title: Ro 44-9883, a new non-peptidic GPIIb-GPIIIa antagonist prevents platelet loss in a guinea pig model of extracorporeal circulation.
abstract: Extensive contact between blood and artificial surfaces causes platelet activation and depletion. The aim of the present study was to test the efficacy of Ro 44-9883, a potent and selective peptidomimetic GPIIb-IIIa antagonist, in preventing platelet loss in guinea pigs undergoing extracorporeal circulation (ECC) with bubble oxygenation. In 15 guinea pigs, an arterio-arterial shunt was created and perfused for 1 h from the aortic arch to the descending aorta. The guinea pigs were divided into three groups: A control group receiving only heparin as an i.v. bolus, a low dose-treated group and a high dose-treated group receiving in addition to heparin and before starting ECC, 1 or 7 mg/kg Ro 44-9883 as an i.v. bolus, respectively. In the control group, the platelet count at 30 and 60 min of ECC was dramatically decreased (35 +/- 4% and 25 +/- 3% of initial value). In the low dose-treated group, Ro 44-9883 partially prevented the drop in platelet count (69 +/- 8% and 54 +/- 9%; p < 0.05) whereas in the high dose-treated group, the platelet count was normal at 30 min (97 +/- 8%) and only slightly decreased at 60 min (80 +/- 7%). Mean arterial pressure and hematocrit were not significantly different between groups during the experiment. We conclude that i) ECC in guinea pigs provides an interesting in-vivo model for studying platelet loss by contact activation and ii) Ro 44-9883 prevents platelet loss during ECC in a dose dependent manner.
authors.affiliation: Pharma Division, Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Carteaux
authors.forename: B
authors.initials: B
authors.lastname: Steiner
authors.forename: S
authors.initials: S
authors.lastname: Roux
mesh_terms: D000085:Acetates / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D005112:Extracorporeal Circulation / Q000009:adverse effects; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000085:Acetates; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; D014443:Tyrosine; D000244:Adenosine Diphosphate; D006493:Heparin; C084062:lamifiban; C046617:arginyl-glycyl-aspartyl-serine