Profiles of aprindine, cibenzoline, pilsicainide and pirmenol in the framework of the Sicilian Gambit. The Guideline Committee for Clinical Use of Antiarrhythmic Drugs in Japan (Working Group of Arrhythmias of the Japanese Society of Electrocardiology).
The Vaughan Williams classification has been used widely by clinicians, cardiologists and researchers engaged in antiarrhythmic drug development and testing in many countries throughout the world since its initial proposal in the early 1970s. However, a major criticism of the Vaughan Williams system arose from the extent to which the categorization of drugs into classes I-IV led to oversimplified views of both shared and divergent actions. The Sicilian Gambit proposed a two-dimensional tabular framework for display of drug actions to solve these problems. From April to December 1996, members of the Guideline Committee met to discuss pharmacologic profiles of 4 antiarrhythmic drugs (aprindine, cibenzoline, pilsicainide, and pirmenol) that were not included in the original spreadsheet but are used widely in clinical practice in Japan. The discussion aimed to fit the drug profiles into the Gambit framework based on all the important literature published to date regarding the actions of the 4 drugs. This report is a summary of that deliberation. (+info)
Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells.
In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K+ currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea-pig hearts. Aprindine (3 microM) inhibited the delayed rectifier K+ current (IK) with little influence on the inward rectifier K+ current (IK1) or the Ca2+ current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). The muscarinic acetylcholine receptor-operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 microM) or by the intracellular loading of GTPgammaS. Aprindine inhibited the carbachol- and GTPgammaS-induced IK.ACh with the IC50 values of 0.4 and 2.5 microM, respectively. In atrial cells stimulated at 0.2 Hz, aprindine (3 microM) per se prolonged the action potential duration (APD) by 50+/-4%. The drug also reversed the carbachol-induced action potential shortening in a concentration-dependent manner. In isolated hearts, perfusion of carbachol (1 microM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold. Addition of aprindine (3 microM) inhibited the induction of AF by prolonging MAP and ERP. We conclude the efficacy of aprindine against AF may be at least in part explained by its inhibitory effects on IKr and IK.ACh. (+info)
Inhibitory effect of aprindine on Na+/Ca2+ exchange current in guinea-pig cardiac ventricular myocytes.
1. Using the whole-cell voltage clamp technique, the effect of aprindine on Na+/Ca2+ exchange current (I(NCX)) was examined in guinea-pig single cardiac ventricular myocytes and CCL39 fibroblasts expressing a dog cardiac Na+/Ca2+ exchanger (NCX1). 2. I(NCX) was recorded by ramp pulses from the holding potential of -60 mV with the external solution containing 140 mM Na+ and 1 mM Ca2+, and the pipette solution containing 20 mM Na+, 20 mM BAPTA and 13 mM Ca2+ (433 nM free Ca2+). 3. External application of aprindine suppressed I(NCX) in a concentration-dependent manner. The IC50 values of outward (measured at 50 mV) and inward (measured at -100 mV) I(NCX) components were 48.8 and 51.8 microM with Hill coefficients of 1.3 and 1, respectively. 4. Intracellular application of trypsin via the pipette solution did not change the blocking effect of aprindine, suggesting that aprindine does not affect the exchanger from the cytoplasmic side. 5. Aprindine inhibited I(NCX) of a mutant NCX1 with a deletion of amino acids 247 - 671 in the large intracellular domain between the transmembrane segments 5 and 6 in a similar manner to that of the wild-type, suggesting that the site of aprindine inhibition is not in the large intracellular domain of NCX1. 6. A kinetic study indicated that aprindine was cooperatively competitive with KB-R7943, another inhibitor of NCX and that aprindine was a competitive inhibitor with respect to external Ca2+. 7. We conclude that aprindine may modestly inhibit I(NCX) in a therapeutic range of concentrations (around 2.5 approximately 6.9 microM) possibly at an external or intra-membranous site of the exchanger. (+info)
Double-blind placebo-controlled trial of aprindine and digoxin for the prevention of symptomatic atrial fibrillation.
