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)

AIMS: This study evaluated the treatment of early coronary stent thrombosis with intracoronary urokinase or the platelet glycoprotein IIb/IIIa receptor inhibitor ReoPro (abciximab). METHODS AND RESULTS: Seventy-four patients (126 stents) were treated immediately after identification of early (0-30 days) coronary stent thrombosis. Twenty-nine patients were treated with intracoronary urokinase (UK) (UK alone in 19; UK and additional balloon angioplasty in 10) and another 45 patients were given ReoPro((R)) (abciximab) (0.25 mg/kg as a bolus alone in 26, abciximab with additional balloon angioplasty in 19) within 30 days of stent implantation. TIMI grade 3 flow was obtained in 23 patients (79%) in the UK group and in 38 (84%) in the abciximab group (nonsignificant). Three patients (10%) in the UK group and one (2%) in the abciximab group underwent repeat percutaneous transluminal coronary angioplasty (PTCA) (nonsignificant). Five patients (17%) in the UK group and three (7%) in the abciximab group were referred for urgent coronary artery bypass graft surgery (CABG) because of residual thrombus and refractory ischemia (nonsignificant). Repeat revascularization was necessary in eight patients (28%) in the UK group versus four (9%) in the abciximab group (p < 0.05). Five patients (17%) in the UK group and eight (18%) in the abciximab group developed myocardial infarction (nonsignificant). Five patients (17%) in the UK group (cardiogenic shock (three), cerebral hemorrhage (one) and pneumonia (one)) and three (6.6%) in the abciximab group (cardiogenic shock (two), heart failure (one)) died within 30 days (nonsignificant). Overall, noncardiac complications (bleeding including surgical repair of groin) were observed in 11 patients (38%) in the UK group and three (7%) in the abciximab group (p < 0.001). CONCLUSION: Compared to urokinase, abciximab reduced the need for repeat revascularization procedures and the risk of noncardiac events, including bleeding complications in patients with early coronary stent thrombosis.
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PMID:Comparison of ReoPro((R)) (abciximab) versus intracoronary thrombolysis for early coronary stent thrombosis. 1247 Mar 68

Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI). In large trials, the GP IIb/IIIa inhibitors tirofiban and eptifibatide were each found to reduce the risk of death or myocardial infarction (MI) in these patients at 30 days. These agents appear to be of greatest benefit in patients with a positive troponin at baseline, diabetes or ST-segment depression, recurrent angina, prior aspirin use, or a Thrombolysis In Myocardial Infarction (TIMI) risk score > or = 4. The Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) TIMI-18 trial was designed to compare the benefits of an early invasive versus a conservative strategy in high-risk UA/NSTEMI patients treated with GP IIb/IIIa inhibition. Patients were treated with tirofiban (for 48 h) plus aspirin and heparin and randomized to either invasive therapy (coronary angiography and revascularization when feasible) or conservative treatment (angiography only for patients with recurrent ischemia at rest or a positive stress test). A significant reduction in death or MI was demonstrated at 30 days (p = 0.02) and at 6 months (p = 0.0498). Death, MI, or rehospitalization for an acute coronary syndrome was also reduced with the invasive therapy at six months (p = 0.025). These results provide evidence to physicians that early GP IIb/IIIa inhibition in combination with a prompt invasive approach should be used more widely in UA/NSTEMI patients, particularly those at high risk.
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PMID:Small molecule glycoprotein IIb/IIIa receptor inhibitors as upstream therapy in acute coronary syndromes: insights from the TACTICS TIMI-18 trial. 1264 40

