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)

The key role of platelets in the pathogenesis of ischemic heart disease has led to the development of new classes of agents to control platelet function. The platelet glycoprotein IIb/IIIa receptor mediates the final common pathway to platelet aggregation. Drugs that block the glycoprotein IIb/IIIa receptor potently inhibit platelet aggregation. Monoclonal antibodies, cyclic peptides, and peptide-derivative glycoprotein IIb/IIIa inhibitors have been developed. The monoclonal antibody Fab fragment, chimeric 7E3, has been shown to significantly reduce ischemic complications and clinical restenosis after high-risk angioplasty in the large-scale Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial. A number of glycoprotein IIb/IIIa inhibitors have been tested in patients with unstable angina with similarly positive results, and initial trials in patients with acute myocardial infarction are also encouraging. Further evaluation of these agents in large scale trials is currently underway and should help determine the place and appropriate use of these agents in the clinical arena.
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PMID:Platelet glycoprotein IIb/IIIa receptor inhibitors in ischemic heart disease. 754 85

Platelet surface immunoglobulin G (PSIgG) was measured ex vivo in nine patients with stable angina pectoris receiving continuous (48-96 h) infusions of Fab fragments of a chimaeric MoAb (human IgG with murine variable regions) to platelet glycoprotein IIb-IIIa. PSIgG was measured using flow cytometry (FC) and an Fc-specific anti-IgG polyclonal antibody, which did not cross-react with the chimaeric Fab fragment (c7E3-Fab). A variable but statistically significant (P < 0.05) elevation of PSIgG was present within 24 h after the onset of the infusion, and was more marked (P < 0.01) several days after the end of the infusion despite an exponential fall in platelet surface c7E3-Fab post-infusion. PSIgG returned to normal within 2 weeks after the end of the infusion. The timing of IgG recruitment to the platelet surface suggested the pre-existence in the patients' plasma of IgG binding to c7E3-Fab-bearing platelets. None of the patients developed thrombocytopenia. In order to assess the incidence of IgG bindable to c7E3-Fab-bearing platelets in controls clinically comparable to the c7E3-Fab infusion patients, normal platelets coated with either chimaeric (c) or murine (m) 7E3-Fab were incubated with plasmas from 21 patients with ischaemic heart disease, and recruitment of IgG to the platelet surface was measured by FC. Fourteen of the 21 plasmas contained IgG bindable to c7E3-Fab-coated platelets, whereas only one of the 21 plasmas contained IgG bindable to m7E3-Fab-coated platelets (a highly significant difference, P < 0.001). These findings indicate that infusions of Fab fragments of the chimaeric anti-platelet antibody 7E3 are often associated with elevations in PSIgG, which are probably due to pre-existing 'naturally occurring' antibodies to the Fab fragments of chimaeric (but not murine) 7E3, and most probably other chimaeric MoAbs. The possible clinical significance of such ex vivo measured activities is at present a matter for speculation, and requires further study.
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PMID:Platelet surface IgG in patients receiving infusions of Fab fragments of a chimaeric monoclonal antibody to glycoprotein IIb-IIIa. 792 85

Recently, the HPA-1b (PlA2) polymorphism of the platelet glycoprotein IIIa has been suggested as a genetic risk factor for coronary artery disease. We conducted two case-control studies of 103 patients with ischaemic cerebrovascular disease (CVD) and 101 patients with ischaemic heart disease (IHD). The groups were matched for age, race and sex. No significant differences regarding selected risk factors (hypertension, diabetes mellitus, hypercholesterolaemia and smoking) were found between case patients and controls. Moreover, we investigated 286 normal individuals from the Mediterranean area. Genotyping of HPA-1 was performed by PCR-allelic specific restriction and single-strand conformation polymorphism analysis. The prevalence of HPA-1b was similar among case patients and controls (29.2% vs. 25.3% and 26.7% vs. 34.6% for CVD and IHD case-control studies, respectively). The HPA-1b allele was found in 36.4% of the normal population. Finally, the analysis of platelet function in nine controls with the three possible HPA-1 genotypes (three a/a, three a/b and three b/b) indicates that HPA-1b genotype does not modify either the in vitro platelet aggregation and activation profile, nor the GP IIb/IIIa interaction with fibrinogen or von Willebrand factor. Our results do not support the role of HPA-1b polymorphism as an inherited risk factor for arterial thrombotic disease.
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PMID:HPA-1 genotype in arterial thrombosis--role of HPA-1b polymorphism in platelet function. 928 92

