Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Review of results of experimental and clinical studies indicates that the area of physiologically impaired, but potentially salvageable, tissue surrounding the central core of focal cerebral ischemia that develops shortly after onset of vessel occlusion is complex and dynamic with severity and duration thresholds for hypoxic stress and injury that are specific to tissue site, cell type, molecular pathway or gene expression investigated, and efficiency of collateral or residual flow and reperfusion. Identification of this ischemic penumbra in the acute stroke clinical setting is an important goal for stroke researchers and clinicians. Recent advances in neuroimaging allowed a better understanding of this physiopathological process. However, there is not a perfect penumbra imaging technique and each one has its own advantages and disadvantages. Numerous thrombolytic and potentially neuroprotective agents have been studied in stroke patients, with little success, as the only approved therapy is thrombolysis with recombinant tissue plasminogen activator within 3 h of stroke onset in highly selected patients (<10% of all acute stroke patients in some specialized centers). One major obstacle in the development of effective therapies for ischemic stroke has been the lack of versatile imaging techniques. The development of penumbra concept and its detection through modern cerebral image techniques can extend the patients' selection for thrombolysis. A number of multicenter clinical trials are now under way to test these models and confirm the utility of penumbra imaging for treatment decisions. Present knowledge about visualization of the salvageable penumbra suggests a promising future in which penumbra imaging studies are performed routinely in the acute stroke setting and the data provided by these studies assist in individualizing therapeutic decisions and identifying effective therapies that can be delivered at late time points. So, the main target of management is 'penumbra', or salvageable tissue, which is primarily dependent upon the expediency of the whole process, better expressed by the phrase 'Penumbra (and not Time) is Brain'.
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PMID:Selecting patients for early stroke treatment with penumbra images. 1632 50

Stroke contributes significantly to death, disability, and healthcare costs; however, recombinant tissue plasminogen activator (rt-PA) is the only approved thrombolytic therapy for acute ischemic stroke. One area of development for new ischemic stroke treatment options is focused on neuroprotection of viable tissue in the ischemic vascular bed. The ischemic penumbra is recognizable on MRI by decreased perfusion, in contrast to the core area of ischemia, which includes diffusion and perfusion abnormalities. Understanding the mechanisms of neuronal death, including the role of excitotoxic neurotransmitters, free radical production, and apoptotic pathways, is important in developing new therapies for stroke. This article reviews these causes and results of stroke, as well as current and future neuroprotective treatment options. Several compounds have shown neuroprotective effects in animal studies, but have failed to be effective in human clinical trials. Several promising therapeutic areas include targeting of free radicals, modulation of glutamatergic transmission, and membrane stabilization via ion channels.
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PMID:Evolving therapeutic approaches to treating acute ischemic stroke. 1700 5

Acute ischemic stroke is one of the leading causes of mortality and chronic disability in the western world. Yet, despite the enormous socioeconomic burden that it imposes, therapies to combat AIS are not widely available. Moreover, revascularization of the ischemic tissue with tissue plasminogen activator, the only FDA-approved therapy for AIS, is hampered by a very narrow therapeutic time window and is only used in a minority of patients. Cerebral ischemia leads to brain damage caused by several pathologic mechanisms that can potentially be blocked by neuroprotective drugs that aim to salvage the ischemic penumbra. However, despite numerous clinical trials, no single drug candidate has proved efficacious in AIS. The current situation calls for novel therapeutic strategies to be used in acute ischemic stroke. This review surveys some of these novel and promising cutting edge therapies.
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PMID:Novel therapies for acute ischemic stroke. 1718 Aug 32

