pyrimidinones and Tachycardia--Ventricular

Amiodarone (AMD) and nifekalant (NIF) are used in the treatment of ventricular fibrillation or tachycardia; however, only few studies have been conducted on their efficacies. Therefore, a meta-analysis was conducted. Relevant sources were identified from PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi. The outcomes were short-term and long-term survival in patients with shock-resistant ventricular fibrillation /pulseless ventricular tachycardia. Thirty-three studies were analysed. The results showed that, compared to the control treatment, AMD did not improve short-term survival (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.91-1.71) or long-term survival (OR: 1.00, 95% CI: 0.63-1.57). However, compared to the control treatment, NIF significantly improved short-term survival (OR: 3.23, 95% CI: 2.21-4.72) and long-term survival (OR: 1.88, 95% CI: 1.36-2.59). No significant difference was observed in short-term survival (OR: 0.85, 95% CI: 0.63-1.15) or long-term survival (OR: 1.25, 95% CI: 0.67-2.31) between AMD- and NIF-treated patients. The results suggest that NIF is beneficial for short-term and long-term survival in shock-resistant ventricular fibrillation/pulseless ventricular tachycardia; however, the efficacy of AMD in either outcome is not clear.

Topics: Amiodarone; Humans; Publication Bias; Pulse; Pyrimidinones; Randomized Controlled Trials as Topic; Survival Analysis; Tachycardia, Ventricular; Treatment Outcome; Ventricular Fibrillation

Ventricular tachycardia (VT) and ventricular fibrillation are the causes of approximately 300,000 deaths per year in the United States. VT is classified based on hemodynamic status and appearance. Stable, monomorphic VT treatment is controversial.. Our aim was to provide emergency physicians with an evidence-based review of the medical management of stable, monomorphic VT.. Stable, monomorphic VT is part of a larger class of ventricular dysrhythmias defined by a rate of at least 120 beats/min with QRS > 120 ms without regularly occurring P:QRS association. Little controversy exists for the treatment of hemodynamically unstable VT. The medical management of hemodynamically stable monomorphic VT is surrounded by controversy. Direct current cardioversion is most efficacious. Guidelines for the treatment of stable VT from the American Heart Association provide a IIa recommendation for procainamide, compared with a IIb recommendation for both amiodarone and sotalol. Studies evaluating procainamide, lidocaine, amiodarone, and sotalol suffer from poor design, difference in inclusion and exclusion criteria, small sample size, and outcome determination. Procainamide demonstrates the greatest efficacy. If procainamide is selected, a maximum dose of 10 mg/kg at 50-100 mg/min intravenous (IV) over 10-20 min should be provided with monitoring of blood pressure and electrocardiogram. Monomorphic VT with acute myocardial ischemia requires further study.. Optimal management of stable, monomorphic VT includes direct current cardioversion. If medical management is chosen, procainamide is most efficacious, though current literature suffers from poor design.

Topics: Amiodarone; Anti-Arrhythmia Agents; Electric Countershock; Electrocardiography; Emergency Service, Hospital; Evidence-Based Medicine; Humans; Lidocaine; Procainamide; Pyrimidinones; Review Literature as Topic; Sotalol; Tachycardia, Ventricular

Acute coronary syndrome causes several types of arrhythmia because of its electrical instability and ischemia. The most important arrhythmia is ventricular tachycardia which degenerates to ventricular fibrillation. Prompt direct current cardioversion will be needed and prevention of ventricular tachyarrhythmia by potassium channel blocker became more popular in Japan. Nifekalant or amiodarone should be selected. Atrial fibrillation also occurred in the patients with acute coronary syndrome, and it may deteriorate hemodynamics condition. Therefore, termination and prevention of atrial fibrillation is another important issue in acute coronary syndrome. Aprindine, amiodarone, or bepridil will be the choice to prevent recurrent atrial fibrillation after direct current cardioversion.

Topics: Amiodarone; Angina, Unstable; Anti-Asthmatic Agents; Aprindine; Atrial Fibrillation; Bepridil; Electric Countershock; Humans; Myocardial Infarction; Potassium Channel Blockers; Pyrimidinones; Recurrence; Syndrome; Tachycardia, Ventricular; Ventricular Fibrillation

Differential effects of sodium channel blockers, an I(Kr) blocker (nifekalant) and amiodarone on the spiral-type reentry, were investigated in rabbit hearts by using a high-resolution optical mapping system. Two-dimensional subepicardial layer of left ventricular myocardium with uniform anisotropy was prepared by endocardial cryoablation. During ventricular tachycardia (VT) elicited by cross-field stimulation, spiral-type excitations rotating around functional block lines (FBLs) were visualized. All the sodium channel blockers stabilized rotors; VT duration was prolonged in association with increases of FBLs and VT cycle length. The rotors in the presence of nifekalant were characterized by large meandering, long FBLs, and frequent front-tail interactions generating wave breaks. Amiodarone (acute application) increased FBLs and VT cycle length, but shortened the VT duration with minimal front-tail interaction. These results suggest that multifaceted drug action on both depolarization and repolarization may be required for the early termination of spiral-type reentry without causing breakup of rotors.

Topics: Amiodarone; Animals; Anisotropy; Anti-Arrhythmia Agents; Heart Conduction System; Humans; Myocardium; Pre-Excitation Syndromes; Pyrimidinones; Signal Processing, Computer-Assisted; Sodium Channel Blockers; Tachycardia, Ventricular

Arrhythmias are commonly occur after cardiac surgery. Recurrent sustained ventricular tachycardia and ventricular fibrillation in the acute phase after cardiac surgery is the most lethal arrhythmia and may warrant acute intervention and aggressive treatment. Although class I agents are usually ineffective and exacerbate the heart failure in cases with a low ejection fraction, nifekalant(a newer class III agent) and amiodarone can be effective. Hemodynamically tolerable sustained monomorphic ventricular tachycardia can be successfully terminated with ramp or burst pacing via an epicardial ventricular pacing lead. Initiation of intra-aortic balloon pumping and emergency percutaneous cardiopulmonary bypass and emergency catheter ablation can be considered for those patients not responding to the conventional resuscitative measures.

