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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.

抗不整脈薬の長期治療の中止による心室性期外収縮 (VPC) の変化をホルター心電図を用いて検討した.対象はLown分類IVa度以下のVPCを呈し, 抗不整脈薬の単独投与が有効と判断された56例である.平均観察期間は3年4カ月であった.基礎心疾患は29例 (52%) に認められた.投与された抗不整脈薬はdisopyramide (DP) 18例, mexiletine (MEX) 23例, aprindine (APR) 15例であった.薬物投与中のVPO数/日別分類では0～99が31例, 100～999が19例, 1, 000以上が8例であった.治療中止により対象群のうち5例は自覚症状が増悪し, ホルター心電図を記録できなかった.ホルター心電図記録可能例でのVPC悪化は61%の例であり, 上記5例を含めると計64%の例にVPC悪化を認めた.基礎心疾患合併例に限れば, 86%とさらに高率であった.抗不整脈薬別では, DP (78%) がAPR (33%) と比べVPC悪化例が有意に多かった.VPC数/日別分類では投与中止後各群間に悪化率に有意差を認めなかった.抗不整脈薬によるVPC抑制効果は長期投与後においても高いことが示唆され, また基礎心疾患合併例では薬物を中止することが比較的困難であると考えられた.

The pharmacokinetic interactions of diltiazem and the antiarrhythmic drugs aprindineand mexiletine were studied in beagle dogs and in patients with arrhythmia.In the animal experiments at 2 hours after diltiazem administration, the plasma concentration of aprindine was significantly higher than in dogs without diltiazem administration (p 0.05). Moreover, the peak plasma concentration of diltiazem at 2 hoursafter oral administration was approximately twice as high with the combination of aprindineand diltiazem compared to diltiazem alone (p

We wished to examine selected class I antiarrhythmic agents for their potential to exhibit proarrhythmic or antifibrillatory actions. Quinidine, lidocaine, aprindine, and flecainide were evaluated in an experimental model that made use of rabbit isolated perfused heart. Hearts were stabilized with oxygenated buffer (95% O2/5% CO2) with or without pinacidil (1.25 microM) and then were subjected to hypoxia (95% N2/5% CO2) for 12 min, followed by 40-min normoxic perfusion (95% O2/5% CO2). Test drugs were added to the perfusion medium 5 min before hypoxia was induced. Prevention of spontaneous ventricular fibrillation (VF) was determined. To characterize the electrophysiologic effects of the selected antiarrhythmic agents, we determined the changes in threshold current and effective refractory period (ERP) before and after drug treatment. Addition of the potassium channel agonist, pinacidil, to the perfusion medium invariably resulted in VF during the hypoxic interval or shortly after reoxygenation. Pretreatment of the heart with glibenclamide prevented pinacidil-induced VF. Quinidine, aprindine, lidocaine, and flecainide each were studied at a single concentration. The respective drug concentrations were selected to produce comparable changes in ventricular refractory period. Of the class I agents selected for study, only quinidine prolonged the ventricular ERP and provided significant protection against pinacidil-induced VF. In contrast, aprindine and lidocaine decreased ventricular ERP and did not prevent VF induced by the combination of pinacidil and hypoxia. Quinidine, aprindine, and lidocaine did not exhibit proarrhythmic effects in the presence of hypoxia when pinacidil was not added to the perfusion medium. Flecainide, when added to the perfusion medium without pinacidil elicited proarrhythmic activity leading to VF when the hearts were made hypoxic. Flecainide-induced VF was antagonized by glibenclamide. The data suggest that VF can be provoked by the potassium channel agonist pinacidil or by flecainide under conditions that reduce intracellular ATP concentration. Glibenclamide, a selective antagonist of the KATP channel prevented the profibrillatory actions of pinacidil and flecainide. Quinidine, but not lidocaine and aprindine, prevented VF induced by pinacidil and hypoxia.

