This proposal involves a series of coordinated, translational studies designed to establish the mechanisms by which important antipsychotic drugs might bring about cardiac arrhythmias and sudden death. While a great deal of research over the past thirty years has resulted in the recent appearance of antipsychotic drugs that have reduced extra-pyramidal side-effects, a number of these novel agents have recently been shown to possess the ability to prolong the electrocardiac QT interval, and cause potentially lethal torsades-de-pointes arrhythmias that are reminiscent of older agents. Using antipsychotic drugs chosen for their wide clinical use, and potential cardiotoxicity the investigator propose to study potential pharmacodynamic and pharmacokinetic mechanisms that might expose vulnerable patients to the risk of these arrhythmias. The present study will have the following specific aims: 1) To test in vitro whether antipsychotic their metabolites or combinations of drug and metabolite modulate cardiac electrophysiology in isolated perfused heart using the characteristics of the action potential (AP), QT interval and early after depolarization (EAD) occurrence. To investigate whether any electrophysiologic changes noted are the result of specific cardiac Na, Ca, or K, channel activity in isolated ventricular cardiomyocytes and Purkinje cells, using currient patch clamp techniques. Since the investigators have preliminary data that indicate that haloperidol can slow cardiac repolarization in vitro, the focus of our studies in the first year will be on this widely-used drug and its metabolites. In subsequent years, the investigators will evaluate thioridazine, fluphenazine and loxapine. 2) To probe the cytochrome P450 isoforms responsible for metabolism of antipsychotic drugs or metabolites that the investigators find to be cardiotoxic. This information will allow assessment of pharmacogenetic and pharmacokinetic influences that might increase the concentration of these agents, and the risk of arrhythmia. The investigators will document the cytochrome P450 isoforms responsible for the metabolism of specific drugs using isolated human hepatic, intestinal and cardiac microsomal preparations, isoform-specific inhibitors and antibodies, and recombinant cytochrome P450 isoforms. 3) To determine if antipsychotic agents that are found to be potentially cardiotoxic in vitro have clinical electrocardiac effects at the doses routinely used in healthy volunteers. The investigator will document the relationship between the serum concentrations of these drugs and their electrocardiac pharmacodynamics. The results of these studies should allow physicians and researchers to more confidently predict patients at risk for lethal torsades-de-pointes arrhythmias while taking neuroleptic drugs, and to gain mechanistic insights that will allow the design of safer drugs in the future.
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