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PubMed1980

The antifibrillatory potency of aprindine, mexiletine, tocainide and lignocaine compared on Langendorff-perfused hearts of rabbits and guinea-pigs.

The effectiveness of three new antiarrhythmic drugs, aprindine, mexiletine and tocainide in elevating ventricular fibrillation threshold measured in the Langendorff-perfused rabbit heart and in protecting against ouabain-induced arrhythmias in the Langendorff-perfused guinea-pig heart has been compared with that of lignocaine. All these drugs have produced a significant rise in the threshold but quantitatively mexiletine was about equal to, tocainide five times less and aprindine thirty-eight times more potent than lignocaine in this effect. Aprindine differed from the other three drugs in that it had a slow onset of action and its effect was not entirely removed upon reperfusion with the drug-free solution. Only aprindine and mexiletine provided complete protection against ouabain-induced ventricular fibrillation while 3 of 6 and 4 of 6 hearts fibrillated in the presence of lignocaine or tocainide respectively.

Anilides↗
PubMed2004

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.

Anti-Arrhythmia Agents↗
PubMed1975

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.

Ajmaline↗
PubMed1996

Effects of aprindine on ischemia/reperfusion-induced cardiac contractile dysfunction of perfused rat heart.

The present study was undertaken to determine whether aprindine, a class Ib antiarrythymic agent, exerts beneficial effects on ischemia/reperfusion-induced cardiac contractile dysfunction and metabolic derangement. Isolated rat hearts were subjected to 35-min global ischemia, followed by 60-min reperfusion, and functional and metabolic alterations of the heart were determined with or without aprindine-treatment. Ischemia induced a cessation of left ventricular developed pressure (LVDP), a rise in left ventricular end-diastolic pressure (LVEDP), and an increase in myocardial sodium content and a decrease in myocardial potassium content. When the hearts were reperfused, little recovery of LVDP and sustained rise in LVEDP and perfusion pressure were observed. Ischemia/reperfusion resulted in a release of ATP metabolites and creatine kinase from perfused hearts, an increase in myocardial sodium and calcium contents, and a decrease in myocardial potassium and magnesium contents. Treatment of the perfused heart with either 10 or 30 microM aprindine for the last 3 min of pre-ischemia improved contractile recovery during reperfusion and suppressed changes in myocardial ion content during ischemia and reperfusion. Treatment with the agent also attenuated the release of ATP metabolites and creatine kinase from the heart. However, treatment with high concentrations of aprindine (70 and 100 microM) improved neither cardiac contractile dysfunction, myocardial ionic disturbance nor the release of ATP metabolites and creatine kinase during reperfusion. Two possible mechanisms for the cardioprotection by the agent have been suggested: suppression of transmembrane flux of substrates and enzymes, and prevention of accumulation of myocardial sodium during ischemia.

Animals↗
PubMed1987

Non-linear pharmacokinetics of aprindine hydrochloride in oral administration.

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

Administration, Oral↗
PubMedDate not supplied

Effects of aprindine and disopyramide on reperfusion-induced arrhythmias and cardiac function in isolated rat hearts.

The effects of aprindine and disopyramide on reperfusion-induced arrhythmias and cardiac function were investigated in the isolated perfused rat heart. Occlusion of the left anterior descending coronary artery for 15 min and subsequent reperfusion provoked ventricular tachycardia in 9 out of 10 hearts and ventricular fibrillation in 7 out of 10. Aprindine or disopyramide was infused 15 min prior to the coronary occlusion in concentrations of 0.1 and 5.4 micrograms/ml, which were comparable to therapeutic free plasma concentrations in patients. Aprindine significantly decreased the incidence of ventricular tachycardia and fibrillation, compared with control (2/10, p less than 0.01 and 1/10, p less than 0.05, respectively). Disopyramide depressed only the occurrence of ventricular tachycardia (3/10, p less than 0.05). Neither of the drugs induced changes in heart rate, left ventricular systolic pressure, coronary flow or PR intervals, but they significantly improved the recovery of the left ventricular systolic pressure within 15 min after reperfusion, at which time most of the hearts had restored sinus rhythm. It is concluded that, at clinically effective concentrations, aprindine and disopyramide inhibit reperfusion-induced arrhythmias without deteriorating cardiac function in the isolated rat heart.