Topics: Amiodarone; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Catheter Ablation; Humans; Intra-Aortic Balloon Pumping; Postoperative Complications; Pyrimidinones; Recurrence; Tachycardia, Ventricular; Ventricular Fibrillation

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

Intravenous amiodarone (AMD) has been used for the treatment of ventricular tachycardia/fibrillation (VT/VF) in emergency care medicine. However, AMD acts slowly and is occasionally accompanied by hypotension and bradycardia. The antiarrhythmic effect of intravenous nifekalant (NIF) was assessed in patients with VT/VF complicating acute coronary syndrome (ACS) according to our study protocol.. Among a series of 1,143 ACS patients, 41 patients who suffered sustained VT/VF were enrolled; 19 failed to respond to a preceding lidocaine (LID) injection. NIF was given first as an intravenous bolus injection (0.2 mg/kg) and then as a continuous intravenous infusion at a relatively low dose level (0.2 mg x kg(-1) x h(-1)). Sustained VT/VF was successfully inhibited by NIF in 34 patients (83%). In subgroup analysis, NIF achieved VT/VF inhibition in 79% of patients who received preceding LID and in 86% of patients who received direct NIF. There were no significant changes in systolic blood pressure or heart rate following NIF therapy. A corrected QT interval was significantly prolonged (P<0.01), whereas torsade de pointes developed in only 1 patient (2%).. An intravenous bolus injection and subsequent continuous infusion of NIF at a relatively low dosage were effective in treating severe ventricular tachyarrhythmias complicating ACS, reducing the potential risk of proarrhythmia.

Topics: Acute Coronary Syndrome; Aged; Amiodarone; Anti-Arrhythmia Agents; Blood Pressure; Electrocardiography; Emergency Medical Services; Female; Heart Rate; Humans; Infusions, Intravenous; Injections, Intravenous; Lidocaine; Male; Middle Aged; Pyrimidinones; Tachycardia, Ventricular; Torsades de Pointes; Ventricular Fibrillation

Although nifekalant hydrochloride (NIFE) has been demonstrated to suppress ventricular tachyarrhythmia, especially electrical storm, the mechanism by which it does so is still unclear. We examined its effects on the spatial dispersion of repolarization (SDR) after implantable cardioverter-defibrillator (ICD) shock.. In twenty five patients with an ICD, we recorded the 87-lead ECG during sinus rhythm (the CONTROL group) under general anesthesia, after NIFE administration alone, and just after termination of induced ventricular fibrillation (VF) by ICD shock with or without NIFE administration. In all recordings, the corrected QT interval (QTc) was measured in each lead. The dispersion of QTc (QTc-D; maximum QTc minus minimum QTc) was also measured. Compared with the CONTROL, the QTc-D exhibited significant deterioration after ICD shock (61 +/- 12, 91 +/- 24 ms(1/2), respectively, p < 0.001). However, the QTc-D after NIFE administration either with or without ICD shock did not differ from the CONTROL group (65 +/- 20, 61 +/- 18, and 61 +/- 12 ms(1/2), respectively, p = 0.99).. NIFE suppressed the deterioration of SDR by ICD shock. This might be a mechanism by which NIFE suppresses recurrence of ventricular tachyarrhythmia after ICD shock.

Topics: Adrenergic beta-Antagonists; Aged; Amiodarone; Anti-Arrhythmia Agents; Defibrillators, Implantable; Electrocardiography; Female; Humans; Male; Middle Aged; Pyrimidinones; Sotalol; Tachycardia, Ventricular; Ventricular Fibrillation; Ventricular Function, Left

Early defibrillation of ventricular tachycardia and fibrillation (VT/VF) is an urgent and most important method of resuscitation for survival in cardiopulmonary arrest (CPA). We have previously reported that nifekalant (NIF), a specific I(Kr) blocker developed in Japan, is effective for lidocaine (LID) resistant VT/VF in out-of-hospital CPA (OHCPA). However, little is known about the differences in the effect of NIF on OHCPA with acidosis and in-hospital CPA (IHCPA) without acidosis.. The present study enrolled 91 cases of DC shock resistant VT/VF among 892 cases of CPA that occurred between June 2000 and May 2003. NIF was used (0.15-0.3 mg/kg) after LID according to the cardiopulmonary resuscitation (CPR) algorithm of Tokai University. The defibrillation rate was higher in the NIF group for both OHCPA and IHCPA than for LID alone, and the VT/VF rate reduction effect could be maintained even with acidosis. However, sinus bradycardia in OHCPA, and torsades de pointes in IHCPA were occasionally observed. These differences in adverse effects might be related to the amount of epinephrine, serum potassium levels, serum pH, and interaction with LID.. NIF had a favorable defibrillating effect in both CPA groups, and it shows promise of becoming a first-line drug for CPR.