Patients presenting with unstable angina and non-ST elevation myocardial infarction (UA/NSTEM) have a highly variable course. Optimal management is critical because of the high risk of death or myocardial infarction (MI) in the ensuing 30 days. In this article, we review the therapeutic options available to clinicians. Anti-ischemic therapy with beta-blockers and nitrates should be considered in all patients without contraindications. Aspirin remains a cornerstone of antiplatelet therapy and has been shown to substantially reduce the risk of death or MI. Although the data are less robust, unfractionated heparin (UFH) also appears to be efficacious, and the low-molecular-weight heparin (LMWH) enoxaparin appears to be superior to UFH. The GP IIb/IIIa inhibitors, highly beneficial in the setting of percutaneous coronary intervention (PCI), should be considered in patients with continuing ischemia or other high-risk features. The ADP receptor blocker clopidogrel has been shown to be beneficial in patients who are managed conservatively and in those who undergo PCI. Lastly, a strategy of early angiography should be considered in patients with recurrent ischemia or in those who present with high-risk features such as elevated troponins or ST deviation. Thus, early risk stratification using clinical features, electrocardiographic data, and biomarkers allows identification of subgroups of patients who are not only at high risk but also enjoy the greatest benefits from these aggressive therapies and thereby enables clinicians to target these interventions most effectively.
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PMID:The management of unstable angina and non-ST-segment elevation myocardial infartion. 1455 14

Elderly patients with unstable angina pectoris/non-ST-segment elevation myocardial infarction should be hospitalized. Precipitating factors should be identified and corrected. Electrocardiogram monitoring is important. Aspirin should be given as soon as possible and continued indefinitely. Clopidogrel should given for up to 9 months in patients in whom an early noninterventional approach is planned or in whom a percutaneous coronary intervention (PCI) is planned. Clopidogrel should be withheld for 5-7 days in patients in whom elective coronary artery bypass graft surgery (CABGS) is planned. A platelet glycoprotein IIb/IIIa inhibitor should also be given in addition to aspirin, clopidogrel, and heparin in patients in whom cardiac catheterization and PCI are planned. Patients whose symptoms are not fully relieved with three 0.4-mg sublingual nitroglycerin tablets or spray taken 5 minutes apart and the initiation of an intravenous beta blocker should be treated with continuous intravenous nitroglycerin. Beta blockers and angiotensin-converting enzyme (ACE) inhibitors should be given and continued indefinitely. The benefit of long-acting nondihydropyridine calcium channel blockers is limited to symptom control. Intra-aortic balloon pump counterpulsation should be used for severe ischemia that is continuing or occurs frequently despite intensive medical therapy or for hemodynamic instability. Statins should be used if the serum low-density lipoprotein (LDL) cholesterol is >or=100 mg/dl and continued indefinitely. Enoxaparin is preferable to intravenous unfractionated heparin in the absence of renal failure and unless CABGS is planned within 24 hours. Thrombolysis is not beneficial. High-risk patients should have an early invasive strategy with CABGS or PCI performed depending on the coronary artery anatomy, left ventricular function, presence or absence of diabetes, and findings on noninvasive testing. Following hospital discharge, patients should have intensive risk factor modification with cessation of smoking, maintenance of blood pressure below 135/85 mmHg, indefinite use of statins if needed to maintain the serum LDL cholesterol <100 mg/dl, intensive control of diabetes, maintenance of optimal weight, and daily exercise. Patients should be treated indefinitely with aspirin, beta blockers, and ACE inhibitors and with clopidogrel for up to 9 months. Nitrates should be given for ischemic symptoms. Hormonal therapy should not be given to postmenopausal women.
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PMID:Treatment of unstable angina pectoris/non-ST-segment elevation myocardial infarction in elderly patients. 1457 Aug 61

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.
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PMID:Antithrombotic effects of FK419, a novel nonpeptide platelet GPIIb/IIIa antagonist, in a guinea pig photochemically induced middle cerebral artery thrombosis model: comparison with ozagrel and argatroban. 1463 48

