Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Platelets play an important role in the pathophysiology of acute myocardial infarction, unstable angina, and ischemic stroke. The expression of the glycoprotein IIb/IIIa (alphaIIb/beta3 integrin) receptor on the surface of activated platelets constitutes the common pathway for platelet aggregation. Glycoprotein IIb/IIIa has low affinity for its soluble ligands (fibrinogen and von Willebrand factor) in resting platelets. In the setting of vascular injury, platelet activation occurs after binding of the glycoprotein Ib-IX-V receptor to von Willebrand factor in the extracellular matrix (at high shear rate) and binding of soluble agonists to specific platelet membrane receptors. The ensuing inside-out signaling increases several-fold the affinity and avidity of alphaIIb/beta3 for its ligands. High affinity ligand binding to alphaIIb/beta3 triggers outside-in signaling, causing microskeletal contraction and platelet retraction. The signaling pathways for inside-out and outside-in signaling are incompletely understood. Glycoprotein IIb/IIIa antagonists were developed under the premise that these agents would abrogate platelet aggregation while preserving platelet monolayer deposition at sites of injury. A number of parenteral and oral agents have been developed and evaluated in clinical trials. Three of them are approved in the United States and other countries: abciximab (ReoPro; the Fab fragment of a chimeric human-mouse antibody), eptifibatide (Integrelin; a cyclic heptapeptide), and tirofiban (Aggrastat; a tyrosine-derived nonpeptide molecule). The greatest clinical impact of these parenteral agents (used in conjunction with aspirin and heparin) has been in the prevention of ischemic complications after percutaneous coronary intervention. In contrast, oral agents have yielded disappointing results in the secondary prevention of acute coronary syndromes, and none of them are approved at present. Eptifibatide and tirofiban are specific for alphaIIb/beta3, whereas abciximab also exhibits cross-reactivity with the alphavbeta3 and alphaMbeta2 integrins. Although alphaIIb/beta3 is unique to platelets and megakaryocytes, alphavbeta3 is more widely distributed and mediates several functions, including endothelial cell migration, monocyte adhesion, angiogenesis, and inhibition of apoptosis. alphaMbeta2 mediates leukocyte-platelet interactions. In the percutaneous coronary intervention trials, abciximab has been more efficacious than the other parenteral agents, perhaps because of cross-reactivity with these other integrins, the pharmacodynamic profile of abciximab, or other effects. Other documented effects of abciximab include acute dethrombosis, reduction of thrombin generation, and improved flow in the coronary microcirculation after percutaneous coronary intervention. Abciximab is presently under evaluation in the treatment of acute ischemic stroke. Promising data have been obtained in experimental models of tumor angiogenesis and sickle cell anemia.
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PMID:Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. 1200 56

Acute myocardial infarction results from thrombotic occlusion superimposed on a ruptured athersoclerotic plaque. Immediate restoration of normal flow in the infarct-related artery can be achieved either with fibrinolytic or with direct mechanical revascularization. Primary PTCA has been shown to be superior to fibrinolytic therapy with respect to mortality, reinfarction, non-fatal stroke and length of hospitalization. Its results can be further improved by the addition of potent platelet inhibitors directed against the final common component of all stimuli for platelet aggregation, the glycoprotein (GP) IIb/IIIa receptor. In randomized clinical trials, primary angioplasty with adjunctive abciximab - a monoclonal antibody against the GP IIb/IIIa - was better than conventional primary angioplasty with heparin only. Abciximab use was associated with a significant reduction in reinfarction, need for urgent target vessel revascularization, microcirculatory dysfunction and regional left ventricular dysfunction as well as with a strong trend towards a reduction in mortality, even in patients receiving coronary stents.
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PMID:Platelet glycoprotein IIb/IIIa receptor inhibition in primary angioplasty for acute myocardial infarction: The new paradigm of direct revascularization. 1243 34

