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)

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

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

Treatment of acute ischaemic stroke aims to recanalize the occluded artery, salvage the at-risk brain tissue and thus minimize neurological sequelae. Efforts a decade ago have led to the only currently approved medical treatment for acute ischaemic stroke, i.e. intravenous alteplase given within 3 hours of stroke onset. Recanalization occurs in only one-half of the patients receiving alteplase, and only approximately 5% of all ischaemic stroke patients in industrialized countries receive this treatment. Studies are currently being carried out to determine whether intravenous alteplase would be safe and effective for up to 4.5 hours after ischaemic stroke onset, and whether it should be followed by an intra-arterial approach. Two novel thrombolytic drugs being studied for acute ischaemic stroke are desmoteplase and tenecteplase. Although the first trials were promising, the most recent evidence suggests that desmoteplase is not superior to placebo, even in carefully selected patients, in the 3- to 9-hour time window after stroke onset. Tenecteplase has only been studied for acute ischaemic stroke in a single noncontrolled, dose-finding trial in the 3-hour time window after stroke onset, which suggested a similar efficacy to that demonstrated in the historical data from the alteplase trials. A trial to compare the safety and efficacy of tenecteplase versus alteplase is ongoing. Safer and more effective thrombolytic drugs for the treatment of ischaemic stroke are thus being sought. Such agents will be welcome, but they are not here yet. While waiting we are likely to see the emergence of additive therapies, including ultrasound insonation, neuroprotective/regenerative agents and invasive intra-arterial techniques. Novel thrombolytic drugs, or other novel therapies, possess great potential to make a difference in the future, but the most urgent priority now is in the organization of stroke treatment in such a way that more patients receive the currently available optimal treatments.
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PMID:Novel thrombolytic drugs: will they make a difference in the treatment of ischaemic stroke? 1860 1

In the present study, we used a modification of the rabbit small clot embolic stroke model (RSCEM), a multiple infarct ischemia model to achieve reperfusion (REP) through the internal carotid artery (ICA) following small clot embolization. We determined if increasing regional cortical blood flow (RCBF) following an embolic stroke is beneficial to neurological outcome. We compared this to cerebral reperfusion induced by the administration of the thrombolytic Tenecteplase (TNK, 1.5 mg/kg, IV bolus) in the presence or absence of REP. In this study, we also measured the incidence of ICH following REP and thrombolytic treatment. Following embolization, RCBF was reduced to 48-55% of baseline. When REP was induced by removal of a CCA ligature, RCBF initially increased to 185% of baseline. REP (P(50)=1.18+/-0.43 mg) had no effect on embolization-induced behavior measured 24 h following embolization compared to control (P(50)=1.01+/-0.48 mg). However, TNK treatment (2-hours post-embolization) in the absence or presence of REP (initiated 2 h following embolization) significantly (p<0.05) increased the group P(50) to 2.92+/-0.55 mg and 2.42+/-0.40 mg, respectively. In addition, ICH was increased in the REP (42%, p<0.05) and REP-TNK (35%, p>0.05) group compared to either the control group (5.5%) or TNK group (10%). This study show that reperfusion of ICA can increase RCBF following embolization, but this is not associated with improved neurological outcome measured using quantal analysis. However, TNK administration significantly increased behavioral outcome when given 2 h following embolization; an increase that is not affected by combining TNK with REP.
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PMID:Effect of internal carotid artery reperfusion in combination with Tenecteplase on clinical scores and hemorrhage in a rabbit embolic stroke model. 1964 97

Tenecteplase in a genetically engineered variant of alteplase. Although the two have the same mechanism of action, tenecteplase has properties that makes it a seemingly more advantageous thrombolytic. Because of its rapid single-bolus administration, its use is favored over alteplase in the treatment of acute myocardial infarction. Over the past few years, several clinical studies have been conducted to assess the safety, feasibility, and efficacy of tenecteplase in ischemic stroke. In spite of the mixed results of these studies, experimentation with tenecteplase continues in from of clinical trials. In this article, the utility of tenecteplase in ischemic stroke will be discussed.
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PMID:Intravenous tenecteplase in acute ischemic stroke: an updated review. 2403 24

Previous clinical trials failed to show the benefit of several potentially protective drugs in acute ischemic stroke. However, there would be three main approaches for brain protection against stroke. The first is to develop a novel thrombolytic agent which is more efficient and safer than alteplase. Tenecteplase and desmoteplase are in progress as a new thrombolytic drug. The second strategy is to augment collateral circulation through leptomeningeal anastomosis. Administration of G-CSF could enhance arteriogenesis, but it takes several days to develop functional collateral. For this purpose, partial aortic balloon clumping or stimulation of pterygopalatine ganglion may be promising. The third one is to protect neurovascular unit against reperfusion injury. Brain hypothermia is the most effective strategy in experimental ischemia, and the clinical trial for hypothermia combined with thrombolysis therapy is in progress. Activation of endogenous protective response, as presented by ischemic tolerance, has focused on remote ischemic conditioning. Although the precise mechanisms of remote preconditioning remain unclear, intermittent limb ischemia is a safe approach. Remote ischemic conditioning is now investigated in acute patients with thrombolysis therapy.
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PMID:[Brain protection against cerebral ischemia]. 2429 17

The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).
J Stroke 2013 May
PMID:Review of stroke thrombolytics. 2432 44


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