EPICARDIAL ADMINISTRATION OF IBUTILIDE FROM POLYURETHANE MATRICES - EFFECTS ON DEFIBRILLATION THRESHOLD AND ELECTROPHYSIOLOGIC PARAMETERS

Polymer-drug composites known as controlled-release systems have been used effectively to prevent and treat ventricular arrhythmias in exper imental studies. We wished to determine if such systems could be usefu l in reducing ventricular defibrillation energy requirements in an acu te canine model without producing undesirable electrophysiologic effec ts. Ibutilide-polyurethane monolithic controlled-release matrices were formulated with ibutilide fumarate and a polyether polyurethane. In v itro drug-release characteristics of the drug matrices were determined . Two formulations were investigated: (a) 20% ibutilide by weight in p olyether polyurethane, and (b) 4% ibutilide/16% dimethyl tartrate in p olyurethane. Based on in vitro release studies, 20% ibutilide matrices (25 mg) would provide a 25-kg dog with a dose of 25 mu g/kg ibutilide in a 2-h acute experimental period, and 4% ibutilide matrices were es timated to provide 3.5 mu g/kg. We used each of these types of matrice s in acute open-chest dog studies to assess electrophysiologic effects and the influence of epicardial controlled-release ibutilide, as comp ared with intravenous (i.v.) administration, on defibrillation energy thresholds (DFTs), using epicardial defibrillation electrodes. In mono phasic defibrillation waveform studies, 20% matrices significantly dec reased DFT as compared with a predrug control period [2.54 +/- 0.59 (m ean +/- SEM) vs. 7.23 +/- 1.73 J, respectively, p = 0.038]. Administra tion of the same dose i.v. did not cause significant reduction in ener gy requirement. With a biphasic defibrillation waveform, 4% ibutilide matrices significantly decreased DFT as compared with control (2.53 +/ - 0.34 vs. 3.42 +/- 0.46 J, respectively, p = 0.003). Administration o f an equivalent i.v. dose did not cause a significant reduction in bip hasic energy requirement. Both types of controlled-release systems sig nificantly prolonged refractoriness and conduction times of ventricula r extrastimuli as compared with vehicle. No proarrhythmia events were observed. Epicardial polymeric controlled-release ibutilide significan tly prolonged ventricular refractoriness and conduction and thus may e nhance antiarrhythmia activity. In addition, controlled-release ibutil ide formulations significantly decreased DFT requirements. Thus, ibuti lide-polymeric controlled-release matrix systems may be useful in conj unction with implantable defibrillators in preventing ventricular arrh ythmias and reducing defibrillation energy requirements.