The benefit of antiplatelet therapy remains unclear, although it does appear that aspirin monotherapy started within 48 hours of stroke onset may result in a modest clinical improvement. Glicoprotein (GP) IIb/IIIa antagonists are currently considered the most powerful specific inhibitors of platelet activation in acute thrombosis. Glicoprotein IIb/IIIa inhibitor therapy could merit a prominent role also in the initial management of patients with acute ischemic stroke. Abciximab may be promising in this setting and should be evaluated in further clinical trials.
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PMID:Glicoprotein (GP) IIb/IIIa inhibitors for acute stroke treatment. 1245 Feb 35

In the area of myocardial infarction one is reminded of the publication of the CADILLAC study which has reopened the debate on the systematic use of GpIIbIIIa inhibitors in the acute phase of myocardial infarction complementing primary angioplasty with the placement of an endoprosthesis. New modalities for thrombolysis are in the course of evaluation, notably Eptibaphide Alteplase combination in the INTRO-AMI study and Tenecteplase Abciximab in association with enoxaparine or non-fractionated heparin in the TIMI 23 study. Several studies comparing angioplasty to lysis have been published. STOPAMI 2 evaluated myocardial salvage in the framework of primary angioplasty with placement of an endoprosthesis combined with abciximab infusion in comparison with half dose fibrinolysis associated with abciximab. CAPTIM is a strategy evaluation comparing the results of pre-hospital fibrinolysis with primary angioplasty. With the RITA 3 study the interventional approach definitely comes top in comparison with a conservative approach for the treatment of unstable angina. One is equally reminded of the changes in the ACC/AHA recommendations for the management of unstable angina. The debate continues on the indications for thrombolysis in submassive pulmonary embolus. In the therapeutic area, one is reminded of the update on the interactions between angiotensin converting enzymes and aspirin in treatment and long term coronary syndrome. Finally, at the end of 2001, the work of French teams was published concerning the evaluation of risk of relapse for cerebral vascular accident in the presence of a foramen ovale or an aneurysm of the inter-atrial septum.
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PMID:[The best of thrombosis in 2002]. 1261 65

Early complications may hamper efforts to hasten discharge after primary percutaneous coronary intervention (PCI) for myocardial infarction (MI). Glycoprotein IIb/IIIa inhibitors, by reducing early recurrent ischemia, may aid in these efforts. We examined whether adjunctive abciximab could accelerate discharge and reduce costs within a trial of primary PCI after acute MI. The CADILLAC trial randomized 2,082 patients with MI to 1 of 4 reperfusion strategies in a 2 x 2 factorial design: angioplasty, angioplasty with abciximab, stent implantation, or stenting with abciximab. Patients randomized to abciximab had postprocedural heparin withheld, and discharge scheduled for days 1.5 to 2 (low-risk patients) or days 2 to 3 (high-risk patients) after MI if they were stable. Other patients were discharged at the physician's discretion. Abciximab treatment was associated with significant reductions in the primary end points of in-hospital death, reinfarction, ischemic target vessel revascularization (TVR), or disabling stroke (5.6% vs 2.7%, p = 0.003)--largely reflecting reduced ischemic TVR (3.8% vs 1.4%, p = 0.002)--and in early subacute thrombosis (1.3% vs 0.2%, p = 0.01). Hospitalization was significantly shorter in abciximab-treated patients (median 3.1 vs 3.5 days, p <0.001), but total in-hospital costs did not differ significantly (13,413 +/- 5,309 US dollars vs 13,000 +/- 6,006 US dollars, p = 0.13). Rates of the composite end point did not differ significantly during the week after discharge (0.8% vs 0.2%, p = 0.10), nor did component event rates. Abciximab during primary PCI is associated with fewer early adverse outcomes, likely contributing to offset its cost. Hospitalizations after primary PCI are so short, however, that efforts to accelerate discharge with abciximab appear unfeasible, and overall costs remain unchanged.
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PMID:Feasibility and implications of an early discharge strategy after percutaneous intervention with abciximab in acute myocardial infarction (the CADILLAC Trial). 1451 75

