Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defibrotide, a polydeoxyribonucleotide, has been found to modulate endothelial cell function, causing an increase in tissue plasminogen activator (t-PA) levels, a decrease in plasminogen activator inhibitor (PAI) levels, and an increase in prostaglandin I2 (PGI2) formation in humans. Defibrotide has no direct anticoagulant effect but has a synergistic action with heparin. A strong antithrombotic effect has been observed in animal models. Thus, defibrotide has a beneficial effect in cases of deep venous thrombosis (DVT), peripheral obliterative vascular disorder (POVD), stroke, vasculitis, and thromboembolism. Defibrotide also inhibits platelet function and activation. A significant decrease in platelet aggregate formation on the suture line in microarterial anastomosis in rats is one way defibrotide can inhibit platelet function and activation. In humans, a slight prolongation' of the lag period in collagen-induced aggregation has been observed. In addition, a slight decrease in the maximum amplitude of the secondary wave of ADP and adrenalin-induced aggregations was also found. Platelet adhesion is diminished, the platelet differential count on formvar membrane is altered, and platelet aggregate formation is significantly inhibited. With an increase in platelet cyclic AMP (cAMP) content and a decrease in malonyl dialdehyde (MDA) and thromboxane B2 (TXB2) formation, the levels of platelet secretion products such as PF-4 and beta-thromboglobulin (beta-TG) in plasma decreased progressively. It was also demonstrated that the 14C-glucose transport defect of the platelet membrane of atherosclerotic patients was partially corrected with defibrotide treatment.
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PMID:Effect of defibrotide on platelet function. 880 24

Clinical experience suggests that thrombolytic-induced bleeding is associated with systemic activation of the thrombolytic system. Using fibrin specific variants of tissue-type plasminogen activator (t-PA) and making use of the apparent fibrin specificity of streptokinase (SK) in the rabbit we tested the hypothesis that minimizing systemic plasmin production and fibrinogenolysis will decrease hemorrhages in models of peripheral bleeding and embolic stroke. t-PA consumed 51% of the available fibrinogen; caused cerebral bleeds and increased peripheral bleeding time. Fibrin-specific variants of t-PA depleted less than 20% of the fibrinogen and did not cause peripheral or cerebral bleeding. However, an equipotent dose of SK converted only 12% of the available fibrinogen but increased bleeding time and caused hemorrhagic conversion in 75% of embolic stroke model animals treated. The data suggest that bleeding associated with tissue-type plasminogen activators is linked to systemic plasmin generation and subsequent fibrinogenolysis. This hypothesis does not explain the mechanism(s) of SK-induced bleeding.
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PMID:Limiting systemic plasminogenolysis reduces the bleeding potential for tissue-type plasminogen activators but not for streptokinase. 882 86

Thrombolysis today has become a routine option not only in the treatment of acute myocardial infarction but also in many other manifestations of thromboembolic disease. Until one decade ago, only two plasminogen activators, streptokinase and urokinase, were available for clinical use. They were characterized by limited thrombolytic potencies and major side effects including systemic fibrinogen breakdown, bleeds and stroke. This has prompted the search for new plasminogen activators with better pharmacological and clinical profiles. The first such new plasminogen activators were Anistreplase, a chemically modified version of the streptokinase-plasminogen-activator-complex and tissue-type plasminogen-activator produced by recombinant technology. Both new substances have fueled the development in modern thrombolytic treatment. While the clinical progress with t-PA was confirmed in large, double-blind, randomized, multicenter trials, no real superiority of anistreplase over the traditional plasminogen activators urokinase and streptokinase has been substantiated. While the clinical use of t-PA today has been established for acute myocardial infarction, pulmonary embolism and deep vein thrombosis, current research is focused on further plasminogen activators with further improved thrombolytic properties. This review summarizes the current knowledge on the biochemical and pharmacological properties of the first, second and future generation of plasminogen activators.
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PMID:Thrombolytic agents--an overview. 885 12

