Iontophoresis for modulation of cardiac drug delivery in dogs.

Abstract

Cardiac arrhythmias are a frequent cause of death and morbidity. Conventional Cardiac arrhythmias are the cause of sudden death due to heart disease, and they complicate the long-term course of hundreds of thousands of patients on a chronic basis. At this time, conventional therapy for the prevention and treatment of cardiac arrhythmias involving oral or intravenous administration is often ineffective when the drug is given at clinically tolerable dosages, and it is frequently associated with toxic drug effects (1). Previous experimental work from our group has demonstrated the enhanced efficacy of cardiac arrhythmia therapy based on drug-polymer implants placed in direct contact with the heart. These controlled-release implants were effective on an acute and chronic basis for preventing and treating cardiac arrhythmias at lower dosages than conventional administration and were free of side effects (2-5). Regional coronary venous drug levels in these previous cardiac controlled-release studies were consistently an order of magnitude greater than simultaneous systemic levels, which were at the lower limits of detection (2-4). Furthermore, these coronary venous drug concentrations resulting from local cardiac drug delivery were in the known therapeutic range based on clinical efficacy data (2-4). However, in all of these prior investigations fixed-rate drug delivery systems were utilized. Therefore, we reasoned that modulation of the drug release kinetics of cardiac controlled-release implants would have the additional hypothetical advantage of controlling dosages depending upon arrhythmia activity. Thus, in the present study, we sought to investigate iontophoresis as a means of modulating the drug administration kinetics for antiarrhythmic agents (6). lontophoresis may be operationally defined as the transport of charged molecules across an electrically conductive barrier with an applied current.In this study, dl-sotalol hydrochloride was used as a model class III antiarrhythmic agent, contained within an epicardial reservoir implant configured with a rate-limiting heterogeneous cation-exchange membrane (HCM). Thus, sotalol transport across the HCM could be modulated by the level of transmembrane electrolytic current controlled by an external constant current source (6). When this approach is used, electrical current passes through only the HCM and not the myocardium. Prior investigations from our group have reported the successful formulation and in vitro characterization of an HCM-iontophoresis system (6-8). In the present studies, we investigated the hypothesis that current-responsive drug transport and current-responsive coronary circulatory drug levels would result from this iontophoretically modulated drug delivery system. EXPERIMENTAL PROCEDURESMaterials. Silicone rubber, Silastic Q7-4840, was provided by Dow-Corning. Cation-exchange resin, Dowex 50W-2X was obtained from Sigma. dl-Sotalol hydrochloride was provided by Bristol-Meyers Squibb. Reagent grade sodium chloride, monobasic potassium phosp...

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“…During iontophoresis, the local concentration of the drug attained depends on the total electrical charge applied. The higher the total electrical charge, the higher the local concentration of the drug attained (Sage & Riviere, 1992; Labhasetwar et al 1995). On the other hand, the ability of a drug to actively migrate depends on molecular weight, lipophilicity or molecular electrical charge (Green, 1996).…”

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“…One class of such devices, known as iontophoretic devices deliver ionised drugs through either open fluidic channels or microporous membranes. 40,41 Other approaches such as organic electronic ion pumps, make use of charge-selective membranes such as polystyrene sulfonate to maximize drug delivery while limiting uptake of oppositely charged ions. The main advantage of electrophoresis is precise temporal control of the delivery rate.…”

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“…These have involved using electromagnetic [25,261 4) have been used to successfully administer sotalol in acute and chronic studies [33]. Rapid responsiveness ( Figure 6) and the robust character of the HCM-reservoir systems make these ideal implantable drug delivery systems for long-term usage for arrhythmia control through localized controlled release of anti-arrhythmic agents.…”