1. 1. The relationship between the negative inotropic and chronotropic effects of tocainide and 5 other class I antiarrhythmic drugs was evaluated in Langendorff-perfused guinea-pig hearts. 2. 2. All 6 drugs reduced the contractile force (Fc) and the heart rate (HR) of spontaneously beating guinea-pig hearts in a dose-dependent manner. The order of crude negative inotropic potency was: quinidine (Qui) = aprindine (Apr) > mexiletine (Mex) > lidocaine (Lid) > disopyramide (Dis) > tocainide (Toc); and the order of negative chronotropic effect was: Apr > Qui > Mex > Dis > Lid > Toc. 3. 3. The order of the negative inotropic potency relative to chronotropic effect (expressed as a ratio: ID 50 for Fc/ID 50 for HR) was Lid > Qui > Dis > Toc > Mex > Apr ( n = 6). 4. 4. For heart electrically stimulated at a constant rate, the order of crude negative inotropic potency was: Apr > Qui > Mex > Dis > Lid > Toc, and the order of negative inotropic potency (determined by the ratio: ID 50 for Fc in driven heart/ID 50 for spontaneously beating HR) was: Mex > Apr > Toc > Dis > Qui > Lid ( n = 6). 5. 5. There was a significant influence of negative chronotropic effect on the inotropic potency and the order was: Lid > Qui > Dis > Toc > Apr > Mex. The potency of various drugs is clinically useful in the choice of drugs when considering cardiac function and heart rate.

The effects of aprindine hydrochloride, an antiarrhythmic drug of the class IB, on heart rate variability were evaluated in 13 patients (eight men and five women), ages 76 ± 11 years, who showed a standard deviation of the R-R interval measured at 5-minute intervals (SDANN) of ⩽100 msec on 24-hour electrocardiograms. After 24-hour electrocardiograms were recorded during the control period, aprindine was administered at a dose of 60 mg/day. After 2 weeks of treatment 24-hour electrocardiograms were again recorded. The SDANN was ⩽100 msec (mean, 69.3 ± 17.0 msec) in all patients during the control period, but increased after aprindine administration (mean, 86.1 ± 31.5 msec, P

Objective: The aim was to study the difference between tonic and use dependent block of the cardiac sodium channel produced by the combined application of the same subclass of antiarrhythmic agents (class la or lb). Methods: Conventional glass microelectrode technique was used to record the maximum rate of depolarisation (dV/dtmax) of action potentials reflecting sodium channel availability, before and after the combined application of quinidine plus disopyramide, aprindine plus lignocaine, aprindine plus mexiletine, and lignocaine plus mexiletine. Guinea pig papillary muscles (n=4-8 per experiment) were used for the study. Results: All combinations increased tonic block additively compared to use of a single drug. On the other hand, use dependent block was increased by the combination of quinidine 10 μM plus disopyramide 30 μM compared to a single drug, and was not changed by lignocaine 50 μM plus mexiletine 20 μM, whereas it was decreased by aprindine 3 μM plus lignocaine 50 μM or mexiletine 20 μM. When concentrations of mexiletine and lignocaine were increased, both tonic and use dependent block in a single drug were increased dose dependently, whereas the combination produced an additive increase in tonic block but no change in use dependent block compared to a single drug. Conclusions: The results suggested that the binding and unbinding process of the drug to produce tonic block was different from that to produce use dependent block, and that combination of different drugs produced diverse effects on use dependent block even though state dependent affinity of individual drugs seemed similar. These two factors must be born in mind in evaluating the combination therapy.

Aprindine is a very effective antiarrhythmic agent with a narrow therapeutic ratio. We report a patient who suffered from granulomatous hepatitis probably due to the administration of aprindine. Evidence of hepatitis appeared within 6 weeks of initiating aprindine therapy and resolved rapidly when the drug was withdrawn. Six months later, fibrosis but no granulomata were found in the expanded portal tracts. Our observations suggest that granulomatous hepatitis can occur during aprindine therapy. J Hepatol

A method is described which allows determination of the threshold of excitability of electrically stimulated, regularly contracting isolated cardiac preparations. The force of the contraction (CF) is isometrically recorded and serves as feed-back signal indicating effective stimulation. The pulse intensity is decreased monoexponentially as long as contractions are elicited. If the mechanical response does not occur, the pulse intensity is immediately reset to the initial high value and the pulse is delivered with a latency of a few milliseconds. A stimulus intensity just below threshold is recorded as the rectangular pulse threshold (RPT). The method was applied in order to compare the effects of a number of antiarrhythmic drugs including the beta-blocker propranolol on the electrical excitability (1/RPT) and on the contractility of guinea pig left atria stimulated at 3 Hz. In general, the drugs depressed excitability and contractility concomitantly. The rank order of potency with respect to the reduction of excitability was: aprindine greater than propafenone greater than propranolol greater than quinidine greater than mexilitine greater than lidocaine. The Ca-antagonist verapamil reduced contractile force most powerful but had no effect on excitability. Presumably, RPT reflects sodium-channel function. In conclusion, the described method offers an easily operable test of drug effects on the excitability threshold and the contractility of isolated cardiac preparations.

