Intrapericardial delivery of amiodarone and sotalol: atrial transmural drug distribution and electrophysiological effects.

Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation. However, oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and is associated with serious extracardiac side effects. We hypothesized that intrapericardial (IPC) delivery produces antiarrhythmic effects at lower plasma drug concentrations than IV delivery. Goats (n = 27) were randomised into 5 groups receiving either IPC vehicle, amiodarone (IV or IPC) or dl-sotalol (IV or IPC). Epicardial and endocardial atrial effective refractory period and atrial response to burst pacing (rapid atrial response, RAR) were assessed before and after 3 hours of drug infusion at 2 mg.kg.h. IPC delivery produced steeply decreasing drug concentrations from epicardium to endocardium in both atria and ventricles. Plasma drug concentrations were significantly lower in IPC than in IV groups. IPC amiodarone and sotalol reduced epicardial RAR inducibility (-74% +/- 20% and -66% +/- 30%, respectively) compared with IV delivery (-11% +/- 17% and -17% +/- 28%, respectively; P < 0.05). Endocardial RAR inducibility was only reduced in the IPC amiodarone group (-70% +/- 17%, P < 0.05). In conclusion, IPC delivery of amiodarone and sotalol increases atrial drug concentration and antiarrhythmic effects at reduced plasma drug concentrations. These potential benefits are particularly prominent for IPC delivered amiodarone.

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias.

BACKGROUND: Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. METHODS: Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. RESULTS: The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up. CONCLUSIONS: Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.

Atrium-targeted drug delivery through an amiodarone-eluting bilayered patch.

OBJECTIVE: Clinical studies have demonstrated the efficacy of oral and intravenous amiodarone therapy to prevent postoperative atrial fibrillation. However, because of significant extracardiac side effects, only high-risk patients are eligible for prophylactic amiodarone therapy. This study addressed the hypothesis that atrium-specific drug delivery through an amiodarone-eluting epicardial patch reduces vulnerability to atrial tachyarrhythmias, whereas ventricular and plasma drug concentrations are minimized. METHODS: Right atrial epicardiums of goats were fitted with electrodes and a bilayered patch (poly[ethylene glycol]-based matrix and poly[lactide-co-caprolactone] backing layer) loaded with amiodarone (10 mg per patch, n = 10) or without drug (n = 6). Electrophysiologic parameters (atrial effective refractory period, conduction time, and rapid atrial response to burst pacing) and amiodarone levels in plasma and tissue were measured during 1 month's follow-up. RESULTS: Epicardial application of amiodarone-eluting patches produced persistently higher drug concentrations in the right atrium than in the left atrium, ventricles, and extracardiac tissues by 2 to 4 orders of magnitude. Atrial effective refractory period and conduction time increased, whereas rapid atrial response inducibility decreased significantly (P < .05) during the 1-month follow-up compared with that seen in animals treated with drug-free patches. Amiodarone concentrations in plasma remained undetectably low (<10 ng/mL). CONCLUSIONS: Atrium-specific drug delivery through an amiodarone-eluting patch produces therapeutic atrial drug concentrations, whereas ventricular and systemic drug levels are minimized. This study demonstrates that sustained targeted drug delivery to a specific heart chamber is feasible and might reduce the risk for ventricular and extracardiac adverse effects. Epicardial application of amiodarone-eluting patches is a promising strategy to prevent postoperative atrial fibrillation.

Determination of the class III antiarrhythmic drugs dronedarone and amiodarone, and their principal metabolites in plasma and myocardium by high-performance liquid chromatography and UV-detection.

Dronedarone, a noniodinated benzofuran derivative of amiodarone, is believed to have a better side effect profile, and is currently undergoing phase III clinical trials. A novel method was developed for the determination of dronedarone and its principal metabolite debutyldronedarone in both plasma and myocardial tissue by high-performance liquid chromatography (HPLC) coupled with UV-detection. The assay was also validated for determination of amiodarone and desethylamiodarone. Samples were obtained from healthy humans (plasma) and goats (plasma and myocardium). Sample preparation included deproteinization with acetonitrile and extraction with a mixture of heptane and dichloromethane (50/50, v/v). Chromatographic separation was performed on a Pathfinder PS polymeric C18 column (50 mm x 4.6 mm, 2.5 microm) with a mobile phase of acetonitrile, isopropanol, water and ammonia (80/10/10/0.025, v/v/v/v) at a flow-rate of 1 ml/min. Calibration curves of all analytes were linear in the range of 0.01-5 microg/ml for plasma samples, with a lower limit of quantification (LLOQ) of 0.04 microg/ml. For myocardial tissue samples, linear curves of all analytes were observed in the range of 0.02-500 microg/g, with a LLOQ of 0.08 microg/g. Within- and between-day precision was <18%, and within- and between-day accuracy ranged from 97.5 to 109.7%, with a recovery of 67.6-79.9%. The present method enables sensitive and specific detection of dronedarone, amiodarone and principal metabolites in plasma as well as myocardial tissue.

Stability of an autologous platelet clot in the pericardial sac: An experimental and clinical study.

OBJECTIVE: Autologous platelet clots serve as slow-release delivery systems for platelet-derived growth factors and cytokines. Their application to the pericardial sac might facilitate salvage and repair of ischemically injured myocardium. However, little is known about platelet clot stability in the pericardial sac. We investigated the stability of platelet clots in vitro and after administration to the pericardial sac in pigs and patients. METHODS: In 5 Yorkshire-Landrace pigs and 10 patients, in vitro manufactured autologous platelet gel (Medtronic Magellan Platelet Separator) and platelet-rich fibrin (Vivolution Vivostat System) were administered to the pericardial sac for 30 minutes. Two antifibrinolytics (tranexamic acid and aprotinin) were tested for their capacity to stabilize autologous platelet gel. In vitro clots, incubated at 37 degrees C for 48 hours, served as controls. Clot weight was measured before and after administration. RESULTS: In vitro, autologous platelet gel clots of either formula liquefied almost entirely within 60 minutes whereas platelet-rich fibrin clots remained intact. In the pig, platelet clot weight decreased to 16.7% +/- 7.8% (P < .05) and 66.4% +/- 3.2% (P < .05) of initial clot weight for autologous platelet gel and platelet-rich fibrin, respectively. Addition of antifibrinolytics to autologous platelet gel did not reduce clot degradation significantly. In patients, autologous platelet gel and platelet-rich fibrin clot weight remained 9.0% +/- 1.5% (P < .05) and 73.7% +/- 2.6% (P < .05) of initial clot weight, respectively. CONCLUSIONS: Autologous platelet gel is unstable both in vitro and in vivo, whereas platelet-rich fibrin remains intact in vitro and, compared with autologous platelet gel, is less subject to degradation in pigs and in patients.