Inflammatory disorders account for a significant percentage of debilitating diseases. It is now apparent that central to the therapeutic control of the inflammatory reaction is the regulation of the phospholipid metabolites, the eicosanoids. In most tissues the systhesis of the eicosanoids is limited by the availability of arachidonic acid (AA) which is first liberated from membrane phospholipids by the activity of phospholipase A2 (PLA2). The goal of the proposed work is therefore to test the biological efficacy of an endogenous inhibitor of PLA2 isolated from human sources. Phase I is directed towards: 1) determining the half-life of the inhibitor when injected I.V. into experimental animals; 2) determining if the inhibitor may disrupt the prostacyclin/thromboxane A2 balance; 3) determining if the inhibitor is effective as an anti-inflammatory therapeutic in acute models of inflammation by assessing its effect on rat hindpaw edema, pleural cavity inflammation and adjuvant induced arthritis. Positive results of the Phase I research will lead to the development in Phase II of an active, synthetic fragment of the PLA2 inhibitor and to its delivery using an adjuvant directed nasal delivery system. The results could lead to the development of an anti-inflammatory therapeutic which does not carry the side effects and toxicity of existing non-endogenous anti-inflammatory drugs and could be used to treat arthritis, systemic lupus, psoriasis and possibly atherosclerosis.
