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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of action of currently available thrombolytic agents, such as streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) and anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC), involves conversion of inactive plasminogen to plasmin, a potent fibrinolytic. However, the relatively weak substrate specificity of first generation agents (streptokinase and urokinase) can result in a state of systemic fibrinolysis and associated bleeding complications. The second generation drugs such as alteplase were developed in an attempt to enhance fibrin specificity, so that only enzymatic conversion of fibrin-complexed plasminogen would take place, thus avoiding systemic fibrinolysis. Results from large clinical trials have failed to consistently show any significant differences between first and second generation thrombolytic agents in the incidence of bleeding. In the clinical setting, thrombolytic agents have been evaluated primarily in patients with acute myocardial infarction and have been shown to significantly reduce morbidity and mortality compared with conservative treatment. The focus of current and future research is to investigate these agents in patients with other vaso-occlusive or ischaemic conditions (e.g. stroke), and also to evaluate different drug administration regimens and the use of adjunctive therapies such as aspirin (acetylsalicylic acid) and heparin.
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PMID:Evaluation of thrombolytic agents. 936 Aug 48

Neuroprotective drugs are known to reduce neurological damage in animal models of stroke, but none are generally accepted for the treatment of patients with acute stroke. Thrombolytic therapy with alteplase (recombinant tissue-type plasminogen activator; rt-PA) has been shown to improve outcomes in patients with stroke, but it must be given quite rapidly after stroke onset. The efficacy of alteplase therapy has proven that acute treatment is possible, and methods used in those trials will be applicable to neuroprotective development. A variety of neuroprotective drugs have already been tested and more trials are likely. Glutamate antagonists have been most extensively evaluated, but they are relatively disappointing since they have phencyclidine-like adverse events that limit the tolerable doses. Several other classes of neuroprotectives are in development, although their mechanisms of action are not well established. Combinations of neuroprotectives and thrombolytics are likely to be tested in clinical trials in the near future.
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PMID:Neuroprotective therapies in stroke. 936 Aug 55

Approximately 80 to 90% of cerebral ischaemic events that occur within 24 hours of symptom onset are due to atherothrombotic or thromboembolic occlusions. This forms the rationale for the use of thrombolytic agents in patients with acute ischaemic stroke. Early studies determined that recanalisation occurred in approximately 21 to 72% of patients with occluded cerebral arteries after intra-arterial or intravenous administration of streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) or duteplase (a 2-chain rt-PA). Initial reports suggested that frequencies of haemorrhagic transformation and parenchymatous haematoma in the carotid territory were similar whether patients with middle cerebral artery stroke received thrombolysis via intra-arterial or intravenous administration. The Multicentre Acute Stroke Trial-Europe (MAST-E), the Australia Streptokinase (ASK), and the Multicentre Acute Stroke Trial-Italy (MAST-I) trials, which evaluated intravenous streptokinase 1.5 x 10(6) IU in patients with acute ischaemic stroke, were terminated prematurely because of excessive early mortality and symptomatic intracranial haemorrhage in streptokinase recipients compared with those treated with placebo. However, those studies had not been preceded by dose-ranging trials. Intravenous administration of alteplase 0.9 mg/kg within 3 hours [National Institute of Neurological Disorders and Stroke (NINDS) trial], or 1.1 mg/kg within 6 hours [European Cooperative Acute Stroke Study (ECASS)], of symptom onset in patients with acute ischaemic stroke resulted in an absolute 11 to 13% treatment-associated improvement in clinical measurement scales; such as the modified Rankin scale and Barthel index, compared with placebo recipients. In the ECASS trial, those results were limited to a 'target population' restricted to those who satisfied all entry criteria. In both trials, the frequency of symptomatic haemorrhage was greater in patients treated with alteplase than with placebo and reinforced the importance of careful patient selection. Strict patient selection remains central to the success of this approach.
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PMID:Thrombolytic therapy in the treatment of stroke. 936 Aug 56