A thrombus occluding a brain artery is the leading mechanism underlying ischemic stroke. In the light of this pathophysiology, antithrombotic therapies have been among the most widely studied and used in the management of patients with ischemic stroke. Aspirin has a significant but modest benefit by reducing recurrent ischemic stroke and death given within 48 h of stroke onset. The use of anticoagulants including heparin, low molecular weight heparin, and heparinoids has not been supported by results of randomized clinical trials. Any reductions in ischemic stroke recurrence were offset by an increase in major bleeding. However, acute anticoagulation is widely used in specific disorders, including patients with high-risk cardiac sources of embolus, arterial dissection, venous sinus thrombosis, and hypercoagulable states. Early recurrent ischemic strokes in patients with atrial fibrillation and acute ischemic stroke have not been shown to be reduced with the heparins, when the effects of major bleeding and hemorrhagic worsening are considered. Recent clinical trials have suggested that other antithrombotic agents may be beneficial in acute ischemic stroke. Two such agents are ancrod and abciximab. Abciximab is currently being investigated in a large randomized clinical trial.
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PMID:Antithrombotic and hypofibrinogenetic therapy in acute ischemic stroke: what is the next step? 1469 91

The only drug approved by the US FDA for use in patients with acute ischemic stroke is the thrombolytic, alteplase. Whereas alteplase rapidly restores blood flow, the drug has to be administered within 6 hours after symptom onset and is associated with an increased incidence of intracerebral hemorrhage (ICH). Moreover, transient and permanent re-occlusions associated with increased mortality continue to occur after thrombolysis with alteplase. Platelets are believed to play a pivotal role in the pathogenesis of atherothrombosis and the binding of the platelet glycoprotein (GP) IIb/IIIa receptor to fibrinogen is the final common pathway leading to platelet aggregation and thrombus formation. Antiplatelet agents such as platelet GP IIb/IIIa receptor antagonists have been studied in numerous multicenter, randomized clinical trials in patients with acute coronary symptoms (ACS). The intravenous GP IIb/IIIa receptor antagonists abciximab, eptifibatide and tirofiban are approved by the FDA for use in patients with ACS, and intravenous tirofiban is also approved for use during coronary intervention. Oral GP IIb/IIIa receptor antagonists such as lotrafiban, xemilofiban, sibrafiban and orbofiban have failed to provide myocardial protection in patients with ACS. Compared with ACS, few trials have evaluated the efficacy and tolerability of platelet GP IIb/IIIa receptor antagonists in patients with cerebrovascular syndromes. Agents such as SM-20302, TP201, ME3277, murine 7E3 F(ab')(2 )and SDZ-GPI 562 have been reported to preserve microvascular patency in different animal models of acute ischemic stroke and they may have neuroprotective properties. Platelet GP IIb/IIIa receptor antagonists may be suitable as a single therapeutic or as an adjunct therapeutic to thrombolysis with alteplase for the treatment of stroke. Platelet GP IIb/IIIa receptor antagonists may enhance the efficacy of thrombolytics and reduce potentially fatal adverse effects such as ICH. Preliminary results from the Abciximab in Emergent Stroke Treatment Trial (AbESTT) indicate that abciximab, administered as a bolus dose 0.25 mg/kg followed by 12-hour infusion, was associated with significant improvement in clinical rating scores and no significant increase in bleeding episodes in patients with acute stroke. The tolerability of argatroban in patients with acute stroke is currently being assessed in the multicenter Argatroban in Ischemic Stroke (ARGIS-1) trial.
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PMID:Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in the management of ischemic stroke. 1472 35

