title: FK419, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, ameliorates brain infarction associated with thrombotic focal cerebral ischemia in monkeys: comparison with tissue plasminogen activator.
abstract: The binding of platelet glycoprotein (GP) IIb/IIIa to fibrinogen is the final common pathway in platelet aggregation, a process known to play a key role in the pathogenesis of ischemic brain damage. We compared the effects of FK419, a novel nonpeptide GPIIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) on middle cerebral artery (MCA) patency and ischemic brain damage in a thrombotic stroke model in squirrel monkeys. FK419 not only inhibited in vitro platelet aggregation (IC50: 88 nmol/L), but also showed disaggregatory activity to aggregated platelet (EC50: 286 nmol/L). FK419 dose-dependently reduced the time to first reperfusion and total occlusion time of MCA blood flow when administered immediately after the termination of photoirradiation. FK419 reduced cerebral infarction and ameliorated neurologic deficits with similar dose-dependency. Although rt-PA reduced the time to first reperfusion, total occlusion time, and cerebral infarction, it did not significantly ameliorate neurologic deficits and induced petechial intracerebral hemorrhages. These results indicate: (1) FK419 restored cerebral blood flow after thrombotic occlusion of MCA, (2) FK419 reduced ischemic brain injury by its thrombolytic actions in a non-human primate stroke model, and (3) FK419 has superior antithrombotic efficacy and is safer than rt-PA.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, Kashima, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Kayoko
authors.initials: K
authors.lastname: Mihara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
authors.forename: Toshio
authors.initials: T
authors.lastname: Goto
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; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D020768:Middle Cerebral Artery / 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; D012453:Saimiri; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: C496616:((S)-2-acetylamino-3-((R)-(1-(3-(piperidin-4-yl)propionyl)piperidin-3-ylcarbonyl))amino) propionic acid trihydrate; D005343:Fibrinolytic Agents; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D010959:Tissue Plasminogen Activator