Ancrod converts fibrinogen into soluble fibrin products, resulting in a decrease in plasma fibrinogen and blood viscosity, and also induces the release of endogenous tissue-type plasminogen activator from the vessel wall. These activities suggest that treating patients with acute ischaemic stroke with ancrod might result in improved cerebral blood flow and patient outcome. Two large randomised placebo-controlled studies have evaluated treatment with ancrod in patients with acute ischaemic stroke. In the first, patients were treated within 6 hours of symptom onset: this was not successful in quickly lowering fibrinogen levels to the target range (0.7 to 1.0 g/L) and the results were inconclusive. However, a post hoc analysis suggested that treatment with ancrod was effective in patients whose fibrinogen level was reduced to less than 1.3 g/L within 6 hours of starting treatment. A second larger study is still in progress, but preliminary results in patients treated within 3 hours of onset of ischaemic stroke are available and indicate that the target fibrinogen level of less than 1 g/L within 6 hours of instituting treatment is being achieved in most patients.
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PMID:Ancrod in the treatment of acute ischaemic stroke. 936 Aug 57

Results from the two National Institute of Neurological Disorders and Stroke (NINDS) studies indicate that administration of alteplase (recombinant tissue-type plasminogen activator; rt-PA) within 3 hours of symptom onset to appropriately selected patients with acute ischaemic stroke improves patient outcome. Several factors that delay time to treatment in patients with stroke have been identified, the most important of which is probably the failure of the patient (or family member) to recognise the signs and symptoms of stroke. Once the need for help is recognised, the initial point of access to emergency medical systems should be the local emergency number (e.g. 911 in the US) rather than the family physician. Patients with suspected stroke should be evaluated and treated by a physician as soon as possible, but this will depend to some extent on the level of expertise of the attending physicians and on available resources. The NINDS-sponsored National Symposium on the Rapid Identification and Treatment of Acute Stroke has recommended ideal time goals for all hospitals that treat patients with acute stroke. These goals include 25 minutes from arrival at an emergency department to computerised tomography scan, and 60 minutes from arrival to treatment. Recommendations for enhancing the logistics of treatment for patients with stroke may involve the following: improved education programmes for at-risk populations and their families and emergency medical system personnel, identification of acute stroke as a level one emergency similar to acute myocardial infarction or trauma, and modelling of treatment algorithms accordingly, acceptance of, and commitment to, the time guidelines recommended by the National Symposium on the Rapid Identification and Treatment of Acute Stroke. Effective and safe use of alteplase will also depend on rapid access to the highest level of neurological and radiological expertise. This may require major changes in the educational curriculum of emergency department residency and ongoing continuing education programmes, and/or more intensive radiological training for neurologists and neurologists-in-training.
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PMID:Logistics in acute stroke management. 936 Aug 58

The use of outcome markers other than mortality reduction alone for evaluating thrombolytic agents in patients with acute myocardial infarction (AMI) is discussed. Mortality has been a primary endpoint in clinical trials evaluating thrombolytic agents for treatment of AMI. However, differences in mortality rates among thrombolytics are 1% or less and require tens of thousands of patients to detect. Broadening the endpoints studied will allow for more extensive data collection and more comprehensive cost-effectiveness analysis, enabling clinicians to make better decisions. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial measured not only mortality but issues related to the patency of the infarct-related artery and complications. Other potentially important outcome markers after AMI are left ventricular function; markers of reperfusion, such as early resolution of ST-segment elevation; and resolution of chest pain. Available long-term data show that the mortality benefit from alteplase is sustained over time and is correlated with enzymatically determined infarct size, left ventricular function, the number of diseased vessels, and Thrombolysis in Myocardial Infarction flow grade at the time of discharge from the hospital. Clinicians must also consider risk factors for stroke. Outcome measures other than mortality alone may help in determining which thrombolytic agent is most effective clinically and in financial decision-making without requiring large, expensive trials.
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PMID:Clinical trials in thrombolytic therapy, Part 1: Outcome markers that go beyond mortality reduction. 939 34

