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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The Cochrane Database of Systematic Reviews summarizes all the existing randomized evidence of all treatments for all diseases, so that doctors can quickly access the most up-to-date information. The trials for the Cochrane systematic review of thrombolytic therapy in acute ischemic stroke were identified from extensive searching of the literature and contact with trial investigators. Data on several prespecified outcomes (death and symptomatic intracranial hemorrhages within the first 7 to 10 days after treatment, and death and poor functional outcome at long-term follow-up) were sought in each identified randomized, controlled trial. There have thus far been 17 completed randomized, controlled trials of thrombolytic therapy versus control in 5,216 patients (including the provisional data from the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS] A and B and Recombinant Prourokinase in Acute Cerebral Thromboembolism [PROACT] II trials). Of these, eight trials tested recombinant tissue plasminogen activator (rt-PA) in 2,889 patients (56% of all data). Overall, there was an increase in the odds of death within the first 10 days (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.48 to 2.32) and symptomatic intracranial hemorrhage (OR 3.53, 95% CI 2.79 to 4.45) with thrombolysis (slightly less with rt-PA). The odds of death at the end of follow-up were also slightly increased with thrombolysis (OR 1.31, 95% CI 1.13 to 1.52), although this increase was not significant in patients receiving rt-PA. Despite this, overall there was a significant reduction in the number of patients with a poor functional outcome (combined death or dependency) at the end of follow-up (OR 0.83, 95% CI 0.73 to 0.94), which was slightly better in patients receiving rt-PA. Most of the data came from trials testing thrombolysis up to 6 hours after stroke, but the subgroup of patients treated within 3 hours showed a greater reduction in poor functional outcome with thrombolysis (OR 0.58, 95% CI 0.46 to 0.74) with a less adverse effect on death. The available data do not allow much further subgroup analysis, although there is reasonable evidence to indicate that aspirin or heparin given within 24 hours of thrombolytic therapy causes a significant increase in intracranial hemorrhage and death. It is hoped that a meta-analysis using individual patient data may be able to address the effect of thrombolysis in further specific subgroups and examine the interaction between the severity of stroke and the effect of thrombolysis.
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PMID:Overview of Cochrane thrombolysis meta-analysis. 1187 75

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in MI. Alteplase is most effective when given early in MI and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in MI can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard MI treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in MI. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.
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PMID:Alteplase: descendancy in myocardial infarction, ascendancy in stroke. 1177 4

As treatments for acute myocardial infarction have grown in number and effectiveness, the post-infarction mortality rate has fallen, and new therapies can provide only a small additional advantage in extending survival. To prove such an advantage of a new drug over its predecessors in the same drug class requires a trial of at least 20,000 patients. Proving 'equivalence' rather than superiority requires only 6000 patients. The INJECT trial was designed with the modest goal of determining whether the novel agent reteplase (recombinant plasminogen activator) has an effect on mortality equivalent to that of streptokinase. Between August 1993 and September 1994, 6010 patients were randomized to receive either reteplase (n = 3004) or streptokinase (n = 3006). Both treatment groups had similar rates of bleeding events, extension or recurrence of myocardial infarction, and in-hospital stroke followed by 6 months of disability. Reteplase recipients had a lower incidence of cardiac events in hospital and fewer allergic reactions. Although the number of diagnosed haemorrhagic strokes was higher in reteplase recipients, more patients receiving streptokinase had strokes of uncertain aetiology. At 35 days, the mortality rate associated with reteplase use was approximately 0.5% lower than that associated with streptokinase administration, and the upper limit of the 90% confidence interval for the difference between these rates was a superiority of streptokinase of 0.73%. Because the INJECT trial provided a probability of 0.95 that the mortality rate associated with reteplase use would be either lower than that with streptokinase administration or at most 0.73% worse, reteplase and streptokinase were proved equivalent according to the trial definition and limits.
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PMID:Mega-trials and equivalence trials: experience from the INJECT study. 1182 1

