IONTOPHORESIS FOR MODULATION OF CARDIAC DRUG-DELIVERY IN DOGS

Cardiac arrhythmias are a frequent cause of death and morbidity. Conve ntional antiarrhythmia therapy involving oral or intravenous medicatio n is often ineffective and complicated by drug-associated side effects . Previous studies from our laboratory ha,e demonstrated the advantage s of cardiac drug-polymer implants for enhanced efficacy for cardiac a rrhythmia therapy compared with conventional administration. However, these studies were based on systems that deliver drugs at a fixed rele ase rate. Modulation of the drug delivery rate has the advantage of re gulating the amount of the drug delivered depending upon the disease s tate of the patient. We hypothesized that iontophoresis could be used to modulate cardiac drug delivery, In this study, we report our invest igations of a cardiac drug implant in dogs that is capable of iontopho retic modulation of the administration of the antiarrhythmic agent sot alol. We used a heterogeneous cation-exchange membrane (HCM) as an ele ctrically sensitive and highly efficient rate-limiting barrier on the cardiac-contacting surface of the implant. Thus, electric current is p assed only through the HCM and not the myocardium. The iontophoretic c ardiac implant demonstrated in vitro drug release rates that were resp onsive to current modulation. In vivo results in dogs have confirmed t hat iontophoresis resulted in regional coronary enhancement of sotalol levels with current-responsive increases in drug concentrations. We a lso observed acute current-dependent changes in ventricular effective refractory periods reflecting sotalol-induced refractoriness due to re gional drug administration. In 30-day dog experiments, iontophoretic c ardiac implants demonstrated robust sustained function and reproducibl e modulation of drug delivery kinetics.