Different voltage dependence of ICaL blockade in nonselective IKr blockers causes their opposite effects on early afterdepolarization in drug-induced arrhythmia.

Several false-positive results in the human ether-à-gogo-related gene test suggest that blockers of the rapid component of delayed rectifier K+ current (IKr) do not necessarily produce drug-induced arrhythmias. Specifically, the occurrence of early afterdepolarization (EAD) differs among IKr blockers, even if the prolonged action potential duration is in the same range. To predict EAD in drug-induced arrhythmias, we proposed a prediction method based on the mechanisms underlying the difference in frequency of EAD among nonselective IKr blockers. The mechanisms were elucidated by examining how different blockade kinetics of L-type Ca2+ current (ICaL) affect the frequency of EAD, using mathematical models of human ventricular myocytes. Addition of voltage-independent ICaL blockade resulted in the suppression of EAD. However, when voltage-dependent ICaL blockade kinetics of amiodarone, bepridil, and terfenadine were incorporated into ICaL in the model, bepridil and terfenadine induced EAD more than the voltage-independent ICaL blockade, while amiodarone suppressed EAD more effectively. Opposite effects were accounted for by the difference in ICaL blockade at negatively polarized potential. EAD occurrence was found to be associated with ICaL blockade measured at -20 mV. These results suggest that voltage dependence of ICaL blockade may be useful in predicting the different risks of nonselective IKr blockers.

Relationship between serum bepridil concentration and corrected QT interval.

OBJECTIVE: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil. MATERIALS AND METHODS: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis. RESULTS: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01). CONCLUSION: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.

Time-to-Onset Analysis of Drug-Induced Long QT Syndrome Based on a Spontaneous Reporting System for Adverse Drug Events.

Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6-204.6), 17.3 (14.7-20.4), 52.0 (43.4-62.4), 13.9 (11.5-16.7), 69.3 (55.3-86.8), 54.2 (43.2-68.0), 4.7 (3.8-5.8), 19.9 (15.9-25.0), 8.1 (6.5-10.1), 3.2 (2.5-4.1), 7.1 (5.5-9.2), and 254.8 (168.5-385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0-35.8) and 18.0 (6.0-43.0) days, respectively. The lower 95% confidence interval of the shape parameter ß of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.

Incidence and outcomes of bepridil-induced interstitial pneumonia.

BACKGROUND: The incidence of bepridil-induced pulmonary toxicity, such as interstitial pneumonia, is still unknown. The aim of the present study was to evaluate the incidence of bepridil-induced pulmonary toxicity. METHODS AND RESULTS: A total of 253 patients treated with bepridil between January 2009 and January 2011 were retrospectively evaluated. Eight out of the 222 evaluable patients (male/female: 5/3, age range: 64-97 years, average age: 80.5 years, median age: 81.0 years) showed bepridil-induced pulmonary toxicity. CONCLUSIONS: The incidence of bepridil-induced pulmonary toxicity was 3.60% in our study population.

Contributing factors to the apparent clearance of bepridil in patients with paroxysmal or persistent atrial fibrillation: analysis using population pharmacokinetics.

BACKGROUND: Bepridil is used as an antiarrhythmic drug due to its class I, class III, and class IV electrophysiological properties, but it has serious adverse effects such as QT prolongation and torsade de pointes. Bepridil has complex pharmacokinetic (PK) properties with large interindividual differences in plasma concentrations. The aim of this study was to evaluate the contributing factors to changes in the dose-concentration relationship of bepridil and the risk factors for excessive QT prolongation in patients with paroxysmal or persistent atrial fibrillation (AF). METHODS: A population PK analysis was performed by using NONMEM based on 425 concentration points from 76 patients receiving bepridil. A 1-compartment model approximating an intravenous model was used to examine the interindividual variability of the apparent systematic clearance (CL/F) of bepridil. A population PK-pharmacodynamic analysis was performed using the linear regression. RESULTS: Age was a contributing factor to the CL/F of bepridil in AF patients. The QTc interval increased as the area under the plasma bepridil concentration time curve (AUC) increased. The AUC in patients without a bundle branch block, the baseline QT interval, and the existence of structural heart disease in patients with a bundle branch block were explanatory variables of excessive QTc prolongation (QTc > 500 ms) during bepridil therapy. CONCLUSIONS: Using population PK methodology, this study showed that age was a contributing factor to the apparent clearance of bepridil in Japanese patients with AF and that excessive QT prolongation might be related to a larger AUC.

Carvedilol is effective and safe in combination with bepridil for persistent atrial fibrillation and decreases the QT prolongation induced by bepridil therapy.

