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)

Thrombolysis has become an accepted form of therapy for acute myocardial infarction. As demonstrated in the Global Utilization of Streptokinase and t-PA for Occluded Arteries trial, early, complete and sustained patency of the infarct-related coronary artery is correlated with reduced mortality. However, current thrombolytic regimens are able to achieve such patency within 90 min in only 81% of cases. To improve the risk/benefit ratio of thrombolytic therapy, newer agents such as reteplase have been developed to establish more rapid, more complete and more stable coronary artery patency, thus reducing mortality. This report summarizes the pharmacological properties of reteplase. It also summarizes the findings from various animal and clinical studies in which reteplase was compared with alteplase and streptokinase and the findings from animal and clinical studies evaluating infusion, single-bolus, double-bolus, doses of reteplase.
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PMID:Clinical trial results with a new plasminogen activator. 944 36

The effective treatment of acute ischemic stroke remains an important goal of modern medicine and substantive advances are occurring. Recently, thrombolytic therapy with tissue-type plasminogen activator was approved for selected patients with acute ischemic stroke when therapy is started within 3 hours of onset. Streptokinase therapy for acute ischemic stroke has not been shown to be effective and is associated with an increased risk of hemorrhage, although it was not evaluated as early after stroke onset as tissue-type plasminogen activator. Various types of neuroprotective interventions are effective in animal models, but none has yet been proven effective in patients. In the future, combinations of thrombolytic and neuroprotective drugs may be used to attempt maximum rates of recovery after acute ischemic stroke. For combination therapy to achieve its maximum potential, patients with acute ischemic stroke will have to be carefully selected and treated.
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PMID:Further evolution toward effective therapy for acute ischemic stroke. 956 13

Increased T-wave amplitude is one of the earliest electrocardiographic (ECG) changes following coronary artery occlusion. Therefore, higher T waves in the presenting electrocardiogram should represent earlier time to treatment and thus be associated with lower mortality following thrombolytic therapy. However, T-wave amplitude has never been evaluated as a prognostic marker in this setting. We examined clinical outcomes in 3,317 patients with acute myocardial infarction (AMI) who underwent thrombolysis in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) Study. Patients were classified as either those with high T waves or those with low T waves. Higher T waves were defined as those >98th percentile of the upper limit of normal. T-wave amplitude was also evaluated as a continuous variable according to infarct location (maximum T-wave amplitude) and as the amount of excess T-wave amplitude above normal (excess T-wave amplitude). Patients with higher T waves had lower 30-day mortality than those without (5.2% vs 8.6%, p = 0.001) and were less likely to develop congestive heart failure (15% vs 24%, p <0.001) or cardiogenic shock (6.1% vs 8.6%, p = 0.023). Higher maximum T-wave amplitude and excess T-wave amplitude were predictive of lower 30-day mortality (chi-square = 67, p <0.001 and chi-square = 33, p <0.001, respectively). These differences remain significant after controlling for other prognostic baseline ECG variables. In addition, T-wave amplitude added prognostic significance after controlling for time to treatment. T-wave amplitude, an often-overlooked component of the electrocardiogram, can add significant prognostic information in initial evaluation of patients with AMI.
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PMID:Higher T-wave amplitude associated with better prognosis in patients receiving thrombolytic therapy for acute myocardial infarction (a GUSTO-I substudy). Global Utilization of Streptokinase and Tissue plasminogen Activator for Occluded Coronary Arteries. 960 45

Streptokinase (SK) is a 414 amino acid bacterial protein that activates human plasminogen. Streptokinase fragments derived from the central portion of the protein bind plasminogen, but are inactive, indicating that the amino- and/or carboxyl-termini are required for normal plasminogen activator activity. To better define the function of the N- and C-termini of SK we generated and characterized 21 N-terminal and 20 C-terminal deletion mutants. All mutants lacking > or = 18 N-terminal or > or = 51 C-terminal amino acids exhibited markedly reduced plasminogen activator activity, while mutants lacking < or = 12 N-terminal or < or = 40 C-terminal residues were fully active. The decrease in SK activity with N-terminal deletion appeared to result not from loss of plasminogen binding capacity, but rather from increased susceptibility of deletion mutants to degradation by plasmin. Point mutations at positions 13 (SK V13D) or 20 (SK V20D) produced functional abnormalities similar to those observed in N-terminal deletion mutants, with SK V13D exhibiting delayed amidolytic activity and SK V20D exhibiting only 1% plasminogen activator activity and marked sensitivity to degradation by plasmin. C-terminal deletion mutants lacking > or = 51 amino acids also bound plasminogen, but did not induce significant amidolytic activity in plasminogen or activator activity in plasmin. Prevention of cleavage at position 59 of SK had no effect on plasminogen activator activity, suggesting that the rapid hydrolysis of this bond that occurs after SK-plasminogen complex formation is not required for normal function of the N-terminus. These results suggest that residues within or near positions 13-20 of SK are important determinants of its capacity to generate amidolytic activity and are a critical determinant of the stability of SK, while residues within or near position 364-374 are required for generating amidolytic activity and for conferring plasminogen activator activity to plasmin(ogen). These results also suggest that SK fragments significantly smaller than SK 13-374 are unlikely to be effective thrombolytic agents.
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PMID:Functional analysis of the amino- and carboxyl-termini of streptokinase. 960 34