Purpose: A comparison study was Preformed for the clinical effects of aprindine (AP) on ventricular extrasystole in the same patient, using mexiletine (MX) as a control, by a cross-over method that used the envelope method.Method: Twenty-two patients from nine facilities with ventricular extrasystole of 5, 000/day or more were administered AP 40mg/day and MX 300mg/day.Prior to treatment and at the completion of each treatment, recordings of DCG, electrocardiogram at rest, and measurements of blood concentration were carried out.Results: A reduction rate of 50% or more in the total number of extrasystoles was observed in 12 patients (54%) administered AP, in 11 administered MX (50%), and although a Lown classification of IV or higher was observed in 16 patients, it improved to III or less in eight AP patients and in seven MX patients. In an analysis by the Lerenz plot method, the coupling interval was prolonged significantly by the administration of AP. The PQ interval and QRS width also were prolonged significantly by the administration of AP.Conclusion: AP was considered to be a drug that strongly suppresses conducting systems of the heart, especially atrial and intraventricular conduction.

A simulation model was developed to predict complex interaction between antiarrhythmic drugs and cardiac sodium channels. This model has four assumptions: (1) Vmax of the action potential is a linear indicator of available sodium channel conductance; (2) antiarrhythmic drugs block the channel by binding to a single common receptor site associated with the channel; (3) binding and dissociation rate constants differ for the three channel states: activated, inactivated and resting, and (4) both drug-free and drug-bound channels change states far more rapidly than binding and dissociation processes. Binding and dissociation rate constants for the three channel states were calculated from single cell experiments using guinea pig hearts. Vmax changes reflecting tonic and use-dependent sodium channel block in the presence of mexiletine and aprindine were simulated and compared with those obtained in the single cell experiments. The model predicted that 'tonic' Vmax inhibition would be enhanced, whereas 'use-dependent' ones would be attenuated after admixture of mexiletine with aprindine. The mechanisms would involve competitive interaction at the common receptor site. Single-cell experiments supported this prediction. We conclude that our simple two-drug binding model provides a useful tool to predict pharmacological interaction between class I antiarrhythmic drugs given in combination.

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 aprindine 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 a 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.

The peroxisomes in the liver of four patients with alcoholic hepatitis and in six patients with drug-induced hepatitis are compared to eight control livers by catalase cytochemistry and morphometry. A decrease of catalase activity is observed in alcoholic, amitriptyline, aprindine, clomipramine and methiomazole hepatitis. Peroxisomes with a heterogeneous distribution of the catalase reaction product are found in most hepatitis livers. The number of organelles is increased 1.5 to 4.2 times in alcoholic, aprindine, methimazole and phenytoin hepatitis livers. In the last case, peroxisomes are also smaller. Changes in shape are seen in all hepatitis livers; they include invaginations, tails, funnel-like constrictions and gastruloid cisternae. In aprindine, phenytoin, methimazole and two alcoholic hepatitis livers, surface density exceeds the upper control value. These data indicate a loss of catalase activity in most hepatitis livers but also peroxisomal proliferation and shape modifications. It has been proposed that the latter changes are favorable for metabolic activity.

To assess the efficacy of combination therapy of aprindine (40 mg/day) and verapamil (160 mg/day), transesophageal programmed atrial stimulation was performed on 21 patients with paroxysmal supraventricular tachycardia (including 12 patients with atrioventricular nodal reentrant tachycardia and nine patients with atrioventricular reentrant tachycardia) under four conditions: a) control, b) aprindine alone, c) verapamil alone, and d) aprindine + verapamil. Results: a) Aprindine, verapamil, and aprindine + verapamil prevented paroxysmal supraventricular tachycardia induction in 2/21, 3/21, and 9/21 patients, respectively;b) aprindine + verapamil prolonged the cycle length of paroxysmal supraventricular tachycardia more than aprindine or verapamil alone; c) aprindine, verapamil, and aprindine + verapamil decreased the AV blocking rate by 15, 23, and 35 beats/min, respectively, in comparison with the control state; d) aprindine, verapamil, and aprindine + verapamil prolonged the effective refractory period of atrioventricular conduction system by 20, 34, and 76 msec, respectively, compared with the control state. In conclusion, aprindine + verapamil appear to be more effective than aprindine or verapamil alone in preventing paroxysmal supraventricular tachycardia with nodal reentry, but there was less benefit in those without nodal reentry (Wolff-Parkinson-White group).

