ANTI-THROMBOTIC EFFECTS OF E-5510 IN EXPERIMENTAL THROMBOSIS MODELS
A new agent developed in our laboratory, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid (E-5510), suppressed various human platelet functions in vitro. The compound also showed quite potent ex vivo anti-platelet effects in many experimentalanimals. It is well known that anti-platelet effects are not always parallel to anti-thrombotic effects. Thus, in order to predict the efficacy of E-5510 in thrombotic disorders, the anti-thrombotic effects were examined in 3 different animal models of thrombosis.(1) Anti-thrombotic effect in an extracorporeal shunt model Two hrs after oral administration of the drug to guinea pigs,an extracorporeal shunt between the right carotid artery and the left jugular vein was performed. The thrombus formation on a silk thread inserted in the shunt tube was quantitated by measuring the time from the onset of circulation to the stenosis of blood flow. E-5510 dose-dependently inhibited thrombus formation, the minimum effective dose being 0.03 mg/kg.(2) Effect on microthrombus formation in mesenteric arteriole In order to evaluate the effect on intravascular platelet thrombus formation, thrombosis was induced in vivo in mesenteric arteriole in guinea pigs with filtered light from a mercury lamp and an intravenous fluorescent dye in an intravital microscope system (M. Sato and N. Ohshima, Thromb. Res.,35, 319, 1984). The thrombus formation was quantitated by measuring the time taken for circulating platelets to begin to adhere to vessel wall and the time taken for blood flow to stop completely due to fully developed thrombus. Both the time required for platelet adhesion to vessel wall and for platelet thrombus formation were significantly prolonged after oral administration of E-5510.(3) Effect on pulmonary thromboembolism Acute pulmonary thromboembolism was induced in mice by a bolus intravenous injection of arachidonic acid, and mortality was determined 3 min later. E-5510 dose-dependently reduced pulmonary thromboembolic mortality, and its ED50 was 0.11 mg/kg. The results described above indicate thatE-5510 may have beneficial effects in clinical treatments of thrombotic disease.