Iontophoresis for modulation of cardiac drug delivery in dogs.
Cardiac arrhythmias are a frequent cause of death and morbidity. Conventional antiarrhythmia therapy involving oral or intravenous medication is often ineffective and complicated by drug-associated side effects. Previous studies from our laboratory have demonstrated the advantages of cardiac drug-polymer implants for enhanced efficacy for cardiac arrhythmia therapy compared with conventional administration. However, these studies were based on systems that deliver drugs at a fixed release rate. Modulation of the drug delivery rate has the advantage of regulating the amount of the drug delivered depending upon the disease state of the patient. We hypothesized that iontophoresis could be used to modulate cardiac drug delivery. In this study, we report our investigations of a cardiac drug implant in dogs that is capable of iontophoretic modulation of the administration of the antiarrhythmic agent sotalol. We used a heterogeneous cation-exchange membrane (HCM) as an electrically sensitive and highly efficient rate-limiting barrier on the cardiac-contacting surface of the implant. Thus, electric current is passed only through the HCM and not the myocardium. The iontophoretic cardiac implant demonstrated in vitro drug release rates that were responsive to current modulation. In vivo results in dogs have confirmed that iontophoresis resulted in regional coronary enhancement of sotalol levels with current-responsive increases in drug concentrations. We also observed acute current-dependent changes in ventricular effective refractory periods reflecting sotalol-induced refractoriness due to regional drug administration. In 30-day dog experiments, iontophoretic cardiac implants demonstrated robust sustained function and reproducible modulation of drug delivery kinetics.
Labhasetwar
V
V
Division of Pediatric Cardiology, University of Michigan, Ann Arbor 48109-0576, USA.
Underwood
T
T
Schwendeman
S P
SP
Levy
R J
RJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D003326:Coronary Circulation; D004285:Dogs; D004337:Drug Carriers; D004343:Drug Implants; D007478:Iontophoresis / Q000295:instrumentation / Q000379:methods*; D013015:Sotalol / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D013997:Time Factors
D004337:Drug Carriers; D004343:Drug Implants; D013015:Sotalol