A thrombolytic agent, recombinant tissue plasminogen activator (rt-PA), was recently approved in Japan for use on patients within 3 hrs of the onset of cerebral infarction. In order to salvage cerebral tissue after an ischemic insult, it is crucial to detect the ischemic lesion before it becomes irreversible and to detect the core and penumbra areas of the lesion for guidance in selecting the suitable therapy. In this symposium we discuss the detection of ischemic lesions using plain CT, perfusion CT, and MRI. In the section on plain CT, we present a typical case with early CT signs. In the section on perfusion CT, we report on the feasibility and limitation of the technique for the diagnosis of acute cerebral infarction. In the section on MRI, we study the usefulness of DWI for the early and highly reliable detection of ischemic stroke.
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PMID:[Early detection of ischemic lesions in the super-acute phase of ischemic cerebrovascular diseases by imaging]. 1743 94

Hospitalists are frequently called upon to manage blood pressure after acute ischemic stroke. A review of both post infarction cerebral perfusion physiology and the data from randomized trials of antihypertensive therapy is necessary to explain why consensus guidelines for blood pressure management after stroke differ from those of other hypertensive emergencies. The peri-infarct penumbra is the central concept in understanding post ischemic cerebral perfusion. This area of impaired cerebral blood flow is dependent on mean arterial blood pressure and acute reduction of blood pressure may expand the area of infarction. Review of clinical trials fails to show benefit from reduction of blood pressure after ischemic stroke and current guidelines suggest antihypertensive therapy be employed if the systemic blood pressure is greater than 180/105 mmHg after tPA is employed, or 220/120 mmHg when tPA is not used. Induced hypertension remains a promising but unproven therapy in the acute setting, but the evidence for long term control of blood pressure to less than 140/80 mmHG for secondary prevention of stroke is strong. Adherence to guidelines is poor but it is recognized that current evidence is limited by a lack of trials in which blood pressure is titrated to a pre-specified goal, as is common in clinical practice.
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PMID:Management of blood pressure after acute ischemic stroke: An evidence-based guide for the hospitalist. 1770 77

Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.
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PMID:Protective role of reactive astrocytes in brain ischemia. 1772 92

Acute ischemic stroke (AIS) is a common disorder that has only one associated approved therapy: intravenous tissue plasminogen activator (iv t-PA). A limiting factor to the use of iv t-PA is that it must be initiated within 3 h of stroke onset. Efforts to expand the therapeutic time window are underway and include image evaluation of the ischemic penumbra to target those patients who are most appropriate for treatment. Intra-arterial t-PA is also used only in some treatment centers despite convincing proof of efficacy of this therapy. Devices to restore perfusion that have been approved in the US for recanalization exist, but these are not approved for use in stroke therapy. Many neuroprotective drugs have been evaluated as potential acute stroke therapies, but none have shown efficacy, hence the future of neuroprotection as a strategy for acute ischemic stroke therapy remains uncertain.
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PMID:Treating acute ischemic stroke. 1872 14

