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Safety of the novel atrial-selective K+-channel blocker AVE0118 in experimental heart failure

H-J Schneider1, O Husser, M Rihm

  • 1Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Germany.

Naunyn-Schmiedeberg'S Archives of Pharmacology
|October 31, 2008
PubMed

Insights

A novel atrial-selective potassium channel blocker, AVE0118, demonstrated safety in experimental congestive heart failure (CHF). Unlike other antiarrhythmic drugs, AVE0118 did not prolong the QTc interval or induce arrhythmias in CHF rabbits.

Area of Science:

  • Cardiology
  • Pharmacology
  • Electrophysiology

Background:

  • Congestive heart failure (CHF) frequently co-occurs with atrial fibrillation.
  • Many antiarrhythmic drugs pose safety risks in CHF due to proarrhythmic effects.

Purpose of the Study:

  • To evaluate the safety of AVE0118, an atrial-selective K(+)-channel blocker, in a rabbit model of CHF.
  • To compare AVE0118's safety profile against dofetilide (selective IKr blocker) and terfenadine (non-selective IKr blocker) in CHF.

Main Methods:

  • Experimental congestive heart failure (CHF) was induced in rabbits via rapid ventricular pacing.
  • Electrocardiograms (ECGs) were recorded digitally after administration of AVE0118, dofetilide, or terfenadine at baseline and in CHF.
  • Drug effects on QTc interval and occurrence of arrhythmias were analyzed.

Main Results:

  • At baseline, dofetilide and terfenadine significantly prolonged the QTc interval, while AVE0118 did not.
  • In CHF rabbits, dofetilide and terfenadine induced arrhythmias (torsades de pointes, bradycardia) and prolonged QTc, even at reduced doses.
  • Full-dose AVE0118 administration in CHF rabbits resulted in no QTc prolongation or observed arrhythmias.

Conclusions:

  • Atrial-selective K(+)-channel blockade with AVE0118 appears safe in experimental congestive heart failure.
  • AVE0118 shows a favorable safety profile compared to non-selective and selective IKr blockers in the context of CHF.

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