A multicenter, placebo-controlled, randomized, double-blind trial compared the preventive effect of aprindine and digoxin on the recurrence of atrial fibrillation (AF) with placebo, and also compare the effectiveness of these 2 drugs in the prevention of AF. Patients with symptomatic paroxysmal or persistent AF who had converted to sinus rhythm (SR) were randomly assigned aprindine (40 mg/day), digoxin (0.25 mg/day) or placebo and followed up on an outpatient basis every 2 weeks for 6 months. Of the 141 patients from 36 participating centers, 47 were given aprindine, 47 digoxin, and 47 were on placebo. After the 6-month follow-up, the Kaplan-Meier estimates of the percentage of patients remaining free of recurrent symptomatic AF on aprindine, digoxin and placebo were 33.3%, 29.2% and 21.5%, respectively. In patients remaining in SR for 15 days after from the start of follow-up, freedom from recurrence was significantly more prevalent in the aprindine group than in the placebo group (p=0.0414), but there was no significant difference between the digoxin and placebo groups. The rate of adverse events was similar in the 3 groups. In conclusion, neither aprindine nor digoxin had a significant effect on preventing relapse of symptomatic AF; however, recurrence of AF occurred later with aprindine than with placebo or digoxin. (+info)
Antiarrhythmic effect of aprindine on several types of ventricular arrhythmias.
The antiarrhythmic effect of aprindine was compared with those of lidocaine and propranolol on several ventricular arrhythmias-epinephrine arrhythmias in cats, ouabain arrhythmias in cats and guinea pigs, ischemic ventricular arrhythmias in coronary-ligated Beagle dogs. Antiarrhythmic effects of aprindine and lidocaine were observed both in ouagain and ischemic arrhythmias, but not in epinephrine arrhythmias. While propranolol had a strong antiarrhythmic effect against epinephrine and ouabain arrhythmias, it did not increase sinus beats in ischemic arrhythmias. Marked anti-arrhythmic effects of aprindine in ischemic arrhythmias were observed in dogs using either single intravenous administration (4 mg/kg) or intravenous infusion (200 mug/kg/min, 2 mg/kg). Antiarrhythmic activity of aprindine is considered to be about twice as strong as that of lidocaine, but lidocaine is less toxic in experimental animals. (+info)
Atrial fibrillation threshold predicted long-term efficacy of pharmacological treatment of patients without structural heart disease.
AIMS: To ascertain if an electrophysiological study could predict long-term efficacy of anti-arrhythmic drugs in the treatment of lone atrial fibrillation. METHODS AND RESULTS: Forty-four patients (36 males, 8 females, age 55.5 +/- 10.6) with paroxysmal atrial fibrillation were enrolled to undergo serial electrophysiological studies at the bedside. Two quadripolar catheters were inserted via the subclavian vein. Disopyramide (D: 2 mg/kg iv), cibenzoline (C: 1.4 mg/kg iv), aprindine (A: 2 mg/kg iv), pilsicainide (P: 2 mg/kg po) and flecainide (F: 3 mg/kg po) were tested. Atrial fibrillation threshold (AFT) was measured as the lowest current amplitude of rapid pacing (50 Hz for 1 s) to induce atrial fibrillation lasting more than 30 s. Before drug treatment, AFT was 3.9 +/- 0.3 mA. Pharmacological treatment raised AFT as follows: D 5.9 +/- 0.9 mA, C 7.6 +/- 1.2 mA, A 8.1 +/-1.1 mA, P 6.0 +/- 0.8 mA, F 7.3 +/- 1.1 mA. Recurrence of atrial fibrillation was observed during 1-year follow-up in 12% of cases when they were treated with a drug that raised AFT by 5 mA or more. On the other hand, the recurrence rate was 87% when patients were treated with a drug that raised AFT by less than 5 mA (P = 0.001). CONCLUSION: AFT was a good predictor of long-term efficacy of pharmacological treatment against atrial fibrillation. (+info)
Maintenance of sinus rhythm and recovery of atrial mechanical function after cardioversion with bepridil or in combination with aprindine in long-lasting persistent atrial fibrillation.
