pyrimidinones and Atrial-Flutter

Little is known about the effect of nifekalant, a pure I(Kr) -selective blocker, on typical atrial flutter (AFL) and its termination mechanism.. The effects of nifekalant on AFL were elucidated in 17 patients. During AFL, the conduction time from the lateral to septal cavotricuspid isthmus (IS) and that through the reminder of the right atrium (nIS); AFL-cycle length (CL) variability, which was quantified by the standard deviation; and the maximum difference in AFL-CL were measured before and after administration of nifekalant (0.2-0.3 mg/kg). A single extrastimulus was delivered from the lateral cavotricuspid isthmus to elucidate the resetting response curves and atrial effective refractory period (AERP) before and after administration of nifekalant.. There was no significant difference in AFL-CL, IS, and nIS before and after nifekalant; however, AERP was increased after nifekalant (155 ± 22 ms vs 184 ± 32 ms, P < 0.001). The standard deviation and the maximum difference in AFL-CL were both increased after nifekalant (1.7 ± 0.7 ms vs 3.6 ± 2.3 ms, P < 0.001 and 4.1 ± 1.9 ms vs 8.5 ± 5.2 ms, P < 0.001). The total excitable gap decreased (94 ± 17 ms vs 66 ± 21 ms, P < 0.001) with rightward shift of the resetting response curves and loss of full excitability after nifekalant. In 11 patients (65%), AFL was terminated spontaneously (n = 7) or by a single extrastimulus (n = 4), which was not observed before nifekalant. Termination was associated with orthodromic block in the cavotricuspid isthmus in all patients.. Nifekalant increases AERP and AFL-CL variability by abolishing a fully excitable gap, without prolongation of AFL-CL. These unique effects facilitate the termination of AFL.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Flutter; Body Surface Potential Mapping; Female; Heart Conduction System; Humans; Male; Models, Cardiovascular; Potassium Channel Blockers; Pyrimidinones; Treatment Outcome

Nifekalant is a class III antiarrhythmic drug, which is usually used for suppression of ventricular tachycardia (VT) and fibrillation. We studied the efficacy of nifekalant for acute conversion of atrial flutter (AFL) in a prospective, open label study in the intensive care unit (ICU) of cardiovascular medicine.. This study consisted of 31 patients. Twenty-six patients (84%) suffered from structural heart diseases. AFL was developed in 15 patients (48%) while on antiarrhythmic therapy with class IA or IC drugs (I-AFL group) for suppressing atrial fibrillation (AF) and in the remaining patients without such drugs (S-AFL group). Patients with prolonged QT interval, hypokalemia were excluded. All patients received one dose of 0.3 mg/kg of nifekalant over 10 minutes under continuous ambulatory monitoring. Four patients with common AFL in each group received nifekalant during electrophysiologic (EP) study.. Nifekalant had an overall AFL conversion efficacy of 77.4% within 60 minutes. Eleven patients in S-AFL group (68.8%) and 13 patients in I-AFL group (86.7%) could be converted with mean conversion times of 10.8 +/- 6.2 and 15.0 +/- 8.0 minutes, respectively (n.s.). Conversion rate was significantly higher in patients with a short duration of arrhythmia. The two modes of AFL termination were mainly demonstrated and the preferential mode significantly differed between the two groups. One patient in each group with excessive QT prolongation (6.5%) developed torsade de pointes (TdP), requiring electrical shock in one patient (3.3%).. Nifekalant can be used for conversion of AFL with a potent efficacy even in patients with structural heart diseases. However, caution should be required for developing TdP.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Flutter; Electrocardiography; Female; Hemodynamics; Humans; Male; Middle Aged; Prospective Studies; Pyrimidinones; Torsades de Pointes

Ventricular tachycardia (VT), ventricular fibrillation (VF), and atrial flutter (AFL) are potentially fatal or serious complications arising after cardiac surgery. Generally, we treat these complications with class I antiarrhythmic agents and/or direct counter shock (DC). However, sometimes these complications do not respond to antiarrhythmic agents and require frequent DC. Moreover, these class I agents induce heart failure due to their negative inotropic effect. Nifekalant hydrochloride (NIF) is a class III antiarrhythmic agent that prolongs the refractory period of the atrial and ventricular myocardium without any negative inotropic action. From July 2003 to September 2004, we treated 11 patients with NIF for perioperative arrhythmias (VT 5, VF 2, and AFL 4). NIF was administered by continuous intravenous infusion (0.3 to 0.4 mg/ kg/h) to prevent the recurrence of VT/VF and AFL. NIF prevented the recurrence of VT in 3 of the 5 cases. No recurrence was observed in 2 cases with VF. Furthermore, NIF prevented the recurrence of AFL in all the 4 patients. None of the patients exhibited changes in heart rate, cardiac output, and QTc interval. Additionally, no occurrence of Torsades de pointes was observed in any of the cases. In conclusion, NIF is an effective and safe antiarrhythmic agent for the treatment of perioperative arrhythmias under continuous monitoring of the QTc interval.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Flutter; Cardiac Surgical Procedures; Female; Humans; Male; Middle Aged; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation

Nifekalant is a class III antiarrhythmic drug, which prolongs the refractory period of the atrial and ventricular myocardium, without negative inotropic action. Intravenous nifekalant was administered in four patients with atrial tachyarrhythmia and severe heart failure to terminate or prevent atrial tachyarrhythmia.. Two of three episodes of atrial tachyarrhythmia were terminated by intravenous nifekalant (0.22 to 0.30 mg/kg) administration. Continuous intravenous infusion of nifekalant (0.15 to 0.40 mg/kg/hr) during six episodes to maintain the sinus rhythm, prevented recurrence of atrial tachyarrhythmia in five episodes in which prolongation of the QTc interval was observed to more than 450 msec. None of the patients showed worsening of the hemodynamics during treatment. One patient developed polymorphic ventricular tachycardia, which deteriorated into ventricular fibrillation.. Nifekalant may be effective for treating atrial tachyarrhythmia in patients with severe heart failure. Further clinical studies are needed to confirm these findings.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrimidinones; Tachycardia

It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor-mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined.. Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 mumol/L)-induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 mumol/L), E-4031 (3 mumol/L), and MS-551 (30 mumol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, IK.ACh was activated by extracellular application of carbachol (1 mumol/L) or adenosine (10 mumol/L) or by intracellular loading of GTP gamma S (100 mumol/L). Sotalol (3 to 1000 mumol/L), E-4031 (1 to 100 mumol/L), and MS-551 (1 to 100 mumol/L) inhibited the carbachol-induced IK.ACh in a concentration-dependent manner, and their IC50 (half-maximal inhibition) values were 35.5, 7.8, and 11.4 mumol/L, respectively. However, the GTP gamma S-induced and adenosine-induced IK.ACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol.. Sotalol may inhibit IK.ACh by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K+ channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on IK.ACh.

Topics: Acetylcholine; Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Atrial Function, Left; Cells, Cultured; Guinea Pigs; Heart Atria; In Vitro Techniques; Myocardial Contraction; Patch-Clamp Techniques; Piperidines; Potassium Channels; Pyridines; Pyrimidinones; Receptors, Muscarinic; Sotalol