Topics: Acidosis; Aged; Anti-Arrhythmia Agents; Electric Countershock; Epinephrine; Female; Heart Arrest; Humans; Hydrogen-Ion Concentration; Inpatients; Male; Middle Aged; Outpatients; Potassium; Pyrimidinones; Resuscitation; Retrospective Studies; Tachycardia, Ventricular

Suppression of implantable defibrillator discharges associated with ventricular tachyarrhythmia (VTA) has been reported for sotalol. This study aimed to investigate the efficacy of intravenous nifekalant hydrochloride in predicting the effects of oral sotalol.. The present study included 14 patients who had sustained VTA associated with structural heart disease. All patients also had inducible VTA. To compare the effects of nifekalant and sotalol, programmed electrical stimulation was performed, in the basal state, after nifekalant administration, and after sotalol administration. Nifekalant and sotalol similarly prolonged the corrected QT interval and ventricular effective refractory periods, but the heart rate was slowed by sotalol only. In 4 of 5 patients whose VTA became non-inducible by nifekalant, subsequent treatment with sotalol also suppressed the inducible VTA. In all of the 9 patients non-responding to nifekalant, VTA remained inducible during sotalol treatment. Nifekalant accurately predicted the response to sotalol during electrophysiologic study in 13 of 14 patients. Of 11 patients who remained on sotalol, VTA recurred in 3 non-responders during a follow-up of 46 +/- 11 months.. Nifekalant and sotalol had similar effects on inducible VTA. The response of inducible VTA to nifekalant may predict the clinical efficacy of sotalol.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Drug Therapy, Combination; Electric Stimulation; Electrocardiography; Electrophysiology; Female; Heart Diseases; Humans; Male; Middle Aged; Pyrimidinones; Secondary Prevention; Sotalol; Tachycardia, Ventricular; Treatment Outcome

Some patients with an implantable cardioverter-defibrillator (ICD) suffer from burst of inappropriate multiple discharges (severe electrical storm), and because the current therapeutic options are limited, the effect of nifekalant hydrochloride, a new class III drug, on severe electrical storm was investigated in the present study.. Ninety-one consecutive patients treated with ICD were included in the study (M 70; mean age 58 years; left ventricular ejection fraction 45+/-15%). Severe electrical storm was defined as more than 10 ICD discharges within 1 h. During a mean follow-up period of 30+/-13 months, 41/91 (45%) patients had appropriate ICD therapy for arrhythmias and severe electrical storm occurred in 11 of them (12%) at 20+/-18 months after ICD implantation. The mean number of ICD discharges/h during severe electrical storm was 18+/-12. In 4 of 10 patients, severe electrical storm was successfully suppressed by a combination of deep sedation and beta-blocking agent; 6 other patients were refractory to this treatment, but severe electrical storm was successfully suppressed by intravenous administration of nifekalant hydrochloride with no adverse effects.. Nifekalant hydrochloride is an effective and safe treatment for severe electrical storm.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Defibrillators, Implantable; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Pyrimidinones; Salvage Therapy; Tachycardia, Ventricular

Many cases have been successfully treated by us with experimented nifekalant hydrocholoride to prevent ventricular tachycardia (VT) during cardiac surgery. The 13 patients who underwent cardiac surgery at our hospital from 1999 to 2002 were retroactively given nifekalant hydrocholoride against VT. Lidocaine hydrochloride was not effective for VT, and it was difficult for 3 patients to be weaned for cardio-pulmonary bypass, while 6 patients needed aortic balloon pumping or percutaneous cardio-pulmonary support. Nifekalant hydrochloride suppressed VT induction in 9 patients (69.2%). Blood pressure and heart rate did not change, but QTc intervals were significantly increased with nifekalant hydrochloride (p < 0.005). Proarrhythmic events (Torsades de pointes) occurred in 2 patients, but none of the cases showed drug-induced worsening of cardiac function. Nifekalant hydrochloride is a class III antiarrhythmic drug that has been found to be effective against VT and ventricular fibrillation. While class I antiarrhythmic drugs are usually ineffective and induce severe heart failure, nifekalant hydrochloride can be effective.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Surgical Procedures; Female; Humans; Infusions, Intravenous; Intraoperative Complications; Male; Middle Aged; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular; Treatment Outcome

In recent clinical trials, class III anti-arrhythmic drugs were found to reduce arrhythmic deaths in patients after myocardial infarction. The purpose of this study was to assess the electrophysiologic properties and anti-arrhythmic efficacy for inducible sustained ventricular tachycardias (VTs) of the pure class III agent nifekalant hydrochloride (MS-551) in comparison with those of procainamide. Programmed ventricular stimulation of up to three extra stimuli was performed for induction of VTs. Effective refractory period (ERP) of the ischemic zone and normal zone was also measured before and after nifekalant. Nifekalant and procainamide suppressed sustained VT induction in four of 15 patients and in six of 15 patients, respectively (p = NS). Sinus cycle length, PR interval, and QRS duration were not changed, but QT and QTc intervals were significantly increased with nifekalant (p < 0.01). Ventricular ERP also increased, whereas there were no significant differences in the increase of ERP between the ischemic and normal zones. The suppression of VT induction did not correlate with the changes in QT, QTc, and ERP after nifekalant administration. There were no significant differences in induced VT cycle length at baseline study between responders and nonresponders to nifekalant. Reverse use dependence was not apparent on review of electrophysiologic parameters. Neither proarrhythmic events nor hemodynamic disturbances occurred after nifekalant administration. It was concluded that nifekalant could be used safely and showed comparable effectiveness to procainamide for the suppression of VT induction.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Electrocardiography; Electrophysiology; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Procainamide; Pyrimidinones; Tachycardia, Ventricular

The potential utility of nifekalant, a new Class III antiarrhythmic drug, to offer long-term protection against ventricular arrhythmia has been investigated in this case report. A 44-year-old male patient with dilated cardiomyopathy complicated with heart failure and persistent ventricular tachycardia was treated with nifekalant. The patient was treated with nifekalant for 31 days, which effectively terminated ventricular tachycardia and maintained sinus rhythm, with no clinical adverse reactions. After heart transplantation, postoperative follow-up showed good cardiac function and no arrhythmia. On the basis of nifekalant's working mechanism, there is a good chance that it can cure ventricular arrhythmia on a long-term basis.

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Humans; Male; Pyrimidinones; Tachycardia, Ventricular

The aim of this study was to prospectively assess the efficacy, safety, and predictive effect of intravenous nifekalant administration for persistent atrial fibrillation (PerAF) after pulmonary vein isolation (PVI) with second-generation cryoballoon ablation (CBA) on 1-year atrial tachyarrhythmia (ATa) -free survival by examining the pharmacological conversion rate.One hundred and two drug-refractory, consecutive PerAF patients undergoing PVI were enrolled in this prospective observational study. After PVI, nifekalant (50 mg) was given followed by 30 minutes of observation and no further intervention. PerAF was successfully converted to sinus rhythm (SR) in 60 patients (58.8%) after a median time of 7.75 (4.13-12) minutes (group N). In the remaining 42 patients (41.2%) (group C), PerAF was successfully converted to SR by external electrical cardioversion. Nonsustained ventricular tachycardia occurred in 1 patient in group N. The left atrial volume (LAV) in group C was larger than that in group N (128.2 ± 28.2 versus 111.8 ± 24.5 mL, P = 0.002). Phrenic nerve injury occurred in 4 of 102 patients (3.9%). No other complications occurred during the procedure or within the 1-year follow-up period. At the 1-year follow-up, after a 3-month blanking period (BP), ATa-free survival during 1-year follow-up in group C was significantly lower than that in group N (50.0% versus 71.7%, P = 0.026), and the overall ATa-free survival rate was 62.7%. Two patients in group C and 4 patients in group N underwent a second procedure with radiofrequency catheter ablation. Multivariate Cox regression analysis demonstrated that unsuccessful conversion to SR (P = 0.025), ATa relapse during the BP (P = 0.000), and larger LAV (P = 0.016) were independent predictors of ATa recurrence at the 1-year follow-up.In conclusion, at the 1-year follow-up, the ATa-free survival rate after PVI with CBA for PerAF patients was 62.7%, and successful conversion to SR with nifekalant could serve as a clinical predictor of reduced ATa recurrence.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Cryosurgery; Electric Countershock; Female; Heart Atria; Humans; Infusions, Intravenous; Intraoperative Care; Intraoperative Complications; Male; Middle Aged; Organ Size; Peripheral Nerve Injuries; Phrenic Nerve; Progression-Free Survival; Prospective Studies; Pulmonary Veins; Pyrimidinones; Recurrence; Tachycardia, Ventricular; Treatment Outcome

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

To compare the efficacy and safety of nifekalant, a pure class III anti-arrhythmic drug, and lidocaine in patients with shock-resistant in-hospital ventricular fibrillation (VF) or ventricular tachycardia (VT).. Between August 2005 and March 2008, we conducted a prospective, two-arm, cluster observational study, in which participating hospitals were pre-registered either to the nifekalant arm or the lidocaine arm. Patients were enrolled if they had in-hospital VF or VT resistant to at least two defibrillation shocks. Congenital or drug-induced long QT syndrome was excluded. The primary end-point was termination of VF or VT with/without additional shock. The secondary end-points were return of spontaneous circulation (ROSC), 1-month survival and survival to hospital discharge. We also assessed the frequency of adverse events, including asystole, pulseless electrical activity and torsade de pointes.. In total, 55 patients were enrolled. After nifekalant, 22 of 27 patients showed termination of VF or VT, as compared with 15 of 28 patients treated with lidocaine with/without additional shock (odds ratio (OR): 3.8; 95% confidence interval (CI): 1.1-13.0; P=0.03). Twenty-three of 27 patients given nifekalant showed ROSC, as compared with 15 of 28 patients given lidocaine (OR: 5.0; 95% CI: 1.4-18.2; P=0.01). There was no difference in 1-month survival or survival to hospital discharge between the nifekalant and lidocaine arms. There was a higher incidence of asystole with lidocaine (7 of 28 patients) than with nifekalant (0 of 27 patients) (P=0.005). Torsade de pointes was not observed.. Nifekalant was more effective than lidocaine for termination of arrhythmia and for ROSC in patients with shock-resistant in-hospital VF or VT (umin-CTR No. UMIN 000001781).

Topics: Aged; Anti-Arrhythmia Agents; Chi-Square Distribution; Female; Humans; Lidocaine; Male; Middle Aged; Prospective Studies; Pyrimidinones; Statistics, Nonparametric; Survival Rate; Tachycardia, Ventricular; Treatment Outcome; Ventricular Fibrillation

An "electrical storm" is a life-threatening condition defined as a recurrent attack of ventricular tachycardia or fibrillation. The current report is a case study of a patient who had electrical storms developing unexpectedly after undergoing coronary artery bypass grafting. The electrical storms were terminated dramatically by the administration of nifekalant hydrochloride. We suggest that nifekalant hydrochloride has great therapeutic potential for the suppression of intractable ventricular tachyarrhythmias refractory to amiodarone.

Topics: Aged; Anti-Arrhythmia Agents; Coronary Angiography; Coronary Artery Bypass; Coronary Stenosis; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Myocardial Infarction; Postoperative Complications; Pyrimidinones; Severity of Illness Index; Tachycardia, Ventricular; Treatment Outcome

A 78-year-old man with chronic renal failure (CRF) on hemodialysis (HD) was diagnosed as having severe aortic regurgitation with left ventricular dysfunction. Aortic valve replacement with a 21 mm ATS mechanical bileaflet prosthesis was performed without intraoperative complications. Sustained ventricular tachycardia suddenly occurred 1 day after surgery, then intravenous administration of nifekalant hydrochloride (NIF) was started at a dose of 0.40 mg/kg/hr. Life-threating ventricular arrhythmia was controlled, hemodynamic compromise was improved dramatically. NIF was regulated with a low-dose of 0.24 mg/kg/hr to prevent malignant side effect such as torsa de pointes. Since QTc was elongated to 0.57 seconds 11 hours after administration, NIF was stopped. Low-dose intravenous administration of NIF in patients with CRF on HD could be useful to prevent ventricular tachyarrhythmias without any adverse effect after cardiac surgery.