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

The mechanism of arterial thrombosis, including coronary thrombosis, is different from that of thrombosis which occurs at sites of blood stasis such as deep venous thrombosis. Considering the onset of arterial thrombus formation, soluble coagulant factors may not play important roles for its onset since they are diluted by the effect of blood flow and cannot reach high enough concentrations to form insoluble fibrin. Platelets, which can stick to damaged vascular lumen even in the presence of shearing effects of blood flow, may play a crucial role in the onset of arterial thrombus formation. Thus, the mechanism of platelet thrombus formation should be assessed in the presence of blood flow. However, current dogma that fibrinogen binding to activated GP IIb/IIIa is the final common pathway for platelet thrombus formation was developed by using the function assay system of aggregometer, in which the effects of blood flow were not seriously considered. We are proposing in this review that plasma ligand protein of von Willebrand factor (vWF) and its interactions with platelet GP lb and GP IIb/IIa, which become apparent only in assays systems under influence of high shear rates of flow condition such as flowchambers or coneplate viscometers, are the key events leading to the onset of arterial thrombosis. A better understanding of the vWF-mediated mechanism of platelet thrombus formation is important for the development of better clinical tools to prevent ischemic heart disease as well as for a complete understanding of the mechanism of coronary thrombosis.
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PMID:Coronary thrombosis. Effects of blood flow on the mechanism of thrombus formation. 992 90

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration for half-maximal platelet activation before and after exercise testing were determined. Additionally, inhibition of thrombin-induced platelet activation by increasing concentrations of the prostacyclin-analog iloprost and the NO-donor SIN-1 was examined. In patients with CAD, a significantly reduced basal activation and a highly significant reduction in sensitivity towards thrombin was measured. The thrombin-induced expression of GP IIb/IIIa and CD 62p was significantly diminished in patients with CAD after physical exercise and their platelets were significantly more sensitive towards the inhibitory effects of iloprost and SIN-1. These data demonstrate a significant reduction in platelet activation in response to physical exercise in patients with CAD and advanced atherosclerosis. Despite exercise induced myocardial ischemia as evidenced by angina and ECG-changes, the platelets are not generally activated, as it could be expected. Thus, patients with myocardial ischemia experienced a reduced platelet activity and enhanced sensitivity towards prostacyclin (PGI2) and nitric oxide, probably due to an augmented release of endogenous platelet inhibitory mediators.
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PMID:Increased platelet sensitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease. 995 Feb 58

