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 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The high fibrin specificity of Desmodus rotundus salivary plasminogen activator alpha1 (desmoteplase) renders it a promising candidate for the treatment of acute ischemic stroke. In the DIAS (Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose Escalation study of Desmoteplase in Acute ischemic Stroke) Phase II studies, doses of 90 microg/kg and 125 microg/kg desmoteplase were reported to have acceptable safety profiles, leading to potentially superior reperfusion compared with placebo, with possible clinical efficacy for up to 9 h after the onset of symptoms in patients with a significant ischemic penumbra selected from magnetic resonance perfusion-diffusion weighted mismatches imaging. However, a Phase III clinical trial (DIAS-2) was unable to detect any benefit from desmoteplase when given 3 - 9 h after stroke onset. In this study with a modest sample size, certain methodological factors may have reduced its potential to detect a desmoteplase effect, as only 30% of these patients had a visible occlusion at presentation, with only small core and mismatched lesion volumes. Indeed, it is surprising that a study testing an occluded vessel 'reopener' was conducted in a cohort of stroke patients, the majority of whom was known not to have a detected vessel occlusion. It has also been claimed that the DIAS-2 patients selection using core/penumbra mismatch calculation may not have followed an appropriate mismatch threshold. However, the corrective value of changing the mismatch threshold remains unclear, because the relative mismatch volumes were in fact higher in the 'negative' DIAS-2 than in the 'positive' DIAS and DEDAS. Two Phase II randomized trials with tPA, Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) provided strong biological support for the relation between infarct growth, reperfusion and clinical outcome in the 3 - 6 h time window after onset of stroke using penumbral imaging. In this frame, why exactly desmoteplase should have specific advantages over tPA, is not clear. Taken together, these findings may also lead to the disappointing conclusion that vessel recanalization after 4.5 - 5 h from stroke onset may generally be inefficacious for tissue salvage. Nevertheless, other randomized Phase III clinical trials (DIAS-3 and DIAS-4) are currently under way with a planned sample size of 320 patients having vessel occlusion or high-grade stenosis on MRI or CT-angiography in the proximal cerebral arteries.
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PMID:Desmoteplase. 1945 11

After onset of ischemic stroke, potentially viable tissue at risk (ischemic penumbra) may be salvageable. Currently, intravenous alteplase is approved for up to 4.5 hours after symptom onset of acute ischemic stroke. Increasing this time window may allow many more patients to be treated. The ability to use MRI to help define the irreversibly damaged brain (infarct core) and the reversible ischemic penumbra shows great promise for stroke treatment. Recent advances in penumbral imaging technology may enable a phase III trial of an intravenous thrombolytic to be performed beyond 4.5 hours using techniques to select patients with penumbral tissue.
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PMID:Role of diffusion and perfusion MRI in selecting patients for reperfusion therapies. 2164 Feb 98

The introduction of thrombolytic therapy has revolutionized the management of acute ischemic stroke, and it has now been conclusively established that tissue plasminogen activator (t-PA) given within 4.5 hours of stroke onset both limits irreversible ischemic neuronal damage by establishing reperfusion of the penumbra and improves outcomes for patients who have undergone stroke. As a regional stroke centre, Hamilton Health Services (HHS) seeks to ensure it meets guidelines and readiness criteria in acute stroke care. This article discusses how HHS developed and used a quality improvement process to ensure all patients receive thrombosis therapy within 60 minutes of arrival at hospital.
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PMID:Using a quality improvement process to create measurable improvement in care delivery for acute stroke. 2184 80

In Japan, time window of IV-t-PA therapy for acute stroke is within 3 hours of stroke onset. Recently, ECASS III study revealed that time window of 3-4.5 hours of stroke onset is effective for acute stroke. Thus, now US, Australia, and many countries in Europe and Asia are available for time window of 4.5 hours. The extension of time window until 4.5 hours is expected in Japan. The target of treatment in acute stroke is penumbra. MRI can estimate the area of penumbra using perfusion MRI and diffusion MRI. IV-t-PA study using MRI was conducted in acute stroke patients with over 3-4.5 hours of onset, but did not reach satisfied results. We reported that M1 susceptibility vessel sign (SVS) on T(2)(*) can predict no early recanalization after t-PA infusion. Next, FLAIR can estimate the onset time of stroke in acute stroke patients within 24h of onset. Our study demonstrated that acute stroke patients with unknown onset time may be able to safely receive intravenous thrombolysis using FLAIR. Extension of time window and development of t-PA therapy using the MRI is expected in future.
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PMID:[The extension of time window until 4.5 hours and development of MRI in t-PA patients]. 2227 25

