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Query: UNIPROT:P00750 (PLA)
 16,800 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

The open-artery hypothesis as supported by thrombolytic study results is discussed. The open-artery hypothesis states that survival after acute myocardial infarction (AMI) is maximized by achieving early and sustained patency of the infarct-related artery. However, two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase, despite previous evidence that alteplase led to earlier recanalization of infarct-related arteries. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial suggested that early and complete patency is essential for short-term survival after AMI. Subsequent observations indicated that an open infarct-related artery at the time of hospital discharge is associated with improved long-term survival. In the Reteplase Angiographic Phase II International Dose-Finding (RAPID-1) trial, complete patency was more frequent in patients who received a double-bolus regimen of reteplase than in patients who received standard-dose alteplase. Similar results were obtained in the Reteplase versus Alteplase Patency Investigation during Myocardial Infarction (RAPID-2) trial, which compared the same double-bolus reteplase regimen with an accelerated regimen of alteplase. In both RAPID studies, mortality was lower and other outcomes were more favorable in reteplase recipients. Reteplase seems more likely to produce normal blood flow soon after AMI than either standard-dose or accelerated alteplase and may be associated with a lower mortality rate. This lends further support to the open-artery hypothesis.
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PMID:Clinical trials in thrombolytic therapy, Part 2: The open-artery hypothesis and RAPID-1 and RAPID-2. 939 35

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

A 5.25-year-old male Yorkshire Terrier was evaluated for suspected thrombosis of the distal portion of the aorta following protein-losing enteropathy. Hind limb paralysis was evident, extremities were hypothermic, and femoral pulses were not palpable. A thrombus was found in the distal portion of the aorta using Doppler ultrasonography. Enteropathy-induced loss of albumin and antithrombin III was the suspected cause of hypercoagulability in this dog. Alteplase, a recombinant tissue-plasminogen activator, was used to recanalize the distal portion of the aorta without inducing clinically evident systemic fibrinogenolysis. Alteplase is a fibrin-specific activator of plasminogen and may be safer and more efficacious than conventional streptokinase treatment. Current information on use in thromboembolic disease in human beings suggests that administration of alteplase as a bolus leads to earlier arterial patency and reduced risk of hemorrhage.
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PMID:Use of recombinant tissue-plasminogen activator for aortic thrombolysis in a hypoproteinemic dog. 949 Nov 62

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

The method of administration of alteplase has evolved since its introduction to clinical practice in the late 1980s. The initial dosage regimen of a graded administration of 100 mg was replaced by the front-loaded weight adjusted regimen, the efficacy of which was demonstrated in the GUSTO 1 trial. Double bolus administration was shown to achieve superior TIMI 3 patency of the infarct related artery in a small angiographic study, but the COBALT trial failed to show equivalence and indeed showed a slightly higher mortality and incidence of stroke, so cannot be recommended. Reteplase, a deletion mutant of alteplase, also showed superior efficacy in achieving coronary patency but no clinical superiority in outcomes in the 15,000 patient GUSTO 3 trial. The case of administration of reteplase, however, has some attraction as an alternative to alteplase. Trials of newer agents based on further modifications of alteplase are ongoing, but at present the front-loaded alteplase regimen remains the standard for clinical practice.
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PMID:Can we improve on front-loaded alteplase (r-TPA)? 977 30

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

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

The clinical file on reteplase is methodologically sound. A trial versus alteplase involving more than 15 000 patients seen less than 6 hours after myocardial infarction showed that mortality at 30 days was identical in the reteplase and alteplase treatment groups (7.3%). The two treatment groups did not differ either in the frequency of strokes or severe bleeding. Another trial involving more than 6 000 patients seen less than 12 hours after myocardial infarction showed that overall mortality 35 days after thrombolysis was 9% in both the reteplase and the streptokinase treatment groups. The two thrombolytics did not differ in terms of overall mortality at 6 months, the number of strokes, the number of bleeding events or the safety profile. Reteplase is easy to administer (2 intravenous boluses of 10 U, 30 minutes apart). Other reference thrombolytics (streptokinase and alteplase) are administered as an intravenous infusion.
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PMID:Reteplase: new preparation. Minimal value: bolus versus infusion. 1034 21

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


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