title: Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression, fibrinogen binding, and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist.
abstract: The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.
authors.affiliation: Experimental Station E400/3255, Bristol-Meyers Squibb Company, Wilmington, DE 19880, USA. dietmar.seiffert@bms.com
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.forename: Beth E
authors.initials: BE
authors.lastname: Thomas
authors.forename: Jodi D
authors.initials: JD
authors.lastname: Bradley
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Munzer
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Tchinnes
authors.forename: David M
authors.initials: DM
authors.lastname: Kornhauser
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Cain
authors.forename: Tsuhung A
authors.initials: TA
authors.lastname: Hua
authors.forename: Giora Z
authors.initials: GZ
authors.lastname: Feuerstein
authors.forename: David E
authors.initials: DE
authors.lastname: Martin
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
mesh_terms: D000244:Adenosine Diphosphate; D000328:Adult; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019007:P-Selectin / Q000096:biosynthesis; D015539:Platelet Activation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs; D018179:Receptors, Thrombin
chemical_list: D000578:Amidines; D015415:Biomarkers; D007555:Isoxazoles; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D018179:Receptors, Thrombin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; C118235:roxifiban