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.

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.

Chronic administration of aprindine during maintenance hemodialysis.

Aprindine was administered for 12 months to 8 hemodialysis patients suffering from arrhythmias. The serum aprindine concentration ranged from 0.3 to 0.6 microgram/ml, and did not increase with time during the 1-year treatment period. The PQ interval was temporarily prolonged in the first and second months, but the QRS and QT intervals were not changed by chronic aprindine treatment. The changes of the PQ interval in the second month of treatment were directly correlated with the serum aprindine concentration. No alterations of the ECG findings were observed when aprindine was discontinued. The cardiothoracic ratio (chest radiography) and laboratory findings were also not influenced by either aprindine treatment or its withdrawal. In conclusion, aprindine may be safely administered for at least 1 year to arrhythmia patients on maintenance hemodialysis.

Kinetics of frequency-dependent conduction delay by class I antiarrhythmic drugs in human atrium.

We investigated use-dependent prolongation of interatrial conduction time (IACT) by class I antiarrhythmic drugs in 16 patients. Changes in IACT at the initiation of atrial pacing were used to evaluate the onset kinetics. We examined recovery kinetics by giving a single extra stimulus with a varying coupling interval after discontinuing train stimulation. Time constants of the onset kinetics were 1.52 +/- 0.15/n(fast) and 0.087 +/- 0.031/n(slow) for mexiletine, 0.075 +/- 0.015/n for aprindine, 0.078 +/- 0.019/n for disopyramide, and 0.050 +/- 0.006/n for pilsicainide. The recovery time constants were 203 +/- 66 ms for mexiletine, 1,021 +/- 162 ms for aprindine, 993 +/- 101 ms for disopyramide, and 2,930 +/- 569 ms for pilsicainide. Class I antiarrhythmic drugs produced use-dependent IACT prolongation in humans, with characteristic kinetics for each agent similar to that of depression of the maximum upstroke velocity of cardiac action potential (Vmax) reported in in vitro studies.

[A case of repetitive monomorphic ventricular tachycardia].

We present a case treated with aprindine and metoprolol combined with a DDD type pacemaker for repetitive monomorphic ventricular tachycardia. A 50-year-old man was admitted because of palpitation and near syncope attack. Electrocardiogram showed repetitive monomorphic ventricular tachycardias (RBBB LAD type) and R-R interval of about 440 msec and I degree A-V block in sinus rhythm. Electrophysiologic study disclosed that overdrive pacing in HRA suppressed ventricular tachycardias. Left ventriculography revealed a dilated left ventricular and decreased contractility. Antiarrhythmic agents such as quinidine sulfate, procainamide, disopyramide, mexiletine, lidocaine and propranolol were not effective. But, the combination of propranolol and aprindine decreased the rate of the ventricular tachycardia. With aprindine 60 mg/day and metoprolol 60 mg/day combined with the atrioventricular sequential pacing at 85/min, ventricular tachycardia completely disappeared.

Transport to intestinal lumen and peritoneal cavity of intravenously administered aprinidine in rats.

Transfer of aprindine from the blood into the intestinal lumen or into the peritoneal cavity was examined after intravenous administration of the drug at a dose of 5 mg/kg in rats. The amount of the drug transferred from the blood into the intestinal lumen was much greater than into the peritoneal cavity. The average amounts of aprindine transported into the intestinal lumen and the peritoneal cavity were 0.12 and 0.03% of the dose (5 mg/kg) in 120 min, respectively. Thus, a notable difference in the clearance values of the drug was obtained between the intestinal lumen (14.8 ml/h) and the peritoneal cavity (4.94 ml/h). The net water flux showed that secretion predominated in the peritoneal transport while absorption overbalanced secretion in the intestinal transport. It seems likely that a solvent drag effect by water movement did not contribute much to the transport of aprindine from the blood to the intestinal lumen or the peritoneal cavity. The differences in transport across the two membranes could be due to differences in the surface area and other geometrical factors. Differences could also be due to a difference in the pharmacologic effects of the drug which causes a decrease in tissue splanchnic perfusion.

[Clinical effects and plasma concentration levels of aprindine hydrochloride in patients with tachyarrhythmias].

Aprindine hydrochloride (aprindine) was administered orally in 17 Japanese patients with supraventricular or ventricular tachyarrhythmias, and the clinical effects and plasma concentration levels were evaluated. The antiarrhythmic effects were defined using Holter ECG recordings. Aprindine was administered orally with a daily dose of 40 mg for 2 weeks in all cases, and aprindine, 60 mg daily, was administered for the next 2 weeks in patients who did not show sufficient antiarrhythmic effects with 40 mg of the drug. Aprindine was effective in 9 of 17 patients, and the mean plasma concentration level reached 0.6 micrograms/ml 2 weeks after the administration was started. Effective results were seen in 2 of the 4 patients receiving a daily dose of 60 mg, and the mean plasma concentration level reached 1.0 microgram/ml 2 weeks after the administration was started. Transient mild elevations of liver transaminases were observed in one patient and mild transient anemia was observed in another. These abnormal data disappeared although the drug administration was continued. In conclusion, the administration of a relatively small dose of aprindine and, consequently, low plasma concentration levels, are effective for cardiac tachyarrhythmias in Japanese patients.

Therapeutic effectiveness and plasma levels of single or combination use of class I antiarrhythmic agents for ventricular arrhythmias.