After large CT-based clinical trials have failed to prove the benefits of intravenous tissue plasminogen activator (tPA) administration for ischemic stroke patients beyond 3 hours of the onset of the concept of PWI/DWI mismatch which is the volume difference between a PWI lesion and DWI lesion on MRI scans, has been proposed to facilitate the selection of patients with a salvageable area. PWI/DWI mismatch is considered to represent the tissue that is not irreversibly injured and can respond to early reperfusion therapy. When an ischemic lesion is divided into 4 regions, namely, ischemic core, reversible DWI lesion, penumbra and benign oligemia, both the reversible DWI lesion and penumbra are considered to be an optimal targets for thrombolysis. In order to clarify the clinical significance of PWI/DWI mismatch in the selection of candidates for tPA therapy, some multicenter trials were performed. The results of DIAS (desmoteplase in acute ischemic stroke)/DEDAS (dose escalation of desmoteplase for acute ischemic stroke)/DIAS-2 did not difinitly demonstrate the clinical benefits of desmoteplase administration in patients with PWI/DWI mismatch between 3 to 9 hours of onset; in fact, DIAS-2 could not prove any effect of the drug. DEFUSE (diffusion and perfusion imaging evaluation for understanding stroke evolution), in which tPA was administered to all participants between 3 to 6 hours of stroke onset, showed that the occurrence of early reperfusion led to a favorable clinical response in patients with PWI/DWI mismatch. In contrast, early reperfusion was not beneficial in patients without PWI/DWI mismatch. In EPITHET (echoplanar imaging thrombolysis evaluation trial), stroke patients who showed PWI/DWI mismatch after 3 to 6 hours of the onset were assigned to receive either alteplase or placebo administration: lesion growth was lesser in patients with alteplase than in those who received placebo, although the difference was not statistically significant because of a small number of participants. Although these results supported the importance of the PWI/DWI concept, there still remain some issues to be resolved. Regarding the definition of PWI/ DWI mismatch, a larger mismatch ratio than the one that has been typically used seems to be recommended. Most useful parameters of PWI should be determined to standardize volume evaluation using MRI scans. For the institutes where MRI scans are not available 24 hours a day, clinical DWI mismatch has been proposed as an alternative to of PWI/DWI mismatch. The application of MRI-based decision making strategy for stroke patients may facilitate the assessment and treatment of stroke patients beyond 3 hours of stroke onset, and is expected to allow the use of tPA for a substantially greater number of patients.
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PMID:[Intravenous administration of a tissue plasminogen activator beyond 3 hours of the onset of acute ischemic stroke--MRI-based decision making]. 1897 5

The management of stroke has progressed significantly over the past 2 decades due to successful treatment protocols including intravenous and intraarterial options. The intravenous administration of tissue plasminogen activator within an established treatment window has been proven in large, well-designed studies. The evolution of endovascular strategies for acute stroke has been prompted by the limits of the intravenous treatment, as well as by the desire to demonstrate improved recanalization rates and improved long-term outcomes. The interventional treatment options available today are the intraarterial administration of tissue plasminogen activator and newer antiplatelet agents, mechanical thrombectomy with the MERCI device and the Penumbra system, and intracranial angioplasty and stent placement. In this review the authors outline the major studies that have defined the current field of acute stroke management and discuss the basic treatment paradigms that are commonly used today.
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PMID:Endovascular management of acute ischemic stroke. 1924 58

The Penumbra Stroke System (PSS) was cleared for use in patients with ischemic stroke by the FDA in January 2008. We describe our experience of using this new system in acute large vessel occlusive disease following thrombolysis. Fifteen consecutive patients (mean age 60 years) suffering from acute ischemic stroke were treated with the PSS after intravenous or intra-arterial standard treatment with tissue plasminogen activator (n = 14) or ReoPro (n = 1). All patients presented with TIMI 3 before use of the PSS. Carotid stenting (n = 3) and intracranial balloon angioplasty or stenting (n = 2) were performed if indicated. Neurological evaluation was performed using the NIHSS score and the mRS score. Initial median NIHSS score in 12 patients with occlusions in the anterior circulation was 15; three patients with basilar artery occlusion presented with coma. Median symptom to procedure start time was 151 min. In the anterior circulation, 9 of the 12 target vessels were recanalised successfully (TIMI 2 and 3). The rate of patients with independent clinical outcome (mRS </= 2) was 42%. One patient died 5 days after unsuccessful treatment, one after 28 days and one after 85 days owing to heart attack. Basilar artery occlusions could be recanalised in all cases to TIMI 3. The clinical result after 90 days was mRS 4 in two cases and mRS 5 in one case. Symptomatic haemorrhage did not occur. The PSS can safely be used for recanalisation in patients with acute ischemic stroke due to large vessel occlusion, who have already received thrombolysis treatment. The recanalisation rate was 80%. Symptomatic haemorrhage did not occur. Randomized trials may demonstrate that endovascular mechanical thrombectomy improves patient outcome.
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PMID:Penumbra Stroke System as an "add-on" for the treatment of large vessel occlusive disease following thrombolysis: first results. 1935 Feb 48


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