This article discusses the impact of previous clinical observations on the development of the GUSTO-I protocol, particularly the absence of a survival benefit of alteplase (rt-PA) over streptokinase in the GISSI-2/International Study Group and ISIS-3 trials in spite of a higher efficacy for clot lysis. The demonstrated superiority of front-loaded alteplase in this large trial is translated into useful guidelines for the practising clinician. Risk-benefit analysis indicates that, in general, this thrombolytic regimen is most indicated in patients presenting with large amounts of jeopardized ischaemic myocardium in the absence of a particularly increased risk of haemorrhagic stroke. Finally, the impact of this study for future development in the field of acute coronary syndromes is evaluated, more specifically for the design of new trials with new fibrinolytic and antithrombotic agents. These include mutants of alteplase, staphylokinase, direct antithrombins and inhibitors of the glycoprotein IIb/IIIa platelet receptor.
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PMID:Implications of the GUSTO trial for thrombolytic therapy. 887 25

Reteplase (BM 06.022; r-PA) is a recombinant peptide which consists of the kringle 2 and protease domains of human tissue-type plasminogen activator. It has been developed as a thrombolytic treatment for acute myocardial infarction (AMI). The half-life of reteplase allows administration as a double-bolus injection (second injection given 30 minutes after the first) rather than by the prolonged and, in some cases, more complex intravenous infusion regimens that are required for most other thrombolytic agents. Reteplase produced rapid and effective coronary artery thrombolysis in a number of dose-finding and comparative studies. Double-bolus administration of reteplase 10U + 10U produced significantly higher coronary artery patency rates than accelerated alteplase (100mg as a 1.5-hour infusion) in patients with AMI in the RAPID-II study. The 10U + 10U reteplase regimen produced a 35-day survival rate at least equivalent to that seen with a 1-hour infusion of streptokinase 1.5 million units in 5986 patients in the INJECT study, which was designed to demonstrate equivalence between treatments. As with other thrombolytics, bleeding was the most common adverse event seen in reteplase recipients. No significant differences in the overall risk of haemorrhage were observed between reteplase and either accelerated alteplase or standard streptokinase treatment in clinical trials. The risk of stroke in reteplase recipients appears to be similar to that for other thrombolytic agents [1.2% incidence in 3288 patients treated with reteplase 10U + 10U in clinical trials (0.76% for haemorrhagic stroke)], although accurate statistical assessment of the relative risk is not possible for the data available to date. Thus, reteplase is an effective thrombolytic agent which can be administered as a double-bolus injection regimen rather than as a prolonged infusion. Together with acquisition cost and general pharmacoeconomic data (which are not yet available), the results of GUSTO-III (a trial comparing double-bolus reteplase with accelerated alteplase in 15 000 patients) will have a major influence on the pattern of use of reteplase. In the meantime, data from the available clinical trials suggest that reteplase is a fast-acting and effective thrombolytic treatment for patients with AMI.
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PMID:Reteplase. A review of its pharmacological properties and clinical efficacy in the management of acute myocardial infarction. 889 69

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

Numerous controlled clinical trials have documented the efficacy of thrombolytic agents in reducing the risk of mortality after myocardial infarction (MI). As a result, it is no longer ethical to test a new thrombolytic regimen against placebo. Rather, promising new therapies must be compared with proven treatments. This has been the direction taken in trials of reteplase, a new recombinant plasminogen activator. Initial studies of double-bolus reteplase demonstrated its superior ability to produce. TIMI grade 2 or 3 flow at 90 minutes when compared with accelerated alteplase. A subsequent randomized, double-blind, 9-country study, the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial was designed to determine whether the efficacy of reteplase is at least equivalent to that of streptokinase. The 2 treatments were associated with similar frequencies of inhospital cardiac events, bleeding, and strokes. Likewise, no significant difference was apparent between the reteplase and streptokinase groups with regard to 35-day mortality (the primary endpoint), the combined endpoint of 35-day mortality plus continuing disability from inhospital stroke, or 6-month mortality. Unadjusted data from the 3 countries that contributed the majority of patients seemed to indicate a survival benefit, irrespective of treatment allocation, among patients who underwent interventional procedures. However, no such benefit was apparent when the data were adjusted for differences in the baseline characteristics of the patients enrolled in the different countries. Rather, intervention within the first 3 days post-MI was found to place patients at a substantially higher risk of 35-day mortality. Further insights into the relative efficacy of reteplase should emerge from the ongoing third Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial.
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PMID:Clinical trials in thrombolytic therapy: what do they tell us? INJECT 6-month outcomes data. 899 Apr 7

