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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 (IC 50  values: 0.43 ± 0.076 and 0.41 ± 0.053 μmol/L) and dispersed aggregated platelets (EC 50  values: 2.3 ± 0.88 and 2.0 ± 0.81 μmol/L). FK419 inhibited retention of platelets and neutrophils in a collagen-coated bead column with greater potency than tirofiban (IC 50  values of 0.90 ± 0.133 and 2.4 ± 0.21 μmol/L for platelet retention and 0.32 ± 0.078 and 0.57 ± 0.180 μmol/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.

journal of cerebral blood flow and metabolism

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