Studies on aspirin derivatives with very little side effect. II. Potent platelet anti-aggregant activity and no mutagenicity of aspirin-isopropylantipyrine (AIA).

Abstract

The effect of a new aspirin derivative, aspirin-isopropylantipyrine (AIA), with very little gastric ulcerogenic activity and very slight acute toxicity and with analgesic, antipyretic anti-inflammatory, and platelet aggregation inhibitory activities was evaluated in vitro and ex vivo and compared with those of aspirin and isopropylantipyrine (IA). In vitro, AIA, aspirin and IA (50-200 microM) caused concentration-dependent inhibition of collagen-induced aggregation in rabbit platelets although AIA was several-fold more active than the others Arachidonic acid-induced aggregation was inhibited by all three agents (200 microM) in the following magnitude; IA greater than aspirin greater than AIA. Three agents did not influence primary ADP-induced aggregation. The in vitro effects on the release-inducing aggregants were confirmed by ex vivo experiments in rats. These demonstrated that AIA and aspirin (50 mg/kg) exhibited almost identical inhibitory potencies in the extent and the rate of collagen-induced aggregation 4 h after subcutaneous injection. AIA was still effective 24 h after administration as well as aspirin. IA was less effective, differing from the results in vitro. AIA had no effect on plasmin activity and blood flow through the common carotid artery. AIA (1 mM) maintained spreading and beating of myocardial cells in a serum-free culture. As special toxicity trials on AIA mutagenecity tests were made by the Rec-assay with Bacillus subtilis, by the plate culture with Escherichia coli, and by the Ames system with Salmonella typhimurium. AIA was found to have no mutagenic effect under any of those methods and to have no effect on the mutagenic action of 3, 4-benzopyrene under the liver microsome test using the Ames system.