion significantly decreased the frequency of angina (by 84-94%), episodes of silent ischaemia (by 71-77%), and the overall duration of ischaemia (by 81-86%). Heparin bolus and aspirin were not effective. Alteplase caused small (non-significant) reductions on the first day only. Only minor bleeding complications occurred.
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PMID:Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina. 196 13

Anistreplase is a second generation thrombolytic agent, an equimolecular streptokinase lys-plasminogen complex the active site of which is temporarily blocked by a p-anisoyle group. Acylation enables the drug to be administered as a bolus intravenous injection over 2 to 5 minutes, and it protects anistreplase against circulating inhibitors, hence a plasma elimination half-life of 90 minutes. Deacylation is slow and progressive (deacylation half-life: 105 minutes), and it begins as soon as the product is injected. It reduces the hypotensive effect of streptokinase, permits a prolonged action in the thrombus and limits the risk of reocclusion. Using lys-plasminogen increases the affinity of the drug for fibrin and potentiates its accumulation and retention in the thrombus. In vitro studies have shown that the affinity of anistreplase for fibrin is similar to that of t-PA. In doses used for myocardial infarction, anistreplase induces a pronounced fibrinogenolysis. The effectiveness of the drug has been demonstrated on numerous animal models and subsequently by clinical trials.
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PMID:[Anistreplase. Pharmacology and biological data]. 210 41

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


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