Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article discusses the impact of previous clinical observations on the development of the GUSTO-I protocol, particularly the absence of a survival benefit of alteplase (rt-PA) over streptokinase in the GISSI-2/International Study Group and ISIS-3 trials in spite of a higher efficacy for clot lysis. The demonstrated superiority of front-loaded alteplase in this large trial is translated into useful guidelines for the practising clinician. Risk-benefit analysis indicates that, in general, this thrombolytic regimen is most indicated in patients presenting with large amounts of jeopardized ischaemic myocardium in the absence of a particularly increased risk of haemorrhagic stroke. Finally, the impact of this study for future development in the field of acute coronary syndromes is evaluated, more specifically for the design of new trials with new fibrinolytic and antithrombotic agents. These include mutants of alteplase, staphylokinase, direct antithrombins and inhibitors of the glycoprotein IIb/IIIa platelet receptor.
 ...
PMID:Implications of the GUSTO trial for thrombolytic therapy. 887 25

Although antiplatelet and anticoagulant drugs are of proven usefulness in the prevention of stroke among high-risk persons, their value in improving outcome after acute ischemic stroke has not been established. Potentially effective drugs include heparin, low molecular weight heparins and heparinoids, aspirin, and the new glycoprotein IIb/IIIa platelet receptor antagonists. Clinical trials are testing these drugs, and the role of emergent administration of anticoagulant or antiplatelet drugs in the acute treatment of persons with ischemic stroke should be clarified in the near future.
 ...
PMID:Brain attack. Acute therapeutic intervention. Antithrombotic and antiplatelet-aggregating drugs. 911 2

Thrombolytic therapy has been a major advance in the management of acute myocardial infarction. Unfortunately, it continues to be underused or is administered later than is optimal. Thrombolytic therapy works by lysing infarct artery thrombi and achieving reperfusion, thereby reducing infarct size, preserving left ventricular function, and improving survival. The most effective thrombolytic regimens achieve angiographic epicardial infarct-artery patency in only approximately 50% of patients within 90 minutes. Bleeding requiring transfusion occurs in approximately 5% of patients and stroke in approximately 1.8% with these regimens, which include adjunctive aspirin and intravenous heparin. There are several ways in which reperfusion rates and thus patient outcomes might be improved, such as different dosing regimens of established agents; combinations of different agents; improved adjunctive therapy such as direct antithrombin agents, low-molecular-weight heparin, or glycoprotein IIb/IIIa receptor antagonists; or the development of novel thrombolytic agents with enhanced fibrin specificity, resistance to native inhibitors, or prolonged half-lives allowing bolus administration. All of these strategies are being tested in clinical trials. The best approach currently is to administer thrombolytic therapy as soon as possible to all patients without contraindications who present within 12 hours of symptom onset and have ST-segment elevation on the ECG or new-onset left bundle-branch block, unless an alternative reperfusion strategy is planned.
 ...
PMID:Thrombolysis for acute myocardial infarction. 959 69

Treatment options in acute stroke are limited by a dearth of safe and effective regimens for recanalization of an occluded cerebrovascular tributary, as well as by the fact that patients present only after the occlusive event is established. We hypothesized that even if the site of major arterial occlusion is recanalized after stroke, microvascular thrombosis continues to occur at distal sites, reducing postischemic flow and contributing to ongoing neuronal death. To test this hypothesis, and to show that microvascular thrombosis occurs as an ongoing, dynamic process after the onset of stroke, we tested the effects of a potent antiplatelet agent given both before and after the onset of middle cerebral arterial (MCA) occlusion in a murine model of stroke. After 45 min of MCA occlusion and 23 h of reperfusion, fibrin accumulates in the ipsilateral cerebral hemisphere, based upon immunoblotting, and localizes to microvascular lumena, based upon immunostaining. In concordance with these data, there is a nearly threefold increase in the ipsilateral accumulation of 111In-labeled platelets in mice subjected to stroke compared with mice not subjected to stroke. When a novel inhibitor of the glycoprotein IIb/IIIa receptor (SDZ GPI 562) was administered immediately before MCA occlusion, platelet accumulation was reduced 48%, and fibrin accumulation was reduced by 47% by immunoblot densitometry. GPI 562 exhibited a dose-dependent reduction of cerebral infarct volumes measured by triphenyltetrazolium chloride staining, as well as improvement in postischemic cerebral blood flow, measured by laser doppler. GPI 562 caused a dose-dependent increase in tail vein bleeding time, but intracerebral hemorrhage (ICH) was not significantly increased at therapeutic doses; however, there was an increase in ICH at the highest doses tested. When given immediately after withdrawal of the MCA occluding suture, GPI 562 was shown to reduce cerebral infarct volumes by 70%. These data support the hypothesis that in ischemic regions of brain, microvascular thrombi continue to accumulate even after recanalization of the MCA, contributing to postischemic hypoperfusion and ongoing neuronal damage.
 ...
PMID:Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. 976 22