INTRODUCTION: We investigated the efficacy of carvedilol for preventing the recurrence of atrial fibrillation and reducing QT prolongation induced by bepridil. METHODS: We assigned 144 subjects with persistent atrial fibrillation. The subjects were divided into 3 groups: carvedilol plus bepridil, candesartan plus bepridil, and bepridil alone. The primary endpoint was length of time to the recurrence of atrial fibrillation. All subjects were followed up for 3 years. Electrocardiographic parameters were measured for QT interval, QTc, heart rate, and QRS duration. RESULTS: The pharmacological conversion rate by carvedilol plus bepridil was 77%, candesartan plus bepridil was 63%, and bepridil alone was 57%. The significant difference was between carvedilol plus bepridil and bepridil alone (P = 0.03). The maintenance of SR at 3 years was 60% in carvedilol plus bepridil, 59% in candesartan plus bepridil, and 40% in bepridil alone. The difference between carvedilol plus bepridil and bepridil alone was statistically significant (P = 0.04). QTc and QT interval were significantly prolonged in candesartan plus bepridil and bepridil alone but not in carvedilol plus bepridil. CONCLUSIONS: The authors demonstrated that the combination therapy with carvedilol plus bepridil is more effective for maintaining SR than bepridil alone therapy and carvedilol reduced QT prolongation by bepridil therapy.

Pharmacological conversion of atrial fibrillation in the patients of Graves' disease.

BACKGROUND: Hyperthyroidism is one of the common causes of atrial fibrillation (AF), and AF is associated with increased morbidity and mortality due to thromboembolism. The sinus rhythm maintenance rate of hyperthyroidism-induced AF patients after conversion to sinus rhythm is excellent. The present study was undertaken to assess the efficacy and safety of bepridil, a multichannel blocker, in patients with hyperthyroidism-induced persistent AF. METHODS AND RESULTS: Sixty-two patients with hyperthyroidism-induced persistent AF were treated with bepridil. Oral bepridil therapy resulted in conversion to sinus rhythm in 32 (51.6%) of the 62 patients. There were no significant differences in clinical characteristics between the responders and non-responders. At the observation period of an average of 23.9 months, the sinus rhythm maintenance rate was found to be 81.3%. Adverse effects consisted of abnormal QTc prolongation in 3 patients and sinus bradycardia in 10 patients. There was one death in which a causal association with bepridil could not be ruled out. CONCLUSIONS: Bepridil is as beneficial treatment to convert AF for the patients with hyperthyroidism-induced persistent AF as it is for the patients with AF due to other causes. However, bepridil should be used with caution to avoid serious side effects.

Bepridil is effective and improves QOL in multidrug-resistant paroxysmal atrial fibrillation.

OBJECTIVE: Efficacy and safety of long-term administration of bepridil as a rhythm and rate controller were comprehensively evaluated in patients with multidrug-resistant paroxysmal atrial fibrillation (PAF). METHODS: A retrospective survey from 1992 to 2006 was conducted on 62 multidrug-resistant PAF patients treated with bepridil from 480 consecutive PAF patients. In addition, a 5-year follow-up study was conducted on 28 of the 62 patients, being continued from 2006 to 2011. The efficacy of bepridil, improvement in symptoms including patients' quality of life (QOL), ECGs, hemodynamics, and its adverse effects were examined. RESULTS: In the retrospective survey, 127 ±â€Š44 mg of bepridil was given for 21 ±â€Š18 months and 40.3% maintained sinus rhythm. Reductions in the frequency and the duration of each episode of PAF and improvement in symptoms were seen in 48.4, 50.0 and 93.5% of the 62 patients, respectively. Reversible torsades de pointes (TdP) occurred in two aged women. Bradycardia and hepatic dysfunction developed in one patient each. In the follow-up study, 100 ±â€Š20 mg of bepridil was given. Sinus rhythm was maintained in 13 patients. Although the occurrences of PAF continued in 14 patients, their symptoms and QOL were improved. No adverse effects were noted in all 28 patients of the follow-up study. CONCLUSIONS: Bepridil was effective in rhythm control in 40% of PAF patients resistant to other antiarrhythmics. Even in those who had failed to maintain sinus rhythm, continued administration of low-dose bepridil improved their symptoms and QOL with few adverse effects. Bepridil is worth returning to use.

Clinical outcome in patients with paroxysmal or persistent atrial fibrillation receiving bepridil.