The efficacy of disopyramide (DP), mexiletine (MX), aprindine (AP) and cibenzoline (CZ) on ventricular arrhythmias was compared (single drug therapy). In addition, the efficacy of the combination therapy of DP with MX was also studied (combination therapy). One hundred of the 106 patients completed the protocol of the single drug therapy. Fifty percent or more reduction in the frequency of ventricular premature contractions (VPCs) was obtained in 24 of 43 patients (56%) with DP, in 24 of 44 (55%) with MX, in 18 of 29 (62%) with AP and 10 of 18 (56%) with CZ. AP was comparatively more effective than the other drugs tested. DP was significantly effective on VPCs with organic heart disease as compared to idiopathic VPCs (p less than 0.05), while the other 3 drugs did not have such a tendency. With MX therapy, 10 of the 12 patients with fast VT rate (greater than or equal to 150 beats/min) showed a significant effect while only 4 of the 12 patients with non-fast VT rate (greater than or equal to 100 and 150 beats/min) had a significant one (p less than 0.05). On the other hand, DP, AP and CZ showed almost the same efficacy at any cycle length of VT. Six patients withdrew from the study, 4 because of digestive troubles with MX therapy, 1 because of micturition disturbances with DP and 1 because of skin rash with AP. The average therapeutic plasma levels of DP, MX, AP and CZ were 1.76 +/- 0.54 microgram/ml, 1.08 +/- 0.41 microgram/ml, 0.85 +/- 0.43 microgram/ml and 268.2 +/- 123.3 ng/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intravenous sotalol, aprindine and the combination of sotalol and aprindine on chronic high frequency ventricular arrhythmias in man.

The comparative antiarrhythmic efficacy of three different intravenous drug regimens was evaluated in 12 symptomatic patients (mean age: 72 years) with chronic high frequency ventricular arrhythmias (mean: 834 PVCs h-1). In a cross-over study with latin square distribution the following drug regimens were administered intravenously to all patients aprindine 2 mg kg-1, sotalol 1.5 mg kg-1, aprindine 1 mg kg-1 & sotalol 0.75 mg kg-1. The mean percentage of PVC reduction was 41% (P less than 0.05) for aprindine 2 mg kg-1; 51% (P less than 0.05) for sotalol 1.5 mg kg-1 and 72% (P less than 0.01) for the combined drug therapy (aprindine 1 mg kg-1 and sotalol 0.75 mg kg-1). The mean plasma concentration was 1371 ng ml-1 after administration of aprindine 2 mg kg-1 and 1730 ng ml-1 after infusion of sotalol 1.5 mg kg-1. After combined drug therapy, mean plasma levels were 942 ng ml-1 for aprindine and 992 ng ml-1 for sotalol. The different drug regimens were well tolerated in all patients and no side-effects occurred. Combination therapy consisting of a drug that prolongs action potential duration with an antiarrhythmic agent that has a high affinity for the inactivated channels may thus achieve an antiarrhythmic efficacy comparable to single agent therapy, permitting the use of lower dosages.

Prophylactic antiarrhythmic therapy of high-risk survivors of myocardial infarction: lower mortality at 1 month but not at 1 year.

To determine whether prophylactic antiarrhythmic therapy influences mortality in high-risk patients after acute myocardial infarction, 143 such patients were randomized in a double-blind individually dose-adjusted, placebo-controlled trial an average of 14 +/- 7 days after myocardial infarction and followed for 1 year. Patients were judged to be at high risk on the basis of (1) ejection fraction less than 40% (n = 60), (2) arrhythmias of Lown class 3 or higher (n = 26), or (3) both (n = 57). Aprindine was chosen because of its long half-life, few side effects, and antiarrhythmic efficacy. Baseline characteristics in the treatment arms did not differ. Holter-detected arrhythmias were reduced in aprindine-treated patients at 3 months (p less than .001) and at 1 year (p less than .001). One patient was lost to follow-up; in the remaining patients 1 year mortality was 20% (28/142; 12 aprindine and 16 placebo). There was no significant difference between the two study arms in overall mortality and sudden death. However, among those who died, median duration of survival was longer in aprindine-treated patients (86 vs 21.5 days) (p = .04). Although antiarrhythmic treatment with aprindine of high-risk patients after myocardial infarction does not affect 1 year survival, mortality appears to be delayed; thus there may be a role for short-term treatment before more definitive therapy such as surgery.

Non-linear pharmacokinetics of aprindine hydrochloride in oral administration.

The pharmacokinetics of oral aprindine hydrochloride (in the following briefly called aprindine; Aspenon) were studied in 38 patients with ventricular premature contractions following single or multiple administration. Oral administration of aprindine in a single dose of 100-150 mg resulted in a mean maximal plasma concentration of 0.77 microgram/ml and a mean elimination half-life of 26.5 h. With multiple oral administration in 10 mg and 20 mg doses at intervals of 8 h, plasma concentration reached a steady state in 1-2 weeks with either dosage rate. Stable plasma concentrations were maintained with little diurnal or day-to-day fluctuation. The mean steady-state minimal plasma concentration with a 10 mg dosage was 0.28 microgram/ml. With a 20 mg dosage, however, this was more than tripled to 0.89 microgram/ml. The elimination process after the final administration of the drug was slower than with single dosage, and deviated from the first-order kinetics to produce a convex curve on a semilogarithmic graph paper. From these results it was apparent that aprindine shows non-linear pharmacokinetic behavior within the therapeutic dosage range.

Dose-dependent pharmacokinetics of aprindine in healthy volunteers.

The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t 1/2 beta) increased from 8.0 +/- 2.1 h (SD) after a 25 mg dose of 9.4 +/- 2.9 h after 50 mg and to 15.8 +/- 2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (V dss/F) and during beta-phase (V d beta/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (C max) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t 1/2 beta after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.