Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intravenous (IV) administration of tissue plasminogen activator (tPA) given to patients during acute cerebral ischemia according to National Institute of Neurological Disorders and Stroke (NINDS) guidelines improves clinical outcome by 11% to 14%. The success of IV tPA stroke therapy is dependent on several previously reported factors. The authors suggest that the presence of calcification within an embolus may represent an additional important factor. This report describes a patient with an acute stroke secondary to a spontaneous calcific cerebral embolus who had a negative outcome despite receiving proper thrombolytic therapy.
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PMID:Unsuccessful tissue plasminogen activator treatment of acute stroke caused by a calcific embolus. 1535 64

In addition to its thrombolytic effect, human recombinant tissue plasminogen activator (tPA) may have parenchymal effects such as protease-dependent neurotoxic and protease-independent neuroprotective effects. The purpose of this study was to examine parenchymal effects of tPA and its non-protease mutant S478A-tPA in permanent focal cerebral ischemia in rats. However, before doing in vivo experiments, effects of tPA and S478A-tPA on zinc or NMDA toxicity were first studied in cortical cultures. Like tPA, which has protease-independent cytoprotective effects, the non-protease mutant S478A-tPA blocked zinc toxicity in cortical cell cultures, but did not affect calcium-mediated NMDA toxicity. Then, effects of tPA and S478A-tPA on infarcts induced by permanent occlusion of middle cerebral artery (MCA) were investigated. tPA and S478A-tPA were administered into the cerebral ventricle 15 min or 1 h after MCA occlusion. Both tPA and its non-protease mutant S478A-tPA, when given 15 min after ischemia, substantially reduced infarcts and ameliorated motor deficits in the MCA occlusion model of focal cerebral ischemia. However, when administered 1 h after MCA occlusion, neither showed protective effects. The protective effects of tPA or S478A-tPA remained unchanged at 7 days after MCA occlusion. Indicating that the native protein conformation is necessary for the protective effect of tPA and S478A-tPA, heat-denatured tPA did not exhibit any protective effect. Since S478A-tPA lacks protease activity, which has been implicated in causing cerebral hemorrhage or aggravating excitotoxicity, its parenchymal neuroprotective effect may be useful in treatment of ischemic stroke.
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PMID:Infarct reduction in rats following intraventricular administration of either tissue plasminogen activator (tPA) or its non-protease mutant S478A-tPA. 1538 Apr 85

Stroke is a common cause of morbidity and mortality throughout the US and the world. Given the highly disabling nature of this disease, it is important to provide acute therapy when indicated to improve individual outcomes. Recombinant tissue plasminogen activator (rt-PA) is, at present, the only approved drug for the treatment of acute strokes due to cerebral ischaemia. It can be given intravenously within a 3-h window of the onset of neurological deficits. Intra-arterial administration of rt-PA within a 6-h window is performed at several academic centres in patients with middle cerebral and other intracranial artery occlusions based on results of a randomised clinical trial. Other thrombolytic agents are being studied in randomised trials. Although acute therapy of ischaemic stroke has received much attention since the approval of rt-PA, only a small percentage of individuals actually receive rt-PA. This article will review the main thrombolytic agents and the trials performed thus far, as well as examine some important ongoing trials. How administration of acute thrombolytic therapy may evolve in the future will also be addressed.
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PMID:Antithrombotic trials in acute ischaemic stroke: a selective review. 1557 87

