The efficacy of controlled release D-sotalol-polyurethane epicardial implants for ventricular arrhythmias due to acute ischemia in dogs

Abstract

Epicardially implanted Dsotalol polyurethane composite matrices for preventing ischemic ventricular arrhythmias were studied in open chest dogs under general anesthesia. D-sotalol was combined with a polyureapolyurethane (3:7) in solvent-cast films, which were characterized in vitro for their drug release at 37°C at pH 7.4 (0.05 M K2HP04). D-sotalol in vitro release occurred rapidly in an initial burst phase, with roughly 20% released within the first five min, and 90% by 60 min. Thereafter, an exponentially decreasing release rate was observed with matrix depletion by live hours. In the animal studies, the left anterior descending coronary artery (LAD) was occluded for 10 min on an hourly basis for up to live occlusions. 10 min prior to the third LAD occlusion, either a D-sotalol matrix or a vehicle matrix (control) was placed on either the ischemic or nonischemic left ventricular epicardium. The study was then continued observing the effects of matrix placement on occlusions 3,4, and 5.200 mg D-SOtdO matrices, which delivered a net dose of 1.2 mg/kg, effectively inhibited ventricular arrhythmias only if placed on the left ventricular ischemic zone. Placement of 200 mg D-sotalol matrices in the nonischemic zone was ineffective for significantly reducing the occurrence of ventricular arrhythmias. Furthermore, D-sotalol controlled release matrices were ineffective for preventing ventricular fibrillation (VF) regardless of dose or placement site. 200 mg ischemic zone D-sotalol matrices resulted in plasma sotalol levels in regional coronary venous samples ranging from 3.5 pg/ml to 10.4 &ml. However, peripheral sotalol levels obtained simultaneously ranged from 0.23 pg/ml to 0.78 ,ug/ ml. It is concluded that epicardial D-sotalol controlled release matrices inhibited ischemic ventricular arrhythmias, but not VF, if placed in the left ventricular ischemic zone during repeated LAD occlusions.

High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: An example with epicardial inotropic drug delivery

“…Locally applied drug must enter the tissue and diffuse through the target area down concentration gradients (Fig. 1) [4, 10, 11, 12, 13]. The very high supratherapeutic drug concentration near the point of release may lead to saturation of proximal binding sites or exceed their capacity for binding.…”

“…While increasing administered systemic dose increases target organ concentrations and biologic effect as long as receptors are available (Fig. 1b), tissue capillaries remove locally released drug from a tissue [11 13] rather than deliver it. Thus, capillary clearance and enzymatic degradation limit the extent of tissue under pharmacologic control even with substantial increments of local drug release and, unlike systemic delivery, extra steps are required for drug to reach receptors suggesting a non-linear nature of the dose-response [4, 5, 6].…”

Iontophoresis for modulation of cardiac drug delivery in dogs.

“…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)(3)(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)(3)(4). However, in all of these prior investigations fixed-rate drug delivery systems were utilized.…”

“…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)(3)(4)(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)(3)(4).…”

“…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)(3)(4)(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)(3)(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)(3)(4).…”