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The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp methods. All of the drugs examined reduced the maximum rate of rise of automatic action potentials. The firing frequency and rate of diastolic depolarization were decreased by aprindine, flecainide and propafenone, but not by cibenzoline, disopyramide and pilsicainide, which correlated with blockade of the sodium current component induced by ramp depolarization mimicking the diastolic depolarization. In conclusion, class I antiarrhythmic drugs which block the diastolic sodium current component inhibit the automaticity of the pulmonary vein myocardium.

Prophylactic doses of droperidol are effective in preventing postoperative nausea and vomiting (PONV). However, due to concerns of QT interval prolongation and ventricular arrhythmias, the safety of droperidol for PONV prophylaxis has been debated. A 70-year-old woman was scheduled for total knee arthroplasty. She had a history of aortic valve replacement. Oral aprindine (40 mg/day) was prescribed. Preoperative electrocardiogram showed mild QT interval prolongation (QTc = 475 ms). Anesthesia was induced using propofol, remifentanil, and rocuronium, and maintained using desflurane, remifentanil, and a bolus dose of rocuronium. The surgery was uneventful. At the time of skin closure, droperidol (1.25 mg) was administered intravenously for PONV prophylaxis. Twenty-three minutes after administration of droperidol, a sudden onset of premature cardiac contraction was observed, which progressed directly to ventricular tachycardia and atrioventricular block. Arrhythmia due to droperidol-induced QT interval prolongation was strongly suspected. Intravenous magnesium sulfate (2 g) and atropine (0.5 mg) were administered immediately. The ventricular tachycardia resolved quickly after the magnesium injection. Following the resolution of the arrhythmia, the patient was extubated. The patient experienced ventricular tachycardia after a prophylactic dose of droperidol that resulted from QT interval prolongation due to the preoperative medication. It may be prudent to avoid even low-dose droperidol in the background of already present QT prolongation, especially when multiple putative QT-prolonging drugs are used.

We previously reviewed our study of the pharmacological properties of cardiac Na+/Ca2+ exchange (NCX1) inhibitors among cardioprotective drugs, such as amiodarone, bepridil, dronedarone, cibenzoline, azimilide, aprindine, and benzyl-oxyphenyl derivatives (Watanabe et al. in J Pharmacol Sci 102:7–16, 2006). Since then we have continued our studies further and found that some cardioprotective drugs are NCX1 stimulators. Cardiac Na+/Ca2+ exchange current (INCX1) was stimulated by nicorandil (a hybrid ATP-sensitive K+ channel opener), pinacidil (a non-selective ATP-sensitive K+ channel opener), flecainide (an antiarrhythmic drug), and sodium nitroprusside (SNP) (an NO donor). Sildenafil (a phosphodiesterase-5 inhibitor) further increased the pinacidil-induced augmentation of INCX1. In paper, here I review the NCX stimulants that enhance NCX function among the cardioprotective agents we examined such as nicorandil, pinacidil, SNP, sildenafil and flecainide, in addition to atrial natriuretic (ANP) and dofetilide, which were reported by other investigators.

Background Approximately one-third of the patients undergoing cardiovascular surgery reportedly experience paroxysmal atrial fibrillation (AF) during the postoperative period. However, the usefulness of antiarrhythmic drugs for preventing postoperative AF recurrence in the Japanese population has not been extensively studied. Methods From a total of 118 patients who developed postoperative paroxysmal AF between April 2009 and March 2011, 72 patients (45 men, mean age 68±8 years) requiring treatment for postoperative AF due to symptoms lasting ≥30 min were enrolled to prospectively investigate the efficacy of oral bepridil (100 mg/day, n =37) or aprindine (40 mg/day, n =35). Result The AF recurrence-free survival rates at 1, 3, 7, and 14 days were 100%, 94%, 57%, and 49%, respectively, in the aprindine group, and 100%, 97%, 86%, and 76%, respectively, in the bepridil group ( P =0.028, aprindine vs. bepridil). Conclusion Bepridil, at a fixed dose of 100 mg/day, was considered to be more effective than a routine dose of aprindine for the prevention of postoperative AF recurrence.

We present a case of a 9-month-old girl in whom malignant polymorphic ventricular tachycardia (VT) was successfully controlled by radiofrequency catheter ablation under guidance with a three-dimensional mapping system. The VTs originated from the left ventricular lateral wall, left ventricular anterior wall, and left ventricular apex. At least six types of VTs were documented during the electrophysiology study. All VTs were successfully controlled after two sessions of radiofrequency catheter ablation, and she was discharged from our hospital on propranolol, mexiletine, flecainide, and aprindine.

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 β 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.

The in vitro bone marrow growth of 2 patients with aprindine-induced agranulocytosis was studied. Granulocyte-macrophage committed stem cell (CFU-C) growth is inhibited by aprindine in a dose dependent manner. 50% inhibition of CFU-colony growth (TD50) was seen at 5.1 and 3.4 micrograms aprindine/ml medium respectively. The TD50 of control marrow CFU-C was 3.2 micrograms/ml. 100% inhibition was seen at 16 micrograms aprindine/ml, both in patients and controls. Pluripotential stem cell growth (CFU-GEMM) in control marrow was equally inhibited in a dose dependent manner by aprindine, though to a lesser extent (TD50: 9.1 micrograms/ml) and with relative sparing of pure megakaryocyte and erythroid colonies. Co-culturing of patients marrows with their respective acute phase serum did not inhibit CFU-C growth.

After the report of the Cardiac Arrhythmia Suppression Trial, a tabular framework of the Sicilian Gambit has been proposed to display actions of antiarrhythmic drugs on ion channels and receptors and to provide more rational pharmacotherapy of arrhythmias. However, because effects of antiarrhythmic drugs on If have not been thoroughly examined, we used patch clamp techniques to determine the effects of various antiarrhythmic drugs on the HCN (hyperpolarization-activated cyclic nucleotide–gated) channel currents. HCN4 channels, a dominant isoform of HCN channels in the heart, were expressed in HEK293 cells. Amiodarone and bepridil potently inhibited the HCN4 channel current with IC50 values of 4.5 and 4.9 μM, respectively, which were close to their therapeutic concentrations. The inhibitory effects of quinidine, disopyramide, cibenzoline, lidocaine, mexiletine, aprindine, propafenone, flecainide, propranolol, and verapamil on the HCN4 channel current were weak in their therapeutic concentrations, with IC50 values of 78.3, 249, 46.8, 276, 309, 43.7, 14.3, 1700, 50.5, and 44.9 μM, respectively, suggesting that the inhibitory effects on If would be clinically small. d,l-Sotalol hardly affected the HCN4 channel current. Information about the HCN4-channel effects of many antiarrhythmic drugs may be useful for determining the appropriate drug for treatment of various arrhythmias while minimizing adverse effects. Keywords:: antiarrhythmic drug, hyperpolarization-activated cyclic nucleotide–gated (HCN) channel subtype 4, pacemaker current, amiodarone, bepridil

We present two cases of markedly decreased serum aprindine levels during anti-tuberculous therapy.Case 1 was a 65year-old man with end-stage renal disease (ESRD) on regular dialysis who was being treated for atrial fibrillation with oral aprindine (40 mg/day).In the 6-month period before treatment with anti-tuberculous drugs,the mean serum aprindine concentration had been 1.01 (SD 0.31)μg/mL (n=6).When anti-tuberculous therapy including rifampicin was commenced for intestinal tuberculosis,there was a marked decrease in the serum aprindine concentration to 0.14μg/mL but after it was discontinued,the serum aprindine concentration rose to 0.48μg/mL.Case 2 was a 76-year-old man with ESRD on regular dialysis who was being treated for paroxysmal atrial fibrillation with oral aprindine (30 mg/day).In the 9-month period before anti-tuberculous therapy,the mean serum aprindine concentration had been 0.67 (SD 0.16)μg/mL (n=9).Anti-tuberculous therapy including rifampicin for soft-tissue tuberculosis of the left arm resulted in a marked decrease in the serum aprindine concentration to 0.09μg/mL.Aprindine is known to be metabolized by cytochrome P 450 (CYP) 2D6 and CYP3A4 and rifampicin is a potent inducer of CYP3A4 but has little effect on CYP2D6.Accordingly,the coadministration of rifampicin is assumed to have caused the substantial decreases in serum aprindine concentrations,probably through the induction of CYP3A4.Concomitant administration with rifampicin may therefore result in the failure of aprindine to ameliorate arrhythmia.

