Safety of the novel atrial-selective K+-channel blocker AVE0118 in experimental heart failure.
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.
Schneider
H-J
HJ
Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Germany.
Husser
O
O
Rihm
M
M
Fredersdorf
S
S
Birner
C
C
Dhein
S
S
Muders
F
F
Jeron
A
A
Goegelein
H
H
Riegger
G A
GA
Luchner
A
A
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
C501729:AVE 0118; D001713:Biphenyl Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels