Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of receptor function of platelet membrane glycoprotein (GP) IIb-IIIa leads to the binding of fibrinogen and is the final common pathway to platelet aggregation. Platelet aggregates provide the structural basis for coronary thrombosis, a major cause of ischemic heart disease. GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and their progenitors, and inhibition of its receptor function has emerged as a promising new therapeutic strategy for management of acute ischemic coronary syndromes and acute ischemic complications of percutaneous coronary interventions. Eptifibatide (INTEGRILIN) is a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharmacophore that is derived from the structure of barbourin, a GP IIb-IIIa inhibitor from the venom of the southeastern pigmy rattlesnake. Like barbourin, eptifibatide is a specific and robust inhibitor of the GP IIb-IIIa receptor function, having a low affinity for other integrins and strongly preventing platelet aggregation. Preclinical pharmacologic studies have established that eptifibatide can inhibit thrombosis effectively, with only modest effects on bleeding time measurements. Pharmacokinetic and pharmacodynamic studies in both animal models and humans have shown that the antiplatelet effect of eptifibatide has a rapid onset of action and that the drug has a short plasma half-life. Furthermore, the rapid reversibility of action of eptifibatide, exemplified by an antihemostatic effect limited to the period of drug administration, was apparent in both healthy volunteers and patients with ischemic heart disease. In clinical trials, eptifibatide has not been found to be immunogenic or to induce thrombocytopenia. These studies have led to the evaluation of eptifibatide in the pivotal Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial, which enrolled 4,010 patients undergoing coronary angioplasty. The combination of a bolus plus either of 2 infusion doses of eptifibatide reduced the incidence of ischemic complications without increasing the risk of bleeding or other complications. Recent pharmacodynamic studies have established that more aggressive dosing of eptifibatide provides greater inhibition of ex vivo platelet aggregation and more robust antithrombotic activity. Higher doses of eptifibatide were therefore selected for the Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, which enrolled patients with unstable angina or non-Q-wave myocardial infarction. The available data suggest that eptifibatide may represent a useful clinical alternative to existing antiplatelet therapies.
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PMID:Clinical pharmacology of eptifibatide. 929 Dec 41

Formation of platelet-rich thrombus superimposed on ruptured atherosclerotic plaque has been implicated in the development of myocardial ischemia and its clinical manifestations. The platelet glycoprotein (GP) IIb-IIIa receptor is the final common pathway leading to platelet aggregation and thrombus formation. GP IIb-IIIa is therefore a logical therapeutic target for management of acute ischemic coronary syndromes and prevention of the ischemic complications of percutaneous coronary procedures. Of the pharmaceutical agents under development, the chimeric monoclonal antibody abciximab (ReoPro) and the cyclic peptide eptifibatide (INTEGRILIN) are the most studied. IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis), the phase III evaluation of eptifibatide in patients undergoing percutaneous coronary intervention, demonstrated the effectiveness and safety of this GP IIb-IIIa receptor inhibitor in reducing the acute adverse outcomes of invasive management of ischemic heart disease. GP IIb-IIIa receptor blockade provides an effective strategy for prevention of ischemic complications related to angioplasty in patients with coronary artery disease.
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PMID:Impact of eptifibatide on early ischemic events in acute ischemic coronary syndromes: a review of the IMPACT II trial. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis. 929 Dec 42

Platelet-mediated coronary thrombosis is the primary pathophysiologic mechanism of acute coronary syndromes (ACS) and acute ischemic complications of percutaneous coronary intervention (PCI). The final common pathway of platelet aggregation that leads to thrombotic occlusion of coronary arteries involves cross-linking of receptor glycoprotein (GP) IIb-IIIa on adjacent platelets by adhesive plasma proteins, primarily fibrinogen. Clinical trials of several GP IIb-IIIa inhibitors have demonstrated an unequivocal clinical benefit of this potent antithrombotic therapy in patients with ACS as well as in those undergoing PCI. Nevertheless, a significant number of patients with ischemic heart disease may still be expected to require elective or emergency coronary artery bypass graft (CABG) after treatment with GP IIb-IIIa inhibitors. In the emergency CABG setting, complications and platelet blockade with GP IIb-IIIa inhibitors may further enhance the already heightened risk of bleeding as compared with elective procedures. This issue became apparent in the first large clinical trial of the GP IIb-IIIa inhibitor abciximab (c7E3 Fab, ReoPro((R)); Centocor, Malvern, Pa, and Eli Lilly and Co, Indianapolis, Ind) in patients undergoing high-risk PCI. In this study, mortality rates and bleeding complications were increased among patients undergoing emergency CABG after treatment with a bolus plus infusion of abciximab. Subsequent clinical experience also suggests that the potential for bleeding complications related to emergency CABG may be increased in patients treated with abciximab, particularly if the drug is discontinued within 6 hours of the operation. Higher bleeding risk with abciximab is a result of its prolonged antiplatelet effect, which is in contrast to the readily reversible platelet blockade provided by more recently developed small-molecule GP IIb-IIIa inhibitors such as the peptide eptifibatide (Integrilin((R)); COR Therapeutics, South San Francisco, Calif, and Key Pharmaceuticals, Kenilworth, NJ) and the nonpeptide tirofiban HCl (MK-383, Aggrastat((R)); Merck & Co, Whitehouse Station, NJ). Therefore, among patients requiring CABG after treatment with GP IIb-IIIa inhibitors, eptifibatide and tirofiban may be associated with fewer bleeding episodes than is abciximab. With recent approval of eptifibatide for patients with ACS and those scheduled for PCI and of tirofiban for patients with ACS, the number of patients receiving GP IIb-IIIa inhibitor therapy who subsequently undergo CABG is expected to increase significantly. Strategies for improved management of bleeding complications in these patients, including the choice of a GP IIb-IIIa inhibitor, are clearly needed and are discussed in detail.
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PMID:Safety of glycoprotein IIb-IIIa inhibitors: A heart surgeon's perspective. 1050 36

Coronary thrombosis is a pivotal event in the pathogenesis of acute coronary syndromes and ischemic complications resulting from coronary intervention. Activation of the platelet glycoprotein (GP) IIb/IIIa receptor is the final common pathway leading to platelet aggregation, coronary thrombus formation, and myocardial ischemia. Inhibitors of platelet GP IIb/IIIa are potent agents to prevent progression to myocardial infarction and death. We prospectively surveyed the indications, frequency, and complications associated with the use of GP IIb/IIIa inhibitors in percutaneous coronary intervention in a tertiary center setting. A total of 170 patients underwent screening over a period of 6 weeks. One hundred four (61%) had coronary intervention, out of which eight (8%) had failed intervention. Glycoprotein IIb/IIIa inhibitors were used in 57 (55%) patients; 47 (45%) did not have any agent periprocedure. Eptifibatide was the most commonly used agent in 35 (33%), followed by abciximab in 19 (18%) and tirofiban in 3 (3%). Out of 57 patients in whom GP IIb/IIIa agents were used, 22 (38%) had visible intracoronary thrombus, 22 (38%) had diffuse disease, 8 (14%) had complex intervention, and 5 (9%) had diabetes. The overall incidence of complications was not increased by the use of GP IIb/IIIa inhibitors; serious complications were rare with the use of GP IIb/IIIa agents; no stroke, thrombocytopenia, gastrointestinal bleed, or death was recorded. The overall use in emergency settings was not associated with increased complications. Bradycardia and vomiting were more common with abciximab group, whereas puncture site pain was commoner in eptifibatide group.
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PMID:An audit of the use and complications of glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention against national UK standards. 1717 71