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.

Bepridil enhances aprindine-induced prolongation of atrial effective refractory period in a canine atrial rapid pacing model.

BACKGROUND: Bepridil in combination with aprindine could restore sinus rhythm in patients with persistent atrial fibrillation (AF). The present study aimed to investigate the electrophysiological mechanisms of the combined effects of bepridil and aprindine. METHODS: Subjects consisted of 6 dogs without and 6 dogs with atrial rapid pacing (ARP) carried out at 400 bpm for 2 weeks. Bepridil was administered for 1 week in both groups (ARP dogs were administered bepridil in the second week). The electrophysiological effects of the intravenous administration of aprindine (1mg/kg) were evaluated before and after the administration of bepridil. RESULTS: In non-paced dogs, the atrial effective refractory period (AERP) became longer after the administration of bepridil (from 151±10 ms to 170±7 ms, p<0.05); however, no additional AERP prolongation was observed after the acute administration of aprindine. In ARP dogs, the AERP shortened with ARP for a week, and tended to lengthen after the administration of bepridil (from 93±5 ms to 118±9 ms, p=0.08). In these dogs, the acute aprindine administration did not prolong the AERP before the administration of bepridil, although it did after the administration of bepridil (from 118±9 ms to 142±8 ms, p<0.01). AF duration did not change after the administration of bepridil, although it shortened significantly after the additional administration of aprindine (from 2.2±0.3s to 1.4±0.8s, p<0.05). CONCLUSIONS: Bepridil enhances the effect of aprindine for the prevention of AF by reversing atrial electrical remodeling.

Relationship between serum aprindine concentration and neurologic side effects in Japanese.

The aim of this study was to evaluate the relationship between the neurologic side effects associated with serum aprindine concentrations and the safety range of aprindine for the prevention of neurologic side effects in 142 Japanese inpatients. Serum aprindine concentrations were determined by high-performance liquid chromatography. A poor positive correlation was observed between dose and serum aprindine concentration (r(2)=0.0419, p=0.0114), and between age and ratio of serum aprindine concentration to the dose per body weight of aprindine (r(2)=0.0159, p=0.121). When aprindine concentration was <1 microg/ml, almost no patients showed neurologic side effects associated with aprindine. On the other hand, about 50% of the patients showed neurologic side effects when aprindine concentrations were >1 microg/ml. Here, the side effects associated with aprindine such as dizziness or intention tremors were observed in 15 patients, which later disappeared after discontinuance of aprindine therapy or a decrease in the dose. In conclusion, serum aprindine concentration should be maintained under approximately 1 microg/ml in Japanese patients to prevent neurologic side effects.

Relation of interleukin-6 and C-reactive protein levels to sinus maintenance after pharmacological cardioversion in persistent atrial fibrillation.

OBJECT: The aim of this study was to investigate whether interleukin-6 (IL-6) and C-reactive protein (CRP) have significant relation to sinus maintenance after pharmacological conversion of long-lasting atrial fibrillation (AF) with respect to use of renin-angiotensin-aldosterone system (RAS) inhibitors. METHODS: We studied 35 consecutive patients with AF lasting > or =1 month who had successful pharmacological cardioversion with bepridil alone or in combination with aprindine. The IL-6 and CRP levels in plasma were measured after pharmacological restoration of sinus rhythm. RESULTS: During the 1-year follow-up period, sinus rhythm was maintained in 20 patients (Group I), and the other 15 patients had recurrence of AF (Group II). Both plasma levels of IL-6 and CRP were significantly lower in Group I than in Group II (IL-6: 1.19 +/- 0.51 versus 1.84 +/- 0.66 ng/L, P < 0.005; CRP: 0.59 +/- 0.40 versus 1.24 +/- 0.79 mg/L, P < 0.005). The use of RAS inhibitors and left atrial dimension and the left ventricular ejection fraction showed no differences between the 2 groups. There was significant positive correlation between levels of IL-6 and CRP. CONCLUSION: In long-lasting persistent AF, lower levels of IL-6 and CRP appear to be associated with maintenance of sinus rhythm after pharmacological cardioversion irrespective of the use of RAS inhibitors. Further studies are needed to clarify the role of RAS inhibitors.