BACKGROUND: It is unknown whether bepridil improves cardiovascular events in atrial fibrillation (AF) patients, so this study evaluated the clinical outcome in paroxysmal or persistent AF patients receiving bepridil. METHODS AND RESULTS: We conducted a cohort study of 284 consecutive patients who received bepridil for AF (25% female, 5913 years) with a median follow-up period of 17 months (4-157 months). A total of 135 (48%) patients had structural heart disease, and 231 patients (81%) had previously received class I or class III antiarrhythmic drugs. The cumulative rates for cardiovascular events were 2.4%, 8.1%, and 10.1% at 1, 3, and 5 years, respectively. The cumulative rates for a composite of mortality, cerebral infarction, systemic embolism, major bleeding and heart failure were 9.7%, 18.2%, and 29.6% at 1, 3, and 5 years, respectively. The probability of progression to permanent AF was 23.5% at 5 years. Sudden death occurred in a patient with a prior myocardial infarction who was taking 200mg daily, and torsade de pointes (Tdp) occurred in two patients without structural heart disease taking 200mg daily. Excessive corrected QT interval prolongation (>0.50s) was observed when plasma concentrations were higher than 800 ng/ml. CONCLUSIONS: Bepridil might not improve the clinical outcome in refractory AF patients. Bepridil-related adverse events, including QT prolongation and Tdp, occurred in a dose- and concentration-dependent manner.

Importance of morphological changes in T-U waves during bepridil therapy as a predictor of ventricular arrhythmic event.

BACKGROUND: Although bepridil is a useful anti-arrhythmic agent for atrial fibrillation, the appearance of serious ventricular arrhythmia, such as torsades de pointes, might be a problem. In this study, T-U wave morphology was evaluated during bepridil therapy and was examined as a predictor of ventricular arrhythmic events. METHODS AND RESULTS: The study population consisted of 113 patients on bepridil therapy. They were divided into 2 groups with and without ventricular arrhythmic events. Morphological changes in T-U waves were analyzed in leads V(2-5). During bepridil treatment, the QTc interval was prolonged from 0.45+/-0.01 to 0.49+/-0.01 s(1/2) in all patients (P<0.0001) and any type of T-U wave change (fused U, slurred, bifid, biphasic or negative) appeared in 73% of event-free and 100% of event groups. In univariate analysis, QTc interval before bepridil (P=0.028), a wide QRS complex (P=0.042) before bepridil, biphasic (P=0.027) or negative (P=0.002) T-U waves in the stable phase, and the new appearance of biphasic (P=0.004) or negative (P<0.0001) T-U waves exhibited significant differences. In multivariate analysis, only newly appeared negative T-U wave exhibited a significant difference (odds ratio 10.13, 95% confidence interval = 0.031-2.302, P=0.041). CONCLUSIONS: In patients with stable bepridil treatment, a change in T-U wave morphology might be a useful predictor of ventricular arrhythmia assisting the QT interval.

Gradual progression of interstitial pneumonia induced by bepridil.

A 74-year-old man was administered bepridil for the treatment of atrial fibrillation since February 2008. However, he developed exertional dyspnea in October 2008. Computed tomography scans of his chest revealed extensive bilateral peribronchial consolidations. Examination of transbronchial lung biopsy specimens revealed moderate infiltration of lymphocytes. Since drug-induced pneumonia was suspected, we initiated steroid therapy. After 3 weeks of treatment, the symptoms were alleviated. In this case, the time taken for the development of dyspnea was 226 days, and the clinical course was gradual. We believe that a long-term periodic follow-up is essential in patients receiving bepridil.

Opposing effects of bepridil on ventricular repolarization in humans. Inhomogeneous prolongation of the action potential duration vs flattening of its restitution kinetics.

BACKGROUND: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action. METHODS AND RESULTS: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172 +/-26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD(90S) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD(90) was greater in RVOT (approximately 13%) than RVA (approximately 8%). Bepridil flattened the MAPD(90) restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65 +/-0.22 vs 0.95 +/-0.38) and RVA (0.65 +/-0.14 vs 0.94 +/-0.29). The T(peak-end) interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response. CONCLUSIONS: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization.

Dose-response effects of bepridil in patients with persistent atrial fibrillation monitored with transtelephonic electrocardiograms: a multicenter, randomized, placebo-controlled,double-blind study (J-BAF Study).

BACKGROUND: A multicenter, randomized, placebo-controlled, double-blind trial was conducted with patients with persistent atrial fibrillation (AF) to determine the dose-response effects and safety of bepridil, using every-day transtelephonic monitorings. METHODS AND RESULTS: A total of 90 patients were randomized to receive placebo, 100 mg/day and 200 mg/day of bepridil treatment for 12 weeks. After the treatment, those patients who converted to sinus rhythm was 3.4% in placebo, 37.5% in those who received 100 mg/day and 69.0% in those who received 200 mg/day, thus demonstrating a linear dose-response relationship for AF conversion. The conversion rate gradually reached a maximal value at approximately 6 weeks after initiation of bepridil. However, the AF recurrence rate was high (91.7% in those receiving 100 mg/day and 75.0% in those receiving 200 mg/day). Adverse events, presumably related to the drug, were also frequent: ventricular tachycardia in 2, QT prolongation in 4 and sinus bradycardia in 2 patients. In those patients treated with 200 mg/day group, 1 patient died suddenly because of ventricular tachycardia. CONCLUSIONS: This study demonstrated the dose response-relationships of bepridil for AF conversion to sinus rhythm. However, the high rate of AF recurrence and substantial drug-related adverse effects, including sudden death, raised caution about using bepridil to treat persistent AF. The balance between benefits and risks of the drug should be individualized.

