ifetroban and Myocardial-Ischemia

This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A2/prostaglandin H2 receptor antagonist. Thromboxane A2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A2 levels in blood, urine, and tissues. The precursors to thromboxane A2, prostaglandin G2, and prostaglandin H2, also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A2/prostaglandin H2, rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A2- and prostaglandin H2-mediated processes.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypertension; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Ischemia; Oxazoles; Platelet Aggregation Inhibitors; Prostaglandin H2; Prostaglandins H; Randomized Controlled Trials as Topic; Receptors, Prostaglandin; Receptors, Thromboxane; Stroke; Thrombosis; Thromboxane A2

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.

Topics: Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Ferrets; Hemodynamics; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophil Activation; Oxazoles; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Thrombosis

We determined the effect of thromboxane A2 (TXA2) prostaglandin endoperoxide (TP) receptor antagonism, using BMS-180291 or aspirin, on the severity of pacing-induced ischemia in anesthetized dogs. Thromboxane receptor antagonists may not only have antithrombotic activity, but may also have direct cardioprotective effects, unlike aspirin. Left anterior descending coronary artery (LAD) stenosis was adjusted so that a significant (10-12 mV) ST segment elevation was observed only when superimposed on atrial pacing. Each heart was subjected to 5-min episodes of pacing-induced ischemia 10, 40, and 70 min after initiation of BMS-180291 (1 mg/kg + 1 mg/kg/h) or vehicle. In the vehicle group, ST segment elevation was reproducible at all pacing-induced ischemia episodes, whereas BMS-180291 significantly reduced it by 30% at the later ischemia episodes. This reduction in ST segment increase was not accompanied by alterations in regional myocardial blood flow (RMBF) nor in hemodynamic status. Aspirin in the same model [10 mg/kg intravenously (i.v.) given 10 min before pacing-induced ischemia] did not significantly reduce ST segment elevation, indicating a lack of protective effect in this model. Thromboxane receptor blockade appears to protect myocardium subjected to pacing-induced ischemia, an effect not produced by aspirin.

Topics: Angina Pectoris; Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Pacing, Artificial; Coronary Circulation; Disease Models, Animal; Dogs; Female; Hemodynamics; Injections, Intravenous; Male; Myocardial Ischemia; Oxazoles; Propionates; Radioligand Assay; Receptors, Thromboxane

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.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Dogs; Female; Ferrets; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Oxazoles; Propionates; Receptors, Thromboxane