The aim of this study was to investigate the effects of different doses of exogenous recombinant human tissue plasminogen activator (rt-PA) on the endogenous cerebral plasminogen-plasmin system in focal ischemia in rats. Ischemia was induced using the suture model. Each group of rats (n = 6) received either treatment (0.9, 9 or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia; a sham-operated group was added. The activity of the plasminogen activators was measured by casein-dependent plasminogen zymography. In the cortex urokinase (u-PA) rose from sham (no ischemia), 91 +/- 7% to ischemia, 176 +/- 10% (P < 0.005). Increasing rt-PA doses led to further significant (P < 0.001) cortical u-PA activation which was maximal at 18 mg: 249 +/- 13%. An extreme increase in the u-PA activity was observed in the basal ganglia to 1019 +/- 22% (P < 0.001). This increase was further aggravated by higher rt-PA doses (18 mg, 1236 +/- 15%; P < 0.001). The t-PA level did not change I3R24 during (3 h ischemia followed by reperfusion for 24 h); however, during low and moderate doses of rt-PA, endogenous t-PA was reduced. In conclusion, while ischemia leads to a significant increase in u-PA, mainly in the basal ganglia, t-PA is not altered. Increasing doses of rt-PA lead to a further elevation of u-PA. Thus, u-PA seems to play a major role in the endogenous plasminogen activator system following focal cerebral ischemia.
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PMID:Rt-PA causes a significant increase in endogenous u-PA during experimental focal cerebral ischemia. 1557 44

Thrombolytic therapy are the most important advance in the management of acute ischemic stroke and has been evaluated in several randomised trials. Thrombolysis with recombinant tissue plasminogen activator (rt-Pa) is effective within 3 h of onset of ischemic stroke and this efficacy is similar between different stroke subtypes. New trials will determine if extension of this time-window can be substantiated. Therapy beyond the 3-hour window, with intra-arterial thrombolysis, appears to improve outcome but are applicable to selected group of patients. Thrombolytic drugs can also carry an important risk (5 % to 10 %) of brain hemorrhage and edema that can prove fatal. The risk of symptomatic intracranial hemorrhage is directly proportional to stroke severity and inversely proportional to time to treatment. There is a growing interest in the use of MRI in acute ischemic stroke. It helps identify location of early cerebral ischemia and provides valuable information not only of the penumbra but also of vessel occlusion. Its use might help in selecting patients who will benefit most from treatment such as thrombolysis. In spite of these results, community use of thrombolytic therapy remains dismally low. Many physicians and medical centers are not presently equipped or willing to give thrombolytic drugs for stroke treatment. Increasing stroke awareness in the community, creating stroke unit and physicians education are necessary to extend the effective use of acute treatment in cerebral infarct to a larger group of patients.
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PMID:[Thrombolysis and acute cerebral infarction]. 1558 64

Despite recent advances in the understanding of the pathophysiology of cerebral ischemia, current approaches attempting to prevent ischemic brain damage after an acute stroke remain quite inadequate. Today, ischemic stroke remains the third leading cause of death in industrialized nations, and the leading cause of disability requiring long term institutional care in the U.S and other industrialized nations. While one treatment, tissue plasminogen activator, has shown efficacy in clinical trials, safety concerns limit its role in clinical practice to a narrow time window of use. Acute cerebral ischemia has been shown to evoke a profound and deleterious upregulation of the inflammatory response, initiated within the cerebral microvasculature. Recently, research efforts have focused on targeting individual components of the inflammatory cascade, such as leukocyte activation and adhesion, in an attempt to develop potential neuroprotective agents. While these strategies have shown promise preclinically, clinical trials have yet to show clear benefit. Here, we review the current understanding of the pathophysiologic consequences of acute cerebral ischemic injury. Additionally, we discuss the role of the inflammatory cascade, with specific attention given to the deleterious role played by leukocyte activation and adhesion in stroke. Finally, relevant efforts to translate these basic science observations into clinical efficacy in acute stroke trials are critically reviewed.
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PMID:Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: a critical review of the literature. 1559 43

Although statins are being used for the secondary prevention of ischemic stroke, recent experimental data have shown new pleiotropic effects of these drugs independent of their lipid-lowering properties that might be responsible for their role in neuroprotection. In fact, statins have been successfully tested in animal models of acute cerebral ischemia. In humans, the possibility that statins could be used for the treatment of acute ischemic stroke has not yet been addressed, however, a pilot trial and observational studies testing this approach showed promising results for a disease in which tissue plasminogen activator is the only available treatment for a reduced number of patients. The aim of this review is to answer the basic question of whether treatment with statins initiated in the acute phase of ischemic stroke is feasible and if it can improve neurologic outcome. The possible benefits of this scenario will be discussed.
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PMID:Treatment with statins in the acute phase of ischemic stroke. 1585 91

Neurotoxic effects of endogenous tissue plasminogen activator (tPA) have recently been reported. Employing a rat model of thromboembolic stroke, we evaluated the extent and degree of extravasation of exogenous tPA administered for the purpose of fibrinolysis. In a thromboembolic model using Sprague-Dawley rats, focal cerebral ischemia was induced at the territory of the middle cerebral artery (MCA). Early reperfusion was induced by administering tPA (10 mg/kg) intravenously at 30 minutes after the onset of ischemia. Extravasated tPA was evaluated by immunohistochemistry, and the concentration of tPA in the brain tissue was quantified by enzyme-linked immunosorbent assay methods. The integrity of the blood-brain barrier (BBB) was examined electronmicroscopically. In a thread model of transient ischemia, reperfusion was induced without tPA administration at 30 minutes or 2 hours after the onset of ischemia, and the tPA content of the brain was quantified. In the rats with thromboembolic stroke, extravasation of tPA was observed at the territory of the MCA. Both the endogenous and exogenous tPA contents were 3.5 +/- 1.6 ng/ml of homogenized brain in saline. Electronmicroscopically, mild ischemic changes were observed, although the integrity of the BBB was preserved. In the thread model rats, the endogenous tPA contents of the ischemic hemisphere were 0.9 +/- 0.1 and 1.0 +/- 0.2 ng/ml in the 30-minute and 2-hour ischemia groups, respectively, and were significantly lower than the tPA contents in the thromboembolic stroke rats (p<0.01). The present findings indicate that significant extravasation of exogenous tPA occurs through the cerebral vessels even though early reperfusion is induced.
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PMID:Tissue plasminogen activator extravasated through the cerebral vessels: evaluation using a rat thromboembolic stroke model. 1627 Jun 32

We previously showed that the neuroactive steroid 3alpha-ol-5-beta-pregnan-20-one hemisuccinate (ABHS), a low-affinity NMDA receptor antagonist, improves behavior in rabbits following spinal cord ischemia. The present study assessed whether this also occurs following cerebral ischemia. We used the rabbit small clot embolic stroke model (RSCEM), a model of multiple infarct ischemia, which has a well-defined behavioral endpoint. Quantal analysis for each treatment determines microclots (mg) that produce neurologic dysfunction in 50% of a group of animals (P(50)), with treatment considered beneficial if it increases the P(50) compared to controls. ABHS (25 mg/kg) injected 5 min post-embolization significantly (P = 0.046) increased the P(50) to 2.60 +/- 0.69 mg compared to 1.15 +/- 0.19 mg in controls but was ineffective at longer intervals. For combination studies with tissue plasminogen activator (tPA), a cumulative control curve (P(50) = 1.18 +/- 0.25 mg) was used for statistical comparisons. Low-dose tPA (0.9 mg/kg) and ABHS, given 60 min post-embolization, improved behavior synergistically (P(50) = 2.44 +/- 0.44 mg), compared to tPA (P(50) = 1.25 +/- 0.25 mg) or ABHS (P(50) = 1.05 +/- 0.24 mg) alone. A standard tPA dose (3.3 mg/kg) significantly increased the P(50) at 60 (2.69 +/- 0.19 mg) but not 180 min (1.28 +/- 0.31 mg) post-embolization. However, when combined with ABHS, an effect was evident even 180 min post-embolization (P(50) = 2.31 +/- 0.48 mg). Although the therapeutic window for ABHS is limited, it significantly enhanced neuroprotection by low-dose tPA and increased the therapeutic window for tPA, suggesting that it may be most useful as a co-therapy with thrombolytics for stroke.
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PMID:3alpha-OL-5-beta-pregnan-20-one hemisuccinate, a steroidal low-affinity NMDA receptor antagonist improves clinical rating scores in a rabbit multiple infarct ischemia model: synergism with tissue plasminogen activator. 1630 Jul 57

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


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