title: FK419, a novel nonpeptide GPIIb/IIIa antagonist, restores microvascular patency and improves outcome in the guinea-pig middle cerebral artery thrombotic occlusion model: comparison with tirofiban.
abstract: The antithrombotic efficacy of FK419, a novel nonpeptide platelet glycoprotein IIb/IIIa antagonist, was compared with tirofiban in guinea-pigs. FK419 and tirofiban similarly inhibited platelet aggregation in vitro (IC50 values: 0.43+/-0.076 and 0.41+/-0.053 micromol/L) and dispersed aggregated platelets (EC50 values: 2.3+/-0.88 and 2.0+/-0.81 micromol/L). FK419 inhibited retention of platelets and neutrophils in a collagen-coated bead column with greater potency than tirofiban (IC50 values of 0.90+/-0.133 and 2.4+/-0.21 micromol/L for platelet retention and 0.32+/-0.078 and 0.57+/-0.180 micromol/L for neutrophil retention). When FK419 or tirofiban were administered after photochemically induced middle cerebral artery (MCA) occlusion in guinea-pigs, they dose-dependently improved MCA patency. FK419 reduced neurological deficits and ischemic brain damage in a dose-dependent fashion, whereas tirofiban did not. Reduced regional cerebral blood flow in the striatum gradually returned to the preoccluded level with FK419 treatment; however, no restoration was observed with tirofiban even though the MCA was recanalized. These results indicate that FK419 ameliorates ischemic brain damage by not only lysing the obstructive thrombus in MCA but also preventing or restoring microcirculation deficits after occlusion/reperfusion, suggesting that FK419 would be an attractive intervention for the treatment of ischemic stroke patients.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima, Yodogawa-ku, Osaka, Japan. akira_moriguchi@po.fujisawa.co.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.forename: Kayoko
authors.initials: K
authors.lastname: Mihara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoki
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020767:Intracranial Thrombosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077466:Tirofiban; D014443:Tyrosine / Q000008:administration & dosage* / Q000031:analogs & derivatives*
chemical_list: C496616:((S)-2-acetylamino-3-((R)-(1-(3-(piperidin-4-yl)propionyl)piperidin-3-ylcarbonyl))amino) propionic acid trihydrate; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D014443:Tyrosine; D000077466:Tirofiban