title: Safety of the novel atrial-selective K+-channel blocker AVE0118 in experimental heart failure.
abstract: Congestive heart failure (CHF) is often associated with atrial fibrillation. The safety of many antiarrhythmic drugs in CHF is limited by proarrhythmic effects. We aimed to assess the safety of a novel atrial-selective K(+)-channel blocker AVE0118 in CHF compared to a selective (dofetilide) and a non-selective IKr blocker (terfenadine). For the induction of CHF, rabbits (n = 12) underwent rapid right ventricular pacing (330-380 bpm for 30 days). AVE0118 (1 mg/kg) dofetilide (0.02 mg/kg) and terfenadine (2 mg/kg) were administered in baseline (BL) and CHF. A six-lead ECG was continuously recorded digitally for 30 min after each drug administration. At BL, dofetilide and terfenadine significantly prolonged QTc interval (218 +/- 30 ms vs 155 +/- 8 ms, p = 0.001 and 178 +/- 23 ms vs. 153 +/- 12 ms, p = 0.01, respectively) while QTc intervals were constant after administration of AVE0118 (p = n.s.). In CHF, dofetilide and terfenadine caused torsades de pointes and symptomatic bradycardia, respectively, and prolonged QTc interval (178 +/- 30 ms vs. 153 +/- 14 ms, p = 0.02 and 157 +/- 7 ms vs. 147 +/- 10 ms, p = 0.02, respectively) even at reduced dosages, whereas no QTc-prolongation or arrhythmia was observed after full-dose administration of AVE0118. In conclusion, atrial-selective K(+)-channel blockade by AVE0118 appears safe in experimental CHF.
authors.affiliation: Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Germany.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Schneider
authors.forename: O
authors.initials: O
authors.lastname: Husser
authors.forename: M
authors.initials: M
authors.lastname: Rihm
authors.forename: S
authors.initials: S
authors.lastname: Fredersdorf
authors.forename: C
authors.initials: C
authors.lastname: Birner
authors.forename: S
authors.initials: S
authors.lastname: Dhein
authors.forename: F
authors.initials: F
authors.lastname: Muders
authors.forename: A
authors.initials: A
authors.lastname: Jeron
authors.forename: H
authors.initials: H
authors.lastname: Goegelein
authors.forename: G A
authors.initials: GA
authors.lastname: Riegger
authors.forename: A
authors.initials: A
authors.lastname: Luchner
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004562:Electrocardiography; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006329:Heart Conduction System / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D010138:Pacemaker, Artificial; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits
chemical_list: C501729:AVE 0118; D001713:Biphenyl Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels