ANTIPLATELET ACTIVITY OF THE LONG-ACTING THROMBOXANE RECEPTOR ANTAGONIST BMS-180,291 IN MONKEYS

被引:17
作者
SCHUMACHER, WA
STEINBACHER, TE
YOUSSEF, S
OGLETREE, ML
机构
[1] Department of Pharmacology, Bristol-Myers Squibb, Pharmaceutical Research Institute, NJ USA 08543-4000, P.O. Box 4000, Princeton
来源
PROSTAGLANDINS | 1992年 / 44卷 / 05期
关键词
D O I
10.1016/0090-6980(92)90135-G
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 1 80,291 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 BMS180,291 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.
引用
收藏
页码:389 / 397
页数:9
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