Tolerance and effects of almokalant, a new selective Ik blocking agent, on ventricular repolarization and on sino-atrial and atrioventricular nodal function in the heart: a study in healthy, male volunteers utilizing transesophageal atrial stimulation.
Almokalant, (4-(3-ethyl(3-propylsulfinyl)propyl)amino)-2-hydroxy-propoxy)- benzonitrile), is a newly developed Ik channel blocker that exhibits pure class III effects. Using a noninvasive approach with transesophageal atrial stimulation (TAS), we wished to identify the dose of almokalant, given as an intravenous bolus infusion, that prolonged ventricular repolarization in the healthy human heart to an extent of potential clinical interest. Furthermore, we defined the electrophysiological effects of this dose on the heart, as well as the pharmacokinetics, safety, and tolerance throughout a wide dosing range. In the titration part, increasing doses were given to identify the dose that produced a reproducible QTend prolongation of approximately 20%. This dose (12.8 mumol) was then given in a placebo-controlled, double-blind, cross-over fashion. In the double-blind part, almokalant significantly prolonged the QTend intervals during sinus rhythm and during TAS at 100 beats/min and increased the effective refractory period of the atria (AERP). There was no alteration in either the cardiac conduction (PQ and QRS), or blood pressure (BP) sinus node function, or the ERP of the atrioventricular (AV) node. Therefore, almokalant exhibited pure class III effects with no signs of beta-blockade or unwanted hemodynamic effects. The plasma concentration-time curve showed a biexponential decrease with a terminal half-life (t1/2) of approximately 3 h. There was a large interindividual variation in the plasma concentration at the end of infusion, Cmax. This variability diminished considerably 60 min after infusion, and the pharmacokinetic characteristics studied appeared to be proportional to the dose. The drug was well tolerated, and the only side effect noted was a brief metallic taste after a dose of 25.6 mumol. Corresponding to high plasma peak values, T-wave morphology changes of short duration were observed, sometimes with the development of pronounced, biphasic T waves.
Darpö
B
B
Division of Cardiology, Sahlgrenska Hospital, Göteborg, Sweden.
Almgren
O
O
Bergstrand
R
R
Bäärnhielm
C
C
Gottfridsson
C
C
Sandstedt
B
B
Edvardsson
N
N
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016275:Atrial Function; D001283:Atrioventricular Node / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D004558:Electric Stimulation; D004594:Electrophysiology; D005500:Follow-Up Studies; D006325:Heart Atria / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012044:Regression Analysis
D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; C074334:almokalant