Topics: Aged; Anti-Arrhythmia Agents; Aortic Valve; Heart Valve Prosthesis; Hemodialysis Solutions; Humans; Kidney Failure, Chronic; Male; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular

Topics: Anti-Arrhythmia Agents; Defibrillators; Electric Countershock; Humans; Out-of-Hospital Cardiac Arrest; Patient Admission; Pyrimidinones; Survival Rate; Tachycardia, Ventricular; Time Factors; Torsades de Pointes; Treatment Failure; Ventricular Fibrillation

We assessed several pharmacological effects on electrocardiogram parameters and effective refractory period (ERP) in a patient with a short QT syndrome (SQTS). Pharmacological challenge tests revealed that disopyramide and selective I(kr) blocker, nifekalant normalized QT interval, and ERP of the atrial and ventricular myocardium. This study suggested that disopyramide and nifekalant should be feasible for the drug treatment of the SQTS. Moreover, QT interval was paradoxically prolonged at higher heart rates induced with isoproterenol infusion or an exercise test, although the mechanism of this QT prolongation remains to be investigated.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Body Surface Potential Mapping; Disopyramide; Humans; Male; Pyrimidinones; Syndrome; Tachycardia, Ventricular; Treatment Outcome; Young Adult

Nifekalant (NF) is a novel class III antiarrhythmic agent that is effective in preventing life-threatening ventricular tachycardia/fibrillation (VT/VF). We investigated mechanisms of destabilization and early termination of spiral-type reentrant VT by NF in a two-dimensional subepicardial myocardial layer of Langendorff-perfused rabbit hearts (n = 21) using a high-resolution optical action potential mapping system. During basic stimulation, NF (0.1 microM) caused uniform prolongation of action potential duration (APD) without affecting conduction velocity and an increase of APD restitution slope. VTs induced by direct current stimulation in the presence of NF were of shorter duration (VTs > 30 s: 2/54 NF vs. 19/93 control). During VTs in control (with visible rotors), the wave front chased its own tail with a certain distance (repolarized zone), and they seldom met each other. The average number of phase singularity (PS) points was 1.31 +/- 0.14 per 665 ms (n = 7). In the presence of NF, the wave front frequently encountered its own tail, causing a transient breakup of the spiral wave or sudden movement of the rotation center (spatial jump of PS). The average number of PS was increased to 1.63 +/- 0.22 per 665 ms (n = 7, P < 0.05) after NF. The mode of spontaneous termination of rotors in control was in most cases (9/10, 90.0%) the result of mutual annihilation of counterrotating wave fronts. With NF, rotors frequently terminated by wave front collision with the atrioventricular groove (12/19, 63.2%) or by trapping the spiral tip in a refractory zone (7/19, 36.8%). Destabilization and early termination of spiral wave reentry induced by NF are the result of a limited proportion of excitable tissue after modulation of repolarization.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Female; Heart Conduction System; Heart Ventricles; Male; Pyrimidinones; Rabbits; Tachycardia, Ventricular; Treatment Outcome

Perioperative ventricular tachycardia (VT) was treated with nifekalant hydrochloride, a pure potassium channel blocker in 2 patients with low left ventricular ejection fraction (LVEF). The first patient is a 34-year-old woman, a chronic hemodialysis patient in whom severe aortic stenosis due to structural valvular deterioration of the previously implanted tissue valve was diagnosed with her LVEF of 26.9%. She underwent urgent redo aortic valve replacement with a mechanical valve. Postoperatively a sustained VT developed. After she received direct-current (DC) shock, nifekalant hydrochloride was administered. The 2nd patient is a 44-year-old man who presented with severe congestive heart failure. A coronary angiogram revealed triple vessel disease as well as decreased LVEF of 16% and ischemic mitral regurgitation. He underwent triple coronary artery bypass grafting and mitral ring annuloplasty. A VT developed requiring DC shock during hemostasis. Nifekalant hydrochloride was given immediately. In both patients, nifekalant hydrochloride was given intravenously in a dose of 0.3 mg/kg followed by a continuous intravenous infusion at a dose of 0.4 mg/kg/hr. Our experience shows nifekalant hydrochloride is effective against perioperative VT, especially in patients with impaired left ventricular function since it has mild positive inotropic effect.

Topics: Adult; Anti-Arrhythmia Agents; Cardiac Surgical Procedures; Electrocardiography; Female; Humans; Male; Perioperative Care; Pyrimidinones; Tachycardia, Ventricular; Ventricular Function, Left

A 75-year-old female complained of severe chest pain and was emergently admitted to our hospital because of anterior acute myocardial infarction. Emergent coronary angiography was performed and revealed occlusion in segment 7, so a stent was implanted. Lidocaine, carvedilol, amiodarone, magnesium, and nifekalant were administered successively because non-sustained ventricular tachycardia (NSVT) frequently appeared like an electrical storm. After nifekalant administration, QTc was significantly prolonged and torsades de pointes was induced. Overdrive pacing was performed and finally the NSVT was completely controlled. If fatal arrhythmias such as NSVT show resistance to medication, overdrive pacing should be considered to stabilize the arrhythmia associated with acute coronary syndrome.

Topics: Acute Coronary Syndrome; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Drug Resistance; Female; Humans; Myocardial Infarction; Pyrimidinones; Stents; Tachycardia, Ventricular; Treatment Outcome

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

Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated.. Eight beagle dogs were created with a myocardial infarction under anesthesia, and then VT/VF induction by continuous stimulation and cardiopulmonary resuscitation (CPR) were repeated. NIF (0.3 mg/kg) was administered under acidotic conditions (pH 7.26). The QTc interval measured by Y-lead ECG showed no significant prolongation before and after NIF. The activation recovery interval (ARI) measured by 64-lead LV surface mapping showed minimum ARI prolongation (40%) by NIF without maximum ARI prolongation, and as a result the ARI dispersion decreased by 67%. The repolarization time (RPT) with the plunge electrode showed 13-19% prolongation in the subendocardium and subepicardium with CPR, but NIF prolonged the RPT in the middle layer alone (17%), and as a result Plunge-TDR decreased by 82% (n=8, p<0.05).. Administration of NIF during CPR decreased the TDR by RPT prolongation selectively in the middle layer. Because the subendocardial and subepicardial RPTs after CPR were already prolonged before NIF administration, it may have been the reason why the QT-prolonging effect of NIF was not reflected in the body surface ECG.

