Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Previous work in this laboratory demonstrated that a series of benzoic acid analogs, with only minor structural variations compared to ASA, displayed a wide variation in biological effects compared to ASA. The compounds studied include 2-propionyloxybenzoic acid (2-PBA), 3-propionyloxybenzoic acid (3-PBA), 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP) and 3-hydroperoxy-3-methylphthalide (3HMP). The purpose of this study was to extend our knowledge of the effects of these compounds and the processes they modify by assessing the in vivo antithrombotic and anti-inflammatory activities and the inhibition of prostaglandin (PG) synthesis (including PGI(,2)) in related in vitro systems. The ultimate aim of this work is the design of agents with more specific anti-inflammatory and antithrombotic activities.;The systems studied were (1) ADP and collagen-stimulated platelet aggregation and release of ATP; (2) platelet PG synthesis products; (3) platelet cyclic nucleotide phosphodiesterase activity (PDE); (4) aorta PGI(,2)-like activity production; (5) aorta arachidonic acid (AA) metabolism; (6) electrical injury-induced thrombosis in a rat model; (7) carrageenin-induced pleurisy in a rat model and; (8) polymorphonuclear neutrophil (PMN) AA metabolism.;ABA appears to be a unique agent with both anti-inflammatory and antithrombotic activity not accountable by PG synthesis or PDE inhibition. This agent appears a likely candidate as an anti-inflammatory agent without antiplatelet activity. The hydroperoxide, 3HMP, appears as a particularly useful tool for the study of the mechanisms of cyclo-oxygenation and lipoxygenation of AA and the activation and inhibition of the enzyme systems involved.;These studies point to unique mechanisms of action of antithrombotic and anti-inflammatory activities with a series of benzoic acid analogs and suggest that PG synthesis does not totally account for either antithrombotic or anti-inflammatory activity.



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