Although hypercholesterolemia is widely accepted as a major risk factor for coronary artery and peripheral vascular diseases, its role in the pathogenesis of stroke is controversial. The objectives of this study were to determine how hypercholesterolemia affects the cerebral microcirculation under resting conditions and after ischemia-reperfusion (I/R). Platelet- and leukocyte-endothelial cell interactions and oxidant production (using the oxidant-sensitive fluorochrome dihydrorhodamine-123) were monitored by intravital videomicroscopy in the cerebral microvasculature of mice placed on either a normal (ND) or cholesterol-enriched diet (HCD). Platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) and leukocytes labeled with rhodamine 6G were seen to roll and firmly adhere, with a corresponding increase in oxidant production, in venules of mice on HCD, but not ND. Immunoneutralization of P-selectin attenuated the platelet- and leukocyte-endothelial cell interactions and the enhanced oxidant production associated with HCD. A GPIIb/IIIa blocking antibody did not alter the blood cell-vessel wall interactions to HCD. Mice deficient in the NADPH oxidase subunit gp91(phox) exhibited significantly blunted platelet and leukocyte recruitment responses to HCD. Focal I/R also elicited inflammatory and prothrombogenic responses in cerebral venules and these were exaggerated in mice on HCD. These results implicate an oxidant-dependent, P-selectin-mediated mechanism in the blood cell-vessel wall interactions induced by hypercholesterolemia in the brain and demonstrate that the deleterious effects of I/R on the brain are exacerbated by this cardiovascular risk factor.
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PMID:Cerebral microvascular responses to hypercholesterolemia: roles of NADPH oxidase and P-selectin. 1467 Aug 46

The uremic state in patients with terminal renal insufficiency is accompanied by a bleeding tendency connected with platelet dysfunction. Prolonged cold ischemia and inflammatory interactions between leukocytes, platelets and endothelial cells contribute to ischemia-/reperfusion (I/R) injury and may impair long-term graft survival. We evaluated the influence of the duration of cold preservation time on the expression of platelet GPIIb/IIIa and P-selectin and on the formation of leukocyte-platelet complexes after kidney transplantation. Fourteen patients undergoing kidney transplantation were divided into group I with long preservation time (26.6 +/- 1.9 h) and group II with short preservation time (8 +/- 6.1 h). Five venous blood samples (3 ml) were taken before induction of anesthesia, 12 h, 2, 7 and 14 d after transplantation. Surface expression of the GPIIb/IIIa, P-selectin and the percentage of platelet-granulocyte complexes were quantified by flow cytometry. Additionally blood from seven healthy volunteers was analyzed. GPIIb/IIIa and P-selectin expression on circulating platelets were significantly decreased in the long and the short-term graft preservation group compared with healthy volunteers. A significantly reduced P-selectin expression was found in the long-term preservation group compared with the short-term group. The percentage of platelet-granulocyte complexes also decreased in both preservation groups in the first 2 d after reperfusion and remained in this state in the long-term preservation group. Reduced expression of P-selectin on circulating platelets may be an indicator of I/R injury after prolonged kidney graft preservation.
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PMID:Reduced P-selectin expression on circulating platelets after prolonged cold preservation in renal transplantation. 1470 28

There is continued debate as to whether a combined reperfusion regimen with platelet glycoprotein IIb/IIIa inhibitors provides additional benefit in optimal myocardial reperfusion of patients with a ST-elevation acute myocardial infarction (AMI). In addition, the best angiographic method to evaluate optimal myocardial reperfusion is still controversial. Patients (n = 144) with a first AMI presenting <6 hours from onset of symptoms were randomized to receive a conjunctive strategy (n = 72) with low-dose alteplase (50 mg) and tirofiban (0.4 microg/kg/min/30 minute bolus; infusion of 0.1 microg/kg/minute), or tirofiban plus stenting percutaneous coronary intervention (PCI). Control patients (n = 72) received standard strategy with either full-dose alteplase (100 mg) or stenting PCI [correction]. All patients were submitted to coronary angiographic study at 90 minutes. The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 90 minutes. Secondary end points were TIMI myocardial perfusion (TMP) rates, a composite end point at 30 days (death, reinfarction, refractory ischemia, stroke, heart failure, revascularization procedures, or pulmonary edema), and bleeding or hematologic variables. The rate of TIMI 3 flow at 90 minutes for patients treated with alteplase alone was 42% compared with 64% for those who received low-dose alteplase and tirofiban. Standard stenting PCI achieved 81% of TIMI 3 flow compared with 92% when tirofiban was used. Significantly higher rates of TMP grade 3 were observed when tirofiban was used as the adjunctive treatment in both alteplase (66% vs 47%) and stenting PCI (73% vs 55%). Higher rates of the composite end point were observed in standard regimens compared with conjunctive regimens (hazard ratio 5.8, 95% confidence interval 1.27 to 26.6, p = 0.023). Regardless of reperfusion regimen, better outcomes were observed when a combination of TIMI 3 flow and TMP grade 3 was achieved. Beyond TIMI 3 flow rate, the TMP grade was an important determinant. The rates of major bleeding were similar (2.8%) for standard versus conjunctive regimens with tirofiban. Thus, tirofiban as a conjunctive therapy for lytic and stenting regimens not only improves TIMI 3 flow rates, but also the TMP3 rates, which are related to a better clinical outcome without an increase in the risk of major bleeding. This study supports the hypothesis that platelets play a key role not only in the atherothrombosis process, but also in the disturbances of microcirculation and tissue perfusion.
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PMID:Comparison of reperfusion regimens with or without tirofiban in ST-elevation acute myocardial infarction. 1475 75