Stroke is a major cause of mortality and morbidity, and thrombolysis has served as a catalyst for major changes in the management of acute ischaemic stroke. Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved thrombolytic agent at present indicated for acute ischaemic stoke. While the licensed time window extends to 3h from symptom onset, recent data suggest that the trial window can be extended up to 4.5 h with overall benefit. Nonetheless, 'time is brain' and every effort must be made to reduce the time delay to thrombolysis. Intracranial haemorrhage is the major complication associated with thrombolysis, and key factors increasing risk of haemorrhage include increasing age, high blood pressure, diabetes and stroke severity. Currently, there is no direct evidence to support thrombolysis in patients >80 years of age, with a few case series indicating no overt harm. Identification of viable penumbra based on computed tomography/magnetic resonance imaging may allow future extension of the time window. Adjuvant transcranial Doppler ultrasound has the potential to improve reperfusion rates. While intra-arterial thrombolysis has been in vogue for a few decades, there is no clear advantage over intravenous thrombolysis. The evidence base for thrombolysis in specific situations (e.g. dissection, pregnancy) is inadequate, and individualized decisions are needed, with a clear indication to the patient/carer about the lack of direct evidence, and the risk-benefit balance. Patient-friendly information leaflets may facilitate the process of consent for thrombolysis. This article summarizes the recent advances in thrombolysis for acute ischaemic stroke. Key questions faced by clinicians during the decision-making process are answered based on the evidence available.
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PMID:Thrombolysis in acute ischaemic stroke: an update. 2325 46

Despite advances in the diagnosis and treatment of acute ischaemic stroke in the past two decades, stroke has remained the third cause of mortality and the single leading cause of disability worldwide. The immediate goal of acute ischaemic stroke therapy is to salvage the ischaemic penumbra through recanalisation of the occluded cerebral blood vessel. This is currently achieved through thrombolytics, which are pharmacological agents that can break up a clot blocking the flow of blood. To date, the only approved thrombolytic for treatment of acute ischaemic stroke is recombinant tissue plasminogen activator (alteplase, rt-PA), however, alteplase is substantially underused because of concerns regarding adverse bleeding risk. This limitation has fuelled the search for other thrombolytic agents, which display greater fibrin dependence and selectivity, but lack detrimental effects within the central nervous system. Development of alternative fibrinolytic agents that might be easier and safer to administer could lead to wider acceptance and use of thrombolytic therapy for stroke. Although other thrombolytic agents (e.g. streptokinase) have failed to show benefit over alteplase, there is still on-going research in search of alternative agents with higher target specificity and better safety profile. The potential thrombolytic agents with trials in progress include desmoteplase, tenecteplase, reteplase, plasmin and microplasmin. This review summarises current therapies with thrombolytics (e.g. alteplase and urokinase), their limitations and side effects, and also discusses ongoing clinical studies with the various potential emerging thrombolytic agents.
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PMID:Thrombolytic agents for acute ischaemic stroke treatment: the past, present and future. 2339 31

Intravenous recombinant tissue-type plasminogen activator (rt-PA) therapy is highly recommended to patients who are diagnosed with ischemic stroke within 4.5 hours after the onset while mechanical clot retrieval can be attempted in patients who are not indicated for or cannot effectively receive intravenous rt-PA therapy. In this article, we report early treatment outcomes and discuss the usefulness of mechanical clot retrieval using the Penumbra system (Penumbra Inc., Alameda, California, USA), especially in terms of technical cautions during the procedure and adaptability to elderly and high National Institutes of Health Stroke Scale (NIHSS) patients. We included 7 patients with thromboembolic occlusion. Pretreatment NIHSS score ranged from 11 to 36 (mean: 24.9). All patients achieved good recanalization [thrombolysis in cerebral infarction (TICI) grade 2a or greater] without complications. The NIHSS score at 30 days after the treatment ranged between 0 and 28 (mean: 12.4), and improved more than 10 points in 4 of the 7 patients (57.1%). To obtain good recanalization without complications, selection of suitable reperfusion catheter and careful manipulation of separator prefiguring the occluded distal vessels are essential. The improved NIHSS score at 30 days after the treatment may have led to favorable results, such as an increased participation in available rehabilitation programs and the alleviation of the burden of care. Our findings suggest that the Penumbra system might be effective for treatment in elderly patients or patients with high NIHSS score wherein rt-PA therapy is inadvisable or ineffective in ischemic stroke secondary to large vessel occlusion. Recanalization can improve their quality of life on condition that the procedure is performed successfully without serious complications.
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PMID:Treatment of acute cerebral artery occlusion using the Penumbra system: our early experience. 2475 97

