Restoration of middle cerebral artery thrombosis by novel glycoprotein IIb/IIIa antagonist FK419 in guinea pig.
We compared the antithrombotic efficacy of FK419 [(S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl)propionyl]piperidin-3-ylcarbonyl]amino] propionic acid trihydrate], a novel nonpeptide glycoprotein IIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) and other antithrombotic agents (aspirin, ozagrel, argatroban and heparin). FK419 not only inhibited ADP- and collagen-induced guinea pig platelet aggregation, but also induced disaggregation for ADP-induced aggregated platelets in vitro. In the photochemically induced middle cerebral artery thrombosis model in guinea pigs, FK419 dose-dependently shortened the time to first reperfusion and the total middle cerebral artery occlusion time and reduced ischemic brain damage and ameliorated neurological deficits measured 24 h after middle cerebral artery occlusion. Rt-PA similarly improved the middle cerebral artery patency, brain damage and neurological deficits. Neither aspirin, ozagrel, argatroban nor heparin restored the middle cerebral artery blood flow and improved the brain damage or neurological deficits. These results demonstrated that novel glycoprotein IIb/IIIa antagonist FK419 could disperse thrombus and ameliorated ischemic brain damage, suggesting that FK419 would be an attractive intervention for stroke patients.
Moriguchi
Akira
A
Department of Neuroscience, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
Mihara
Kayoko
K
Aoki
Toshiaki
T
Maeda
Masashi
M
Tojo
Nobuteru
N
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy*; D013997:Time Factors
D005343:Fibrinolytic Agents; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011804:Quinolines; C496617:SB 223956