The thrust of these efforts remains directed principally at aiding those especially predisposed to thromboembolic complications because of their blood's exposure to biomaterials (implanted prosthetic devices, renal dialysis, blood oxytenation, cardiac catheterization, etc.). We seek to continue our exploratory work on the design, synthesis and evaluation of compounds capable of reinforcing the integrity of human blood platelets against biodynamic impacts which could trigger platelet aggregation. The range of structural diversities facilitates identification of platelet aggregation inhibitors with superior or preferable biodistribution and biotransformation profiles; this is of prominent importance since the nature of prophylaxis sought may require the administration of these agents for years and decades. Undergirding platelet aggregation-inhibitory specific functions with components enhancing appropriately interfacial activity,we have developed expertise to """"""""fine-tune"""""""" molecular configuration for optimal effect on platelet function. One U.S. and one foreign patient have been issued; in addition, two American and ten foreign patents are pending on several series of our compounds previously not associated with antiplatelet activity. Having established the effectiveness of our previously reported compounds, their intrinsic cellular toxicity, acute lethality and in vivo activity (in dogs) will be studied. Pharmacokinetic and bioavailability evaluations will be performed on the most promising congeners of the respective series. The striking relationships between the influence of these compounds on polymer-induced platelet cluster formation and their inhibitory action in ADP- and thrombin-stimulated blood platelet aggregation will be further investigated. In cooperation with Doctor Larry V. McIntire, at Rice University, their impact will be studied on the kinetics of human blood platelet adhesion and thrombus growth effected by collagen, biomaterials and related polymers in a parallel plate flow chamber system. Among other studies, emphasis will be placed on evaluating the effect of our compounds on serotonin intake and release in human platelets, and we will endeavor to relate these findings to transport across the platelet plasma membrane and across organelle membranes of granules which store this endogenous agent. The effect of our compounds on platelet factor 3 availability will be evaluated, and their influence on platelet factor 4 will be also examined.
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