Topics: Animals; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Disease Models, Animal; Dogs; Heart Arrest; Heart Conduction System; Humans; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation

We experienced 2 effective cases of nifekalant hydrochloride. One patient was 76-year-old female who underwent emergent coronary artery bypass grafting (CABG) because of unstable angina pectoris (AP) and ventricular fibrillation (Vf). Her cardiac function had been decreased preoperatively due to old myocardial infarction (OMI). One day after CABG, she revealed sustained ventricular tachycardia (VT) and Vf. Although administrations of neither lidocaine hydrochloride nor magnesium sulfate were effective, nifekalant hydrochloride finally stopped the life-threatening arrhythmia without hypotension. Another patient was 77-year-old male who underwent CABG and Dor operation. His cardiac function also had been decreased due to OMI. He revealed VT attack at midnight 3 days after operation. VT attack still appeared at next 2 midnight under lidocaine hydrochloride infusion, but finally it has disappeared after starting a drip infusion of nifekalant hydrochloride. Nifekalant hydrochloride is quite useful as a new therapeutic strategy for uncontrollable VT and Vf and for the patient who has a reduced left ventricular function because it has an inotropic effect.

Topics: Aged; Anti-Arrhythmia Agents; Coronary Artery Bypass; Female; Humans; Injections, Intravenous; Male; Myocardial Ischemia; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular

Ventricular tachycardia (VT), which causes hemodynamic instability, and ventricular fibrillation (VF) sometimes occur in patients with severe underlying cardiovascular disease such as myocardial ischemia or infarction, and are associated with high mortality. This report presents the efficacy of nifekalant hydrochloride (nifekalant), a pure class III antiarrhythmic agent, in treating life-threatening ventricular arrhythmia in such patients. From June 2000, when nifekalant became commercially available in Japan, to May 2003, 30 ischemic heart disease (IHD) patients with VT/VF resistant to direct-current (DC) countershock received nifekalant in our hospital. These 30 patients served as the nifekalant group in this study. As a control group, we also included 33 IHD patients with VT/VF that had been resistant to DC countershock upon or during hospitalization between January 1996 and May 2000 before nifekalant became commercially available. No significant differences were observed in patient background factors and treatments between the two groups. The rates of death within 48 hours of occurrence of VT/VF were significantly lower in the nifekalant group (7%, 2/30) than in the control group (27%, 9/33; P < 0.03). The rates of cardiac death during hospitalization were also significantly lower in the nifekalant group (40%, 12/30) than in the control group (67%, 22/33; P < 0.03). The rates of survival until hospital discharge were significantly higher in the nifekalant group (57%, 17/30) than in the control group (30%, 10/33; P < 0.03). Multivariate analysis of all 63 patients revealed nifekalant administration was the factor that significantly improved the mortality (odds ratio for cardiac death, 0.26; 95% confidence interval (CI), 0.07 to 0.95; P = 0.041). Nifekalant improves the prognosis for life-threatening ventricular arrhythmia in IHD patients.

Topics: Aged; Anti-Arrhythmia Agents; Drug Administration Schedule; Electrocardiography; Female; Humans; Male; Multivariate Analysis; Myocardial Ischemia; Prognosis; Pyrimidinones; Survival Rate; Tachycardia, Ventricular; Ventricular Fibrillation

A 52-year-old male with ischemic cardiomyopathy and severe ventricular dysfunction underwent coronary artery bypass grafting and left ventricular reconstruction (Dor operation). The patient developed acute onset of incessant ventricular tachycardia in the early postoperative period that was refractory to therapy with class I antiarrhythmic agents, and multiple attempts at electrical cardioversion were required. A combination of intravenous nifekalant hydrochloride and enteral amiodarone was elected as treatment for this recurrent incessant ventricular tachycardia. Nifekalant hydrochloride was administered as a loading dose (0.3 mg/kg/5 min), followed by an intravenous infusion (0.4 mg/kg/hr). Several days after initiating therapy, the patient no longer experienced episodes of ventricular tachycardia, and there was no compromise in hemodynamics. We conclude that nifekalant hydrochloride is a useful agent for suppression of ventricular tachycardia in patients with severe left ventricular dysfunction, especially during the early postoperative period.

Topics: Anti-Arrhythmia Agents; Cardiac Surgical Procedures; Cardiomyopathies; Electric Countershock; Humans; Male; Middle Aged; Myocardial Ischemia; Pyrimidinones; Tachycardia, Ventricular; Treatment Outcome; Ventricular Dysfunction, Left