Pharmacological cardioversion of persistent atrial fibrillation with and without a history of drug-resistant paroxysmal atrial fibrillation.

BACKGROUND: Suppression by antiarrhythmic drugs of the maintenance mechanisms could convert persistent atrial fibrillation (AF) to sinus rhythm (SR). Whether a history of drug-resistant paroxysmal AF (PAF) would affect the outcome of pharmacological conversion of persistent AF by bepridil or in combination with aprindine was evaluated in the present study. METHODS AND RESULTS: The study group comprised 51 consecutive patients (24 men, 61+/-8 years) undergoing pharmacological conversion of persistent AF lasting >1 month. Drug-resistant PAF was defined as AF and at least 2 ineffective antiarrhythmic drugs for suppression of AF recurrence. Fast Fourier transform analysis of fibrillation waves was used to measure fibrillation cycle length (FCL) from the peak frequency. Fifteen patients had a history of drug-resistant PAF (Group I), and the remaining 36 did not (Group II) before diagnosis of persistent AF. Ten patients (67%) in Group I and 26 patients (72%) in Group II were restored to SR by bepridil alone or in combination with aprindine after 29+/-15 days of drug administration. Before conversion to SR, bepridil increased the FCL more in Group II than in Group I. During a 12-month follow-up period, 4 of 10 patients in Group I and 2 of 26 patients in Group II (p<0.01) had recurrence of persistent AF with bepridil alone or in combination with aprindine. CONCLUSIONS: A history of drug-resistant PAF does not affect the efficacy of pharmacological conversion by bepridil or in combination with aprindine. However, recurrence of AF was significantly higher in patients with such a history.

[Strategy for cardiac arrhythmias in acute coronary syndrome].

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.

Nonlinear mixed effects model analysis of the pharmacokinetics of routinely administered bepridil in Japanese patients with arrhythmias.

This study was performed to evaluate variability in the pharmacokinetics of bepridil in 38 Japanese patients with arrhythmias, and to investigate the effects of aprindine as well as CYP2D6 and CYP3A5 polymorphisms on the oral clearance of bepridil. We determined the polymorphic alleles of CYP2D6 and CYP3A5 in each subject. The plasma concentration of bepridil at steady-state following repetitive oral administration was measured with an HPLC-based method, and the oral clearance was estimated using the nonlinear mixed effects model (NONMEM) program. Mean oral clearance was significantly greater in the patients with the CYP2D6*10 allele than in those without it. On the other hand, no significant effect of the CYP3A5 polymorphism was observed on the pharmacokinetics of bepridil. In addition, aprindine seemed to reduce the oral clearance of bepridil in the patients with the CYP2D6*10 allele.

Effect of antiarrhythmic agents on heart rate variability indices after myocardial infarction: comparative experimental study of aprindine and procainamide.

The cardiac arrhythmic suppression trial (CAST) reported that antiarrhythmic treatments in post-myocardial infarction (MI) patients resulted in poor outcome and decreased in heart rate variability indices (HRV). The goal of the present study was to determine whether aprindine and procainamide, antiarrhythmic agents that increase HRV, result in beneficial effects in post-MI rabbits. Four weeks before experiment, MI was induced in four rabbits by ligating the major branch of left coronary artery. A total of eight rabbits (four post-MI and four normal rabbits) were randomly assigned to treatment with either intravenous aprindine (1 mg/kg) or intravenous procainamide (15 mg/kg). Frequency domain HRV (low frequency spectra, LF, 0.04-0.15 Hz; high frequency spectra, HF, 0.15-0.40 Hz) were assessed by MemCalc software. Aprindine significantly increased HF and LF in both MI and normal rabbits, whereas procainamide tended to decrease HF and LF in MI and normal rabbits (in total rabbits; aprindine, LF, from 6.3 +/- 7.9 to 16.5 +/- 15.0 ms(2)/Hz, P < 0.05; HF, from 8.0 +/- 11.7 to 17.5 +/- 15.0 ms(2)/Hz, P < 0.05; procainamide, LF, from 4.9 +/- 7.4 to 4.8 +/- 8.5 ms(2)/Hz, NS; HF, from 11.1 +/- 23.0 to 5.1 +/- 10.6 ms(2)/Hz, NS). Under pharmacological denervation with propranolol (0.1 mg/kg) and atropine (0.04 mg/kg), aprindine increased LF and HF (LF, from 0.2 +/- 0.2 to 0.8 +/- 0.7 ms(2)/Hz, P < 0.05; HF, from 0.1 +/- 0.0 to 0.2 +/- 0.0 ms(2)/Hz, P < 0.05). These data suggest that aprindine can increase HRV in post-MI rabbits. Further experiments in human subjects would be of benefit.

Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine.

ATP-sensitive K+ channels (K(ATP):SUR2A+Kir6.2) play a pivotal role in cardiac protection against ischemia and reperfusion injury. When expressed in COS cells, Kir6.2 was short-lived with a half-life time of 1.9 h. The half-life time of Kir6.2 was prolonged by proteasome inhibitors MG132, ALLN, proteasome inhibitor 1, and lactacystine, but not at all by a lysosomal inhibitor chloroquine. MG132 also increased the level of ubiquitinated Kir6.2 without affecting its localization in the endoplasmic reticulum and Golgi apparatus. In electrophysiological recordings, MG132 augmented nicorandil-activated K(ATP) currents in COS cells expressing SUR2A and Kir6.2 as well as the same currents in neonatal rat cardiomyocytes. Like MG132, a Na+ channel blocker aprindine prolonged the half-life time of Kir6.2 and augmented K(ATP). Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance K(ATP) currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia.

Drug-induced changes in fibrillation cycle length and organization index can predict chemical cardioversion of long-lasting atrial fibrillation with bepridil alone or in combination with aprindine.

BACKGROUND: The aim of this study was to investigate whether drug-induced changes in fibrillation wave characteristics can predict pharmacological conversion of long lasting persistent atrial fibrillation (AF). METHODS AND RESULTS: The study group comprised 23 consecutive patients with AF lasting > or =1 month. Patients first received bepridil (200 mg/day) for 2-4 weeks. When sinus rhythm was not restored with bepridil, oral aprindine (40 or 60 mg/day) was added to bepridil. Fast Fourier transform analysis of fibrillation waves using lead V1 was performed to calculate the fibrillation cycle length (FCL). The spectral areas were measured and the maximum area divided by the total area was termed the fibrillation organization index (FOI). Sinus rhythm was restored in 16 of 23 patients (70%); 8 of these 16 patients received only bepridil (Group I) and the other 8 responders received bepridil and aprindine (Group II). In Group I bepridil increased both FCL (p<0.001) and FOI (p<0.01) and terminated AF after 20+/-12 days. In Group II bepridil increased FCL (p<0.001), but did not change FOI. The addition of aprindine terminated AF in association with an increase in both FCL (p<0.005) and FOI (p<0.005) within 19+/-8 days. In the remaining 7 patients who did not have restoration of sinus rhythm, bepridil increased both FCL and FOI significantly, but less than in Group I, and the addition of aprindine did not further increase either of them. Chemical cardioversion of AF occurred in all patients with FCL > or =190 ms and FOI > or =45% after drug administration. CONCLUSION: Bepridil alone or in combination with aprindine converted long lasting persistent AF in association with an increase in both FCL and FOI. The combination of FCL and FOI after drug administration is helpful in predicting chemical cardioversion of persistent AF.

Maintenance of sinus rhythm and recovery of atrial mechanical function after cardioversion with bepridil or in combination with aprindine in long-lasting persistent atrial fibrillation.