Effects of nicotine treatment (4.5 mg/kg of nicotine-free base/day administered s.c. by osmotic minipumps for 14 days) on focal ischemic stroke and expression of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in cerebral microvessels were studied in rats in vivo using a reversible (1 h) middle cerebral artery occlusion model. Plasma levels of nicotine and its major metabolite cotinine after 14 days of treatment were 88 and 364 ng/ml, respectively. Nicotine treatment resulted in 35-40% (p < 0.001) decrease in the blood flow in the periphery of the ischemic core during reperfusion, an increase in the neurologic score of 2.6-fold (p < 0.01), and 36% (p < 0.05) and 121% (p < 0.01) increases in the injury and edema volume in the pallium, respectively. A free pool of brain microvascular t-PA antigen was completely depleted by nicotine, while the expression of the PAI-1 antigen and/or PAI-1-t-PA complexes remained unchanged. The relative abundance of cerebromicrovascular t-PA mRNA transcript versus beta-actin mRNA transcript did not change with nicotine. It is concluded that chronic nicotine treatment impairs the restoration of blood flow, worsens the neurologic outcome, and enhances brain injury following an ischemic insult. These nicotine effects are associated with depletion of brain microvascular t-PA antigen.
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PMID:Chronic nicotine treatment enhances focal ischemic brain injury and depletes free pool of brain microvascular tissue plasminogen activator in rats. 904 Apr 92

Utilization of angiography after acute myocardial infarction (AMI) treated with thrombolytics has been shown in large clinical trials to be related primarily to the availability of the procedure and not individual clinical circumstances. This study evaluated the regional influence of overall population cardiovascular mortality on utilization of angiography in the United States participants of the Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO-1) trial. Published summary statistics from GUSTO-1 and U.S. Census Bureau 1991 data were evaluated using simple and multiple linear regression with analysis for outliers. Region predictor variables (age adjusted) included mean total cardiovascular deaths/100,000/year (ICD/9 codes 390 to 459), mean coronary artery disease deaths/ 100,000/year (ICD/9 codes 410 to 414), and mean stroke deaths/100,000/year (ICD/9 codes 430 to 438), with the major outcome being regional proportion of GUSTO-1 patients undergoing angiography during the hospital stay after treatment with thrombolysis. All 3 cardiovascular death rates varied significantly by region (p < 0.00002) with no significant difference in GUSTO-1 mortality by region (p = 0.25). Simple linear regression analysis revealed associations between regional death rates and angiography use (r = 0.60, p = 0.12; r = 0.39, p = 0.33; r = 0.81, and p = 0.015). Multiple stepwise linear regression analysis found regional death rate due to stroke as the strongest predictor of angiography use with 65.86% of the variation explained by the model. New England was found to be a consistent outlier with reduced angiography use because of its background regional disease burden. This study confirms regional bias in the use of angiography in GUSTO-1. This form of operator bias appears to be due to more aggressive practice patterns in regions, except New England, where the overall cardiovascular disease burden is greater in terms of lives lost per 100,000 per year.
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PMID:Influence of regional cardiovascular mortality on the use of angiography after acute myocardial infarction. 906 11

Ischemic stroke occurs after an abrupt reduction in cerebral blood flow, usually related to thrombosis of an intracranial or extracranial artery. The presenting symptoms and signs of stroke vary greatly, depending on the region of the brain involved. Most individuals are unaware of the warning signs or symptoms of stroke and do not seek medical care immediately after stroke onset. Recently, thrombolytic therapy with intravenous tissue plasminogen activator (t-PA) has been shown to be effective for treatment of selected stroke patients if administered <3 hours after stroke onset. This therapy is now approved for stroke treatment, but relatively few stroke patients currently receive t-PA. Neuroprotective agents that improve the intrinsic ability of brain parenchyma to withstand ischemia are currently undergoing intensive clinical evaluation. Their development has been facilitated by significant scientific advances in the understanding of the pathophysiology of acute ischemic neuronal injury. Strategies aimed at interfering with these fundamental processes of ischemic neuronal injury have shown encouraging results in several preliminary clinical trials. However, these agents probably must also be administered within a few hours of stroke onset to be beneficial. Eventually, combined neuroprotective and thrombolytic therapy will likely be used for acute stroke treatment. This strategy's success will depend on increased public and professional education efforts dealing with stroke recognition, evaluation, and treatment.
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PMID:Rationale for early intervention in acute stroke. 928 38


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