title: The antithrombotic activity of EP224283, a neutralizable dual factor Xa inhibitor/glycoprotein IIbIIIa antagonist, exceeds that of the coadministered parent compounds.
abstract: EP224283 combines in a single molecule idraparinux and tirofiban, which allows obtaining a predictable and sustained antiplatelet effect through the transfer of the pharmacokinetics properties of idraparinux to the anti-αIIbβ3 antagonist. The activity can be instantaneously neutralized by injection of avidin, a specific antidote. We have tested the effects of this new profile anticoagulant in various thrombosis models. The antithrombotic effect of EP224283 was compared with those of the parent compounds used alone or in association at doses achieving low to moderate inhibition of platelet aggregation ex vivo. In a model of systemic thromboembolism independent of thrombin generation, tirofiban and EP224283 had similar effects at equimolar doses. On the other hand, EP224283 was more potent than tirofiban or idraparinux under thrombin-dependent conditions. In a ferric chloride-induced thrombosis model, EP224283 was more potent than either parent compound or their combination. Similar results were obtained after atherosclerotic plaque rupture in ApoE(-/-) mice. Thus, the dual action of EP224283 exceeds that of the parent compounds used in combination. A possible explanation is that EP224283 could concentrate antithrombin inside the thrombus by binding to αIIbβ3 through the tirofiban moiety, as shown by immunolabeling of the occluded vessel. No prolongation of the bleeding time was observed at doses achieving strong antithrombotic effects, suggesting that low to moderate αIIbβ3 inhibition combined with factor Xa inhibition minimizes the bleeding risk. The favorable antithrombotic profile of EP224283 together with its possible neutralization by avidin makes it an interesting drug candidate for the treatment and prevention of acute ischemic events.
authors.affiliation: Unité Mixte de Recherche S949, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Etablissement Français du Sang-Alsace, 10 Rue Spielmann, BP 36, 67065 Strasbourg Cedex, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Hechler
authors.forename: Monique
authors.initials: M
authors.lastname: Freund
authors.forename: Ghina
authors.initials: G
authors.lastname: Alame
authors.forename: Cécile
authors.initials: C
authors.lastname: Leguay
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gaertner
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cazenave
authors.forename: Maurice
authors.initials: M
authors.lastname: Petitou
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
mesh_terms: D000818:Animals; D001710:Biotin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004195:Disease Models, Animal; D004338:Drug Combinations; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009844:Oligosaccharides / Q000008:administration & dosage* / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013923:Thromboembolism / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077466:Tirofiban; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D004338:Drug Combinations; C561312:EP 224283; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009844:Oligosaccharides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; C479958:idraparinux; D001710:Biotin; D015951:Factor Xa; D000077466:Tirofiban