Several modes of reperfusion therapy for evolving myocardial infarction (MI) have been developed, which differ in terms of effectiveness, complexity and costs. Reperfusion resources are often restricted by budgetary or logistical circumstances. To arrive at an equitable distribution of treatment options, physicians should therefore consider which treatment to apply in which patient. Two major questions which arise in this respect are discussed here: what is the treatment effect in an individual patients, and what is an equitable resource allocation? Currently, the most relevant treatment options are: streptokinase (1.5MU over 1h), reteplase (2 boluses of 10MU), alteplase (tissue plasminogen activator; t-PA) [100mg over 1.5 hours] and immediate angioplasty. In combination with aspirin, streptokinase leads to an almost 40% mortality reduction at 1 month compared with placebo [from 13.2 to 8.0%; Second International Study of Infarct Survival (ISIS-2) trial]. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-1) study demonstrated a further mortality reduction by early combination therapy of aspirin, intravenous heparin and alteplase vs aspirin, heparin (either intravenous or subcutaneous) plus streptokinase (from 7.3 to 6.3%). The clinical effects of reteplase fall somewhere between those of streptokinase and alteplase. Combined analysis of the angioplasty trials suggests that angioplasty is superior to thrombolysis, especially in patients with a high cerebral bleeding risk. The noticed gradient of efficacy runs parallel to a gradient of costs and complexity: streptokinase is the least costly treatment option while direct angioplasty is the most expensive and complex. Subgroup analyses indicate that there are neither apparent deviations in the relative effect of reperfusion therapy as compared to control treatment, nor in the additional effect of more intensive therapy (alteplase) upon 'standard' therapy (streptokinase). Consequently, the absolute number of deaths avoided by reperfusion therapy appears to be greatest in those groups with a high mortality risk without therapy. There is one major exception: in patients treated early after symptom onset a much greater relative mortality reduction is observed than in those treated later. Owing to the higher mortality risk, the life expectancy of a patient with MI is shorter than that of an 'average' person of the same community and the same age. Since mortality reduction of reperfusion therapy is maintained at long term follow-up, part of this potential loss can be regained. This 're-gain of lost years' is judged to be the ultimate treatment effect in an individual patient. An equitable treatment allocation should be such that patients who will benefit most will receive the most effective therapy, while patients with similar expected benefit will be offered the same mode of therapy. The conclusion is that treatment guidelines or protocols can be very useful in clinical practice, especially if rapid decision making is of vital importance.
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PMID:Reperfusion therapy for acute myocardial infarction. Which strategy for which patient? 966 97

Thrombolytic therapy dates back to animal studies performed in the early 1940s, although clinical trials did not begin until the early 1980s. Many large, placebo-controlled trials conclusively recorded improved survival with thrombolytics in the treatment of acute myocardial infarction. However, only recently did clinical trials compare tissue plasminogen activator (tPA) and streptokinase (SK), and only one study showed a difference in mortality between them. This discrepancy, in part, led to the open-artery hypothesis that early and sustained infarct-related artery patency improves outcome. This theory was tested in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) study. The angiographic substudy of GUSTO-I provided strong evidence for the relationship between 90-minute thrombolysis in myocardial infarction (TIMI) grade 3 flow and lower mortality. However, despite significantly higher 90-minute TIMI grade 3 flow (54% vs 32%) with accelerated tPA versus SK plus intravenous heparin, the absolute difference in mortality rate was less than 1%. The recently completed GUSTO-III trial compared accelerated tPA with reteplase (rPA). Based on the open-artery hypothesis and previous data showing an absolute difference of 15% in 90-minute TIMI grade 3 flow between the agents, it was anticipated that mortality would be lower with rPA than with accelerated tPA. The GUSTO-III study showed no significant difference in 30-day mortality for the agents (7.47% vs 7.24%, p=0.61), respectively. These results raise questions about the validity of the hypothesis: if 90-minute TIMI grade 3 flow is such a strong predictor of mortality, why is there not a greater difference in mortality rates for thrombolytic agents?
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PMID:TIMI grade flow, mortality, and the GUSTO-III trial. 969 44

Streptokinase is a plasminogen activator widely used in treating blood-clotting disorders. Complexes of streptokinase with human plasminogen can hydrolytically activate other plasminogen molecules to plasmin, which then dissolves blood clots. A similar binding activation mechanism also occurs in some key steps of blood coagulation. The crystal structure of streptokinase complexed with the catalytic unit of human plasmin was solved at 2.9 angstroms. The amino-terminal domain of streptokinase in the complex is hypothesized to enhance the substrate recognition. The carboxyl-terminal domain of streptokinase, which binds near the activation loop of plasminogen, is likely responsible for the contact activation of plasminogen in the complex.
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PMID:Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. 973 10

