TOLERANCE AND EFFECTS OF ALMOKALANT, A NEW SELECTIVE I-K BLOCKING-AGENT, ON VENTRICULAR REPOLARIZATION AND ON SINOATRIAL AND ATRIOVENTRICULAR NODAL FUNCTION IN THE HEART - A STUDY IN HEALTHY, MALE-VOLUNTEERS UTILIZING TRANSESOPHAGEAL ATRIAL STIMULATION

Almokalant, yl)propyl)amino)-2-hydroxy-propoxy)-benzonitrile), is a ne wly developed I-k 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 intra venous bolus infusion, that prolonged ventricular repolarization in th e healthy human heart to an extent of potential clinical interest. Fur thermore, we defined the electrophysiological effects of this dose on the heart, as well as the pharmacokinetics, safety, and tolerance thro ughout a wide dosing range. In the titration part, increasing doses we re given to identify the dose that produced a reproducible QTend prolo ngation of similar to 20%. This dose (12.8 mu mol) was then given in a placebo-controlled, double-blind, crossover fashion. In the double-bl ind part, almokalant significantly prolonged the QTend intervals durin g sinus rhythm and during TAS at 100 beats/min and increased the effec tive refractory period of the atria (AERP), There was no alteration in either the cardiac conduction (PQ and QRS), or blood pressure (BP) si nus node function, or the ERP of the atrioventricular (AV) node. There fore, almokalant exhibited pure class III effects with no signs of bet a-blockade or unwanted hemodynamic effects. The plasma concentration-t ime curve showed a biexponential decrease with a terminal half-life (t 1/2) of similar to 3 h. There was a large interindividual variation in the plasma concentration at the end of infusion, C-max. This variabil ity diminished considerably 60 min after infusion, and the pharmacokin etic characteristics studied appeared to be proportional to the dose. The drug was well tolerated, and the only side effect noted was a brie f metallic taste after a dose of 25.6 mu mol. Corresponding to high pl asma peak values, T-wave morphology changes of short duration were obs erved, sometimes with the development of pronounced, biphasic T waves.