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 thromboxane receptor antagonist ifetroban ([1S-(1 alpha,2 alpha,3 alpha, 4 alpha)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]- 7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid) and aspirin were evaluated for direct and combined effects on myocardial infarct size in anesthetized ferrets subjected to coronary artery occlusion (90 min) and reperfusion (5 h). Aspirin (10 mg/kg) or vehicle was administered as an i.v. bolus dose at the 45th min of occlusion in an initial assessment of its cardioprotective potential in this species. In interaction studies, aspirin was injected i.v. 10 min prior to occlusion (10 mg/kg) and at the 45th min of ischemia (5 mg/kg) both with and without subsequent administration of ifetroban (0.3 mg/kg + 0.3 mg/kg per h) beginning at the 75th min of occlusion. Aspirin administration alone caused non-significant (P > 0.05) 5-7% reductions in tissue damage (19.8-21.8% of left ventricle) from that observed in vehicle-controls (20.4-22.9% of left ventricle). Ifetroban alone significantly (P < 0.05) reduced infarct size compared to vehicle treatment (13 +/- 1% vs. 23 +/- 2% of left ventricle), and this was not prevented by combination with aspirin (12 +/- 2% vs. 22 +/- 3% of left ventricle). In the absence and presence of aspirin, ifetroban reduced infarct size by 42% and 43%, respectively. Concurrently, thromboxane A2-generating capacity in blood (measured as thromboxane B2 in clotted serum) was decreased ca. 99% by aspirin treatment. Thus, virtually complete platelet cyclooxygenase inhibition by aspirin afforded no cardioprotective action in the ferret and, more importantly, this inhibition did not interfere with the myocardial salvage efficacy of ifetroban.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Failure of aspirin to interfere with the cardioprotective effects of ifetroban. 770 47

The dose-related cardioprotective efficacy of the thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-180291), was investigated in an anesthetized ferret model of myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of ischemia or 5 min after initiating reperfusion. The magnitude of TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619. Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 92% of ferret platelet TP receptors. Thus, ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90% TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.
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PMID:Dose-related cardioprotection by ifetroban in relation to inhibition of thrombosis and ex vivo platelet function. 771 79

The effects of the thromboxane A2 (TXA2)/prostaglandin endoperoxide (TP) receptor antagonist ifetroban (BMS-180291) on infarct size (IS) resulting from coronary occlusion/reperfusion was determined in anesthetized dogs and ferrets. In dogs, ifetroban (1 + 1 mg/kg/h, intravenously, i.v.) or vehicle administration was initiated 10 min before left circumflex coronary artery (LCX) occlusion. In ferrets, the left anterior descending coronary artery (LAD) was occluded; after 75 min, a continuous infusion of ifetroban (0.3 + 0.3 mg/kg/h i.v.) or vehicle was started. After 90-min ischemia in both species, the LCX or LAD occlusion was released; reperfusion was continued for 5 h, at which time IS was determined. Regional myocardial blood flow (RMBF) before and during occlusion and during reperfusion were measured with radioactive microspheres. Ifetroban significantly decreased the extent of infarction to 39 +/- 5% of the area at risk (AAR) from 64 +/- 5% in dogs and to 15 +/- 2% of the left ventricle as compared with a control of 22 +/- 2% in ferrets. The protective effect of ifetroban in both species occurred with no increase in collateral BF or treatment-related alterations in peripheral hemodynamic status. Ifetroban, at the doses that reduced IS in ferrets, inhibited 99% of platelet TP receptors throughout the experiment, as measured by inhibition of the ex vivo platelet shape change response to U-46,619, a TP receptor agonist. Thus, doses of ifetroban causing profound TP receptor blockade also salvaged jeopardized myocardium in dogs and ferrets without changing collateral BF or peripheral hemodynamics.
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PMID:Myocardial salvage efficacy of the thromboxane receptor antagonist ifetroban in ferrets and dogs. 789 80