title: Electrophysiologic and pharmacokinetic profile of the new antiarrhythmic drug TYB-3823 in humans.
abstract: 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.
authors.affiliation: Department of Cardiology, University Hospital Groningen, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Crijns
authors.forename: B
authors.initials: B
authors.lastname: Oosterhuis
authors.forename: A C
authors.initials: AC
authors.lastname: Wiesfeld
authors.forename: H
authors.initials: H
authors.lastname: De Bruin
authors.forename: C K
authors.initials: CK
authors.lastname: Mensink
authors.forename: J H
authors.initials: JH
authors.lastname: Jonkman
authors.forename: C
authors.initials: C
authors.lastname: Kozma
authors.forename: K I
authors.initials: KI
authors.lastname: Lie
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D004562:Electrocardiography; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D014018:Tissue Distribution
chemical_list: D000889:Anti-Arrhythmia Agents; D006146:Guanidines; C059816:restacorin