Class I antiarrhythmic agents are not always effective in the treatment of life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) especially in patients with cardiopulmonary arrest. Nifekalant hydrochloride(NIF) is a novel class III antiarrhythmic agent for malignant VT/VF. This study prospectively evaluated NIF efficacy for life-threatening VT/VF observed after cardiopulmonary arrest.. Thirty-two of 145 patients who were transferred to the emergency room in Tokai University Hospital showed VT/VF after resuscitation from cardiopulmonary arrest from June 2000 to March 2001. These 32 patients were treated with 12 mg (mean) epinephrine and 1.0-2.0 mg/kg lidocaine following direct current application(200 to 360J), and then classified into two groups. Eleven patients received intravenous 0.15 to 0.3 mg/kg NIF followed by intravenous infusion of 0.3 to 0.4 mg/kg/hr NIF(NIF group). The other 21 patients received 1.0 to 2.0 mg/kg of lidocaine(non-NIF group).. Sinus rhythm was restored in the nine patients(82%) in the NIF group but only four patients (19%) in the non-NIF group. QTc was not prolonged(0.45 +/- 0.04 sec, n = 9) and no torsades de pointes was observed in the NIF group. Two patients survived but the remaining nine patients died in the NIF group. Five patients died of cardiac standstill following sinus bradycardia and repeated sinus arrest within 2 to 27 hr after admission, two patients died of sudden cardiac arrest from sinus rhythm, and two patients died of persistent VT/VF. In contrast, all 21 patients in the non-NIF group died. Seventeen patients died of persistent VT/VF before hospitalization, one patient died of recurrent VT/VF, and three patients died of cardiac standstill following sinus bradycardia.. NIF effectively suppresses VT/VF which is refractory to direct current shock in patients with cardiopulmonary arrest. However, NIF may rather worsen electrophysiological function in the sinus node after administration of high doses of epinephrine, and may induce sinus bradycardia and/or sinus arrest. Careful observation, such as monitoring of electrocardiography and blood pressure and temporary cardiac pacemaker use, is needed to prevent death in patients surviving after cardiopulmonary arrest if NIF is administered following high dose epinephrine infusion.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Drug Resistance; Emergency Medical Services; Epinephrine; Female; Heart Arrest; Humans; Lidocaine; Male; Middle Aged; Prospective Studies; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation

A patient with 3-vessel coronary artery disease and left ventricular aneurysm underwent coronary artery bypass grafting combined with the Dor approach. Five days later, ventricular tachycardia following short-coupled ventricular premature contractions suddenly occurred and was not responsive to class IB drugs (lidocaine and mexiletine), requiring frequent electrical cardioversion. After the administration of a novel class III drug, nifekalant hydrochloride, this electrical storm of ventricular tachycardia was completely suppressed together with the disappearance of ventricular premature contractions. Nifekalant hydrochloride (MS-551), a pure K(+) channel blocker, might be effective for postoperative recurrent ventricular tachyarrhythmias that are refractory to other antiarrhythmic agents.

Topics: Aged; Anti-Arrhythmia Agents; Coronary Artery Bypass; Drug Resistance; Electric Countershock; Electrocardiography; Humans; Lidocaine; Male; Mexiletine; Potassium Channel Blockers; Pyrimidinones; Tachycardia, Ventricular

Excretion in the urine is an important pathway for the elimination of nifekalant hydrochloride (NIF), a novel class III antiarrhythmic agent. Three patients with renal failure were undergoing hemodialysis and receiving NIF for the prevention of ischemia-induced ventricular tachyarrhythmia. Because NIF is not dialyzed, dose adjustment at relatively low concentrations was required, with monitoring of the QT interval.

Topics: Aged; Anti-Arrhythmia Agents; Diabetic Nephropathies; Drug Monitoring; Electrocardiography; Humans; Injections, Intravenous; Male; Myocardial Ischemia; Pyrimidinones; Renal Dialysis; Renal Insufficiency; Tachycardia, Ventricular

Pure class III antiarrhythmic agents cause reverse use-dependent QT prolongation. Nifekalant is a new class III antiarrhythmic agent and blocks rapid component of the delayed rectifier K+ current (Ikr) selectively. To prevent recurrent ventricular tachycardia in a patient with old myocardial infarction, nifekalant was administered by continuous intravenous infusion. There was little variation in the blood level of nifekalant during the 1-day period, but the QTc interval became shorter with an increase of the heart rate early in the morning. It is therefore considered advisable to monitor the heart rate and QTc interval during administration of nifekalant by continuous intravenous infusion.

Topics: Anti-Arrhythmia Agents; Electrocardiography; Heart Ventricles; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Pyrimidinones; Tachycardia, Ventricular

The most common mechanism of sustained ventricular tachycardia (VT) is re-entry with an excitable gap, but the electrophysiologic properties and response to antiarrhythmic drugs in the area of slow conduction are not yet fully known. The purpose of this study was to assess the effects of a class I antiarrhythmic drug (procainamide) and class III agents (amiodarone, E-4031, and MS-551) on re-entrant VT using the width of the zone of entrainment. The cycle length (CL) of VT (VTCL), the block CL that was the longest paced CL that interrupted the VT, and the width of the zone of entrainment, defined as the difference between VTCL and block CL, were compared before and after treatment with antiarrhythmic drugs. The VTCL was prolonged significantly from 308+/-63 to 410+/-77 msec after procainamide (p<0.005) but was not changed after the administration of the class III agents: from 294+/-50 to 292+/-13 msec after amiodarone, and from 305+/-47 to 313+/-31 msec after E-4031 or MS-551 (p=NS). The block CL was prolonged from 255+/-61 to 331+/-70 msec after procainamide (p <0.01), from 256+/-20 to 260+/-25 msec after amiodarone, and unchanged after E-4031 or MS-551 (253+/-31 msec before and 270+/-43 msec after) (p=NS). The width of the zone of entrainment as a representative of the width of the excitable gap was changed from 52+/-26 to 79+/-35 msec (p<0.05) after procainamide, whereas it was unchanged after amiodarone (48+/-7 msec before and 43+/-7 msec after) and after E-4031 or MS-551 (50+/-10 msec before and 40+/-9 msec after). Therefore, amiodarone, E-4031, and MS-551 did not affect VTCL and block CL whereas procainamide increased these parameters. The excitable gap substituting as the zone of entrainment was increased by procainamide but slightly reduced by amiodarone, E-4031, and MS-551. The effects of these antiarrhythmic drugs on the excitable gap of re-entrant VT were variable and should be examined further.

