Antiplatelet activity of the long-acting thromboxane receptor antagonist BMS 180,291 in monkeys.
The effects of the novel TxA2/prostaglandin endoperoxide (TP) receptor antagonist BMS 180,291 on platelet reactivity was determined ex vivo in conscious African green monkeys. Platelet aggregation responses to U-46,619 were decreased 50% and 100% at 23 to 24 hrs after BMS 180,291 oral doses of 1 and 3 mg/kg, respectively. In addition to inhibiting aggregation, a 3 mg/kg oral dose of BMS 180,291 also produced an 11 +/- 3-fold shift to the right in the U-46,619 concentration-response relationship for platelet shape change at 24 hrs after dosing. When the 3 mg/kg oral dose was continued for 11 days, the shift in this concentration-response relationship increased to 26 +/- 10- and 93 +/- 30-fold at 24 hrs after the 8th and 11th doses, respectively. This progressive inhibition corresponds to 93 +/- 3 and 99 +/- 1% blockade of platelet TP-receptors responsible for shape change, respectively. Comparable levels of TP-receptor blockade have been previously correlated with antithrombotic and antiischemic activities of TP-receptor antagonists in vivo. Platelet reactivity to U-46,619 had completely recovered on the 7th day after the final dose of BMS 180,291, indicating effective elimination from the circulation over this interval. In separate experiments, a 3-mg/kg i.v. dose of BMS 180,291 produced only marginal and transient hemodynamic effects in anesthetized African green monkeys. Overall, these data demonstrate that BMS 180,291 given orally once a day produces a sustained and therapeutically-relevant level of TP-receptor antagonism.
Schumacher
W A
WA
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
Steinbacher
T E
TE
Youssef
S
S
Ogletree
M L
ML
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D010080:Oxazoles / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; C054215:SQ 30741; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C078904:ifetroban