The mechanisms of action of currently available and newer antiplatelet agents and evidence of the efficacy of antiplatelet agents for primary and secondary prevention of coronary artery disease are reviewed. Available data do not support the widespread use of aspirin for primary prevention of cardiovascular disease. Patients over the age of 50 years with at least one additional risk factor for coronary artery disease may benefit, although possibly at an increased risk of hemorrhagic stroke. Aspirin is recommended for secondary prevention of vascular disease in patients with stable or unstable angina, clinical or laboratory evidence of coronary artery disease, history of myocardial infarction, or history of stroke or transient ischemic attack. There are no data supporting a role for dipyridamole for primary or secondary prevention of ischemic heart disease. Abciximab has been shown to reduce the risk of cardiovascular complications at 30 days after percutaneous transluminal coronary angioplasty in patients with refractory unstable angina. Studies with other glycoprotein IIb/IIIa-receptor antagonists, including eptifibatide, tirofiban, and lamifiban, have yielded promising results. Ticlopidine may be used for secondary prevention of cardiovascular disease in patients with unstable angina who are allergic to or intolerant of aspirin. Clopidogrel has been shown to be safe and effective for secondary prevention of vascular events. Aspirin has a role in secondary prevention of coronary artery disease; among patients who are allergic to or intolerant of aspirin, ticlopidine has a role in patients with unstable angina and clopidogrel has a potential role in patients with ischemic heart or vascular disease.
 ...
PMID:Antiplatelet therapy in coronary artery disease: review and update of efficacy studies. 978 97

The role of the platelet and the endothelium in the pathogenesis of atherosclerosis and subsequent ischemic events has been the subject of extensive investigation. Arterial sites where endothelial function is severely impaired are often the sites of atheroma development. Lesion evolution impairs endothelial function, leading to a self-perpetuating cycle of growth. During early lesion development, overt thrombotic events are rare. However, rupture of an advanced, necrotic plaque or intimal ulceration triggers arterial thrombosis, at which point the importance of platelet function may be seen clearly. The Antiplatelet Trialists' Collaboration meta-analysis demonstrated the benefit of antiplatelet therapy to patients with atherosclerotic disease. Aspirin is the most widely studied agent and is considered the standard of antiplatelet therapy. Newer agents that intervene at different stages of the platelet activation pathway have been developed. Clopidogrel, a new adenosine diphosphate receptor antagonist, is more effective than aspirin in reducing vascular events in patients with prior myocardial infarction, stroke, or established peripheral arterial disease. The glycoprotein IIb-IIIa antagonists such as abciximab have proven effective in the setting of active arterial thrombosis and percutaneous revascularization, but their value in secondary prevention remains unknown. All patients with atherosclerosis should be treated with an antiplatelet drug. Current evidence suggests that either aspirin or clopidogrel are appropriate first-line agents. There is urgent need for an analysis of the risk/benefit ratio in various populations and clinical settings to determine the most appropriate type and intensity of therapy for a given patient.
 ...
PMID:Platelet-endothelial interactions in atherothrombotic disease: therapeutic implications. 1055 82

Acute stroke is a neurologic emergency which should be preferentially treated in a Stroke Unit. The applications of general therapeutic measures in these units decreases the mortality or dependence in 29% of the cases. Thrombolytic treatment with rt-PA in the first 3 hours of cerebral ischemia reduces the risk of mortality or dependence at 3 months by 51%. This treatment should be used in centers with an adequate organization and experience in the management of stroke. Careful patient selection allows a favorable conscious risk/benefit when rt-PA is used in clinical practice. In the last decade numerous neuroprotector drugs have been developed which, despite decreasing the volume of the infarction in animal models, have not currently achieved a reduction in the mortality and morbidity of cerebral infarction in clinical trials. Ebselen, citicoline, piracetam and clomethiazol have shown beneficial effects in preliminary studies or in some subgroups of patients, but their use based on evidence is not recommendable. Anticoagulants and antiplatelet drugs have not been shown to be effective in the acute phase of cerebral infarction. The neuroprotector effect of unfractionated heparin and glycoprotein IIb IIIa antagonists is still under study. Clopidogrel and the association of aspirin and dipiridamol are new alternatives to aspirin in the secondary prevention of cerebral infarction. Both options provide a lower risk of recurrence, and clopidogrel also shows better tolerance. The preventive effect of low intensity anticoagulation and statins is being analyzed in clinical studies.
 ...
PMID:[New treatments in cerebrovascular diseases]. 1065 7

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activities will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.
 ...
PMID:Stroke: antithrombin versus antiplatelet therapy. 1106 Jun 82

Platelets play a major role in thrombus formation, as well as in the pathogenesis of atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all vascular diseases, since thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicylic acid (aspirin) has been shown to reduce the incidence of myocardial infarction and stroke, its effect is weak and more effective antithrombotic agents are required to manage patients at high-risk for recurrent vascular events. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen and von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and secondary prevention of thrombosis as chronic treatment, especially in high-risk patients. Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic attack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a worldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/IIIa receptor to avoid vascular occlusion) is currently underway. In general, GPIIb/IIIa blockade seems clinically very promising. A number of unresolved issues, however, remain to be elucidated.
 ...
PMID:Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker. 1106 Aug 29

We provide an overview of recent developments in carotid interventional technique and equipment, including new stents and emboli protection devices. The newer self-expanding stents lessen the problem of external stent compression associated with balloon expandable stents, but precise deployment and the matching (by length) of stents to lesions remain problematic. We also discuss emerging pharmacologic strategies for cerebral protection in stroke. Multiple randomized clinical trials and multicenter registries are under way to compare percutaneous with surgical strategies for the treatment of carotid stenosis. These include the evaluation of emboli protection devices, and, to a lesser degree, intravenous glycoprotein IIb/IIIa antagonists. Other clinical trials are aimed towards refining the ability to stratify patients by risk, in order to identify the subsets that would benefit most from these complex and expensive procedures.
 ...
PMID:New developments in endovascular interventions for extracranial carotid stenosis. 1109 12


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