restacorin and Arrhythmias--Cardiac

In an open-label study, electrophysiology and pharmacokinetics of TYB-3823, a new antiarrhythmic compound, were investigated. Sixteen patients underwent an electrophysiologic study before and after intravenous (i.v.) administration of TYB-3823. Two patients each received the following increasing doses: 0.2, 0.4, 0.8, and 1 mg/kg. Eight patients received 1.2-mg/kg. TYB-3823 concentrations followed a biexponential decrease with a terminal half-life (t1/2) of 3.88 +/- 0.87 h. Clearance was 47.2 +/- 18.5 L/h, and volume of distribution was 250 +/- 77 L. Dose-dependent pharmacokinetics were evident. Significant effects of TYB-3823 were apparent at doses > or = 0.8 mg/kg (n = 12), including increase in the AH and HV interval from 92 +/- 17 to 105 +/- 19 ms (p < 0.002) and 47 +/- 7 to 60 +/- 12 ms (p < 0.005), respectively. QRS duration was prolonged from 100 +/- 16 to 126 +/- 22 ms (p < 0.001), accompanied by an increase of the corrected QT interval from 425 +/- 28 to 465 +/- 37 ms (p < 0.002). The corrected JT interval remained unchanged, however, refractoriness did not change, but monophasic action potential duration (APD) tended to decrease. TYB-3823 appeared effective against reinduction of all arrhythmias observed during the control study [atrial fibrillation, atrioventricular (AV) nodal tachycardias]. TYB-3823 depresses conduction velocity significantly without prolonging refractoriness. Therefore, TYB-3823 may be classified as a class 1C antiarrhythmic. On the basis of the present results, additional class 1B activity cannot be excluded. TYB-3823 has antiarrhythmic properties, appears to be devoid of proarrhythmic effects, and is well tolerated.

Topics: Action Potentials; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Guanidines; Half-Life; Heart Conduction System; Humans; Injections, Intravenous; Male; Middle Aged; Tissue Distribution

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, TYB-3823 [1-(2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine hydrochloride], were investigated. To determine the antiarrhythmic effects, spontaneously occurring adrenaline-, digitalis-, and two-stage coronary ligation-induced arrhythmias were used. TYB-3823 suppressed these three arrhythmia models. The antiarrhythmic plasma concentrations, IC50, of TYB-3823 for digitalis-, coronary ligation-, and adrenaline-induced arrhythmias were 7.8, 16.8, and 5.0 micrograms/ml, respectively. In the blood perfused sinoatrial (SA) node and papillary muscle (PM) preparations, TYB-3823 decreased the sinoatrial rate (SAR) and contractile force following an initial small positive inotropic effect and increased the intraventricular conduction time and coronary blood flow. These results indicate that TYB-3823 is similar to other class I antiarrhythmic agents, such as aprindine and nicainoprol, in the antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Epinephrine; Female; Guanidines; Male; Ouabain; Ventricular Function

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Guanidines; Hemodynamics; Myocardial Reperfusion