The continuing program will investigate the hypothesis that regulatable controlled release drug delivery systems implanted by cardiac catheter in direct endocardial contact with the heart can provide optimal treatment for ventricular arrhythmias and ventricular fibrillation. This approach is hypothesized to have advantages because of the regional enhancement of drug concentrations, reduction of the possibilities of systemic side effects, sustained action, and elimination of bioavailability limitations associated with conventional routes of administration. Progress in the program has supported this hypothesis thus far. Results from our program to date were the first to demonstrate superior efficacy without side effects for direct cardiac controlled release anti-arrhythmia therapy, by either the epicardial or endocardial route. The goals of the research program will be to address a number of basic issues and questions central to the use of cardiac drug delivery systems for antiarrhythmia therapy and other disorders. These include the following considerations: What are the optimal formulations of matrix and modulatable iontophoretic drug delivery systems? What are the special pharmacokinetic considerations for cardiac drug delivery? What are the biocompatibility and drug stability issues of interest for chronic use of cardiac implantable drug delivery systems? Are there significant adverse effects associated with cardiac administration of antiarrhythmic agents such as proarrhythmia or diminished cardiac function? The aims of the next program period are as follows: 1) Formulation investigations and characterization of catheter-tip antiarrhythmic-controlled release matrices, and iontophoresis systems: We will focus on questions related to mechanisms of drug release, release kinetics, and drug stability using polymer matrices and iontophoresis systems based on heterogeneous cationic membranes (HCM). These mechanistic considerations will be investigated through basic drug delivery formulation studies, and animal model (dog) experiments. The model compound to be studied will be the Class III antiarrhythmic agent, ibutilide. 2) The mechanism and efficacy of Ibutilide matrix (fixed release rate) and HCM iontophoresis (variable release rate) drug delivery systems will be assessed in acute dog studies. Electrophysiologic, pharmacokinetic, and cardiac function outcomes will be the focus of these experiments. 3) Chronic canine implants will investigate the long-term efficacy of this therapeutic strategy by investigating endocardial monolithic matrices and a series of iontophoretic HCM-ibutilide implants. In addition to the above issues of interest, long-term biocompatibility will be a focus of the chronic studies. The long-term objective of this research program is to elucidate the principles and mechanisms governing regional controlled release therapy of cardiovascular disease, since this drug delivery approach has significance for a broad spectrum of therapeutic strategies.
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