Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves

Abstract

The objective of this study was to examine the electrophysiologic and antiarrhythmic effects of the new antiarrhythmic agent tert-butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non3-yl}ethyl)carbamate (AZD1305) in canine pulmonary vein (PV) sleeve preparations isolated from untreated and long-term amiodarone-treated animals. Ectopic activity arising from PV sleeves plays a prominent role in the development of atrial fibrillation (AF). Delayed afterdepolarizations (DADs) and late phase 3 early afterdepolarizations (EADs), originating from the PV have been proposed as potential triggers in initiation of AF. Action potentials were recorded from canine superfused PV sleeves using standard microelectrode techniques. Acetylcholine (1 M), isoproterenol (1 M), or their combination was used to induce EADs, DADs, and triggered activity (TA). The effects of AZD1305 (0.1-10 M) were evaluated in PV sleeve preparations isolated from untreated and amiodarone-treated (40 mg/kg daily for 6 weeks) dogs. AZD1305 (0.1-10 M, 30 min) significantly prolonged action potential duration and reduced excitability. Abbreviating basic cycle length from 1000 to 300 ms resulted in a decrease of V max from 314 Ϯ 79 to 251 Ϯ 55 V/s (⌬ ϭ Ϫ20%) in control and from 177 Ϯ 53 to 76.5 Ϯ

QT Response after a Test Dose and during Maintenance Therapy with AZD1305 in Patients with Atrial Fibrillation

“…In canine pulmonary vein sleeves, AZD1305 depressed excitability, prolonged action potential duration, and suppressed ectopic triggered activity, supporting its potential antiarrhythmic utility. [15] Moreover, AZD7009, the predecessor compound to AZD1305, was very effective in converting AF episodes of up to 90 days' duration, and was as effective as DC cardioversion in AF episodes of less than 30 days' duration. [16,17] The development of AZD7009 was discontinued due to unexplainable flu-like symptoms, especially in the el- : AZD1305 43 39 38 35 32 31 31 31 31 30 30 22 20 19 17 13 13 12 12 12 12 12 Placebo 1 2 3 4 5 Time from randomization (d) derly, on repeated exposure with extended-release preparations.…”

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

“…Under these conditions, the number of TdP episodes was decreased (2 [1-3] versus 7 [3][4][5][6][7][8][9][10][11]; Pϭ0.05) compared with dofetilide alone.…”

“…QT intervals were corrected for heart rate changes according to Van de Water et al (QTcVϭQT-0.087[RRϪ1000]). 16 Most data were averaged from 30 consecutive beats measured at Ϫ5 and 0 minutes (baseline) and at 5,10,15,30,35,45, and 60 minutes after the start of AZD1305 or dofetilide infusion. If extrasystolic activity was seen, parameters were measured before the first extrasystole.…”

“…7 AZD1305 has been shown to depress excitability and suppress delayedafterdepolarization-induced triggered activity in canine pulmonary-vein sleeve preparations. 10 Recent clinical data suggest that this compound has electrophysiological effects that may translate into antiarrhythmic efficacy in patients with AF and may have a reduced proarrhythmic potential as compared with selective I Kr blockers. 11,12 In the present study, we investigated the electrophysiological effects of AZD1305 in anesthetized dogs with remodeled hearts with our hypothesis being that due to the composite ion-channel blockade by AZD1305, less ventricular proarrhythmia will be seen when compared with I Kr blockade alone despite leading to equivalent repolarization prolongation.…”

“…9,10 It causes an atrial-predominant blockade of I Na (particularly tonic inhibition), which is suggested to translate into high antiarrhythmic efficacy. 9 Previously, the predecessor to AZD1305, AZD7009, was shown to restore sinus rhythm in up to 82% of patients with AF episodes lasting up to 30 days and with minimal proarrhythmic side effects.…”