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

A prerequisite for the successful treatment of acute ischaemic stroke is the existence of viable tissue that is morphologically intact but functionally impaired due to a flow decrease below a certain threshold. At this stage, tissue at risk of infarction can be identified only by functional imaging. This penumbral tissue can be classified as having a critical flow decrease with preservation of oxygen consumption and therefore increased oxygen extraction. Such 'misery-perfused' tissue has been observed consistently in the first few hours following ischaemic stroke but usually develops into necrosed tissue at follow-up observations. Several studies have indicated that penumbral tissue can be identified up to 17 h or even 48 h after stroke in the border zones of ischaemic tissue and that this condition is occasionally reversible without resulting in permanent infarction. Positron emission tomography studies of cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral metabolic rate of glucose (CMRglc) can be used to demonstrate the effect of treatment on functional variables within tissue showing perfusional disturbances. Such studies have shown the value of these markers of ischaemia, which also correlate with clinical efficacy. However, when therapeutic strategies, such as thrombolysis, do not permit arterial blood sampling, quantitative determinations of CBF and CMRO2 are not feasible. In such cases relative indices, such as those for CBF, must be applied. Such qualitative assessments of perfusion, which were calibrated in an independent cohort of patients with acute stroke, were used to demonstrate the effect of early systemic treatment of acute ischaemia with recombinant tissue plasminogen activator. By applying operationally defined thresholds for tissue viability and the penumbra, and co-registering these tissue compartments to infarcted and non-infarcted tissue on late magnetic resonance imaging, the proportions of at-risk tissue salvaged from infarction could be revealed in individual patients. In the future, functional imaging modalities that could eventually include tracers for neuronal integrity could be used to select patients for thrombolytic therapy. In some instances such techniques may permit the extension of the critical time period for inclusion of patients to aggressive stroke management strategies.
 ...
PMID:Quantitative neuroimaging for the evaluation of the effect of stroke treatment. 957 23

Neuroserpin, a recently identified inhibitor of tissue-type plasminogen activator (tPA), is primarily localized to neurons within the central nervous system, where it is thought to regulate tPA activity. In the present study neuroserpin expression and its potential therapeutic benefits were examined in a rat model of stroke. Neuroserpin expression increased in neurons surrounding the ischemic core (ischemic penumbra) within 6 hours of occlusion of the middle cerebral artery and remained elevated during the first week after the ischemic insult. Injection of neuroserpin directly into the brain immediately after infarct reduced stroke volume by 64% at 72 hours compared with control animals. In untreated animals both tPA and urokinase-type plasminogen activator (uPA) activity was significantly increased within the region of infarct by 6 hours after reperfusion. Activity of tPA then decreased to control levels by 72 hours, whereas uPA activity continued to rise and was dramatically increased by 72 hours. Both tPA and uPA activity were significantly reduced in neuroserpin-treated animals. Immunohistochemical staining of basement membrane laminin with a monoclonal antibody directed toward a cryptic epitope suggested that proteolysis of the basement membrane occurred as early as 10 minutes after reperfusion and that intracerebral administration of neuroserpin significantly reduced this proteolysis. Neuroserpin also decreased apoptotic cell counts in the ischemic penumbra by more than 50%. Thus, neuroserpin may be a naturally occurring neuroprotective proteinase inhibitor, whose therapeutic administration decreases stroke volume most likely by inhibiting proteinase activity and subsequent apoptosis associated with focal cerebral ischemia/reperfusion. (Blood. 2000;96:569-576)
 ...
PMID:Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. 1088 20

