title: The in vitro and in vivo pharmacological profiles of a platelet glycoprotein IIb/IIIa antagonist, NSL-9403.
abstract: The in vitro and in vivo pharmacological profiles of NSL-9403 [orotyl-serylarginyl-glycyl-asparatyl-tryptophane], a platelet glycoprotein IIb/IIIa (GpIIb/IIIa) antagonist, has been studied. NSL-9403 inhibited platelet aggregation of human platelet-rich plasma (PRP) with IC50 values of 4.3 +/- 0.4 microM (collagen) and 1.8 +/- 0.3 microM (ADP), which was about 100 times more potent than RGDS. It also inhibited the binding of fibrinogen to activated platelets. Ex vivo collagen and ADP-induced platelet aggregation in a guinea pig was inhibited after a bolus intravenous administration of NSL-9403 at 1.25 mg/kg and above. NSL-9403 had an anti-thrombotic effect in in vivo thrombosis models. In a platelet agonist-induced pulmonary embolic sudden death model, where a bolus injection of collagen and epinephrine induced sudden death in mice, intravenous administration of NSL-9403 before an injection of collagen and epinephrine inhibited this platelet-agonist induced death in a dose dependent manner. In an arterio-venous shunt, infusion of NSL-9403 at 3 mg/kg/hour prevented an increase in circulation pressure due to thrombus formation in the shunt circuit and platelet loss. Infusion of NSL-9403 at 1 to 10 mg/kg/hour produced a complete inhibition of platelet-dependent arterial thrombosis in a dog femoral arterial thrombosis model. Thus NSL-9403 is a potent inhibitor or platelet aggregation in vitro and a potent anti-thrombotic agent in vivo with a relatively short duration of action.
authors.affiliation: Life Science Research Center, Nippon Steel Corporation, Kawasaki, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Katada
authors.forename: Y
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.forename: T
authors.initials: T
authors.lastname: Fujiyoshi
authors.forename: I
authors.initials: I
authors.lastname: Uno
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011655:Pulmonary Embolism / Q000139:chemically induced; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C109907:orotyl-seryl-arginyl-glycyl-aspartyl-tryptophane; D000244:Adenosine Diphosphate; D005340:Fibrinogen