Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of therapy in acute myocardial infarction is complete and timely restoration of coronary blood flow. Current strategies for reperfusion fail to achieve ideal results and resolution of ischemia in all patients. The platelet plays a pivotal role in the pathophysiology of an acute myocardial infarction, and antiplatelet therapy has been shown to improve clinical outcomes. The final common pathway for platelet activation and aggregation in acute myocardial infarction is the activation of the glycoprotein (GP) IIb/IIIa receptor. Newer reperfusion strategies target the GP IIb/IIIa receptor, thereby preventing the prothrombotic effects of platelets in an acute myocardial infarction. In the past decade, several strategies targeting the use of GP IIb/IIIa inhibitors have been evaluated. GP IIb/IIIa inhibitors have been shown to improve angiographic Thrombolysis in Myocardial Infarction (TIMI) 3 flow rates when used as reperfusion therapy given with heparin and aspirin as compared with heparin and aspirin alone. When GP IIb/IIIa inhibitors are used with full-dose fibrinolytics, early studies have suggested a trend toward more rapid and more complete reperfusion in an acute myocardial infarction. Later trials have examined the use of GP IIb/IIIa inhibitors in conjunction with reduced-dose fibrinolytics. Results from TIMI 14 and Global Use of Strategies to Open occluded arteries-IV pilot trials support the use of combination therapy with reduced- dose fibrinolytics and the GP IIb/IIIa inhibitor abciximab. Given the promising role of GP IIb/IIIa inhibitor therapy in acute myocardial infarction, investigators questioned the need for concomitant antithrombin therapy. However, data from several investigations suggest that antithrombin therapy is required when GP IIb/IIIa inhibitors are used with fibrinolytics, although it appears that the dose of heparin may be reduced. Finally, recent investigations have addressed the safety and efficacy of facilitated early percutaneous intervention. In this strategy, patients presenting with an acute myocardial infarction are treated with reduced-dose fibrinolytics and GP IIb/IIIa inhibitors and are taken to the interventional cardiac catheterization laboratory within the first 60 minutes of therapy.
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PMID:The use of glycoprotein IIb/IIIa inhibitor therapy in acute ST-segment elevation myocardial infarction: current practice and future trends. 1277 11

Recently, the selectin family of glycoprotein adhesion molecules (P-selectin, E-selectin, and L-selectin) has been implicated in the pathogenesis of a number of inflammatory disease states. The selectins modulate the early adhesive interactions between circulating neutrophils and the endothelium. Both P-selectin and E-selectin can be expressed on the surface of endothelial cells following stimulation by a number of inflammatory mediators. In contrast, L-selectin is constitutively expressed on the surface of neutrophils at very high levels. In addition, neutrophils also express ligands for the endothelial selectins, including the carbohydrate sialyl Lewis(x) and the high-affinity ligand P-selectin glycoprotein ligand 1, which facilitate neutrophil-endothelial interactions. Selectins have been extensively investigated in ischemia/reperfusion injury states. The study of selectin involvement in ischemia/reperfusion injury has been facilitated by the development of highly specific selectin antagonists, including monoclonal antibodies, carbohydrates, small molecule inhibitors, and soluble forms of P-selectin glycoprotein ligand 1. This article reviews the results of current studies of selectin antagonists in experimental models of ischemia/reperfusion injury.
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PMID:Pharmacology of selectin inhibitors in ischemia/reperfusion states. 1083 37