Antithrombotic medication is a cornerstone of acute ischemic stroke treatment and secondary prevention. The efficacy of thrombolysis with alteplase in acute stroke has been demonstrated in several clinical trials. This safe and costeffective therapy has transformed the practice of stroke care and has led to subsequent trials of other antithrombotic medications for treatment of ischemic stroke in the acute phase. These antithrombotics include thrombolytic, antiplatelet and anticoagulant agents. While, no other medication has yet demonstrated adequate efficacy, our current and evolving understanding of infarct expansion, ischemic penumbra, collateral circulation and the blood brain barrier is allowing testing of antithrombotic medications tailored to individual patient pathophysiology in clinical trials. This understanding accompanies developments in neuroimaging and organization of stroke care that allow for wide-spread recruitment in these trials. Alteplase remains the mainstay treatment of arterial acute ischemic stroke; however, anticoagulation is the standard therapy for cerebral venous sinus thrombosis. Antithrombotic use in acute stroke, arterial and venous, has demonstrated efficacy but leaves many questions unanswered. This patient population is a fertile ground for novel research, especially as it relates to; combination antithrombotic therapy, combination of pharmacological and mechanical thrombolysis, and the transition to secondary prevention. Here we review the current antithrombotics in the acute phase of ischemic stroke highlighting the evidence-base and areas of uncertainty.
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PMID:Acute antithrombotic treatment of ischemic stroke. 2484 24

Ischemic stroke accounts for 80% strokes and originates from a reduction of cerebral blood flow (CBF) after vascular occlusion. For treatment, the first action is to restore CBF by thrombolytic agent recombinant tissue-type plasminogen activator (rt-PA). Although rt-PA benefits clinical outcome, its application is limited by short therapeutic time window and risk of brain hemorrhage. Different to thrombolytic agents, neuroprotectants reduce neurological injuries by blocking ischemic cascade events such as excitotoxicity and oxidative stress. Nano-neuroprotectants demonstrate higher therapeutic effect than small molecular analogues due to their prolonged circulation lifetime and disrupted blood-brain barrier (BBB) in ischemic region. Even enhanced BBB permeability in ischemic territories is verified, the pore size of ischemic vasculatures determining how large and how efficient the therapeutics can pass is barely studied. In this work, nanoprobes (NPs) with different diameters are developed. In vivo multimodal imaging indicates that NP uptakes in ischemic region depended on their diameters and the pore size upper limit of ischemic vasculatures is determined as 10-11 nm. Additionally, penumbra defined as salvageable ischemic tissues performed a higher BBB permeability than infarct core. This work provides a guideline for developing nano-neuroprotectants by taking advantage of the locally enhanced BBB permeability in ischemic brain tissues.
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PMID:Multimodal nanoprobes evaluating physiological pore size of brain vasculatures in ischemic stroke models. 2489 8

Intravenous thrombolysis using tissue plasminogen activator (IV t-PA) and endovascular recanalization therapy are performed for neurological recovery in hyperacute ischemic stroke patients. Antithrombotic agents are given to prevent neurological worsening and recurrence in acute ischemic stroke patients. Therapeutic strategies for hyperacute and acute ischemic stroke have been in the process of change since the Merci retriever and Penumbra system as mechanical thrombectomy devices were approved in 2010 and 2011, and the therapeutic time window of IV t-PA was extended from 3 hours to 4.5 hours in 2012. The authors discussed on new evidences and future prospects of hyperacute recanalization therapy and acute antithrombotic therapy, bringing about a revolution to routine clinical practice in Japan.
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PMID:[Recent advances in therapeutic strategies of hyperacute and acute ischemic stroke in Japan]. 2516 19


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