Studies on the Mode of Action of Non-Steroidal Anti-Inflammatory Agents

Abstract

The recent proposal by Vane and his associates at the Royal College of Surgeons in London (Vane, 1971; Smith and Willis, 1971; Ferreira et al, 1971) that the antiinflammatory activity of indomethacin may be related to its ability to inhibit prostaglandin biosynthesis prompted the present studies. Our purpose was to compare the ability of a substantial number of established nonsteroidal anti-inflammatory agents and related compounds to inhibit prostaglandin biosynthesis with their antiinflammatory activity in vivo, as defined by the carrageenin foot edema assay. This latter assay (Winter et al, 1963), following its initial application to the development of indomethacin analogs, has been widely employed in the search for other anti-inflammatory agents, These compounds, consisting chiefly of the aryl acid type, as exemplified by substituted indole acetic acids, phenylacetic acids and anthranilic acids, have been shown to possess a wide spectrum of biological activities which include inhibition of mucopolysaccharide biosynthesis, suppression of proteolysis and other less well-defined functions involving membrane structures, such as prevention of platelet aggregation, inhibition of leukocyte migration (Bertelli and Houck, 1969) and erythrocyte stabilization (Gorog and Kovacs, 1970). The multiplicity of effects of the non-steroidal antiinflammatory agents and the doses required to elicit them suggest that these properties are not associated with their primary action as anti-inflammatory agents.