pyrimidinones and Long-QT-Syndrome

Topics: Animals; Anti-Arrhythmia Agents; Cation Transport Proteins; Drug Design; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Ether-A-Go-Go Potassium Channels; Long QT Syndrome; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyrimidinones; Torsades de Pointes

Ventricular tachycardia (VT) and ventricular fibrillation are the main reasons causing sudden cardiac death. This study aimed to investigate the effects of nifekalant hydrochloride (NIF) on QT dispersion (QTd) in treating VT.. A total of 16 consecutive patients suffered sustained VT was included and then randomly divided into two groups according to the administration duration of NIF. In long-time group (group L), patients were injected with NIF continuously for at least 12 hours after a bolus dose. The patients in short-time group (group S) were injected with NIF just for 1 hour.. There were 7 of all 10 episodes of VT which were terminated by NIF, including 4 episodes in group L were stopped over 1 hour after continuous infusion of NIF. One patient suffered from torsade de pointes. Electrocardiography analysis indicated that QTd was significantly decreased 12 hours after stopping of infusing NIF compared with that when VT stopped ((45.4 +/- 22.1) ms vs. (73.4 +/- 33.2) ms, P < 0.01), and the corrected QTd (QTcd) decreased too ((47.8 +/- 22.9) ms vs. (78.3 +/- 36.5) ms, P < 0.01). There was a positive correlation between the increase in QTd and dose of administrating NIF (P < 0.01), so was QTcd (P < 0.01).. More administration of NIF indicates higher terminating rate of VT and more QTd prolongation. However, the safety is acceptable if several important issues were noticed in using NIF, such as serum potassium concentration, stopping side-effect related agents, and carefully observing clinical responses.

Topics: Adult; Anti-Arrhythmia Agents; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Middle Aged; Pyrimidinones; Tachycardia, Ventricular; Treatment Outcome

This clinical study was designed to compare rate-dependent effects of class III agents on QT prolongation.. Clinical data that compare the electrophysiologic differences among class III agents with different selectivity for potassium channels are still lacking.. QT intervals were measured over a wide range of preceding RR intervals during sinus rhythm by 24-h Holter electrocardiography before and after oral administration of four class III agents: E4031, dofetilide, MS551 and d-sotalol. Rate-dependent changes in the QT interval were assessed by the slope of the linear regression line estimating the QT-square root of RR relation.. All agents significantly increased the mean slope: E4031 increased the mean [+/- SD] value from 0.32 +/- 0.05 to 0.42 +/- 0.13 (p < 0.01), dofetilide from 0.32 +/- 0.03 to 0.50 +/- 0.12 (p < 0.03), MS551 from 0.35 +/- 0.06 to 0.45 +/- 0.10 (p < 0.02) and d-sotalol from 0.31 +/- 0.05 to 0.33 +/- 0.04 (p < 0.05). However, in those patients given either E4031, dofetilide or MS551, the degree of QT prolongation was smaller at shorter square root of RR intervals and was better preserved at shorter square root of RR intervals by d-sotalol, with a smaller increase in slope (p < 0.02 vs. dofetilide and MS551).. On ambulatory electrocardiography, reverse use dependence in QT prolongation was least prominent with d-sotalol among the four study drugs. In the range of physiologic heart rates, class III agents could manifest different profiles of rate dependence in their QT-prolonging effect.

Topics: Adult; Aged; Analysis of Variance; Anti-Arrhythmia Agents; Electrocardiography, Ambulatory; Female; Humans; Long QT Syndrome; Male; Middle Aged; Phenethylamines; Piperidines; Pyridines; Pyrimidinones; Regression Analysis; Sotalol; Statistics, Nonparametric; Sulfonamides

Agents with α-2 adrenoreceptor (AR) agonistic action have reportedly suppressed tachyarrhythmias..  We hypothesized that α-2 AR agonists would have an inhibitory effect on abnormal repolarization-related ventricular tachyarrhythmias (VTs). To test this hypothesis, the effects of 2 clinically available α-2 AR agonists (dexmedetomidine and clonidine) on the occurrence of VTs were assessed in a methoxamine-sensitized rabbit model of acquired long QT syndrome (Study 1: n=45). In control rabbits, administration of methoxamine and nifekalant almost invariably caused VTs (14/15). In contrast, incidence of VT significantly decreased during the treatment with dexmedetomidine (1μg·kg(-1)·min(-1): 5/12 [P<0.01 vs. control]) or with clonidine (33.3μg·kg(-1)·min(-1): 10/18 [P<0.01]). To verify that VTs in this animal model are triggered by early afterdepolarization (EAD), the monophasic action potential on the left ventricular surface was recorded in 28 open-chest rabbits (Study 2). EAD-like hump was less frequently detected during treatment with clonidine or dexmedetomidine (2/14) than in saline-treated rabbits (9/10, P<0.005). Presence of a hump was significantly related to the advent of VTs (P<0.05)..  Agents with α-2 AR agonistic action have an inhibitory effect on VTs in a rabbit model of long QT syndrome. Alpha-2 AR agonists, especially dexmedetomidine, may be a therapeutic choice for abnormal repolarization-related VTs that are resistant to conventional treatment. 