Ischaemic penumbra is defined as the area of brain tissue that maintains some blood flow following ischaemic accident. This zone may be rescued by both neuroprotection and arterial revascularization. Early thrombolysis has been used with encouraging results since 1995 in several trials testing both streptokinase and recombinant tissue plasminogen activator (r-TPA): the r-TPA results are definitely more positive than those of streptokinase, despite an increased incidence of symptomatic haemorrhagic transformation, r-TPA significantly reducing death or dependency at the end of follow-up. Despite the fact that some experimental periods of application of these therapeutic strategies demonstrated real cost-effective benefits, only 1% of patients reaching hospital in time for thrombolysis are currently treated. This is because the profile of patients at risk of haemorrhagic transformation, which is definitely the most feared side-effect of thrombolysis in stroke, is yet to be clearly defined. Extended computerized tomography (CT) signs of the index stroke have been repeatedly indicated as reliable predictors of haemorrhagic transformation even if currently there are significant discrepancies in the criteria adopted by different researchers to define early CT signs. Based on experimental ischaemia, strategies for protecting the basal lamina during thrombolysis are suggested: neuroprotection is the second approach to stroke therapy; pharmacological reperfusion and brain protection are probably mutually dependent.
 ...
PMID:Treatment of cerebrovascular diseases: state of the art and perspectives. 1181 86

'Brain' attack' is a new term to describe the acute presentation of stroke which emphasises the need for urgent action. The article describes the basis for this new approach to acute stroke treatment. Rational treatment requires individual causes of stroke to be identified early and treatment targeted at the mechanism. Acute stroke treatment aims to preserve the ischaemic penumbra, protect neurons against further ischaemia and enhance brain plasticity to maximise recovery. There is a strong evidence base supporting the routine use of aspirin, but not heparin, in acute ischaemic stroke. There is also convincing evidence supporting intravenous thrombolysis using recombinant tissue plasminogen activator in selected patients within 3 hours of stroke onset. Surprisingly, as many as 33% of suspected-stroke patients arrive in Accident & Emergency departments in the UK within 3 hours of onset. New techniques in MR imaging, particularly diffusion weighted imaging, are transforming the approach to diagnosis of acute stroke. Although neuroprotective drugs have proved disappointing, active neuroprotection in acute stroke should include control of blood pressure within certain limits, antipyretic therapy, maintenance of blood glucose, and early feeding and fluid replacement. Surgical hemicraniectomy should be considered in patients with malignant cerebral oedema. There is good evidence that the best way to enhance recovery from stroke is to admit the patient to a stroke unit. To enable patients to benefit from the early active approach outlined in the article, the following are needed: the development of acute stroke units; imaging protocols; and education of patients, general practitioners and the ambulance services. Stroke care has become a specialised field, requiring input from stroke physicians, as well as the multidisciplinary rehabilitation team. The British Association of Stroke Physicians (BASP) has therefore developed a curriculum which is designed to lead to the development of a new sub-specialty of stroke medicine.
 ...
PMID:Brain attack: a new approach to stroke. 1187 41

The development of additional acute stroke therapies to complement and supplement intravenous recombinant tissue-type plasminogen activator within the first 3 hours after stroke onset remains an important and pressing need. Much has been learned about the presumed target of acute stroke therapy, the ischemic penumbra, and clinically available imaging modalities such as magnetic resonance imaging and computed tomography hold great promise for at least partially identifying this region of potentially salvageable ischemic tissue. Understanding the biology of ischemia-related cell injury has also evolved rapidly. New treatment approaches to improve outcome after focal brain ischemia will likely be derived by looking at naturally occurring adaptive mechanisms such as those related to ischemic preconditioning and hibernation. Many clinical trials previously performed with a variety of neuroprotective and thrombolytic drugs provide many lessons that will help to guide future acute stroke therapy trials and enhance the likelihood of success in future trials. Combining knowledge from these three areas provides optimism that additional acute stroke therapies can be developed to maximize beneficial functional outcome in the greatest proportion of acute stroke patients possible.
 ...
PMID:New perspectives on developing acute stroke therapy. 1250 43

Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
 ...
PMID:Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. 1498 20

