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)

Thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction. Therapeutic benefit seems to be directly correlated with completeness of reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) of the infarct-related coronary artery, as well as the timeliness of reperfusion. To determine which regimen of reteplase (r-PA), a deletion mutant of wild-type tissue plasminogen activator (t-PA), is most effective for clinical thrombolysis, several reteplase regimens were compared with the most successful standard regimens of recombinant t-PA (alteplase) in 2 large-scale, randomized studies. All patients received aspirin and intravenous heparin. In the Reteplase Angiographic Phase II International Dose Finding Trial (RAPID-1), results in 606 randomized patients showed that a 10 + 10 U double bolus of reteplase was more effective than a 15 U single bolus, a 10 + 5 double bolus, or conventional alteplase (100 mg over 3 hours). In the Reteplase versus Alteplase Patency Investigation During Acute Myocardial Infarction (RAPID-2) trial, results in 324 patients showed that significantly more patients achieved patency of the infarct-related artery (TIMI grade 2 or 3 flow) at 90 minutes with reteplase (10 + 10 U double bolus) than with accelerated alteplase (100 mg over 90 minutes): 83.4% versus 73.3%, respectively (p = 0.03). The incidence of complete patency (TIMI grade 3 flow) at 90 minutes was likewise greater with reteplase than with accelerated alteplase (59.9% vs 45.2%, respectively; p = 0.01). At 60 minutes, the incidence of TIMI grade 2 or 3 flow was also significantly higher with reteplase than with alteplase (81.8% vs 66.1%, respectively; p = 0.01), as was the incidence of TIMI grade 3 flow (51.2% vs 37.4%, respectively; p < 0.031). The 35-day mortality rate was 4.1% for reteplase and 8.4% for alteplase (p = not significant). Reteplase and alteplase did not differ significantly with regard to the occurrence of severe bleeding (12.4% vs 9.7%, respectively) or hemorrhagic stroke (1.2% vs 1.9%, respectively). The results of these trials show that reteplase, given as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and is associated with significantly fewer acute coronary interventions when compared with front-loaded alteplase. The benefits of reteplase are achieved without any apparent increased risk of complications.
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PMID:Patency trials with reteplase (r-PA): what do they tell us? 899 Apr 6

Thrombolytic therapy has been recognized as a significant improvement in the management of acute myocardial infarction. Thrombolytic agents however have been limited by short half-lives that necessitate complex administration protocols and by the potential for bleeding complications. The native t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. Reteplase is a third-generation recombinant mutant of tissue-type plasminogen activator (t-PA) that is expressed in Escherichia coli cells and consists of the kringle 2 and the protease domains of t-PA. Compared with t-PA, reteplase has a lower fibrin binding, which may translate to improved clot penetration. As well as a longer half-life and a more rapid initiation of thrombolysis. Preclinical pharmacology studies have indicated that reteplase has potent in vivo thrombolytic activity and leads to rapid reperfusion; these findings have been confirmed by promising results obtained in large-scale clinical trials. Other new agents developed by modifying the native t-PA molecule include the n-PA and the TNK mutants of t-PA. These novel, genetically modified thrombolytic agents all lyse clots better than the native t-PA; however, they differ with respect to their half-lives and fibrin-binding activity. Although all the third-generation thrombolytic agents have shown considerable potential in improving the efficacy of thrombolytic therapy, their risk of intracranial bleeding remains problematic and is still somewhat uncertain.
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PMID:Pharmacological and clinical impact of the unique molecular structure of a new plasminogen activator. 944 35

Recombinant tissue-type plasminogen activator (rt-PA) is indicated for the treatment of acute myocardial infarction as a dose of up to 100 mg. Several clinical trials have suggested that higher patency rates can be achieved with a rapid drug administration. A study was conducted in rabbits to determine whether pharmacokinetics provides an explanation for the higher patency rates. Alteplase plasma concentration versus time profiles were compared following three dosing regimes: an accelerated 90 min, a standard 3 h, and a double-bolus regimen. The accelerated and double-bolus regimens resulted in higher initial rt-PA plasma concentrations compared to the standard regimen. No difference in the rt-PA clearance was noted between the standard and accelerated regimens. The rt-PA plasma clearance was slower following the double-bolus administration compared to either infusion regimen, suggesting a saturation of rt-PA clearance in rabbits. The estimated Vmax/K(m) ratio, the intrinsic metabolic clearance, was 14-19 h-1 using a Michaelis-Menten model. The infusion regimens resulted in a approximately 15% maximum depletion of alpha 2-antiplasmin levels compared to 29% for the double-bolus regimen. In summary, the higher patency following rapid rt-PA administration may be due, at least in part, to the higher rt-PA plasma concentrations.
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PMID:Pharmacokinetics and pharmacodynamics of recombinant tissue-type plasminogen activator following intravenous administration in rabbits: a comparison of three dosing regimens. 951 Sep 83