Myocardial infarction and thrombolysis are proven to be associated with platelet activation. However, the time relationship of platelet activation with the onset of symptoms and with thrombolysis, and the response to aspirin are not well defined. In this study we measured platelet activity in the early phase of myocardial infarction treated with either streptokinase or recombinant tissue-type plasminogen activator (rt-PA) and evaluated whether and to what extent it may be counteracted by aspirin. Fourty-one patients (mean age 57 +/- 6 years) received thrombolytic therapy after coronary occlusion: 1.5 million units of streptokinase (Group 1; 21 patients) or 100 mg of rt-PA (Group 2; 20 patients). Ten randomly selected patients in either group were given 500 mg aspirin i.v. prior to infusion of the thrombolytic compound and, then, 325 mg/die of aspirin orally. Beta-thromboglobulin (BTG), a marker of platelet activity, was determined at admission, after thrombolysis and in the subsequent 48 hours. At admission, BTG plasma levels averaged 125 +/- 31 IU/ml in Group 1 and 134 +/- 35 IU/ml in Group 2 (NS). Thrombolysis produced a similar increase in platelet activity in both groups, and maximal values were reached at the third hour (196 +/- 43 IU/ml in Group 1 and 192 +/- 39 in Group 2, p < 0.001 vs baseline and NS between groups). Levels of BTG were higher in streptokinase-treated group starting from 24 hours (p < 0.05). Differences in BTG levels between aspirin-treated and aspirin-untreated patients became significant at 48 hours after thrombolysis in both groups. An inverse correlation was found between time elapsed from onset of symptoms and BTG value on admission (r = -0.86, p < 0.001); in patients admitted within 2 hours after the beginning of symptoms, and having the higher BTG levels, thrombolysis did not induce a significant increase in platelet activity; this, on the contrary, was observed in patients admitted later. Platelet activation is greater early after myocardial infarction and is differently influenced by thrombolytic treatment, depending on the delay of the patient's admission. Streptokinase and rt-PA induce a similar increase in platelet activity which is more persistent after streptokinase; cycloxygenase inhibition with aspirin seems to influence platelet activity only starting from the second day.
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PMID:[Platelet activation in the early phases of acute myocardial infarction]. 980 73

Thrombolytic therapy with streptokinase and other agents reduces mortality and is now well accepted as the mainstay of revascularisation options for most patients after an acute myocardial infarction. Streptokinase is as efficacious as alteplase (recombinant tissue plasminogen activator; rt-PA) when given as a 3-hour infusion, anistreplase, reteplase and saruplase in reducing mortality. However, in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, an accelerated alteplase regimen (1.5-hour infusion) plus intravenous heparin demonstrated a statistically significant 1% absolute mortality reduction compared with streptokinase plus heparin. Treatment with streptokinase is consistently clinically superior to conventional treatment and is cost effective: the marginal cost per year of life saved (cost/YLS) is less than $US/$Can20,000 (1990 or 1991 currency) assuming 5-year survival. In addition, streptokinase treatment is associated with fewer intensive care days and total days spent in hospital and a decrease in the use of intensive care services compared with conventional therapy. Importantly, the cost/YLS of treating older patients (70 to 80 years) with streptokinase is similar to that in younger patients (approximately $US22,000, 1990 currency). In 1 study, the cost of in-hospital treatment and associated 1-year follow-up costs did not differ significantly regardless of whether patients received streptokinase or anistreplase. In the most comprehensive cost-effectiveness analysis to date, GUSTO investigators determined that the incremental cost/YLS in patients who received the accelerated alteplase regimen instead of streptokinase was $US32,678 (1993 currency); the projected life expectancy was about 15 years. Thrombolytic therapy is generally more cost effective in patients at high risk than in those at low risk. The cost effectiveness of streptokinase is dependent on infarct location and time to treatment, but is more favorable in patients with anterior than inferior infarctions and those treated as soon as possible after symptom onset. There are as yet no comparative data to indicate a clinical benefit for one thrombolytic agent over another in patients treated more than 6 hours after symptom onset; therefore, in all likelihood, streptokinase will be preferred on the basis of cost minimisation. Streptokinase is associated with a slightly higher rate of severe bleeding than alteplase but a lower incidence of stroke. Although quality-of-life information comparing thrombolytics is unavailable, most patients who received streptokinase or alteplase rated their quality of life as high on the basis of results from time trade-off assessments and health surveys. In summary, streptokinase is undeniably cost effective compared with conventional treatment. It is up to individual healthcare systems to determine whether the mortality advantage and cost differential of the accelerated alteplase regimen over streptokinase, as seen in the GUSTO trial, are affordable and justifiable. However, it is important to realise that treatment options may be limited by healthcare resources; thus, streptokinase can be regarded as a cost-effective thrombolytic strategy which is both efficacious and affordable within the constraints of most healthcare budgets.
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PMID:Streptokinase. A pharmacoeconomic appraisal of its use in the management of acute myocardial infarction. 1016 75

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


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