PT  - JOURNAL ARTICLE
AU  - Akira Moriguchi
AU  - Toshiaki Aoki
AU  - Kayoko Mihara
AU  - Nobuteru Tojo
AU  - Nobuya Matsuoka
AU  - Seitaro Mutoh
TI  - Antithrombotic Effects of FK419, a Novel Nonpeptide Platelet GPIIb/IIIa Antagonist, in a Guinea Pig Photochemically Induced Middle Cerebral Artery Thrombosis Model: Comparison with Ozagrel and Argatroban
AID  - 10.1124/jpet.103.058073
DP  - 2004 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1094--1101
VI  - 308
IP  - 3
4099  - http://jpet.aspetjournals.org/content/308/3/1094.short
4100  - http://jpet.aspetjournals.org/content/308/3/1094.full
SO  - J Pharmacol Exp Ther2004 Mar 01; 308
AB  - Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin αIIbβ3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A2 synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke. The American Society for Pharmacology and Experimental Therapeutics