Using a catheter electrode developed by the authors for recording monophasic action potentials (MAPs), the atrial and ventricular MAPs of seven mongrel dogs were simultaneously recorded. The results were used to evaluate the effect of the new antiarrhythmic drug aprindine on MAPs. An electrophysiologic study was also carried out to evaluate the effect of aprindine on the conduction system. Aprindine caused a significant increase in both the AH interval (at a basic cycle length of 400 ms) and the HV interval (at basic cycle lengths of 400 and 500 ms). The effective refractory period increased in both the right atrium and the right ventricle. Although an increase in MAP duration at repolarizations to 90% MAP (MAPD90) was not observed in the right atrium, a significant increase was noted in MAPD90 in the right ventricle. There were no significant changes in the ratio between the effective refractory period and MAPD90 of the right ventricle before and after administration of aprindine. This result suggests that increases in MAPD90 contribute to an increase in the effective refractory period of the right ventricle.

Monitoring of plasma concentrations of antiarrhythmic drugs may assist in individualizing dosage regimens and in assessing patient compliance. A rapid high-performance liquid chromatographic assay using solid-phase column extraction was developed for the following antiarrhythmic drugs: amiodarone, aprindine, disopyramide, flecainide, lidocaine, lorcainide, mexiletine, procainamide, propafenone, sotalol, tocainide, and verapamil. As most of the antiarrhythmic drugs are basic compounds, good adsorption on the extraction columns was obtained by alkalinization; aprindine, however, was applied at neutral pH and amiodarone at pH 3.5. After washing with water, the compounds were eluted with methanol, but amiodarone was eluted with a mixture of acetonitrile and acetate buffer at pH 5 (8/2, vol/vol). Most of the eluates were evaporated to dryness and reconstituted in the mobile phase; for amiodarone, disopyramide, and tocainide, direct injection onto the column was performed. Separation was done on a Spherisorb hexyl 5 mu column (150 x 4.6 mm I.D.) and the mobile phases consisted of mixtures of acetonitrile or methanol with phosphate or acetate buffers at different pH values. Detection was performed by UV or fluorescence detector. Coefficients of variation were lower than 10% with good recovery and linearity in the expected therapeutic ranges.

Data are limited on the use of serial electrophysiologic testing of drug therapy in patients with supraventricular tachycardia associated with accessory pathways, including the Wolff-Parkinson-White syndrome. Twenty-four highly symptomatic patients (aged 36 ± 11 years) with SVT related to accessory pathways underwent electrophysiologic studies to select an effective chronic oral treatment. Conventional (verapamil, propranolol, quinidine, disopyramide) and investigational (amiodarone, aprindine, propafenone) drugs were used alone and in combination if necessary. It was determined that serial electrophysiologic studies could identify potentially effective treatments in 6 6 % of patients with reentrant S V T involving accessory pathways, and the findings were highly predictive of long-term clinical outcome.

Identification of the antiarrhythmic drugs ajmaline, aprindine, diltiazem, disopyramide, flecainide, gallopamil, lidocaine, lorcainide, mexiletine, phenytoin, prajmaline, propafenone, quinidine, sparteine, tocainide and verapamil and their metabolites in urine is described. After acid hydrolysis of the conjugates, extraction and acetylation, the urine samples were analysed by computerized gas chromatography-mass spectrometry. Using ion chromatography with the selective ions m/z 58, 72, 84, 86, 136, 224, 266, and 426, the possible presence of antiarrhythmic drugs and/or their metabolites was indicated. The identity of positive signals in the reconstructed ion chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The ion chromatograms, reference mass spectra and gas chromatographic retention indices (OV-101) are documented. The method presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs.