Background: Class I antiarrhythmic drugs can promote the organization of atrial fibrillation (AF) and sometimes converts AF into atrial flutter (AFL) concomitant with difficulty of rate control. We studied the usefulness of Bepridil, which exhibits a class III-like effect, for class I drug-induced AFL in patients with paroxysmal AF. Methods: The study population consisted of 17 consecutive patients (15 men, mean age 65 ± 8 years) with AFL converted from paroxysmal AF following oral treatment of class IA or IC antiarrhythmic agents including pilsicainide (n = 8), cibenzoline (n = 5), flecainide (n = 2), aprindine (n = 1), and propafenone with cibenzoline (n = 1). After the occurrence of AFL, class I drug was replaced by bepridil with a dose of 100–200 mg per day in all patients. Results: After the treatment with bepridil, 15 (88%) out of the 17 patients restored sinus rhythm after 1 to 68 days (average of 21 days). In 12 (80%) of the 15 patients, sinus rhythm was maintained for an average of 23.6 months (range of 1 to 62 months) follow-up period. Although torsade de pointes was not recognized, a marked QT prolongation (0.60 sec) was observed in one patient during the administration of bepridil at a daily dose of 200 mg. In this patient, QT interval was normalized (0.45 sec) after reduction of bepridil to 150 mg daily. Conclusion: Bepridil treatment may be safe and effective for class I drug-induced AFL in patients with paroxysmal AF to restore and maintain sinus rhythm as an alternative therapy for catheter ablation. However, the QT interval must be carefully monitored during this medication.

Human beings suffer from two different kinds of fibrillations: one is atrial fibrillation (AF) and the other is ventricular fibrillation (VF). AF is the most common sustained arrhythmia and VF is the most serious. Pharmacological cardioversion with conventional class I antiarrhythmic drugs is usually little help in terminating long-lasting AF. However, bepridil, a multi-channel blocker, alone or in combination with aprindine restored the sinus rhythm in about 70% of patients. The average time to conversion was one month, and cardioversion was associated with a significant increase in fibrillation cycle length. After cardioversion, atrial contraction recovered within one week, and sinus rhythm was maintained better than after conventional electrical cardioversion. Pharmacological cardioversion of long-lasting AF with bepridil could become a new therapeutic option targeting remodeled atria. Patients with idiopathic VF have a characteristic J wave and ST elevation along with a lower QT-RR slope and short QT interval at slower heart rates. Although an implantable cardioverter defibrillator (ICD) is the most reliable therapy for idiopathic VF, both bepridil and disopyramide normalized repolarization dynamics (slope of the QT-RR relationship) and reduced the frequency of spontaneous VF episodes and ICD shocks. Pharmacological therapy for cardioversion of persistent AF and prevention of idiopathic VF may play a key role in improving not only quantity but also quality of life.

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

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.

ATP-sensitive K+ channels (KATP: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 KATP 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 KATP. Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance KATP currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia.

Additional Mutations in LQT1. Introduction: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. Methods and Results: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. Conclusion: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.

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 ≥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

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 ≥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.

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.

Summary: After intravenous bolus administration of aprindine (AP) to conscious guinea pigs, the semi-logarithmic plasma concentration versus time curve was linear at a dose of 2 mg/kg, but convex at doses of 5 and 10 mg/kg. AP concentrations immediately after administration (C p0 ) were almost identical, irrespective of the dose received. The areas under the plasma concentration-time curves (AUCs) were proportional to the AP doses. At 2 mg /kg, the plasma total clearance (CL tot ) of AP was high (279 ± 80 mL/h), and its volume of distribution (Vd ss ) was large (245±99mL). Total blood clearance and time- averaged blood clearance (CL ave ) values for AP were similar to those for R(+) propranolol (PL) after intravenous coadministration of R( + ) PL (0.25 mg/kg) and AP (2 or 10 mg /kg). An in vitro serum protein binding study showed that the unbound fraction of AP was concentration-dependent. In guinea pigs pretreated with turpentine oil (2 mL /kg/day), the elimination of AP after intravenous doses of 2 and 5 mg/kg closely followed first-order kinetics, while C p0 and AUC increased in proportion to the AP doses. The bound fraction of AP in the serum was larger after turpentine oil pretreatment than in normal guinea pig serum in vitro. From these observations, the nonlinear pharmacokinetics of AP observed in guinea pigs can be attributed to nonlinear serum protein binding.

A 56-year-old woman inpatient that had been administrated warfarin, digoxin, verapamil and disopyramide after undergoing surgery for a mitral and aortic valve replacement associated with artrial fibrillation received a 300mg daily dose of disopyramide therapy before and after the operation. Although the serum disopyramide concentration was within the normal therapeutic range, dry mouth appeared as a side effect. Disopyramide was thus changed to pirmenol. The trough level of pirmenol was 2.1μg/mL at seven days after starting pirmenol therapy at the dose of 300 mg/day, and the dose was there after decreased to 200mg/day. About two weeks after pirmenol therapy was started, liver injury was observed. At approximately 30 days after pirmenol administration was stopped, the liver function returned to a normal level.On the other hand, according to recent reports pirmenol was suggested to show a high level in the liver. The reported levels of pirmenol were also similar to for amiodarone and aprindine, which are both well known to induce side effect in the liver. Therefore, one of the reasons that pimenol induced liver injury may be due to its high levels in the liver.

