Glycoprotein IIb/IIIa receptor number and occupancy during chronic administration of an oral antagonist

作     者：Quinn, MJ Cox, D Foley, JB Fitzgerald, DJ 

作者机构：Royal Coll Surgeons Ireland Dept Clin Pharmacol Ctr Cardiovasc Sci Dublin 2 Ireland St James Hosp Dept Cardiol Core Res Engn Sci & Technol Directorate Dublin 8 Ireland 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第295卷第2期

页      面：670-676页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

主　　题：腺苷二磷酸/药理学 投药 口服 抗体 单克隆/血液 苄脒类/血液 苄脒类/药理学 血小板/药物作用 血小板/代谢 双盲法 用药计划表 血小板聚集/药物作用 血小板聚集抑制剂/药理学 成年人 老年人 老年人 80以上 女(雌)性 人类 男(雄)性 中年人 

摘      要：Long-term treatment with oral glycoprotein (GP) IIb/IIIa antagonists has failed to produce significant clinical benefit. We have examined the pharmacology of xemilofiban in the evaluation of oral xemilofiban in controlling thrombotic events (EXCITE) trial. The EXCITE trial was a multicenter study of xemilofiban in 7232 patients undergoing percutaneous coronary intervention. Thirty-two patients randomized to xemilofiban (10 or 20 mg three times daily) or placebo were followed for up to 6 months. GPIIb/IIIa receptor number and occupancy were quantified using two monoclonal antibodies mAb1 and mAb2. mAb1 was used to quantify receptor number. mAb2 recognizes an epitope that is lost due to a ligand-induced conformational change in GPIIb/IIIa and is a marker of receptor occupancy. Platelet aggregation was performed by light transmission. In vitro, the active metabolite of xemilofiban (SC-54701) inhibited mAb2 binding (IC50 of 0.5 +/- 0.1 X 10(-8) M) but not mAb1. In vivo, long-term therapy with xemilofiban did not alter GPIIb/IIIa receptor number. mAb2 binding was inhibited throughout the treatment period and recovered slowly after drug withdrawal. Maximum inhibition of ADP-induced aggregation occurred at 4 to 7 h after the first dose of study medication. However, inhibition of platelet aggregation was low (between 24 and 45%) before dosing on days 60 and 180. There was no significant rebound increase in platelet aggregation after drug withdrawal. Long-term xemilofiban therapy does not alter platelet GPIIb/IIIa receptor number. Inhibition of platelet aggregation was poor at the end of each dosing interval and this may explain the failure of xemilofiban to alter clinical events.