Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

"NEWWINE IN AN OLD BOTTLE OR OLD WINE IN A NEW BOTTLE?" IN VIVO AND CELLULAR ANTIARRHYTHMIC AND CARDIAC ELECTROPHYSIOLOGICAL EFFECTS OF DESETHYLAMIODARONE IN DOGS N. Jost 1,2 , Z. Kohajda 2 , L. Virag 1 , T. Hornyik 1 , Z. Husti 1 , A. Sztojkov-Ivanov 3 , N. Nagy 2 , J. Prorok 1,2 , N. Toth 1 , A.- L. Tamás 1 , I. Koncz 1 , S. Deri 1 , V. Demeter-Haludka 1 , B. Ordog 1 , M. Patfalusi 4 , L. Talosi 5 , L. Tiszlavicz 6 , I. Foldesi 7 , I. Baczko 1 , A. Varro 1,2 1 Department of Pharmacology and Pharmacotherapy, University of Szeged, Hungary; 2 MTA SZTE Research Group for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary; 3 Department of Pharmacodynamics and Biopharmacy, University of Szeged, Hungary; 4 ATRC Aurigon Toxicological Research Center Ltd, Dunakeszi, Hungary; 5 Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Hungary; 6 Department of Pathology, Faculty of Medicine, University of Szeged, Hungary; 7 Department of Laboratory Medicine, Faculty of Medicine, University of Szeged, Hungary Aims: The aim of the present study was to study the antiarrhythmic effects and cellular mechanisms of desethylamiodarone (DEA), the main metabolite of the most powerful antiarrhythmic drug amiodarone, following 4-week oral treatment (25-50 mg/kg/day) in in vivo and cellular canine experiments. Methods and Results: Acute and chronic administration of DEA and amiodarone exerted marked antiarrhythmic effects in atrial fibrillation models. DEA and amiodarone similarly influenced ECG parameters. DEA prolonged action potential duration in atrial and ventricular muscle without changing it in Purkinje fibre, and decreased the amplitude of several outward potassium currents such as IKr, IKs, IK1, Ito and IKACh. The L-type ICa and late INa inward currents were also depressed by chronic DEA treatment. Pharmacokinetic studies following a single intravenous dose of 25 mg/kg revealed better drug bioavailability and higher volume of distribution with DEA than with amiodarone treatment. Chronic toxicological investigations (91 days with 25mg/kg/day orally) showed no neutropenia and less severe pulmonary fibrosis following DEA compared to that of amiodarone treatment. Conclusion: Chronic DEA treatment in animal experiments has similar antiarrhythmic and electrophysiological effects as its parent compound with better pharmacokinetics and lower tissue accumulation and related toxicity. These results suggest that the active metabolite, DEA should be tested in clinical trials as a possible new, more favorable option for the treatment of cardiac arrhythmias including atrial fibrillation.

Keywords: desethylamiodarone, atrial fibrillation, cardiac electrophysiology, canine

Funding: National Research Development and Innovation Office ((NKFIH K 119992, NKFIH PD 125402, FK-129117, K 128851 and GINOP-2.3.2.-15-2016-00048; Ministry of Human Capacities Hungary (20391 3/2018/FEKUSTRAT and EFOP 3.6.2 16 2017 00006; Loránd Eötvös Research Network.

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