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-2 Receptor Agonists; Animals; Anti-Arrhythmia Agents; Clonidine; Dexmedetomidine; Disease Models, Animal; Heart Conduction System; Humans; Long QT Syndrome; Methoxamine; Pyrimidinones; Rabbits; Tachycardia

Anesthesia sometimes suppresses ventricular tachyarrhythmias (VT) resistant to conventional pharmacological treatment.. To know (1) whether deep anesthesia inhibits abnormal repolarization-related VT and (2) if α2-adrenoreceptor (AR) agonistic action is associated with the antiarrhythmic effect of anesthetics, the incidence of VT in a rabbit model of acquired long QT syndrome using different anesthetic regimen was assessed. In Study 1 (n = 30), 15 rabbits were lightly anesthetized with ketamine (123 ± 46 mg/kg) and an α2-AR agonist, xylazine (9.4±3.0mg/kg), while combination of these anesthetics at high doses were used in the other 15 rabbits (343 ± 78 mg/kg and 38.9 ± 3.0 mg/kg). Administration of α1-AR stimulant, methoxamine and nifekalant (Ikr blocker) caused VT in all lightly anesthetized rabbits. In contrast, VT was observed only in 1 of the 15 deeply anesthetized rabbits (P < 0.01). In Study 2 (n = 15), 10 rabbits were anesthetized with high-dose ketamine and low-dose xylazine. In the other 5 rabbits, low-dose ketamine and high-dose xylazine were used. QTc interval in the latter was longer than that of the former (399 ± 56 ms vs. 494 ± 57 ms, P < 0.01). Although no VT appeared in high/low-rabbits, VT occurred in 3 out of 5 low/high-rabbits (P < 0.05).. These results suggest that (1) deep anesthesia suppresses abnormal repolarization-related VT and (2) antiarrhythmic effect of anesthesia on this type of VT is not dependent on α2-AR agonistic action.

Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia, General; Anesthetics, Combined; Animals; Anti-Arrhythmia Agents; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Ketamine; Long QT Syndrome; Male; Methoxamine; Pyrimidinones; Rabbits; Tachycardia, Ventricular; Time Factors; Xylazine

Increased action potential duration (APD) induces early afterdepolarization (EAD) in vitro and torsade de pointes in vivo, and ATP-sensitive K(+) channel openers decrease APD in cardiac tissue. We tested whether the ATP-sensitive K(+) channel opener nicorandil has antiarrhythmic effects on class III antiarrhythmic drug-induced ventricular arrhythmia. In 10 anesthetized dogs with chronic atrioventricular block, we recorded monophasic action potentials (MAPs) from the left and right ventricular (LV and RV) endocardium. The class III antiarrhythmic drug nifekalant (1 mg/kg, IV) was administered at 5 minute intervals (total doses; 2-6 mg/kg) until the appearance of EADs, premature ventricular contractions (PVCs), or polymorphic ventricular tachycardias (PVTs). Five minutes after the end of nifekalant administration, nicorandil (1.0 mg/kg) was administered over 5 minutes. Nifekalant decreased the ventricular escape rate from 75 ± 5 beats/minute to 45 ± 10 beats/minute and increased RV-MAP duration (MAPD) from 217 ± 32 msec to 308 ± 2 msec (P < 0.01) and LV-MAPD from 232 ± 32 msec to 353 ± 82 msec (P < 0.01). EADs were recorded in 9 dogs, frequent premature ventricular contractions (PVCs) developed in 10 dogs, incessant PVTs developed in 3 dogs, and monomorphic ventricular tachycardia developed in 3 dogs after nifekalant administration. Nicorandil decreased RV-MAPD to 267 ± 57 msec and LV-MAPD to 279 ± 44 msec. It suppressed EADs, decreased the incidence of PVCs, and abolished PVT. Nicorandil may be clinically useful for treatment of PVCs and PVTs accompanying acquired long QT syndrome.

Topics: Animals; Anti-Arrhythmia Agents; Dogs; Dose-Response Relationship, Drug; Electrocardiography; KATP Channels; Long QT Syndrome; Nicorandil; Pyrimidinones; Torsades de Pointes; Ventricular Premature Complexes

In vivo antiarrhythmic effects of diltiazem hydrochloride and nifekalant hydrochloride, a pure class III antiarrhythmic drug (Vaughan Williams' classification), on adrenaline induced ventricular arrhythmias were examined in halothane anesthetized guinea pigs. Continuous adrenaline infusion (12.5 microg/kg per min) induced ventricular arrhythmias. Arrhythmogenicity was significantly increased with vagotomy and higher concentration of halothane. After injection of diltiazem at 0.5 mg/kg, the arrhythmic ratio (the number of ventricular ectopic beats divided by the total heart beats) was significantly reduced compared with the predrug control value (0.69 vs 0.04, P<0.05). No significant change of arrhythmic ratio was observed after injection of nifekalant (0.57 vs 0.61, ns). After administration of nifekalant, the mean minimum adrenaline infusion rate that induced ventricular arrhythmia decreased from 9.29 to 6.43 microg/kg per min. On the other hand, before administration of diltiazem, the mean arrhythmogenic rate of adrenaline was 8.50 microg/kg per min, but ventricular arrhythmias were no longer induced during continuous infusion of diltiazem at 0.5 mg/kg per min. These results were qualitatively consistent with previous experiments using the canine halothane-adrenaline model. In conclusion, the halothane-adrenaline arrhythmia model using the in vivo guinea pig is useful for screening drugs with potential anti- or pro-arrhythmic properties.

Topics: Adrenergic alpha-Agonists; Anesthetics, Inhalation; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Diltiazem; Electrocardiography; Epinephrine; Guinea Pigs; Halothane; Long QT Syndrome; Male; Pyrimidinones; Vagotomy