Topics: Adolescent; Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Child; Electrophysiology; Female; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Pyridines; Pyrimidinones; Tachycardia, Ventricular

The effects of intravenous MS-551, a new class III antiarrhythmic drug, on atrium and ventricle were evaluated in 6 patients with ventricular tachyarrhythmias (4 males and 2 females; mean age 45 +/- 21 years) in an electrophysiologic study. Two patients had sustained ventricular tachycardia (VT) and 4 patients had ventricular fibrillation (VF). Electrophysiologic study was performed before and after the administration of MS-551 (loading infusion 0.3 mg/kg for 5 min + 0.01 mg/kg/min). The QT and QTc intervals were significantly prolonged by MS-551 from 359 +/- 52 to 411 +/- 63 msec (p = 0.01) and from 410 +/- 36 to 452 +/- 47 (p = 0.0172), respectively. No effect was observed on the sinus cycle length, QRS duration, or AH and HV intervals in sinus rhythm. The effective refractory periods of the right atrium (AERP) were significantly prolonged at paced cycle lengths of 600 (from 222 +/- 19 to 250 +/- 23 msec, p = 0.0009), 400 (from 207 +/- 15 to 228 +/- 15, p < 0.0001) and 300 (from 193 +/- 10 to 205 +/- 8 msec, p = 0.0127) msec. Similarly, the right ventricular ERP (VERP) were significantly prolonged at paced cycle lengths of 600 (from 240 +/- 23 to 268 +/- 23 msec, p < 0.0001), 400 (from 225 +/- 22 to 250 +/- 24 msec, p = 0.0007), and 300 msec (from 213 +/- 14 to 228 +/- 18 msec, p = 0.0071). MS-551 prolonged AERP and VERP in a "reverse" use-dependent manner without changing the conduction time in patients with ventricular tachyarrhythmias. MS-551 prevented the induction of VT in 1 patient and VF in only 1 patient in this electrophysiologic study. Further evaluation of the therapeutic potential of MS-551 using higher dosages is necessary.

Topics: Adolescent; Adult; Analysis of Variance; Anti-Arrhythmia Agents; Drug Evaluation; Electrocardiography; Electrophysiology; Female; Heart; Heart Atria; Heart Ventricles; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrimidinones; Tachycardia, Ventricular

Electrophysiologic effects of intravenous E-4031 and MS-551, novel class III antiarrhythmic agents, were evaluated in 5 and 6 patient with ventricular tachyarrhythmia, respectively. Six patients had sustained ventricular tachycardia (VT) and 5 had ventricular fibrillation (VF). Electrophysiologic study was performed before and after administration of E-4031 and MS-551 [E-4031; loading infusion 9 micrograms/kg for 5 min + 0.15 microgram/kg/min, MS-551; loading infusion 0.3 mg/kg for 5 min + 0.01 mg/kg/min]. The QT intervals were significantly prolonged after administration of E-4031 and MS-551 from 409 +/- 37 to 455 +/- 49 msec (11%), and from 359 +/- 52 to 411 +/- 63 msec (14%), respectively. The QTc intervals were significantly prolonged from 457 +/- 17 to 494 +/- 24 msec (8%), and from 410 +/- 36 to 452 +/- 47 (10%), respectively. There were no significant differences in the QT and QTc intervals between these two agents. The right ventricular effective refractory period (VERP) with E-4031 was prolonged at 600 (from 244 +/- 27 to 270 +/- 31 msec, 11 +/- 2%), 400 (from 222 +/- 23 to 242 +/- 24 msec, 9 +/- 3%), and 300 msec (from 206 +/- 19 to 218 +/- 25 msec, 6 +/- 4%), and those with MS-551 were prolonged at 600 (from 240 +/- 23 to 268 +/- 23 msec, 12 +/- 2%), 400 (from 225 +/- 22 to 250 +/- 24 msec, 11 +/- 4%), and 300 msec (from 213 +/- 14 to 228 +/- 18 msec, 7 +/- 4%). Both E-4031 and MS-551 prolonged VERP in a "reverse" use-dependent manner without changing the conduction velocity. E-4031 prevented the induction of VT in one patient. MS-551 prevented the induction of VT and VF in one patient each. Further evaluation of these selective class III agents may be needed to determine if higher doses are required to achieve the pharmacological effects in patients with ventricular tachyarrhythmias.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Heart Ventricles; Humans; Infusions, Intravenous; Male; Middle Aged; Piperidines; Pyridines; Pyrimidinones; Tachycardia, Ventricular; Treatment Outcome

We examined the effects of MS-551 (1,3-dimethyl-6-[(2-[N-(2-hydroxyethyl)-3-(4- nitrophenyl)propylamino]ethylamino] 2,4(1H,3H)-pyrimidinedione hydrochloride), a new class III antiarrhythmic drug, on programmed electrical stimulation (PES)-induced ventricular arrhythmias, the effective refractory period (ERP), intraventricular conduction, and hemodynamics in a canine myocardial infarction (MI) model. MS-551 was administered intravenously (i.v.) in two consecutive doses; the first dose (low dose) was 0.5 mg/kg/min after a bolus injection of 0.3 mg/kg, and a second dose (high dose) was 0.1 mg/kg/min after a bolus injection of 0.3 mg/kg. PES induced ventricular tachycardia (VT) or ventricular fibrillation (VF) in 10 of 12 animals. MS-551 abolished or lessened the ventricular arrhythmias in 7 of 10 animals at both doses. ERP was significantly prolonged by MS-551 in both the normal and infarcted zones in a dose-dependent fashion. Ventricular conduction of a premature excitation induced by a premature stimulation with various coupling intervals was decreased only at a coupling interval approximating that of ERP. MS-551 at either low or high dose did not significantly change the heart rate (HR), mean blood pressure (MBP), cardiac output (CO), or maximum rate of increase in left ventricular pressure (LVP) significantly. MS-551 produced a suppression of the PES-induced ventricular arrhythmias through prolongation of ERP without having any significant effect on hemodynamics in a canine MI model.

Topics: Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Dogs; Electrocardiography; Hemodynamics; Myocardial Infarction; Pyrimidinones; Refractory Period, Electrophysiological; Tachycardia, Ventricular