SYNTHESIS AND ANTIPLATELET EFFECTS OF THE NEW ANTITHROMBOTIC AGENT ASPALATONE WITH LOW ULCEROGENICITY

A new compound, aspalatone (acetylsalicylic acid maltol ester), was sy nthesized by esterification of acetylsalicylic acid (ASA) and maltol, an antioxidant, and studied for its bleeding time prolongation effect in rats, for its antiplatelet aggregation activity in vitro and ex viv o in rats, and for its antithrombotic activity in vivo using the mouse thromboembolism test. Aspalatone treatment (15 mg/kg p.o.) for 10 day s prolonged bleeding time by 57% (p < 0.005) in Sprague-Dawley rats vs control, while ASA treatment (15 mg/kg p.o.) prolonged by 44 %. At th e low dose of is mg/kg p.o. at least 8 days of treatment were necessar y for aspalatone and ASA to prolong the bleeding time significantly. O n the other hand salicylic acid maltol ester which lacks the acetyl gr oup did not significantly affect bleeding time at a dose of 15 mg/kg. Aspalatone produced a potent inhibition of collagen-induced platelet a ggregation in vitro with IC50 of 1.8 X 10(-4) mol/l, but, similar to A SA, did not significantly inhibit ADP-induced aggregation. The ability of oral aspalatone to inhibit platelet aggregation in rats ex vivo wa s compared with other reference antiplatelet drugs. Relative potency w as ASA > dipyridamole congruent to aspalatone > ticlopidine. A single dose of aspalatone potently prevented death due to collagen-induced pl atelet aggregation in mice in vivo with ED(50) value of 32 mg/kg p.o., but failed to prevent death due to ADP-induced platelet aggregation. When given for 10 days, aspalatone prevented collagen-induced death by 90% (p < 0.001) at 20 mg/kg, and this antithrombotic effect lasted af ter 4 days of wash-out period. In addition, aspalatone caused negligib le gastric mucosal damage (ulcer index = 0.71 mm, 800 mg/kg p.o.) in a sharp contrast to ulcerogenic ASA (ulcer index = 29 mm, 200 mg/kg p.o .) Antioxidant activity of aspalatone was comparable to that of maltol ; IC50 values for malondialdehyde generation in vitro were 1.1 x 10(-4 ) mol/l and 8.4 x 10(-5) mol/l, respectively. These results suggest th at aspalatone might be a potential antithrombotic agent with low ulcer ogenicity