Clinical reports of cocaine's cardiovascular toxicity have a paradoxical quality; for example, toxicity has been reported to occur after relatively low-dose initial use in some patients as well as after years of use at relatively constant dosage in others. Attempts to determine the mechanism of cocaine's toxic effects have been hampered by the lack of a suitable animal model that demonstrates consistent and reproducible cardiac and vascular responses to administration of the drug. This is underscored by the failure of in vitro studies (which have primarily reported local anesthetic effects and blockade of neuronal catecholamine uptake) to provide testable hypotheses to explain the clinical paradox discussed above. What is needed is a coordinated approach between the clinical and basic sciences in which the effects of cocaine in the intact animal and human can be documented and the appropriate in vitro studies conducted to delineate cellular mechanisms. This Program Project consists of four individual research projects supported by three Core Units: Administrative (Core A) and Patient Registry (Cores B and C). The individual research projects have been selected to provide a spectrum of experimental approaches ranging from intact animal models of cocaine toxicity to clinical patient trials. Project I is a whole animal study to be performed in minipigs with hyper-responsive coronary arteries. These animals closely model vasospasm in man. Project II will examine in a conscious, chronically instrumented dog model the influence of cocaine on cardiovascular function. Project III will study the effects of recreational or habitual cocaine use on human blood platelets and determine whether platelet aggregation could account for the cardiovascular manifestations of cocaine toxicity. Project IV will make use of cocaine- induced changes in neurophysiologic function to develop a new prognostic marker for high risk of sudden death in man. Core B will determine the effects of acute and chronic cocaine ingestion on the cardiovascular status of various groups of cocaine abusers undergoing therapy in a treatment center. Core C will study the effects of maternal cocaine abuse on maternal and fetal cardiovascular function during pregnancy, delivery and the neonatal period. Considered together, the projects will provide a body of complementary new data that will either sharpen our focus on the toxic cardiovascular effects of cocaine use--or tell us that this aspect of cocaine toxicity is of relatively small consequence clinically.
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