Platelet aggregation plays an important role in pathological situations such as myocardial infarction, unstable angina, peripheral artery disease, and stroke. Thus, pharmacological agents that specifically inhibit platelet aggregation are of great interest in the treatment and prevention of these cardiovascular diseases. Since binding of activated glycoprotein IIb/IIIa complex, a platelet surface integrin, to fibrinogen is the final step leading to platelet aggregation regardless of the initial stimulus, many researches have focused on the development of drugs that could antagonize this integrin. Three intravenous glycoprotein IIb/IIIa antagonists are currently marketed for the prevention of myocardial infarction in patients undergoing percutaneous intervention: Abciximab, Eptifibatide and Tirofiban. To further test the clinical efficacy of these agents, oral glycoprotein IIb/IIIa antagonists have been developed but only led to disappointing clinical results. Nevertheless, due to recognized usefulness of oral agents for the prevention and treatment of cardiovascular diseases, a great number of new orally active compounds are under clinical or preclinical evaluation. The aim of this review is to describe the chemical, pharmacological and clinical properties of existing and forthcoming glycoprotein IIb/IIIa antagonists.
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PMID:Progress in the field of GPIIb/IIIa antagonists. 1532 Jul 98

Platelets play a central role in maintaining biological hemostasis. Inappropriate platelet activation is responsible for thrombotic diseases such as myocardial infarction and stroke. Therefore, novel agents that can inhibit platelet activation are necessary. However, assays that monitor platelet aggregation are generally time-consuming and require high volumes of blood and specialized equipment. Therefore, a medium- to high-throughput assay that can monitor platelet aggregation would be considered useful. Such an assay should be sensitive, comparable to the "gold standard" assay of platelet aggregometry, and able to monitor multiple samples simultaneously but with low assay volumes. We have developed such a microtiter assay. It can assay an average of 60 independent treatments per 60 ml blood donation and demonstrates greater sensitivity than the current gold standard assay, namely platelet aggregation in stirring conditions in a platelet aggregometer. The microtiter plate (MTP) assay can detect known inhibitors of platelet function such as indomethacin, aspirin, and ReoPro. It is highly reproducible when using standard doses of agonists such as thrombin receptor-activating peptide (20 microM) and collagen (0.19 mg/ml). Finally, the MTP assay is rapid and sensitive and can detect unknown platelet-modulating agents from a library of compounds.
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PMID:Monitoring modulators of platelet aggregation in a microtiter plate assay. 1692 64

Coronary syndromes, stroke and other ischaemic arterial diseases are the leading cause of death in the world and will probably remain it at least until 2020. Cardiovascular diseases kill 17 million people each year with an expected increase to 20 million in 2020 and 24 million in 2030. The global impact of recurrence and death during the 6 months following an acute coronary syndrome remains at 8-15% in the present state of medical practice. Acute ischaemic syndromes have a common aetiology that is the formation of a platelet-rich clot at the site of severe coronary stenosis and of eroded atherosclerotic plaques. Therapy consists of medical treatments associating thrombolysis, antiplatelet drugs, and the re-opening of the coronary artery by angioplasty. But these treatments do not prevent morbidity and mortality reaching 15% at 6 months. Finally the treatment of stroke is very limited. There is thus a real clinical need to improve existing treatments and to discover new molecules. Platelet activation is a critical step in ischaemic cardiovascular diseases. This is the reason why antiplatelet drugs are most often prescribed in these cases. Currently, only one recombinant antithrombotic antibody is used in therapy. This is a chimeric Fab, c7E3 or abciximab, which inhibits the final phase of platelet aggregation. Abciximab is prescribed in acute coronary syndromes treated by angioplasty. However, treatment by abciximab can induce severe complications, principally, hemorrages and thrombopenia. Other platelet receptors involved in the earlier steps of platelet activation, such as the phases of contact with and of activation by the subendothelium matrix, have been identified as potential targets for the development of antithrombotic antibodies and are described in this revue.
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PMID:[Antithrombotic recombinant antibodies]. 1765 72


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