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)

Ischemic penumbra was first defined by Astrup in 1981 as perfused brain tissue at a level within the thresholds of functional impairment and morphological integrity, which has the capacity to recover if perfusion is improved. It exists, even for a short period of time in the center of ischemia, from which irreversible necrosis propagates to the neighboring tissues over time. Penumbra has become the focus of intense imaging research to differentiate it from infarction. Accurate detection of this 'tissue at risk' could be used to identify patients who would benefit most from acute treatment. Currently, recombinant tissue plasminogen activator (rtPA) is the only approved drug that has shown significant benefits in acute stroke patients when administered intravenously less than 4.5 h after stroke. However, its use is limited. Discrimination between infarct core and the surrounding potentially salvageable tissue is useful to better identify patients suitable for treatment. This can be achieved by positron emission tomography, single-photon-emission computed tomography, computed tomography perfusion scan and perfusion-weighted and diffusion-weighted magnetic resonance imaging. Identification of the penumbra might enable selective rtPA use in patients with large penumbras and small infarct cores, even beyond the 4.5-hour time window, where the penumbra may persist for more than 12 h. The purpose of this review was to describe neuroimaging modalities capable of identifying penumbra tissue so as to provide surrogate markers for new trials in acute ischemic stroke patients.
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PMID:The concept of ischemic penumbra in acute stroke and therapeutic opportunities. 1936 24

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

Reperfusion with intravenous tissue plasminogen activator (tPA) has been the goal of therapy for acute ischemic stroke; however, tPA is contraindicated in many patients, has low recanalization rates in major occlusions, and carries a substantial risk of symptomatic intracerebral hemorrhage. In the present study, we hypothesized that partial intra-aortic occlusion of the abdominal aorta would increase salvage of ischemic penumbra and reduce infarct volume after focal embolic stroke in rats. We examined the effects of aortic occlusion on infarct volume, expression and activation of matrix metalloprotease-9, and hemorrhagic transformation with or without treatment with tPA. We then examined the effects of aortic occlusion on perfusion deficits following embolic occlusion. Results showed that partial aortic occlusion significantly reduces brain infarction volume with or without treatment with tPA after focal ischemia, but does not increase risk for hemorrhagic transformation or matrix metalloprotease-9 expression and activation. Partial intra-aortic occlusion also reduces perfusion deficits after focal cerebral ischemia as compared to control. The present study shows that partial intra-aortic occlusion significantly decreases infarction volume and perfusion deficits following ischemic injury in an embolic model of cerebral ischemia. Moreover, combination treatment with tPA and partial intra-aortic occlusion further reduces infarction volume without any increase in hemorrhagic transformation.
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PMID:Partial intra-aortic occlusion improves perfusion deficits and infarct size following focal cerebral ischemia. 1988 34

The author presents a novel endovascular treatment approach to extensive dural venous sinus thrombosis using the Penumbra clot aspiration system and local administration of recombinant tissue plasminogen activator. The clinical course, technical treatment aspects, and follow-up are described.
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PMID:Extensive dural sinus thrombosis: successful recanalization with thrombolysis and a novel thrombectomy device. 2020 11

With the advent of new therapeutic options for acute ischemic stroke, expeditious evaluation of patients with suspected stroke has become imperative. Goals of the initial evaluation are to determine the time of symptom onset, severity of the neurologic deficit, and to exclude intracranial hemorrhage and other mimics of acute ischemic stroke. CT and MRI perfusion studies may demonstrate the presence of an ischemic penumbra and aid in identification of patients who may benefit from thrombolysis. Intravenous recombinant tissue plasminogen activator (IV rtPA) remains the gold standard for acute ischemic stroke treatment, and the therapeutic time window recently has been extended to 4.5 h in certain patients. Catheter-based intra-arterial thrombolysis is being used increasingly as "rescue therapy" after IV rtPA and as primary therapy in select patients who are ineligible for intravenous therapy. Trials investigating the efficacy and safety of intra-arterial therapy are ongoing.
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PMID:Emergency management of acute ischemic stroke. 2045 74

Current acute therapies for ischemic stroke are limited. Only a small proportion of stroke patients are eligible to receive reperfusion therapy. Acute hyperglycemia has a deleterious effect in stroke patients by accelerating ischemic brain damage. The complex relationship between hyperglycemia and stroke is discussed. In tPA-treated patients, the acute but not chronic hyperglycemic state may hamper fibrinolytic process, delaying reperfusion of ischemic penumbra. Early measures to reduce hyperglycemia may favor early recanalization.
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PMID:[Acute hyperglycemia and reperfusion therapy in stroke patients]. 2046 99