BACKGROUND: The aim of this study was to evaluate pharmacological cardioversion of long-lasting persistent atrial fibrillation (AF) using bepridil in terms of recovery of atrial mechanical function and maintenance of sinus rhythm. Bepridil alone or in combination with aprindine is effective for termination of persistent AF. METHODS AND RESULTS: The study group comprised 38 consecutive patients (24 men, 58.8+/-9.3 years) with successful conversion of persistent AF lasting >1 month either pharmacologically (Group I) or electrically (Group II). Fast Fourier transform analysis of fibrillation waves was performed and fibrillation cycle length (FCL) was calculated from the peak frequency. In Group I, sinus rhythm was pharmacologically restored in 22 patients after an average 30 days (7-49 days) of bepridil administration, either alone (11) or in combination with oral aprindine (11); they were followed up while using the same drugs. In Group II, electrical conversion restored sinus rhythm in 16 patients, and they were followed up with conventional antiarrhythmic drugs other than bepridil and aprindine. After bepridil treatment FCL increased and became significantly longer in Group I than in Group II (190+/-39 vs 150+/-29 ms, p<0.001). Atrial peak velocity in transmitral flow within the first week after cardioversion was greater in Group I than in Group II (68+/-35 vs 32+/-20 cm/s, p<0.05). By Kaplan-Meier analysis, 83% of Group I patients were free of AF recurrence at the 12-month follow-up, compared with 36% in Group II (p<0.005). CONCLUSIONS: In patients with long-lasting AF, pharmacological conversion with bepridil alone or in combination with aprindine recovered atrial mechanical function better and maintained sinus rhythm longer than electrical conversion.

Usefulness and safety of bepridil in converting persistent atrial fibrillation to sinus rhythm.

The aim of this study was to investigate the efficacy and safety of bepridil (a multichannel blocker including several potassium channels) for conversion of long-lasting atrial fibrillation (AF). Bepridil restored sinus rhythm alone or in combination with aprindine in 69% of 32 patients with persistent AF lasting > or = 3 months. The time to conversion after starting bepridil was 30 +/- 12 days. An increase in fibrillation cycle length with bepridil was greater in responders (31 +/- 10%), but an increase in QTc did not differ between responders and nonresponders. Bepridil is effective and safe for terminating long-lasting persistent AF.

[Comparison of the efficacies of disopyramide, cibenzoline and aprindine for the termination of paroxysmal and persistent atrial fibrillation in elderly and non-elderly patients].

OBJECTIVES: The relationship between the efficacy of the anticholinergic action of disopyramide, cibenzoline and aprindine and age was examined in patients with paroxysmal and persistent atrial fibrillation. METHODS: This prospective, randomized study included 278 patients (200 men, 78 women, mean age 61 +/- 11 years) divided into two groups; the non-elderly group (age below 60 years) and the elderly group (age over 60 years). Successful termination was defined as conversion of sinus rhythm within 30 min of intravenous administration of 50 mg disopyramide (n = 91), 70 mg cibenzoline (n = 93) or 100 mg aprindine (n = 94) in this prospective and randomized study. RESULTS: No statistically significant difference was found in patient characteristics between the three agents. 1) The rate of conversion to sinus rhythm after disopyramide administration in the non-elderly group(37.8%) was significantly higher than that in the elderly group (17.4%, p = 0.0361). 2) The rate of conversion to sinus rhythm after cibenzoline administration in the non-elderly group (62.2%) tended to be greater than that in the elderly group (43.8%, p = 0.0972). 3) The rate of conversion to sinus rhythm after aprindine administration in the non-elderly group (25.6%) was not significantly higher than that in the elderly group (18.2%, p = 0.4474). CONCLUSIONS: The anticholinergic action of antiarrhythmic agents has an effect on successful termination in non-elderly patients with paroxysmal and persistent atrial fibrillation.

Atrial fibrillation threshold predicted long-term efficacy of pharmacological treatment of patients without structural heart disease.

