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 (IC 50 : 88 nmol/L), but also showed disaggregatory activity to aggregated platelet (EC 50 : 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.

Targeting Platelets in Acute Experimental Stroke

“…46 Several experimental studies reported a beneficial effect of GPIIb/IIIa antagonists on stroke size and functional outcome. 44,47,48 GPIIb/IIIa antagonists also have been successfully used in experimental and clinical settings in conjunction with recombinant tissue-type plasminogen activator thrombolysis therapy without major complications reported. 49,50 This is in contrast to our study in which no effect on stroke volume or functional deficit was observed, regardless of the anti-GPIIb/ IIIa F(ab) 2 dosage used.…”

Safety of Tirofiban for Patients With Acute Ischemic Stroke in Routine Clinical Practice

“…After administration of lower doses was found after staining with triphenyltetrazolium chloride, a significantly smaller infarct volume than expected [11]. Other studies in experimental stroke models in guinea pigs and squirrel monkeys with the non-peptide GPIIb/IIIa blocker FK419 could uncover no bleeding complications, but showed reduced infarct volume as an indication of their effectiveness [12,13].…”

Bioethical Considerations in Translational Research: Primate Stroke

“…Further evidence for this contention comes from the fact that baboons do not rub or pick at their exenterated orbit, show no favoritism to it and show no physiological evidence of pain such as increased blood pressure, heart or respiratory rate. Femoral vascular access sites are similarly ignored (Maeda et al 2005;Marshall et al 2003;Qureshi et al 2005).…”