Unanticipated reports of lethal arrhythmias associated with clinically approved drugs, such as terfenadine (Seldane(r)) and cisapride (Propulsid(r)), have led the Food and Drug Administration to recommend that all new drug candidates be screened for cardiac toxicity, particularly for proarrhythmic potential. Currently, there are no commercially available, cost-effective in vitro screens that can be used to determine a compound's functional effects on the myocardium. A model whereby rabbit myocardium is isolated and sustained ex vivo via perfusion with a buffer would be ideal to quickly and simultaneously assess the electrophysiologic, hemodynamic and potential proarrhythmic effects of new drug candidates. The goal of this project is to validate the use of the rabbit isolated heart to rapidly evaluate the potential toxicity of pharmaceutical compounds for commercial application. Commercializing this model to screen new drug candidates would provide a much needed service to improve the attrition rate of compounds selected for further testing, and thus reduce overall drug development costs and timelines. In this Phase I proposal, validation will be achieved by exposing rabbit isolated hearts to drugs with known effects on human myocardium, in order to confirm that the results from the rabbit isolated heart correspond with those of the human heart. The responses of isolated hearts to these drugs will also be examined under bradycardic and hypokalemic (low potassium) conditions, which can precipitate ventricular arrhythmias. The specific aims are: 1) determine the electrophysiologic and hemodynamic effects of recognized drugs on bradycardic rabbit isolated hearts compared to normal rabbit hearts; 2) determine the electrophysiologic and hemodynamic effects of recognized drugs on rabbit isolated hearts perfused with hypokalemic buffer; and 3) determine the electrophysiologic and hemodynamic effects of recognized drugs on bradycardic rabbit isolated hearts perfused with hypokalemic buffer. For Phase II, we plan to use the data obtained in the Phase I project as groundwork to modify and refine the ability of the rabbit isolated heart to more accurately differentiate between compounds which are truly proarrhythmic versus those that merely alter the cardiac electrophysiologic profile. Our ultimate goal is to utilize this model to screen compounds for pharmaceutical sponsors that lack the facilities and/or expertise to to perform this type of toxicologic testing.
Thesaurus Terms: biological model, ex vivo perfusion, heart electrical activity, heart pharmacology, hemodynamics, model design /development atrioventricular node, bradycardia, cardiovascular pharmacology, hypokalemia buffer, laboratory rabbit