Although stent thrombosis has been greatly reduced by adequate stent expansion with high-pressure balloon inflations and by the use of antiplatelet drugs, this event is still frightening, as it may lead to acute myocardial ischemia resulting in acute myocardial infarction or sudden death. Therefore, the definition of factors associated with stent thrombosis may provide a better understanding of the mechanisms underlying this phenomenon and may permit us to define therapeutic strategies to further reduce its occurrence. The purpose of this study was to assess factors responsible for the occurrence of stent thrombosis after coronary stent implantation in 939 consecutive patients enrolled in the Registro Impianto Stent Endocoronarico (R.I.S.E. Study Group). Consecutive patients undergoing coronary stent implantation at 16 medical centers in Italy were prospectively enrolled in the registry. Clinical data, and qualitative and quantitative angiographic findings were obtained from data collected in case report forms at each investigator site. The study group consisted of 781 men and 158 women with a mean age of 59 yr: 1,392 stents were implanted in 1,006 lesions and expanded at a maximal inflation pressure of 14.7 +/- 3 atm. The great majority of patients (92%) received only antiplatelet drugs after coronary stenting. During hospitalization there were 45 major ischemic complications in 39 patients (4.2%): 13 events were related to acute or subacute thrombosis (1.4%). Another stent thrombotic event occurred in the first month of follow-up. On multivariate logistic regression analysis, stent thrombosis was related to the following factors: unplanned stenting (OR 3.46, 95% CI 1.65-7.23), unstable angina (OR 3.37, 95% CI 1.11-10.14) and maximal inflation pressure (OR 0.83, 95% CI 0.75-0.93). In conclusion, this registry shows that in an unselected population of patients undergoing coronary stenting, stent thrombosis occurs in less than 2% of patients and is significantly related to unplanned stent implantation, unstable angina, and maximal inflation pressure. The incidence of this phenomenon is likely to be further reduced by the use of new potent antiplatelet drugs, such as platelet glycoprotein IIb/IIIa antagonists.
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PMID:Stent thrombosis: incidence and related factors in the R.I.S.E. Registry(Registro Impianto Stent Endocoronarico) 1034 59

Acute coronary syndromes and the postpercutaneous coronary intervention state share the common feature of atherosclerotic plaque disruption and subsequent intraluminal thrombus formation. In most cases, vascular patency is maintained but partial occlusion causes myocardial ischemia and can either progress to complete occlusion or result in distal embolization with subsequent small vessel obstruction, the core section of an intraarterial thrombus is platelet-rich and can serve as a nidus for further thrombosis. Aspirin, by virtue of its anticycloxygenase activity inhibits platelet activation and aggregation to a mild degree. Clinically, aspirin has been shown to reduce the rates of myocardial infarction in patients with acute coronary syndromes and to reduce the number of ischemic complications which follow coronary angioplasty. More potent inhibitors of platelet aggregation antagonize the interaction between the platelet surface protein GP IIb-IIIa and fibrinogen. The result is profound inhibition of platelet aggregation. Three intravenous antagonists of platelet GP IIb-IIIa are clinically available and a fourth is under phase III study. When used in addition to aspirin therapy, these agents have been shown to produce further reductions in either peri-interventional infarctions or in recurrent myocardial infarctions in patients with acute coronary syndromes.
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PMID:Antiplatelet therapy for treatment of acute coronary syndromes. 1038 31

Acute coronary syndromes (ACS) are the major cause of mortality and morbidity in Western countries. The primary pathophysiologic mechanism of ACS involves the formation of thrombus in coronary arteries in response to spontaneous or intervention-induced endothelial damage. This leads to myocardial ischemia. The final common pathway to the coronary thrombosis underlying ACS involves the aggregation of platelets mediated by the binding of soluble fibrinogen to the platelet receptor glycoprotein (GP) IIb-IIIa. Several GP IIb-IIIa inhibitors have been developed that promise greater antithrombotic potential than aspirin and heparin alone. Over the past 2 years, 4 major trials involving more than 18,000 patients have evaluated the therapeutic potential of 3 small-molecule, intravenous GP IIb-IIIa inhibitors as a component of first-line management of unstable angina or non-ST-segment elevation myocardial infarction. Results of these studies show that administration of a GP IIb-IIIa inhibitor in combination with aspirin and heparin provides a significant reduction in mortality and morbidity rates compared with aspirin plus heparin alone. Recent approvals of 2 GP IIb-IIIa inhibitors, the peptide eptifibatide and the peptidomimetic tirofiban, mark the beginning of a new era in the management of non-ST-segment elevation ACS.
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PMID:Overview of clinical trials of glycoprotein IIb-IIIa inhibitors in acute coronary syndromes. 1050 33


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