The relationships between inhibition of platelet prostaglandin (PG) synthesis and aggregation, and suppression inflammation were investigated with a number of benzoic acid (aspirin-like) chemicals. The compounds studied were 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP), 3-propionyloxybenzoic acid (3-PBA) and 2-propionyloxybenzoic acid (2-PBA). At 0.5--0.6 mM, 3-MP inhibited the second phase of ADP-induced aggregation in human platelets, and reduced collagen-induced aggregation by 50%. Previous studies have shown 2-PBA to inhibit aggregation at similar concentrations. In contrast, ABA required 10 times higher concentrations, and low concentrations actually potentiated aggregation. Inhibition of PG synthesis from 14C-arachidonic acid (AA) by human platelets was shown for 2-PBA, but not to 3-BPA, or ABA. At high concentration (1 mM), 3-MP showed modest inhibitory activity. Significant inhibition of AA aggregation was produced by ASA (83%), 2-PBA (76%) and 3-MP (69%), an order reflecting their inhibition of PG synthesis, where ABA and 3-PBA did not inhibit AA aggregation. Carrageenin-induced edema of the rat paw was suppressed by 3-MP, ABA and 2-PBA; all being roughly equipotent with aspirin. In contrast, 3-PBA did not suppress edema. Following oral administration of the drugs to rats, PG synthesis from labeled AA by rat platelets showed similar profiles to effects of the drugs on PG synthesis in human platelets. This suggests that biotransformation or species differences are not explanations for the observed differences in activity in the various test systems. The results indicate that, in a related series of chemicals there is not a good correlation between ability to inhibit platelet PG synthesis, anti-aggregatory activity and anti-inflammatory activity. Multiple mechanisms of action, differing sensitivities of various tissue PG synthetases, or unidentified factors could be involved.
3-Hydroperoxy-3-methylphthalide (3-HMP), a structural analog of acetylsalicylic acid (ASA), was found to have some antiinflammatory properties which are distinct from those of ASA. 3-HMP inhibits human platelet aggregation and ATP release in response to low concentrations of collagen but is less effective than ASA. 3-HMP inhibits prostaglandin and thromboxane production from exogenous [14C]arachidonic acid by human platelet lysates in vitro and does so at lower concentrations than ASA (3-HMP IC50 = 10 microM; ASA IC50 = 50 microM). 3-HMP is also more effective than ASA as an inhibitor of prostacyclin-like activity production by rings of rabbit aorta. Human polymorphonuclear (PMN) leukocyte [14C]arachidonic acid metabolism is inhibited by 3-HMP but not ASA. In urethane-anesthetized rats, 3-HMP (10 mg/kg intravenously) is effective in inhibiting PMN leukocyte accumulation in response to intrapleural carrageenan administration whereas ASA is ineffective (100 mg/kg intravenously). This hydroperoxy analog of ASA has antiinflammatory activity which may result from a combination of the ASA-like and hydroperoxide-related pharmacological properties.
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