ifetroban and Thrombosis

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

An experimental model of acute thrombosis was developed in pentobarbital- anesthetized ferrets. A 10-min anodal electrical stimulation of 1 mA was delivered to the external surface of the carotid artery while measuring carotid blood flow (CBF). This produced an occlusive thrombus in all vehicle-treated ferrets within 41 +/- 3 min with an average weight of 8 +/- 1 mg (n = 7). These thrombi were enriched in both platelets and fibrin and were adherent at the site of transmural vascular injury as determined by light and electron microscopy. To determine the model's sensitivity to antiplatelet drugs, aspirin or a thromboxane (TxA2) receptor antagonist (ifetroban) were administered 15 min before electrical stimulation. Thrombus weight was reduced 58% by aspirin (10 mg/kg, i.v.) and 74% by ifetroban (1 mg/kg + 1 mg/kg per hr, i.v.). Both drugs also improved CBF and decreased vascular occlusion. Ferrets were more sensitive than rats to aspirin's inhibition of collagen-induced platelet aggregation as determined ex vivo in whole blood. Separate in vitro platelet aggregation studies revealed species differences in reactivity to U-46619 (TxA2 receptor agonist) and collagen in the order of human > ferret > rat, with relatively lesser variations in ADP responses. These studies identify the ferret as a useful species for evaluating antithrombotic drugs in a model in which aspirin is efficacious.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aspirin; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Carotid Arteries; Carotid Artery Injuries; Collagen; Disease Models, Animal; Electric Stimulation; Ferrets; Fibrin; Humans; In Vitro Techniques; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Oxazoles; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Prothrombin Time; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Species Specificity; Thrombosis; Thromboxane A2; Vasoconstrictor Agents

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 effects of aspirin and a novel thromboxane A2/prostaglandin endoperoxide (TP)-receptor antagonist, BMS-180291, on thrombosis and bleeding times in skin and mesenteric arteries. In anesthetized rats, occlusive thrombosis was induced in the carotid artery by topical application of ferrous chloride and in the vena cava by blood flow stasis combined with either infusion of thromboplastin or hypotonic saline. Aspirin (1, 10, and 50 mg/kg) did not reduce arterial or venous thrombus weight significantly. BMS 180,291 (150 micrograms/kg/min) decreased arterial thrombus weight and hypotonic saline-induced caval thrombus weight by 58 and 57%, respectively. BMS-180291 lacked antithrombotic activity at a lower dose (50 micrograms/kg/min) and failed to inhibit thromboplastin-induced caval thrombosis. BMS-180291 (150 micrograms/kg/min) significantly reduced arterial thrombus weight by 40% when plasma epinephrine concentration was increased to 5 ng/ml. BMS-180291 and aspirin produced increases of only < or = 30% in bleeding times. These results demonstrate that BMS-180291 has antithrombotic activity in experimental aspirin-resistant arterial and venous thrombosis. Both aspirin and BMS-180291 have only modest effects on small artery hemostasis in rats.

Topics: Animals; Aspirin; Bleeding Time; Bridged Bicyclo Compounds, Heterocyclic; Carotid Artery Thrombosis; Disease Models, Animal; Epinephrine; Male; Mesenteric Arteries; Oxazoles; Platelet Aggregation Inhibitors; Propionates; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Thrombosis; Venae Cavae