Two patients with bepridil-induced interstitial pneumonia.

Two patients developed bepridil-induced interstitial pneumonia during treatment of arrhythmia. The first patient was a 69-year-old man who received bepridil to maintain sinus rhythm in atrial fibrillation and who developed dyspnea on the 20th day after administration. The second patient was a 72-year-old man who received bepridil for paroxysmal atrial fibrillation and who developed dyspnea on the 60th day after administration. They were diagnosed with interstitial pneumonia on the basis of physical and imaging findings. The first patient was discharged after steroid pulse therapy, and the second patient after improvement of physical and imaging findings when bepridil was discontinued. Although a limited number of cases of bepridil-induced interstitial pneumonia have been reported, the disorder should be kept in mind as an important adverse reaction when breathlessness or dyspnea develops during administration of the drug.

Beat-to-beat variability of repolarization differentiates the extent of torsadogenic potential of multi ion channel-blockers bepridil and amiodarone.

Bepridil and amiodarone are known to have a multiple ion channel-blocking property in the heart. In this study, we compared the effects of bepridil on beat-to-beat variability of repolarization, a new predictive marker of torsades de pointes arrhythmia, with those of amiodarone. Bepridil (30 mg/kg, n=4) or amiodarone (200 mg/day for initial 7 days and 100 mg/day for following 21 days, n=4) was orally administered to chronic atrioventricular block dogs under the Holter ECG monitoring. The QT interval was prolonged after the administration of bepridil and amiodarone, and torsades de pointes arrhythmia was induced in 3 out of 4 dogs after the bepridil administration, which was not observed during the chronic administration of amiodarone. Beat-to-beat variability of repolarization, quantified as the short-term variability of the QT interval, increased after the administration of bepridil by +3.0 ms, whereas no significant change was detected in this parameter after the administration of amiodarone. These results suggest that the beat-to-beat variability of repolarization is a useful marker for differentiating the extent of torsadogenic potential of multi ion channel-blockers bepridil and amiodarone.

Bepridil produces prominent bradycardia-dependent QT prolongation in patients with structural heart disease.

The aim of the present study is to elucidate the effect of bepridil on heart rate-dependent QT prolongation in patients with or without structural heart disease. QT intervals and the preceding R-R intervals were randomly measured by 24-hour Holter electrocardiogram in 29 patients with symptomatic arrhythmias. The slope of the regression curve was used as a marker of bradycardia-dependent QT prolongation. The slope was not different in patients without structural heart disease (0.34 +/- 0.10) as compared with the apparently normal control subjects (0.32 +/- 0.057, n = 29), whereas it was larger than that in patients with structural heart disease (0.57 +/- 0.17; P < .01). Steep slopes (>0.43) were observed in 11 of the 14 patients with structural heart disease, whereas they were observed only in 1 patient without structural heart disease (P < .01). In conclusion, we need to pay attention to bradycardia-dependent QT prolongation by bepridil, especially when dealing with structural heart disease.

Clinical evaluation of adverse effects during bepridil administration for atrial fibrillation and flutter.

BACKGROUND: Bepridil hydrochloride (Bpd) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported. METHODS AND RESULTS: Adverse effects of Bpd requiring discontinuation of treatment were evaluated. Bpd was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during Bpd administration, particularly in elderly patients.

[A case of drug-induced pneumonitis due to bepridil].

A 66-year-old man had been given bepridil for the treatment of atrial fibrillation since April 28, 2002. The patient developed exertional dyspnea with hypoxemia in the middle of June 2002 and was admitted to our hospital. The chest X-ray and chest CT scans showed diffuse reticulonodular infiltrates in the lower lung fields. Pulmonary function tests revealed depletion of diffusion capacity for carbon monoxide. Bronchoalveolar lavage fluid contained increased percentages of lymphocytes, neutrophils and eosinophils, and a CD4/8 ratio was low. The transbronchial lung biopsy specimens demonstrated alveolar septal thickening with infiltration of mononuclear cells and intraalveolar organization. As drug-induced pneumonitis was suspected, bepridil was discontinued, resulting in improvement of dyspnea and hypoxemia. The patient was then treated with corticosteroid, which led to complete resolution of infiltration on chest X-ray. According to the clinical data consistent with drug-induced pneumonia, the prompt improvement after cessation of bepridil and the absence of other possible causes, we diagnosed this case as bepridil-induce pnemonitis.