title: Ethanol enhances the inhibitory effect of an oral GPIIb/IIIa antagonist on human platelet function.
abstract: Ethanol is a commonly used substance that can significantly influence platelet responses when combined with therapeutic drugs. In in vitro studies, we combined ethanol with LY309562, a novel 2,6-disubstituted isoquinolone RGD mimic that competes for fibrinogen binding to GPIIb/IIIa. Ethanol inhibits aggregation and secretion, partly by inhibiting thromboxane A(2) formation. We measured aggregation and secretion of dense granule contents by platelets labeled with [(14)C] serotonin in plasma from blood anticoagulated with FPRCH(2)Cl (PPACK). Alone, LY309562 dose-dependently inhibited aggregation induced by 10 micromol/L adenosine diphosphate, 1 microg/mL collagen, 2 micromol/L U46619 (a thromboxane A(2) mimetic), or 15 micromol/L SFLLRN (protease-activated receptor-1-activating peptide); inhibition was complete at 1 micromol/L LY309562 and partial at 0.1 micromol/L (50% inhibitory concentration [IC(50)] 0.19-0.33 micromol/L). Secretion induced by collagen, U46619, and SFLLRN was also inhibited by LY309562 (IC(50) 0.08-0.31 micromol/L). At inhibitory concentrations of LY309562, ethanol (2 or 4 mg/mL) further inhibited responses to collagen, U46619, and SFLLRN (IC(50) for aggregation 0.12-0.16 micromol/L; for secretion 0.04-0.12 micromol/L). Responses of aspirin-treated platelets to U46619 were also inhibited, indicating that ethanol was not acting solely by inhibiting thromboxane A(2) formation. Because it is likely that our results with LY309562 are representative of results with other GPIIb/IIIa antagonists, our in vitro data suggest that the concomitant use of GPIIb/IIIa antagonists and consumption of alcoholic beverages may result in further impairment of platelet participation in hemostasis and thrombosis.
authors.affiliation: Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. margaret.rand@sickkids.ca
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Rand
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: Amar
authors.initials: A
authors.lastname: Chahil
authors.forename: Raelene L
authors.initials: RL
authors.lastname: Kinlough-Rathbone
authors.forename: Marian A
authors.initials: MA
authors.lastname: Packham
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D015363:Quinolones / Q000494:pharmacology*; D012727:Sex Characteristics
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D004338:Drug Combinations; C470350:LY309562; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D015363:Quinolones; D000431:Ethanol; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone