Anti-Thrombotic Action of DZ-697b, a Novel Anti-Platelet Agent, on Photochemically Induced Thrombosis with Lower Bleeding Risk in Guinea Pigs.

Introduction: DZ-697b, a novel anti-platelet compound, selectively inhibits ristocetin- and collagen-induced platelet aggregation, whose pharmacological profile is different from any current medicines. In order to clarify the benefit and risk balance as an anti-thrombotic agent, effects of DZ-697b and aspirin were compared on thrombus formation and gastric bleeding model in guinea pigs.

Materials and Methods: Fasted male Hartly guinea pigs under anesthesia were used. DZ-697b (3 - 200 mg/kg) or aspirin (100–300 mg/kg) was orally administered 60 min prior to evaluation.

PIT model: Left carotid artery was exposed. Photochemically induced thrombosis (PIT) was initiated by intravenous injection of rose-bengal (10 mg/kg) and exposure of green light (540 nm) to the carotid artery. The time to occlusion by thrombus formation was measured by pulse Doppler blood flow meter.

Gastric bleeding model: The stomach was exposed, and esophagus and pylorus were ligated. A cannula was inserted into stomach and gastric hemorrhagic erosion was induced by intraluminal application of 0.7N HCl in a volume of 5mL. Gastric contents were collected every 10 min and measured hemoglobin (Hb) leakage as indices of bleeding.

Results: DZ-697b at 3 mg/kg to 100 mg/kg dose-dependently prolonged the time to occlusion in the PIT model, and significant anti-thrombotic effects were observed from 10 mg/kg. However, gastric bleeding induced by 0.7N HCl in gastric lavage was not affected by DZ-697b up to 100 mg/kg. Statistically significant increase in gastric bleeding was observed when DZ-697b was administered at 200 mg/kg. Aspirin at doses of 100–300 mg/kg tended to lengthen the time to thrombotic occlusion in a dose-dependent manner, but there was no statistically significant difference. In contrast, aspirin dose-dependently increased gastric bleeding in the lavage and significant enhancement was found at doses of 200 and 300 mg/kg. Both DZ-697b and aspirin did not give any influences on the area of hemorrhagic erosion induced by gastric application of 0.7N HCl. Thus, the balance between anti-thrombotic effect and bleeding risk of DZ-697b seemed more favorable than that of aspirin.

Conclusion: DZ-697b showed anti-thrombotic effects at doses much lower than those inducing gastric bleeding in comparison with aspirin. These results suggest that inhibitors of vWF and collagen related signaling pathway are promising target in the development of new anti-platelet drugs with lower bleeding risk.