Alteplase (recombinant tissue plasminogen activator; rt-PA) is a thrombolytic agent that when given in an accelerated regimen with intravenous heparin has survival advantages compared with streptokinase in the treatment of acute myocardial infarction, as shown by the results of the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial. Although alteplase is more fibrin-specific than streptokinase, alteplase therapy is associated with a small relative increase in the incidence of haemorrhagic stroke, but appears to cause a small relative decrease in the incidence of major bleeding. Because alteplase has a higher acquisition cost than alternative thrombolytic agents, analyses have been undertaken to assess whether administration of alteplase after myocardial infarction is a cost-effective use of healthcare resources. In retrospective analyses undertaken before completion of the GUSTO trial, it was generally assumed, on the basis of better 90-minute patency rates, that alteplase would provide survival advantages compared with streptokinase or conventional nonthrombolytic therapy. Alteplase had acceptable cost-effectiveness ratios compared with conventional therapy and streptokinase therapy from both third-party payer and hospital perspectives. Subgroup analyses demonstrated that alteplase was more cost effective when given early after symptom onset and when given to patients with large infarcts. Prospective evaluations of the cost effectiveness of alteplase in 3-hour and accelerated regimens have similarly demonstrated that alteplase therapy after myocardial infarction improves survival at an 'acceptable' cost. The largest prospective evaluation undertaken to date was performed in conjunction with the GUSTO trial. Primary analysis, on the basis of the clinical findings of the GUSTO trial and prospective collection of cost data from US patients, revealed that the cost-effectiveness ratio for accelerated alteplase therapy compared with streptokinase was $US32,687 (1993 dollars) per year of life saved (YLS). This value is most relevant for US patients and lies within the definition of 'cost effective' if $US50,000/YLS is the benchmark for acceptable use of resources. The cost-effectiveness ratio for alteplase was most sensitive to assumptions regarding long term survival and cost differences after the first year following treatment. In subgroup analyses, alteplase was a cost-effective treatment option for all elderly patients (> 60 years of age) and all patients > 40 years of age with anterior infarction. Alteplase therapy appears to have in-hospital costs/charges similar to those for primary percutaneous transluminal coronary angioplasty (PTCA), mainly because PTCA appears to have a favourable effect on duration of hospitalisation. Given the technical expertise and facilities required for PTCA, it is likely that thrombolytic therapy will remain the management option of choice in most centres. In conclusion, under the conditions of the GUSTO study, accelerated alteplase in combination with intravenous heparin confers survival advantages compared with streptokinase therapy. While decision-makers must choose how best to use their available healthcare resources, pharmacoeconomic evaluations have confirmed that, on the basis of accepted benchmark values, alteplase therapy is a cost-effective therapeutic option for the treatment of acute myocardial infarction, especially in elderly patients with either anterior or inferior infarcts and nearly all patients with anterior myocardial infarction. Thus, on the basis of clinical and economic data, predominantly provided by the GUSTO trial, alteplase is a cost-effective first-line management option for acute myocardial infarction.
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PMID:Alteplase: a pharmacoeconomic evaluation of its use in the management of myocardial infarction. 1017 69

A number of cell types have previously been shown to bind tissue plasminogen activator (tPA), which in some cases can remain active on the cell surface resulting in enhanced plasminogen activation kinetics. We have investigated several cultured cell lines, U937, THP1, K562, Molt4, and Nalm6 and shown that they bind both tPA and plasminogen and are able to act as promoters of plasminogen activation in kinetic assays. To understand what structural features of tPA are involved in cell surface interactions, we performed kinetic assays with a range of tPA domain deletion mutants consisting of full-length glycosylated and nonglycosylated tPA (F-G-K1-K2-P), DeltaFtPA (G-K1-K2-P), K2-P tPA (BM 06.022 or Reteplase), and protease domain (P). Deletion variants were made in Escherichia coli and were nonglycosylated. Plasminogen activation rates were compared with and without cells, over a range of cell densities at physiological tPA concentrations, and produced maximum levels of stimulation up to 80-fold with full-length, glycosylated tPA. Stimulation for nonglycosylated full-length tPA dropped to 45-60% of this value. Loss of N-terminal domains as in DeltaFtPA and K2P resulted in a further loss of stimulation to 15-30% of the full-length glycosylated value. The protease domain alone was stimulated at very low levels of up to 2-fold. Thus, a number of different sites are involved in cell interactions especially within finger and kringle domains, which is similar to the regulation of tPA activity by fibrin. A model was developed to explain the mechanism of stimulation and compared with actual data collected with varying cell, plasminogen, or tPA concentrations and different tPA variants. Experimental data and model predictions were generally in good agreement and suggest that stimulation is well explained by the concentration of reactants by cells.
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PMID:Regulation of tissue plasminogen activator activity by cells. Domains responsible for binding and mechanism of stimulation. 1021 15