Alteplase (t-PA), a recombinant analogue of human tissue plasminogen activator, became the first genetically engineered thrombolytic approved by the Food and Drug Administration in 1987 for acute myocardial infarction (AMI). In addition to AMI, alteplase is currently approved for the treatment of acute ischemic stroke and pulmonary embolism, and we anticipate approval for catheter clearance in late 2001 in a 2-mg vial configuration. With the withdrawal of human neonatal kidney cell-derived urokinase, alteplase has become an alternative agent in peripheral vascular applications. Because few interventionalists had prior experience with the handling and dosage of alteplase, the Advisory Panel to the Society of Cardiovascular and Interventional Radiology established practice guidelines for use in noncoronary applications. Emerging clinical experience with contemporary dosing regimens shows a safety and efficacy profile similar to urokinase but with significantly reduced drug costs. Tenecteplase (TNK) is a genetically modified version of alteplase. TNK is the only plasminogen activator available that has shown a significantly enhanced safety profile versus alteplase in AMI. Approved for a 5-second, single-bolus injection in AMI, TNK possesses a longer half-life, increased resistance to plasminogen activator inhibitor, and improved fibrin specificity compared with alteplase. Because of its enhanced safety profile, TNK may be a desirable agent for peripheral vascular applications. Initial clinical studies with TNK in acute arterial and venous disease are ongoing. This article outlines the Advisory Panel guidelines for using alteplase and highlights features of tenecteplase.
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PMID:Alteplase and tenecteplase: applications in the peripheral circulation. 1198 95

(1) Alteplase is the standard thrombolytic agent for treating patients under 75 years with myocardial infarction if they are seen within 6 hours. It is given as an intravenous infusion over 90 minutes in combination with aspirin and unfractionated or low-molecular-weight heparin. (2) Tenecteplase has been authorized for use in myocardial infarction as an intravenous bolus over 5 to 10 seconds. (3) The evaluation file on tenecteplase contains data from three dose-finding studies and one double-blind trial against alteplase in nearly 17 000 patients. The trial found no difference in mortality between the two treatments (6% at 30 days). Nor was there any substantial difference in serious adverse events (stroke, intracranial haemorrhage or heart failure). (4) Major haemorrhage was slightly less frequent in patients given tenecteplase, but there was no difference between groups in the incidence of intracranial haemorrhage or stroke. (5) A comparative trial suffering from a number of biases suggests that combined treatment with tenecteplase + enoxaparin has a similar risk-benefit ratio to combined treatment with tenecteplase + unfractionated heparin. The combination of tenecteplase and enoxaparin makes treatment simpler, which could be particularly useful prior to hospital admission. A smaller trial of alteplase + enoxaparin against alteplase + unfractionated heparin gave similar findings. (6) In practice, tenecteplase has the advantage of a more convenient administration; a very large trial strongly suggests that its effects are almost identical to those of alteplase.
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PMID:Tenecteplase: new preparation. Another thrombolytic agent for myocardial infarction: a slightly simpler treatment. 1206 43

The field of intravenous and intra-arterial thrombolysis for the treatment of acute ischemic stroke is rapidly advancing. Limitations of existing thrombolytic agents have prompted the development of new thrombolytic agents over the last decade. These new agents are broadly classified as third generation thrombolytics. Two of the several third generation thrombolytic agents have been investigated for the treatment of acute ischemic stroke and include tenecteplase (Genentech Inc) and reteplase (Roche Holding AG). By virtue of structural modifications, third generation thrombolytics have longer half-lives and greater penetration into the thrombus matrix. Tenecteplase has been evaluated in experimental models of ischemic stroke. These experimental studies have observed faster and more complete recanalization of occluded arteries compared with second-generation thrombolytics. The first prospective human clinical trial evaluated the safety and efficacy of intra-arterial reteplase in 16 patients with ischemic stroke who were poor candidates for intravenous alteplase therapy. Near complete or complete recanalization was observed after treatment in 88% of the patients. The development and use of third generation thrombolytics is expected to increase the rate of recanalization and clinical recovery in patients with ischemic stroke. Clinical trials are required to determine the appropriate dose and patient selection for these emerging pharmacological agents.
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PMID:Third generation thrombolytics for the treatment of ischemic stroke. 1252 7

Causes of stroke in children include congenital heart malformations, sickle cell disease, infections, and metabolic disorders. Up to 80% of children with ischemic stroke have cerebrovascular disease, and case control studies demonstrate an association of ischemic stroke in children with hereditary prothrombotic risk factors. There have been no randomized, clinical trials for primary prevention, short-term treatment, or secondary prevention of pediatric ischemic stroke. Treatment recommendations are based on small case series or case reports, and have mainly been adapted from adult stroke studies. Antiplatelet agents (e.g. aspirin [acetylsalicylic acid]) and heparins (e.g. low molecular weight heparin), have been used on an individual patient basis. Warfarin is administered in children with cardioembolic stroke, arterial dissection, or persistent hypercoagulable states. Alteplase has been used in a few patients within 3 hours of the onset of symptoms. In each patient treated the benefit of anticoagulation has to be weighed up against the individual bleeding risk.
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PMID:Antithrombotic drug treatment of pediatric patients with ischemic stroke. 1260 81