Ischemic stroke is a major cause of mortality and morbidity in industrialized countries and is almost always caused by occlusion of a cerebral artery by a clot. As the reversibly injured brain tissue evolves into irreversible infarction within a short period of time after onset of ischemia, it is extremely important and urgent to reverse the serious consequences of brain ischemia in the hyperacute phase when the ischemic brain tissue is still salvageable. 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 (r-tPA) within 3 h of stroke onset in highly selected patients (approximately 5 to 10 % of all acute stroke patients). One major obstacle in the development of effective therapies for ischemic stroke has been the lack of versatile imaging techniques. New magnetic resonance imaging (MRI) modalities, specially diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) have been used in experimental studies with great success for over a decade and now are gradually entering clinical use. DWI and PWI can detect brain ischemia in the early phase in its full extent thus ensuring a definite diagnosis, allowing for follow-up of the ischemic lesion size over time with good spatial and temporal resolution, demonstrating perfusion deficit and reperfusion and the existence and the extent of penumbra while only requiring a few minutes of imaging time. DWI and PWI do not just give us the correct diagnosis of ischemic stroke, but allow us to acquire in vivo lesion size before therapeutic regimen is started and monitor the therapeutic efficacy thereafter, thus overcoming the potential pretreatment bias. We used DWI and PWI to evaluate novel therapeutic approaches for ischemic stroke in numerous experimental studies and lately in humans. With DWI and PWI, we are able to determine the in vivo efficacy (or lack of efficacy) of new therapeutic regiments (both neuroprotective and thrombolytic agents, or combination therapies) in a rapid, safe, and reliable way and in a relatively small number of well-selected, well-defined, and homogeneous patients. This approach may, therefore, significantly accelerate the development of new remedies for stroke patients.
 ...
PMID:The role of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke: from laboratory to clinics. 1532 Aug 14

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.
 ...
PMID:[Thrombolysis and acute cerebral infarction]. 1558 64

Stroke is the third most common cause of death in the United States following heart disease and cancer. Following the success of thrombolysis for myocardial infarction in the early 1990s, major trials for evaluation of this new therapeutic approach for ischemic stroke were initiated. The majority of ischemic strokes are due to occlusion of a cerebral vessel by a blood clot. Occlusion of a cerebral blood vessel leads to a core of infracted tissue surrounded by a relatively hypoperfused but viable brain tissue (the ischemic penumbra), which can be potentially salvaged by rapid recanalization of the target vessel. The underlying rationale for introduction of thrombolytic drugs is the lysis of an obliterating thrombus and reestablishment of blood flow. In this article we review the major intravenous thrombolysis trials leading to approval of intravenous recombinant tissue plasminogen activator, the only FDA approved treatment available today for acute ischemic stroke.
 ...
PMID:Hyperacute therapy of ischemic stroke: intravenous thrombolysis. 1619 55

Neuroprotection of patients with acute ischemic stroke should start at the scene and continue in the ambulance with the assessment and treatment of the airway, breathing, circulation, body temperature, and blood glucose. The key goal in eligible patients should be fast vessel recanalization with intravenous recombinant tissue-type plasminogen activator Results from a meta-analysis suggest that systemic thrombolysis is effective when given within 4.5 hours after stroke onset. The time window extends to 6 hours for patients undergoing intravascular thrombolysis. Acute stroke patients should be admitted to stroke care units. A crucial component of neuroprotection is the prevention of secondary brain damage, which can be caused by hypoxemia, hypotension, hyperthermia and hyperglycemia. This can be achieved by avoiding complications, e.g. aspiration, and intensive control of oxygenation, hydration and blood pressure, body temperature, blood glucose, and cardiac monitoring. Neuroprotective agents are designed to try to salvage brain tissue within the penumbra. Thus far, despite promising preclinical studies, clinical trials with neuroprotective drugs in acute ischemic stroke have been disappointing. However, we have been able to identify many of the factors that were responsible for these failures, and better-designed clinical trials with neuroprotective drugs should look more promising. Mild induced hypothermia is another form of neuroprotective treatment that is currently being investigated in acute stroke.
 ...
PMID:Neuroprotection in acute ischemic stroke. 1625 52


1 2 3 4 5 6 7 8 9 10 Next >>