Synthesis and antiplatelet effects of the new antithrombotic agent aspalatone with low ulcerogenicity
Han, B.H.; Suh, D.Y.; Yang, H.O.; Park, Y.H.; Kang, Y.H.; Kim, Y.C.
Arzneimittel-Forschung 44(10): 1122-1126
1994
ISSN/ISBN: 0004-4172 PMID: 7818584 Document Number: 425641
A new compound, aspalatone (acetylsalicylic acid maltol ester), was synthesized 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 vivo in rats, and for its antithrombotic activity in vivo using the mouse thromboembolism test. Aspalatone treatment (15 mg/kg p.o.) for 10 days prolonged bleeding time by 57% (p lt 0.005) in Sprague-Dawley rats vs control, while ASA treatment (15 mg/kg p.o.) prolonged by 44 %. At the low dose of 15 mg/kg p.o. at least 8 days of treatment were necessary for aspalatone and ASA to prolong the bleeding time significantly, On the other hand, salicylic acid maltol ester which lacks the acetyl group did not significantly affect bleeding time at a dose of 15 mg/kg. Aspalatone produced a potent inhibition of collagen-induced 'platelet aggregation in vitro with IC-50 of 1.8 times 10-4 mol/l, but, similar to ASA, did not significantly inhibit ADP-induced aggregation. The ability of oral aspalatone to inhibit platelet aggregation in rats ex vivo was compared with other reference antiplatelet drugs. Relative potency was ASA gt dipyridamole simeq aspalatone gt ticlopidine. A single dose of aspalatone potently prevented death due to collagen-induced platelet 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 lt 0.001) at 20 mg/kg, and this antithrombotic effect lasted after 4 days of wash-out period In addition, aspalatone caused negligible 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; IC-50 values for malondialdehyde generation in vitro were 1.1 times 10-4 mol/l and 8.4 times 10-5 mol/l, respectively. These results suggest that aspalatone might be a potential antithrombotic agent with low ulcerogenicity.