We studied the effects of rt-PA (recombinant tissue type-plasminogen activator) treatment on the blood-brain barrier (BBB) after thromboembolic stroke in rat. New MRI methods of diffusion and perfusion imaging to observe the hemodynamic and biophysical effects of thrombolysis were combined with methods for assessment of BBB disturbances. In untreated animals clot embolism produced a rapid drop in MRI perfusion values and the ADC (apparent diffusion coefficient), with subsequent infarction. BBB disturbances, visualised as extravasation of serum proteins on cryostat sections, were manifest in nearly all animals in the borderzone of infarcts. In animals treated with rt-PA 15 min after clot embolism thrombolysis resulted in reperfusion of affected brain regions with subsequent improvement of ADC values. Final lesion size on ADC maps was reduced by 36% relative to untreated animals. However, BBB disturbances were not improved after treatment. To the contrary, rt-PA treated animals showed further regions with serum protein extravasation in the infarcted territories and in distant non-ischemic brain regions. MR imaging with the BBB tracer GdDTPA showed more pronounced and widespread contrast enhancement in the rt-PA treated than in the untreated group. Increased blood-brain barrier disturbances have to be taken into account even when thrombolytic therapy is started very early after the onset of stroke.
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PMID:Blood-brain barrier disturbances after rt-PA treatment of thromboembolic stroke in the rat. 941 23

Despite the increased risk of intracranial haemorrhage associated with the use of thrombolytic treatment of stroke. American studies have shown patients treated with rt-PA (recombinant plasminogen activator) within three hours of the onset of symptoms to manifest 30 per cent less disability at three-month follow-up than those placebo. However, until satisfactory criteria for the use of rt-PA are available, caution is essential, and thrombolytic therapy should be restricted to specialised centres. It is also important to promote public awareness of the stroke patient's need of immediate treatment at a specialised stroke unit.
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PMID:[Thrombolytic therapy in stroke. What do clinical tests prove?]. 942 2

Traditional risk factors, e.g. hyperlipidemia, cigarette consumption, blood pressure, family history, and diabetes, predict < 50% of all future cardiovascular events. This paper reviews the use of novel hemostatic and thrombotic markers, such as intrinsic fibrinolysis and systemic micro-inflammation, for the prediction of the risk of arterial thrombotic disease. It has been hypothesized that relative abnormalities in the hemostatic and thrombotic systems are common on a population basis, and that they predispose certain individuals to clinically pathologic thrombosis. Abnormal levels of fibrinolytic parameters have been shown to predict future cardiovascular events, and tissue-type plasminogen activator antigen appears to be the most useful of these markers. Low-grade chronic inflammation may play an important role in atherogenesis. Of the newer inflammatory parameters, C-reactive protein has been the best studied and evidence suggests that elevated levels of C-reactive protein can predict the future risk of both myocardial infarction and stroke, both in healthy individuals and in patients with known coronary artery disease. Results from clinical trials to evaluate whether modification of novel risk factors results in a net clinical benefit are limited at present. However, novel markers will probably provide new directions in both thrombosis research and disease prevention.
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PMID:Intrinsic fibrinolytic capacity and systemic inflammation: novel risk factors for arterial thrombotic disease. 943 52

Fibrinolytic therapy substantially reduces mortality from acute myocardial infarction. Patient selection is, however, important. The patient must present within 12 hours of the onset of ischaemic symptoms, have definite ECG changes of ST elevation or left bundle branch block and no contraindications. The major contraindications are those for risk of an intracerebral bleed, recent stroke, intracranial tumour or risk of a major systemic bleed. Age and hypertension are not contraindications but may modify the regimen used. Heparin is required with recombinant tissue plasminogen activator but is optional with streptokinase. The recent COBALT trial suggests that the accelerated weight related t-PA regimen given over 90 minutes is more satisfactory than double bolus t-PA. However, in patients under 75 years of age, the two regimens were equivalent. For patients suffering acute myocardial infarction, practitioners should now individualise choice of therapy, rather than give the same cocktail to all patients. The choice of regimen will depend on the cardiac risk, the stroke risk, the bleeding risk and the cost.
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PMID:The current status of thrombolytic therapy. 944 5


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