Neuroimaging in ischemic stroke continues to be one of the most developing fields in nuclear medicine. Many studies have established the efficacy of blood flow and metabolism measurements in acute ischemic stroke. Although the release of recombinant tissue plasminogen activator in clinical practice has minimized the use of SPECT or PET in the first few hours of ischemic stroke onset, implementing these techniques into a set of initial examinations is still beneficial to exclude risky patients for reperfusion therapy beyond several hours after onset. Rescuing of viable tissue suffering ischemic penumbra is an important target of early therapeutic strategy. Ischemic penumbra can be visualized by means of perfusion imaging, central type benzodiazepine receptor imaging, and hypoxy imaging. In the later phase of subacute ischemic stroke, inflammation and apoptosis can be visualized by means of peripheral-type benzodiazepine receptor imaging and annexin V imaging, respectively. Imaging of the penumbra and cellular responses will help evaluate the effects of drugs and interventions for ischemic stroke, suggesting its potential as a marker of the efficacy of future therapeutic regimens.
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PMID:Nuclear neuroimaging in acute and subacute ischemic stroke. 2095 42

Stroke is a major cause of mortality in the U.K. accounting for 53,000 deaths every year. There are few options for the treatment of acute ischemic stroke and recombinant tissue plasminogen activator (rt-PA) remains the only approved and currently available thrombolytic therapy given within the first 3 hours after symptom onset. Mechanical thrombectomy is a promising new treatment modality for patients who are ineligible for or failing intravenous rt-PA, or presenting beyond the narrow 3-hour therapeutic window, and emerged with the development of the Merci retrieval system. A number of devices are now available and can be divided into two major subgroups according to their mode of action. Those using a proximal approach such as aspiration devices (Penumbra system) act by applying a vacuum to the proximal aspect of the thrombus whereas distal devices (Merci retrieval system, Phenox clot retriever, and Catch device) such as coil-like and basket-like devices are advanced through the thrombus thereby contacting its distal aspect. In this review, we discuss the procedure and technique, as well as evidence associated with four mechanical retrieval systems currently available: the Merci Retriever System, the Penumbra system, the Catch device, and the Phenox clot retriever. We also consider potentialnovel approaches for stroke treatment including waterjet thrombectomy and laser recanalization.
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PMID:The start of a new era for stroke treatment: mechanical thrombectomy devices. 2120 64

This review summarizes the current state-of-the-art regarding the endovascular management of acute ischemic stroke. Beginning with intravenous tissue plasminogen activator, this paper traces the gradual shift of systemic thrombolysis from a competing to complementary treatment modality. Intra-arterial thrombolysis, mechanical thrombectomy with the Merci (Concentric Medical, Mountain View, California) and Penumbra (Penumbra, Inc., Alameda, California) systems, angioplasty, primary intracranial stenting, and emerging stentriever devices are sequentially reviewed. Ultimately, this paper lays the foundation for current endovascular stroke management and considers future areas of progress and research.
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PMID:Acute stroke intervention. 2143 2

Intra-arterial therapy (IAT) for acute ischemic stroke refers to endovascular catheter-based approaches to achieve recanalization using mechanical clot disruption, locally injected thrombolytic agents or both. IAT may be used in addition to intravenous tissue plasminogen activator (tPA) or in patients who do not qualify for tPA, usually because they are outside the approved 3-h timeframe window or have contraindications, such as elevated international normalized ratio or partial thromboplastin time. Recanalization rates correlate with clinical improvement, and with the newest catheters it is possible to achieve recanalization in roughly 80% of patients treated. However, while the catheters are approved by the Food and Drug Administration, there are still no randomized trial data demonstrating the role of current IAT therapy vs either tPA or standard management. IAT is reserved for patients with large artery occlusions in the basilar, distal carotid, or proximal middle cerebral arteries. Imaging the penumbra using magnetic resonance imaging or computed tomographic perfusion is currently the most frequently used way to identify patients who might benefit. However, the imaging and clinical criteria for identifying which patients benefit, and perhaps more importantly those who will do poorly despite IAT, remain unclear.
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PMID:Intra-arterial therapy for acute ischemic stroke. 2171 63


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