The state-dependent sodium channel block by mexiletine, tocainide, lidocaine, OPC-88117, aprindine, quinidine, disopyramide and AN-132 was investigated in single ventricular myocytes isolated from guinea-pig hearts. A single conditioning clamp pulse with a duration from 10 ms to 1000 ms was applied from the resting potential (-82 mV) to 0 mV level using a suction pipette whole-cell voltage clamp technique, and the maximum upstroke velocity (Vmax) of a test action potential elicited 100 ms after termination of the clamp pulse was measured as an index of sodium channel availability. In myocytes treated with the eight drugs, such clamp pulse caused a significant decrease in Vmax. With mexiletine, tocainide, lidocaine, OPC-88117 and aprindine, the Vmax reduction was enhanced progressively as the clamp pulse duration was prolonged. With quinidine, disopyramide and AN-132, an appreciable Vmax reduction at the shortest clamp pulse was followed by an additional small enhancement of the Vmax decay. These findings suggest that the former group of drugs may block the sodium channel mainly during the inactivated state (inactivation blockers), whereas the latter one may do so mainly during the activated state (activation blockers). Multiple short clamp pulses caused a greater Vmax reduction than a single prolonged clamp pulse for the activation blockers, and vice-versa for the inactivation blockers. Molecular dimensions of the eight drugs, which were estimated by X-ray diffraction of crystals, did not satisfy a simple size criterion as proposed by Courtney (1988) to explain such different types of sodium channel block by Class-I drugs.

The relationship between the negative inotropic effect and the effect on maximal upstroke velocity of action potentials (Vmax) induced by class 1 antiarrhythmic drugs [aprindine (A); cibenzoline (C); disopyramide (D); lidocaine (L); pirmenol (P); quinidine (Q)] was evaluated in the guinea-pig myocardium using electrophysiological techniques. Each drug reduced the force of contraction (Fc) and Vmax of fast action potentials dose-dependently. Tetrodotoxin and verapamil also decreased Fc in a dose-dependent manner. Class 1 an-tiarrhythmic drugs also reduced Vmax of the Ca-dependent slow response together with Fc. These drugs might be divided into three types according to the regression patterns of Fc. Type 1: The reduction of Fc was mainly due to Na channel blockade, resembling the pattern of tetrodotoxin (A). Drugs of this type show weaker negative inotropic than antiarrhythmic properties compared with drugs of types 2 and 3. Type 2: The reduction of Fc was predominantly due to Ca channel blockade, resembling the pattern of verapamil (Q). Type 3: Other type (C, D, L, P). This classification of class 1 antiarrhythmic drugs seems to be clinically useful in choice of drugs considering the patient's condition, such as cardiac function, and possible mechanism of arrhythmia.

In order to investigate the usefulness of antiarrhythmic drugs in patients with dilated cardiomyopathy (DCM), 42 patients with DCM were studied using 24 h ambulatory ECG monitoring, echocardiography and right ventricular endomyocardial biopsy. All 42 patients had ventricular arrhythmias with a Lown's classification of grade II or greater (grade IVb, 25; IVa, 7; III, 7; II, 3). The patients with grade IV arrhythmias tended to have greater dilating of the left ventricle and more pronounced interstitial myocardial fibrosis than patients with lower grades. Following procainamide and/or disopyramide treatment the severity of the ventricular arrhythmias improved in 12 (29%) of the 42 patients, did not change in 27 patients (64%), and deteriorated in 3 patients (7%). Treatment with aprindine or mexiletine was effective in 7 (50%) of the 14 patients who did not respond to procainamide and/or disopyramide. Although there were no significant differences in left ventricular dimension and contractility between patients in each group who did and did not respond to antiarrhythmic treatment, those who did respond had less interstitial myocardial fibrosis. Thus, in the procainamide and/or disopyramide treated group the percent interstitial fibrosis in responding vs nonresponding patients was 10.3 +/- 4.1% vs 18.7 +/- 8.3% (p less than 0.05) respectively, while in the group treated with aprindine or mexiletine these figures were 13.0 +/- 3.2% vs 26.1 +/- 7.9% (p less than 0.02), respectively. In conclusion, the effect of antiarrhythmic drugs in DCM was dependent on the severity of the pathological changes in the myocardium, and antiarrhythmic drugs should be appropriately used for the management of ventricular arrhythmias in DCM.