BACKGROUND: The aim of this study was to evaluate pharmacological cardioversion of long-lasting persistent atrial fibrillation (AF) using bepridil in terms of recovery of atrial mechanical function and maintenance of sinus rhythm. Bepridil alone or in combination with aprindine is effective for termination of persistent AF. METHODS AND RESULTS: The study group comprised 38 consecutive patients (24 men, 58.8+/-9.3 years) with successful conversion of persistent AF lasting >1 month either pharmacologically (Group I) or electrically (Group II). Fast Fourier transform analysis of fibrillation waves was performed and fibrillation cycle length (FCL) was calculated from the peak frequency. In Group I, sinus rhythm was pharmacologically restored in 22 patients after an average 30 days (7-49 days) of bepridil administration, either alone (11) or in combination with oral aprindine (11); they were followed up while using the same drugs. In Group II, electrical conversion restored sinus rhythm in 16 patients, and they were followed up with conventional antiarrhythmic drugs other than bepridil and aprindine. After bepridil treatment FCL increased and became significantly longer in Group I than in Group II (190+/-39 vs 150+/-29 ms, p<0.001). Atrial peak velocity in transmitral flow within the first week after cardioversion was greater in Group I than in Group II (68+/-35 vs 32+/-20 cm/s, p<0.05). By Kaplan-Meier analysis, 83% of Group I patients were free of AF recurrence at the 12-month follow-up, compared with 36% in Group II (p<0.005). CONCLUSIONS: In patients with long-lasting AF, pharmacological conversion with bepridil alone or in combination with aprindine recovered atrial mechanical function better and maintained sinus rhythm longer than electrical conversion. (+info)
Drug-induced changes in fibrillation cycle length and organization index can predict chemical cardioversion of long-lasting atrial fibrillation with bepridil alone or in combination with aprindine.
BACKGROUND: The aim of this study was to investigate whether drug-induced changes in fibrillation wave characteristics can predict pharmacological conversion of long lasting persistent atrial fibrillation (AF). METHODS AND RESULTS: The study group comprised 23 consecutive patients with AF lasting > or =1 month. Patients first received bepridil (200 mg/day) for 2-4 weeks. When sinus rhythm was not restored with bepridil, oral aprindine (40 or 60 mg/day) was added to bepridil. Fast Fourier transform analysis of fibrillation waves using lead V1 was performed to calculate the fibrillation cycle length (FCL). The spectral areas were measured and the maximum area divided by the total area was termed the fibrillation organization index (FOI). Sinus rhythm was restored in 16 of 23 patients (70%); 8 of these 16 patients received only bepridil (Group I) and the other 8 responders received bepridil and aprindine (Group II). In Group I bepridil increased both FCL (p<0.001) and FOI (p<0.01) and terminated AF after 20+/-12 days. In Group II bepridil increased FCL (p<0.001), but did not change FOI. The addition of aprindine terminated AF in association with an increase in both FCL (p<0.005) and FOI (p<0.005) within 19+/-8 days. In the remaining 7 patients who did not have restoration of sinus rhythm, bepridil increased both FCL and FOI significantly, but less than in Group I, and the addition of aprindine did not further increase either of them. Chemical cardioversion of AF occurred in all patients with FCL > or =190 ms and FOI > or =45% after drug administration. CONCLUSION: Bepridil alone or in combination with aprindine converted long lasting persistent AF in association with an increase in both FCL and FOI. The combination of FCL and FOI after drug administration is helpful in predicting chemical cardioversion of persistent AF. (+info)