Monoclonal antibodies to adhesive molecules have been used in many trials to decrease ischemia-reperfusion injury, which is considered to occur in areas such as the distal region of the random pattern flap. The monoclonal antibody to the primary neutrophil adherence-mediating glycoprotein CD18 improves the survival length of the random pattern flap. Sulfatide binds strongly with L- and P-selectin. We found that sulfatide has a protective effect against ischemia-reperfusion injury. The purpose of this study was to evaluate the effect of sulfatide on the survival length of the random pattern flap in rats. Sulfatide was administered intravenously just before elevation of the cranially based dorsal skin flap. Administration of sulfatide significantly augmented flap survival length (49.5 +/- 1.7 mm vs control 41.5 +/- 2.1 mm, P = 0. 01). Flap survival length was significantly longer than dye distance (49.1 +/- 2.0 mm vs 39.7 +/- 1.1 mm, P = 0.01). In the control flap, no significant difference between survival length and dye distance was detected. Histological examination 48 h after flap elevation showed leukocyte invasion in the dermal layer of control flaps, whereas little leukocyte invasion was observed in the flaps of rats administered sulfatide.
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PMID:Sulfatide elongates dorsal skin flap survival in rats. 1086 79

Inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor complex have recently been approved for the treatment of patients with unstable angina and non-Q-wave myocardial infarction (MI). We performed a meta-analysis to ascertain the effect of these agents on the individual endpoints of death, myocardial infarction, refractory ischemia, and major bleeding after 30 days of follow-up. Five randomized, placebo-controlled trials involving 17,255 patients were identified. The odds ratios for each of the endpoints in each trial were calculated and combined using a fixed-effects model. There was no significant reduction in death (OR, 0.87; 95% CI, 0.73-1.03; P = 0.1), myocardial infarction (OR, 0.91; 95% CI, 0.82-1.004; P = 0.06), or refractory ischemia (OR, 0.92; 95% CI, 0.78-1.1; P = 0.36) in patients treated with GP IIb/IIIa inhibitors. There was a significant increase in major bleeding following treatment with GP IIb/IIIa inhibitors (OR, 1.2; 95% CI, 1.06-1.4; P = 0.005). When used to treat unstable angina and non-Q-wave MI, this new class of agents appears to be associated with minimal clinical benefit and an increase in major bleeding complications.
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PMID:Effect of glycoprotein IIb/IIIa inhibitors on the individual components of composite endpoints used in clinical trials of unstable angina and non-Q-wave myocardial infarction. 1093 47

Clinical experience suggests that patients treated with the glycoprotein (GP) IIb/IIIa inhibitor abciximab (ReoPro , Eli Lilly and Company, Indianapolis, Indiana) may be at increased risk of thrombocytopenia. This case report details the successful use of the GP IIb/IIIa inhibitor eptifibatide (Integrilin , COR Therapeutics, South San Francisco, California) in a patient who developed acute thrombocytopenia (platelet count: 67,000/mm3) approximately 10 hours after initiation of abciximab therapy. Five hours after abciximab was discontinued, platelet count returned to normal (191,000/mm3) and eptifibatide was started because of persistent electrocardiographic evidence of ischemia. The patient underwent diagnostic catheterization during eptifibatide therapy, which was administered for approximately three days. Four days after the initial course of therapy with eptifibatide was discontinued, percutaneous revascularization with adjunct eptifibatide was performed. During both courses of eptifibatide therapy, platelet counts remained in the normal range (> 100,000/mm3) and no adverse ischemic or bleeding events occurred.
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PMID:Platelet receptor glycoprotein IIb/IIIa inhibition with eptifibatide in a patient with thrombocytopenia after treatment with abciximab. 1102 16

Reperfusion injury after coronary occlusion is in part mediated by leukocyte activation and adhesion. Platelets may interact with polymorphonuclear granulocytes (PMNs), causing aggravated reperfusion injury. We studied whether c7E3Fab, a chimeric Fab fragment blocking platelet glycoprotein (GP) IIb/IIIa, decreases PMN-platelet-dependent myocardial dysfunction after ischemia. Isolated guinea pig hearts (n=5 per group) perfused at a constant flow of 5 mL/min were subjected to ischemia (15 minutes, 37 degrees C) and reperfusion. Human PMNs (10x10(6) cells, 3 mL), platelets (400x10(6), 3 mL), and fibrinogen (1 mg/mL) were infused for 3 minutes after 2 minutes of reperfusion, with or without c7E3Fab. Flow cytometry detected GPIIb/IIIa (platelets) and MAC-1 (aMbeta2, PMNs) as well as coaggregates of both in the effluent, whereas double-fluorescence microscopy visualized intracoronary PMN-platelet coaggregates. Postischemic recovery of pressure-volume work (12-cm H(2)O preload and 60-mm Hg afterload) was defined as the ratio of postischemic to preischemic external heart work (mean+/-SEM). c7E3Fab reduced platelet GPIIb/IIIa detection to 10% of controls, blocked a transcoronary MAC-1 increase (+25% without versus -23% with c7E3Fab), and inhibited PMN-platelet coaggregation in the effluent (49+/-12% without versus 17+/-2% with c7E3Fab) as well as in the hearts themselves (5.0+/-0.7/cm(2) without versus 1.2+/-0.3/cm(2) surface area with c7E3Fab). Postischemic recovery of external heart work (83+/-5% in cell-free hearts) declined to 46+/-4% after postischemic PMN-platelet infusion, but not in the presence of c7E3Fab (74+/-11%) or LPM19c (71+/-6%). We conclude that c7E3Fab inhibits formation of PMN-platelet aggregates during myocardial reperfusion, an effect that protects against PMN-platelet-dependent stunning.
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PMID:c7E3Fab reduces postischemic leukocyte-thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury. 1103 Dec 8

The dramatic improvements in outcomes in acute cardiac ischemia because of therapeutic advances has led to "diminishing returns" with increasingly intensive therapies. This article explores the potential of electrocardiograph (ECG)-based prognostic instruments to identify patients likely to benefit from intense regimens, even in the absence of overall average benefit in the population, with 2 clinical examples: 1) Reperfusion therapy in acute myocardial infarction (AMI); and 2) anticoagulation/antiplatelet therapy in unstable angina. Based on previously developed, ECG-based prognostic instruments we explored the distribution of potential benefits in individual patients from increasingly intense therapy in both AMI and unstable angina. Predictions were obtained on community-based patient samples with both AMI and unstable angina to examine the distribution of effectiveness and cost-effectiveness. For both AMI and unstable angina, much of the benefit of intensifying therapy can be obtained by targeting a subgroup of patients that can be identified in multivariable dimensions by clinical and ECG characteristics. Treatment of these patients with more potent agents (such as hirudin or the glycoprotein inhibitors in unstable angina) is likely to be both effective and cost-effective. However, treatment of "low benefit" patients is unlikely to be effective or cost-effective, and some candidates for therapy are more likely to be harmed, than to benefit, by the more intensive regimens. Multivariable stratification can improve clinical and economic outcomes in acute cardiac ischemia, particularly when such models help identify "high benefit" patients early in their clinical course. Additionally, using validated models in the planning and execution of clinical trials of new therapies can improve the power of the trial and help target the therapies to patients most likely to benefit.
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PMID:The potential use of ECG-based prognostic instruments in clinical trials and cost-effectiveness analyses of new therapies in acute cardiac ischemia. 1126 32