AIMS: To ascertain if an electrophysiological study could predict long-term efficacy of anti-arrhythmic drugs in the treatment of lone atrial fibrillation. METHODS AND RESULTS: Forty-four patients (36 males, 8 females, age 55.5 +/- 10.6) with paroxysmal atrial fibrillation were enrolled to undergo serial electrophysiological studies at the bedside. Two quadripolar catheters were inserted via the subclavian vein. Disopyramide (D: 2 mg/kg iv), cibenzoline (C: 1.4 mg/kg iv), aprindine (A: 2 mg/kg iv), pilsicainide (P: 2 mg/kg po) and flecainide (F: 3 mg/kg po) were tested. Atrial fibrillation threshold (AFT) was measured as the lowest current amplitude of rapid pacing (50 Hz for 1 s) to induce atrial fibrillation lasting more than 30 s. Before drug treatment, AFT was 3.9 +/- 0.3 mA. Pharmacological treatment raised AFT as follows: D 5.9 +/- 0.9 mA, C 7.6 +/- 1.2 mA, A 8.1 +/-1.1 mA, P 6.0 +/- 0.8 mA, F 7.3 +/- 1.1 mA. Recurrence of atrial fibrillation was observed during 1-year follow-up in 12% of cases when they were treated with a drug that raised AFT by 5 mA or more. On the other hand, the recurrence rate was 87% when patients were treated with a drug that raised AFT by less than 5 mA (P = 0.001). CONCLUSION: AFT was a good predictor of long-term efficacy of pharmacological treatment against atrial fibrillation.

Double-blind placebo-controlled trial of aprindine and digoxin for the prevention of symptomatic atrial fibrillation.

A multicenter, placebo-controlled, randomized, double-blind trial compared the preventive effect of aprindine and digoxin on the recurrence of atrial fibrillation (AF) with placebo, and also compare the effectiveness of these 2 drugs in the prevention of AF. Patients with symptomatic paroxysmal or persistent AF who had converted to sinus rhythm (SR) were randomly assigned aprindine (40 mg/day), digoxin (0.25 mg/day) or placebo and followed up on an outpatient basis every 2 weeks for 6 months. Of the 141 patients from 36 participating centers, 47 were given aprindine, 47 digoxin, and 47 were on placebo. After the 6-month follow-up, the Kaplan-Meier estimates of the percentage of patients remaining free of recurrent symptomatic AF on aprindine, digoxin and placebo were 33.3%, 29.2% and 21.5%, respectively. In patients remaining in SR for 15 days after from the start of follow-up, freedom from recurrence was significantly more prevalent in the aprindine group than in the placebo group (p=0.0414), but there was no significant difference between the digoxin and placebo groups. The rate of adverse events was similar in the 3 groups. In conclusion, neither aprindine nor digoxin had a significant effect on preventing relapse of symptomatic AF; however, recurrence of AF occurred later with aprindine than with placebo or digoxin.

Inhibitory effect of aprindine on Na+/Ca2+ exchange current in guinea-pig cardiac ventricular myocytes.

1. Using the whole-cell voltage clamp technique, the effect of aprindine on Na+/Ca2+ exchange current (I(NCX)) was examined in guinea-pig single cardiac ventricular myocytes and CCL39 fibroblasts expressing a dog cardiac Na+/Ca2+ exchanger (NCX1). 2. I(NCX) was recorded by ramp pulses from the holding potential of -60 mV with the external solution containing 140 mM Na+ and 1 mM Ca2+, and the pipette solution containing 20 mM Na+, 20 mM BAPTA and 13 mM Ca2+ (433 nM free Ca2+). 3. External application of aprindine suppressed I(NCX) in a concentration-dependent manner. The IC50 values of outward (measured at 50 mV) and inward (measured at -100 mV) I(NCX) components were 48.8 and 51.8 microM with Hill coefficients of 1.3 and 1, respectively. 4. Intracellular application of trypsin via the pipette solution did not change the blocking effect of aprindine, suggesting that aprindine does not affect the exchanger from the cytoplasmic side. 5. Aprindine inhibited I(NCX) of a mutant NCX1 with a deletion of amino acids 247 - 671 in the large intracellular domain between the transmembrane segments 5 and 6 in a similar manner to that of the wild-type, suggesting that the site of aprindine inhibition is not in the large intracellular domain of NCX1. 6. A kinetic study indicated that aprindine was cooperatively competitive with KB-R7943, another inhibitor of NCX and that aprindine was a competitive inhibitor with respect to external Ca2+. 7. We conclude that aprindine may modestly inhibit I(NCX) in a therapeutic range of concentrations (around 2.5 approximately 6.9 microM) possibly at an external or intra-membranous site of the exchanger.

Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells.