In the area of myocardial infarction one is reminded of the publication of the CADILLAC study which has reopened the debate on the systematic use of GpIIbIIIa inhibitors in the acute phase of myocardial infarction complementing primary angioplasty with the placement of an endoprosthesis. New modalities for thrombolysis are in the course of evaluation, notably Eptibaphide Alteplase combination in the INTRO-AMI study and Tenecteplase Abciximab in association with enoxaparine or non-fractionated heparin in the TIMI 23 study. Several studies comparing angioplasty to lysis have been published. STOPAMI 2 evaluated myocardial salvage in the framework of primary angioplasty with placement of an endoprosthesis combined with abciximab infusion in comparison with half dose fibrinolysis associated with abciximab. CAPTIM is a strategy evaluation comparing the results of pre-hospital fibrinolysis with primary angioplasty. With the RITA 3 study the interventional approach definitely comes top in comparison with a conservative approach for the treatment of unstable angina. One is equally reminded of the changes in the ACC/AHA recommendations for the management of unstable angina. The debate continues on the indications for thrombolysis in submassive pulmonary embolus. In the therapeutic area, one is reminded of the update on the interactions between angiotensin converting enzymes and aspirin in treatment and long term coronary syndrome. Finally, at the end of 2001, the work of French teams was published concerning the evaluation of risk of relapse for cerebral vascular accident in the presence of a foramen ovale or an aneurysm of the inter-atrial septum.
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PMID:[The best of thrombosis in 2002]. 1261 65

Tenecteplase (TNK) was engineered to have increased fibrin specificity and an increased half-life compared to Alteplase. Although Tenecteplase is currently being tested in a Phase II clinical trial in acute ischemic stroke patients, little is known about the pharmacology and dose-response or therapeutic window for Tenecteplase in embolic stroke models. In the present study, we compared Tenecteplase with Alteplase on behavioral outcome in rabbits with embolic strokes. Male New Zealand white rabbits were embolized by injecting a suspension of small blood clots into the middle cerebral artery (MCA) via a catheter. The rabbit small clot embolic stroke model (RSCEM) was used for a dose-response profile analysis of Tenecteplase (0.1 mg/kg-3.3 mg/kg) and Alteplase (0.9 mg/kg-3.3 mg/kg) given intravenously 1 h following embolization. In additional studies, Tenecteplase (0.9 mg/kg) or Alteplase (3.3 mg/kg) was administered 3 (or 6) h following embolization to determine the therapeutic window for the thrombolytics. For both studies, behavioral analysis was conducted 24 h following embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a drug is considered beneficial if it significantly increases the P50 compared with the control group. The P50 of controls 24 h after embolization was 1.13 +/- 0.15 mg. Rabbits treated 1 h post-embolization with Tenecteplase (0.1, 0.25, 0.9, 1.5 or 3.3 mg/kg) had P50 values of 1.48 +/- 0.33, 2.20 +/- 0.44, 2.76 +/- 0.37, 2.15 +/- 0.29 and 2.78 +/- 0.31 mg, respectively. In Alteplase-treated rabbits, only the 3.3 mg/kg dose significantly increased the group P50 by 189% compared to control. Tenecteplase was also effective at increasing the P50 value to 2.21 +/- 0.43 mg if there was a 3-h delay following embolization, but not if there was a 6-h delay before administration. Alteplase was only effective if administered 1 h following embolization where it significantly increased the P50 value to 3.27 +/- 0.40 mg. This study indicates that Tenecteplase has a wide therapeutic range, a therapeutic window of at least 3 h and a durable effect. Moreover, the safety profile for Tenecteplase is similar to that of Alteplase. Tenecteplase does not increase the rate of intracerebral hemorrhage (ICH) above that produced by Alteplase. However, the therapeutic range and window for Alteplase is more limited than that for Tenecteplase. Our preclinical studies suggest that Tenecteplase has a better pharmacological profile than Alteplase and supports further investigation of Tenecteplase in randomized double-blinded clinical trials in stroke patients.
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PMID:Comparison of Tenecteplase with Alteplase on clinical rating scores following small clot embolic strokes in rabbits. 1469 26


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