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)

Evidence from randomized clinical trials indicates that systemic administration of recombinant tissue plasminogen activator (rtPA) is a highly effective treatment for acute ischemic stroke, provided that treatment is administered within the first 3 h after stroke onset. An absolute increase in favorable outcome of up to 13% has been reported, and a pooled analysis of six randomized trials has shown that, although the sooner rtPA is given the greater the benefit, efficacy is present up to 4.5 h after stroke onset. Despite of the spreading use of tPA in different countries and continents, there are still a number of burdens and failures in the optimal accomplishment of thrombolytic treatment. rtPA is used in less than 4% of patients, reperfusion and complete recovery is achieved in less than 50% of patients, and treatment is denied to many patients. However, important advances in clinical investigation suggest that new aims and hopes will be achieved in the near future. Ultrasound-enhanced systemic thrombolysis, the use of MRI for selecting acute stroke patients for IV or IA thrombolysis after 3 h, mechanical embolus disruption or removal in proximal artery occlusions, and the potential usefulness of new biomarkers of blood brain barrier disruption and hemorrhagic risk are promising strategies that may improve the risk/benefit ratio and increase the number of patients who will benefit from thrombolytic therapy.
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PMID:Thrombolysis in acute ischemic stroke: successes, failures, and new hopes. 1632 64

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

Intravenous thrombolysis with tPA is the only approved and effective treatment for acute ischemic stroke. The approval, however, is restricted to treatment within 3 hours of stroke onset, and it is not recommended to treat patients beyond 80 years of age. Due to these restrictions, thrombolysis is only given to a small number of acute stroke patients. At the same time there is growing evidence that patients can be treated with thrombolysis safely and effectively even beyond these restrictions. We give an overview over the published data regarding thrombolysis beyond the 3 hour time window and in patients aged 80 or over. Based on these data we conclude that (1.) intravenous thrombolysis in MRI selected patients is safe and effective within an extended time window of up to 6 hours, and (2.) there is no increase in mortality or symptomatic intracerebral bleeding complications in patients aged 80 or over treated with thrombolysis. A great number of acute stroke patients reaches the hospital beyond the 3 hour time window, and there is a growing number of old and very old stroke patients in the western world. Treating patients up to a 6 hour time window and beyond the age of 80 years would clearly increase the number of patients, which might benefit from this effective treatment. To summarize, we recommend experienced stroke centres to treat acute stroke patients with thrombolysis up to 6 hours using MRI criteria for patient selection, and to treat also patients aged 80 years or older.
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PMID:[Effective acute stroke treatment beyond approval limitations: intravenous thrombolysis within an extended time window (3-6 h) and in old patients (aged 80 or older)]. 1736 77

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

Intracerebral haemorrhage (ICH) still represents the most feared complication of thrombolysis. Our aim was to review the literature regarding clinical, biological and imaging predictors of ICH following thrombolysis for acute ischaemic stroke. Relevant studies were identified through a search in Pubmed, using the following key words: "intracerebral", "haemorrhage", "stroke" and "thrombolytic". The query was limited to studies published in the English literature. The reference lists of all relevant articles were reviewed to identify additional studies. The main predictors of clinically significant ICH were age, clinical stroke severity, as assessed by the National Institute of Health Stroke Scale score on admission, high blood pressure, hyperglycaemia, early CT changes, large baseline diffusion lesion volume and leukoaraiosis on MRI. The contribution of biomarkers in the prediction of the ICH risk is currently under evaluation. Available data on patients with limited number of microbleeds on pretreatment gradient echo MRI sequences suggest safe use of thrombolysis. ICH after stroke thrombolysis is a complex and heterogeneous phenomenon, which involves numerous parameters whose knowledge remains partial. To minimise the risk of tissue plasminogen activator (tPA) related symptomatic ICH, careful attention must be given to the pre-therapeutic glycaemia value, and a strict protocol for the control of elevated blood pressure is needed during the first 24 h. Future research should focus on predictors of severe intracerebral haemorrhagic complications (parenchymal haematomas type 2 according to the European Cooperative Acute Stroke Study (ECASS) classification). The input of multimodal MRI and biological predictors of ICH deserves further investigation.
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PMID:Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. 1822 14

A 49-year-old woman with an acute ischemic stroke was treated by the intravenous administration of tissue plasminogen activator within 2 h of symptom onset. She complained of severe upper thoracic back pain the following day. Progressive paraparesis was detected on the third admission day. Spinal MRI demonstrated an acute anterior subdural hematoma from the C7 to T2 level. An urgent laminectomy was performed. Neurologists must be aware of the possibility that neck or back pain after thrombolysis for ischemic stroke may be the first presenting symptom of spinal hematoma.
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PMID:Spinal subdural hematoma following tissue plasminogen activator treatment for acute ischemic stroke. 1863 96

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 for acute stroke has been changed greatly in Japan. Because use of intravenous administration of tissue plasminogen activator (IV-t-PA) for acute brain infarction within 3 hours of onset has been approved by Japanese government from October, 2005. Now, if acute stroke patient arrivals at hospital within 3 hours of onset, we consider that such patients should be treated with t-PA therapy. The accurate diagnosis should be made by systematic evaluation using CT/MRI, neurosonology including transcranial Doppler, carotid echography, and echocardiography (TEE and TTE), SPECT, and angiography. In particular, it is important to assess the arteries from heart and brain. The grad A for treatment of acute stroke is recommended as IV-t-PA therapy, aspirin administration within 48 hours of stroke onset, and the management in stroke unit. In particular, stroke unit can improve functional outcome and to reduce the length of hospital stay. The evidence directing therapy for acute stroke is changing rapidly.
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PMID:[Diagnosis and management for acute ischemic stroke]. 1919 2

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

The use of the only proven therapy for acute ischemic stroke, intravenous tissue plasminogen activator (tPA), remains disappointingly low. One potential way to increase the use of tPA is by the implementation of telemedicine stroke care networks. Preliminary data from several studies indicate that the safe and expanded use of tPA for ischemic stroke can be accomplished with the help of telemedicine. Telemedicine stroke care networks can also be used in the future to enhance stroke diagnosis with advanced CT and MRI technology and to potentially increase the number of patients referred to tertiary stroke centers for intra-arterial therapies. It is highly likely that telemedicine stroke care will substantially enhance acute stroke therapy for remote and underserved populations.
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PMID:Use of telemedicine to increase thrombolysis and advance care in acute ischemic stroke. 1954 36


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