Primary PCI is an effective reperfusion strategy for acute MI patients, which has evolved significantly in the last decade. While many adjunctive therapies have contributed to its success, substantial obstacles remain before optimal reperfusion can be achieved. Anti-platelet therapy with aspirin, clopidogrel and GP IIb/IIIa inhibitors reduces early ischemic complications, improves microvascular function and, potentially, affects the inflammatory response to ischemic injury. Current anti-thrombin therapy with UFH can be improved with LMWH, and, possibly with direct thrombin inhibitors. A number of important aspects of this strategy, though, need still to be elucidated. We need to optimize microvascular protection before and during PCI in order to capitalize on the myocardial sparing effects of reperfusion therapy. This will be probably achieved with a combination of pharmacological interventions and mechanical emboli protection devices. Improved and more targeted anti-inflammatory therapy should decrease the effects of neutrophil-related reperfusion injury, while a variety of metabolic interventions might preserve myocardial function during ischemia and after reperfusion.
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PMID:Adjunctive therapy for percutaneous revascularization in acute myocardial infarction. 1496 1

Platelet-leukocyte conjugates are increased in patients with coronary artery disease but the relationship between conjugate formation and myocardial ischemic outcome is unknown. We prospectively evaluated the relationship between conjugate formation and the development of recurrent myocardial ischemia in patients with acute coronary syndromes (ACS). Platelet-leukocyte conjugate formation (induced by thrombin receptor activating peptide (TRAP)) and platelet aggregation (induced by ADP and arachidonic acid) were assessed in 30 patients with unstable angina or non-ST elevation myocardial infarction. All patients were treated with beta-blockers, aspirin, heparin, and GPIIb-IIIa antagonists and were followed for in-hospital recurrent myocardial ischemia. Troponin I and C-reactive protein (CRP) were also measured. Seven patients (23%) experienced recurrent ischemia. Platelet-neutrophil conjugates were greater in ischemic patients (59 +/- 9 and 36 +/- 4%, P = 0.007, for + ischemia and -ischemia, respectively). Platelet aggregation did not differ between ischemic and nonischemic patients, and there was no significant relationship between aspirin resistance and ischemic outcome. Troponin I was greater in patients who developed recurrent ischemia (3.04 +/- 1.73 vs. 0.70 +/- 0.21 ng/ml, P = 0.03, for +ischemia and -ischemia, respectively) but CRP was not. TRAP-induced platelet-neutrophil conjugate formation was an independent predictor of ischemic outcome (OR 1.07, 95% CI 1.00-1.15, for each 1% increase in conjugate formation). Receiver operator characteristic analysis showed platelet-neutrophil conjugates to have good ability to discriminate between ischemic and nonischemic patients (AUC of 0.84, P < 0.05). TRAP induced platelet-neutrophil conjugate formation is related to in vivo ischemic risk in ACS patients.
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PMID:Prospective evaluation of the relationship between platelet-leukocyte conjugate formation and recurrent myocardial ischemia in patients with acute coronary syndromes. 1498 71


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