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

Two trials of thrombolysis for acute myocardial infarction are contrasted and compared using a systematic approach developed for the interpretation of studies where equivalence is claimed. Reteplase has been compared with streptokinase in a true equivalence trial (International Joint Efficacy Comparison of Thrombolytics [INJECT] trial) and with tissue plasminogen activator in a failed superiority trial (Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] III). Important methodological distinctions and economic insights are highlighted. Using this approach one can conclude that the INJECT investigators have shown that reteplase is at least as effective as streptokinase and that the test for equivalence was satisfied. The point estimate of the treatment effect for the primary outcome event favours reteplase over streptokinase, and the confidence intervals essentially eliminate the possibility of streptokinase superiority. The GUSTO III primary outcome event, 30-day mortality, provides no convincing evidence that reteplase is equivalent to tissue plasminogen activator. Selective emphasis on one or two post hoc outcome event clusters, such as death and nonfatal stroke, or death and disabling stroke, provides some suggestive, but not conclusive, evidence for equivalence. Moreover, for some of the outcome events, and in particular the primary outcome event, the point estimate suggests that reteplase is, in fact, slightly less effective than tissue plasminogen activator.
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PMID:Evidence-based medicine and reteplase: inductive arguments over deductive reasoning. 1050 81

Tenecteplase is a site-specific engineered tissue plasminogen activator (t-PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose-ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t-PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt-PA as the accelerated 90-minute infusion regimen in this randomized, open-label study. Tenecteplase and r-tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half-life of 22 minutes and a mean terminal half-life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt-PA has a fourfold faster plasma clearance. Pharmacokinetic-pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r-tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt-PA, allowing dosing as an i.v. bolus injection. Weight-adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.
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PMID:Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction. 1080 4

The publication of the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) trial of alteplase (a recombinant tissue plasminogen activator; rt-PA) for acute stroke patients in 1995 and its approval by the US Food and Drug Administration as well as the American Academy of Neurology and American Heart Association increased the interest and attention of the medical community in acute stroke treatment. However, the implication of this NINDS Stroke Study and other thrombolytic trials in clinical practice remains controversial and debated. Furthermore, the recent publication of the results from the European Cooperative Acute Stroke Study II (ECASS II) and Alteplase Thrombolysis of Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) studies will feed the controversy, since the results of these two studies are disappointing and do not confirm the positive results of the NINDS Stroke Study as expected by clinicians managing patients with acute stroke. The Standard Treatment with Alteplase to Reverse Stroke (STARS) and Cleveland studies, which involved a large number of community hospitals to assess the safety profile and the benefit of rt-PA thrombolysis for acute stroke patients in clinical practice, have shown controversial results. Consequently, the issue arises of which is the more reasonable position concerning thrombolysis by alteplase, which seems to work but has not been proven yet beyond reasonable doubt? The recent publication of the results from the Prolyse in Acute Cerebral Thromboembolism (PROACT II) study has shown that intra-arterial thrombolysis with prourokinase is a benefit treatment in stroke patients with a proven middle cerebral artery occlusion within 6 h of stroke onset. Numerous trials devoted to neuroprotection against acute ischemic stroke have been prematurely stopped because of safety concerns or poor risk-benefit ratios, but some new neuroprotective drugs seem promising and are being tested in ongoing studies. The third issue under study concerns the use of antithrombotic drugs in the acute phase of stroke, particularly the new potent platelet glycoprotein IIb/IIIa antagonists such as abciximab. In this paper, we have reviewed selected recent clinical trials focusing on recent advances in acute stroke therapy.
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PMID:Recent progress in drug treatment for acute ischemic stroke. 1124 3

Intraoperative intraarterial thrombolysis is a valuable adjunct for the removal of residual arterial thrombi after mechanical thromboembolectomy. Early reports by some investigators indicated high rates of bleeding complications, most likely caused by inappropriately high doses of plasminogen activators infused over long periods of time, which led to systemic lytic effects. Animal models and controlled human experiments subsequently have shown the potential efficacy and safety of intraarterial thrombolysis. Since urokinase (UK) has been withdrawn from the market, recombinant tissue-type plasminogen activator (rt-PA) has become the plasminogen activator of choice. Reteplase and other plasminogen activators may be beneficial (and safe); however, data on intraoperative use currently are not available. The most common methods of delivery into the distal arterial tree are bolus infusion with inflow occlusion, drip infusion after restoration of arterial inflow, and the isolated limb perfusion technique. The number of distal vessels involved, the amount of residual thrombus, and severity of ischemia guide the dose of plasminogen activator, volume of perfusate, and the technique and duration of infusion.
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PMID:Intraoperative lytic therapy: agents and methods of administration. 1140 89


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