In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K+ currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea-pig hearts. Aprindine (3 microM) inhibited the delayed rectifier K+ current (IK) with little influence on the inward rectifier K+ current (IK1) or the Ca2+ current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). The muscarinic acetylcholine receptor-operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 microM) or by the intracellular loading of GTPgammaS. Aprindine inhibited the carbachol- and GTPgammaS-induced IK.ACh with the IC50 values of 0.4 and 2.5 microM, respectively. In atrial cells stimulated at 0.2 Hz, aprindine (3 microM) per se prolonged the action potential duration (APD) by 50+/-4%. The drug also reversed the carbachol-induced action potential shortening in a concentration-dependent manner. In isolated hearts, perfusion of carbachol (1 microM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold. Addition of aprindine (3 microM) inhibited the induction of AF by prolonging MAP and ERP. We conclude the efficacy of aprindine against AF may be at least in part explained by its inhibitory effects on IKr and IK.ACh.

Profiles of aprindine, cibenzoline, pilsicainide and pirmenol in the framework of the Sicilian Gambit. The Guideline Committee for Clinical Use of Antiarrhythmic Drugs in Japan (Working Group of Arrhythmias of the Japanese Society of Electrocardiology).

The Vaughan Williams classification has been used widely by clinicians, cardiologists and researchers engaged in antiarrhythmic drug development and testing in many countries throughout the world since its initial proposal in the early 1970s. However, a major criticism of the Vaughan Williams system arose from the extent to which the categorization of drugs into classes I-IV led to oversimplified views of both shared and divergent actions. The Sicilian Gambit proposed a two-dimensional tabular framework for display of drug actions to solve these problems. From April to December 1996, members of the Guideline Committee met to discuss pharmacologic profiles of 4 antiarrhythmic drugs (aprindine, cibenzoline, pilsicainide, and pirmenol) that were not included in the original spreadsheet but are used widely in clinical practice in Japan. The discussion aimed to fit the drug profiles into the Gambit framework based on all the important literature published to date regarding the actions of the 4 drugs. This report is a summary of that deliberation.

Effect of aprindine on heart rate variability indices in patients with ischemic heart disease.

BACKGROUND: Decreased heart rate variability indices (HRV) are associated with untoward outcome of patients with ischemic heart disease (IHD). Most class I antiarrhythmic agents decrease HRV, but aprindine (a new class I antiarrhythmic agent) is reported to increase HRV in patients without ischemia. HYPOTHESIS: The study was undertaken to determine whether apridine might increase HRV in patients with IHD. METHODS: To investigate the effect of aprindine on HRV in patients with IHD, we performed 24-h ambulatory electrocardiogram (ECG) at the end of placebo and aprindine (60 mg daily) treatment phases on 38 patients with IHD and at least isolated premature ventricular contractions (PVC). The study protocol utilized a single blind, 4-week, placebo-controlled design. Heart rate variability from ambulatory ECG included SDNN (ms), SDANN (ms), SD (ms), rMSSD (ms), pNN50 (%); frequency analysis of HRV consisting of total (ms, 0.01-1.00 Hz), low (ms, 0.04-0.15 Hz), and high (ms, 0.15-0.40 Hz) components. RESULTS: Study patients were divided into three groups according to the severity of IHD and antiarrhythmic efficacy of aprindine. Group 1 consisted of 15 patients with angina with single-vessel disease, and Group 2 was composed of 10 patients with either multivessel disease or post myocardial infarction; PVCs decreased in both groups as result of aprindine treatment. Group 3 consisted of 13 patients who showed no decreased PVC after aprindine treatment. RMSSD increased, and pNN50 and high-frequency spectra tended to increase in Group 1, while SD, rMSSD, pNN50, and total and low-frequency spectra decreased in Group 3; no significant changes were observed in Group 2. Aprindine significantly augments vagal activity, as reflected by the increase of rMSSD, pNN50, and high-frequency spectra in mild IHD. CONCLUSION: These salutary effects are less in more severe IHD, but aprindine does not aggravate HRV. Thus, if there are salutary effects on arrhythmias and no proarrhythmic effects, aprindine could be prescribed to patients with IHD without concern about decreasing HRV.