Secondary prevention of stroke and other manifestations of atherothrombosis is essential if the burden of disease associated with these events is to be reduced. Therefore, it is important to identify patients most likely to benefit from antiplatelet therapy. There is a good rationale for combining antiplatelet agents with different modes of action, since different signalling pathways contribute to platelet activation. Based on the promising results obtained with an adenosine diphosphate receptor antagonist-aspirin combination in coronary stenting, several additional trials with clopidogrel plus aspirin are ongoing. They include CURE (Clopidogrel in Unstable angina to prevent Recurrent Events, in unstable angina and non-Q-wave myocardial infarction) and COMMIT (in acute myocardial infarction), which compare clopidogrel with placebo in patients receiving aspirin, and CREDO (Clopidogrel for Reduction of Events During extended Observation), a 1-year treatment follow-up to the clopidogrel arms of the CLASSICS trial (Clopidogrel Aspirin Stent International Cooperative Study). Planned trials with clopidogrel in neurology include SPS3 (Secondary Prevention of Small Subcortical Strokes, in patients with symptomatic lacunar stroke), and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients, in patients with stroke or transient ischaemic attack plus one additional risk factor), which will compare the efficacy of clopidogrel plus aspirin versus clopidogrel in reducing important ischaemic events. Combination therapy with an oral glycoprotein (GP) IIb/IIIa receptor antagonist plus aspirin has so far been less promising. Trials of three compounds--orbofiban, xemilofiban and sibrafiban--in combination with aspirin for secondary prevention in cardiac patients have reported increased mortality compared with aspirin alone. A similar effect was seen when sibrafiban monotherapy was compared directly with aspirin alone. Trials of newer oral GP IIb/IIIa inhibitors are under way or are planned. The combination of dipyridamole plus aspirin appears to be superior to aspirin alone for the prevention of stroke in patients with stroke or transient ischaemic attack; the effectiveness of this combination is being further investigated in ESPRIT (European/Australian Stroke Prevention in Reversible Ischaemia Trial).
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PMID:Future perspectives for optimizing oral antiplatelet therapy. 1131 19

The results of recent trials suggest that an aggressive antiplatelet regimen that includes a glycoprotein (GP) IIb/IIIa antagonist, in conjunction with an early revascularization strategy, may be the optimal treatment plan for patients presenting with a non-ST-elevation acute coronary syndrome (ACS). However, whether all patients presenting to the emergency room with a suspected ACS really benefit from the addition of a GP IIb/IIIa receptor inhibitor, and in those who do, the optimal time to start therapy has not yet been clearly identified. Patients with objective evidence of ischemia, especially elevated myocardial enzymes, as well as patients on chronic aspirin therapy at the time of their ACS, appear to derive the greatest benefit from the addition of a GP IIb/IIIa antagonist. Trial results strongly support the use of a GP IIb/IIIa inhibitor at the time of a percutaneous coronary intervention in this patient population, but starting therapy prior to the procedure is best supported by the data in those patients who have refractory ischemia despite good medical therapy, or patients who will be medically stabilized for greater than 24 hours.
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PMID:Optimal Platelet Inhibition for PCI in ACS: Pretreatment, In-laboratory, Both or Neither. 1132 17

Using an in vivo rat model of unilateral renal ischemia, we previously showed that the expression and distribution of fibronectin (FN), a major glycoprotein of plasma and the extracellular matrix, dramatically changes in response to ischemia-reperfusion. In the distal nephron in particular, FN accumulates in tubular lumens, where it may contribute to obstruction. In the present study, we examine whether the tubular FN is the plasma or cellular form, each of which is produced by alternative splicing of a single gene transcript. We demonstrate that FN in tubular lumens does not contain the extra type III A (EIIIA) and/or the extra type III B (EIIIB) region, both of which are unique to cellular FN. It does, however, contain the V95 region, which in the rat is a component of FNs in both plasma and the extracellular matrix. Expression of FN containing EIIIA increases dramatically in the renal interstitium after ischemic injury and continues to be produced at high levels 6 wk later. V95-containing FN also increases in the interstitial space, albeit more slowly and at lower levels than FN containing EIIIA; it also persists 6 wk later. FN containing the EIIIB region is not expressed in the injured kidney. The presence of V95 but not the EIIIA or EIIIB regions of FN in tubular lumens identifies the origin of FN in this location as the plasma; tubular FN is ultimately voided in the urine. The data indicate that both plasma and cellular FNs containing the V95 and/or EIIIA regions may contribute to the pathogenesis of acute renal failure and to the repair of the injured kidney.
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PMID:Expression of fibronectin splice variants in the postischemic rat kidney. 1135 44


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