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 was1 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 were1 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.

Objective: To study the interaction between salicylate and class 1 antiarrhythmic agents. Methods: The effects of salicylate on class 1 antiarrhythmic agent-induced tonic and phasic block of the Na+ current (INa) of ventricular myocytes and the upstroke velocity of the action potential (Vmax) of papillary muscles were examined by both the patch clamp technique and conventional microelectrode techniques. Results: Salicylate enhanced quinidine-induced tonic and phasic block of INa at a holding potential of −100 mV but not at a holding potential of −140 mV; this enhancement was accompanied by a shift of the h∞ curve in the presence of quinidine in a further hyperpolarized direction, although salicylate alone did not affect INa. Salicylate enhanced the tonic and phasic block of Vmax induced by quinidine, aprindine and disopyramide but had little effect on that induced by procainamide or mexiletine; the enhancing effects were related to the liposolubility of the drugs. Conclusions: Salicylate enhanced tonic and phasic block of Na+ channels induced by class 1 highly liposoluble antiarrhythmic agents. Based on the modulated receptor hypothesis, it is probable that this enhancement was mediated by an increase in the affinity of Na+ channel blockers with high lipid solubility to the inactivated state channels.

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.

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.

The calcium channel blocker diltiazem (DTZ) is widely used alone or in combinationwith other drugs in the treatment of hypertention, angina pectoris and cardiac arrhythmias. Aprindine (AP) is a potent class I antiarrhythmic drug. The combination of antiarrhythmic agents, such as DTZ and AP, is often used when single drug therapy is ineffective or poorly tolerated. We previously reported on the drug interaction between DTZ and AP in beagle dogs and in patients with arrhythmia. DTZ is metabolized mainly in the liver, and the N-demethylated species (MA) is a major metabolite through the cytochrome P-450 isoform CYP3A. In the present study, therefore, we investigated the influence of AP on N-demethylation of DTZ using human liver microsomes.We showed that the N-demethylation of DTZ is inhibited by AP in a dose-dependent manner. Especially, at high concentrations of AP (200μM and 250 μM), the production of MA was reduced to 46.5 ± 5.7% and 31.9 ± 2.1% of the control value, respectively. Lineweaver-Burk plots showed that AP competitivery inhibited the N-demethylation of DTZ in hepatic microsomes with a Km value of 248.7μM.CYP3A is responsible for a major part of AP metabolism in the higher concentration range. This enzyme is present in the liver and the gut wall, therefore the gut wall seems to be an important metabolic site. These results suggested that the mechanism of interaction between DTZ and AP is competitive inhibition and it is dependent on intestinal CYP3A.

i-OHAP, a major metabolite of aprindine (AP), was isolated by TLC from rat feces and identified as N-13-(N,N-diethylamino)propyl]-N-phenyl-2-aminoindan-5-ol, based on 1H-NMR, the H-H correlation spectroscopy (COSY) spectrum, MS and LC-MS. Its structure was also confirmed by comparison with the synthesized compound. The hydroxy group of i-OHAP was located at the 5-position of the indan ring. AP is a prochiral compound, and the metabolism of AP to i-OHAP was stereoselective. The ratio of (+)/(-)-i-OHAP in rat feces and in human urine was about 5 and 15, respectively.

The pharmacokinetic parameters were estimated and the pharmacokinetic models of aprindine were evaluated in patients. Two pharmacokinetic models were used, comprising a linear elimination model and a non-linear elimination model, both one-compartment models in which first-order absorption is assumed. Twenty-two serum levels of patients in terms of TDM were measured and the pharmacokinetic parameters were estimated using the simple pool method. The pharmacokinetic parameters estimated using a linear model were ka= 0.244 (hr-1), ke=0.020 (hr-1) and Vd=1.778 (1/kg), while those using a non-linear model were ka=0.666 (hr-1), Km=2.022 (μg/ml), Vmax=0.106 (mg/hr/kg) and Vd=2.754 (1/kg).The non-linear model was more suitable than the linear model for the AIC (linear model:-12.59, non-linear model:-19.61). The parameters estimated using the non-linear model were therefore more accurate and were found to have a smaller bias than those estimated using the linear model.