Evaluation of a GPIIb/IIIa antagonist YM337 in a primate model of middle cerebral artery thrombosis.
We compared the antithrombotic effect of anti-GPIIb/IIIa antibody Fab fragment YM337 with that of a thromboxane A2 synthetase inhibitor, sodium ozagrel. With the monkeys under halothane anesthesia, the right middle cerebral artery was observed via a transorbital approach without cutting the dura mater. Photoillumination (wavelength 540 nm) was applied to the middle cerebral artery, and then rose bengal (20 mg kg(-1)) was administered intravenously. The experimental drugs were intravenously injected 15 min before rose bengal injection and followed by continuous infusion for 3 h after dye injection. The thrombotic occlusion induced by this photochemical reaction in monkey middle cerebral artery was reproducible. YM337 significantly prolonged the time to first occlusion and the total time of arterial patency during the 3-h observation period after dye injection. In contrast, sodium ozagrel had no significant effect. YM337 but not sodium ozagrel significantly inhibited ex vivo ADP-induced platelet aggregation. However, while sodium ozagrel significantly inhibited the thromboxane B2 generation accompanying arachidonic acid-induced platelet aggregation, YM337 had no effect on this variable. Neurological deficit in the YM337-treated animals was significantly milder than that in the control group. The area of infarct in the YM337 treatment animals was smaller than that in the control group. The novel selective GPIIb/IIIa antagonist YM337 was effective in ameliorating the decrease in patency of the middle cerebral artery and reducing the area of cerebral infarction in monkeys.
Kaku
S
S
Department of Pharmacology, Hamamatsu University School of Medicine, Japan. kaku.seiji@yamanouchi.co.jp
Umemura
K
K
Mizuno
A
A
Yano
S
S
Suzuki
K
K
Kawasaki
T
T
Nakashima
M
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use*; D002542:Intracranial Embolism and Thrombosis / Q000188:drug therapy*; D008689:Methacrylates / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology*; D012453:Saimiri; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007140:Immunoglobulin Fab Fragments; D008689:Methacrylates; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013930:Thromboxane-A Synthase; C034364:ozagrel