Animals↗
PubMed1977

Effects of disopyramide and aprindine on arrhythmias after acute myocardial infarction.

The incidence of ventricular arrhythmias after myocardial infarction was compared in a double blind study of disopyramide (33 patients), aprindine (34 patients) and placebo (31 patients). Total ventricular arrhythmias were less frequent in the aprindine group than in the disopyramide group (P less than 0.05) or than in the combined disopyramide and placebo groups (P less than 0.05). The incidence of life-threatening arrhythmias and of ventricular arrhythmias in high risk patients was also reduced by aprindine compared to disopyramide (P less than 0.001) or placebo (P less than 0.001). It is concluded that aprindine is effective in reducing ventricular arrhythmias and that further investigations on its preventive use after the onset of myocardial infarction are justified.

Acute Disease↗
PubMed1985

Effect of aprindine, verapamil and nifedipine on ventricular fibrillation threshold in isolated rabbit hearts.

The effect of aprindine, verapamil and nifedipine on electrical stimulation threshold (EST) and ventricular fibrillation threshold (VFT) was studied in isolated rabbit hearts. Aprindine steeply raised EST and VFT in a dose-dependent manner. With the highest concentration of aprindine tested (0.56 mumol/l), protection against electrically-induced ventricular fibrillation was achieved in 4 out of 6 hearts after 60 min exposure to the drug. Perfusion with verapamil (0.1 and 0.2 mumol/l) and nifedipine (0.14 and 0.21 mumol/l) produced significant rise in both thresholds. When the hearts were perfused with higher concentration (0.3 mumol/l verapamil, 0.28 mumol/l nifedipine), EST and VFT did not continue to be increased in a dose-dependent manner but actually dropped below the control value in most hearts. These results suggest that the effect of aprindine on EST and VFT is different from that of verapamil and nifedipine and further indicate a limited effectiveness of these two slow channel blockers against ventricular fibrillation.

Animals↗
PubMed1983

Aprindine therapy for refractory ventricular tachycardia.

Aprindine hydrochloride has been extensively used in Europe for the management of ventricular and supraventricular arrhythmias. Success has been achieved even in those cases that have proven refractory to standard antiarrhythmic agents. In this report, we describe our experience with aprindine therapy in seven patients with ventricular tachycardia in whom standard antiarrhythmic agents had proven either ineffective or had caused intolerable side effects. Aprindine was effective in five cases, and it failed in two. Neurologic side effects, although common, were easily controlled with adjustment of the dose. Agranulocytosis, a rare but serious side effect, was encountered in one of our patients. Relevant literature on aprindine is reviewed.

Agranulocytosis↗
PubMed1980

[Effect of aprindine in patients with normal and pre-damaged impulse forming and excitation conducting system/First communication; Sinus node function (author's transl)].

In 18 patients the influence of aprindine on sinus node function has been evaluated. The criteria were heart rate in spontaneous rhythm, sinus node recovery time (SRT), and the warm-up period after atrial stimulation with frequencies between 90 and 140/min. After aprindine the spontaneous rate increased significantly, whereas SRT and the warm-up period were not affected significantly. The patients with sinu-atrial disease showed a shortening of the spontaneous cycle-length and a decrease in SRT after aprindine. The results are discussed regarding the electrophysiological characteristics of the sinus node (slow current, automaticity) and their changes produced by stimulation and aprindine.

Aprindine↗
PubMed1984

Dose-dependent pharmacokinetics of aprindine in healthy volunteers.

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

Adult↗
PubMed1979

Aprindine.

Aprindine is a long-acting antiarrhythmic agent, effective when administered orally or intravenously in the treatment of ventricular arrhythmias of varying etiologies. It may be especially useful in the treatment of the Wolff-Parkinson-White syndrome. To a lesser extent, it may be useful in the treatment of atrial arrhythmias. Side effects can be minimized by careful titration of the dose of aprindine. If the frequency of such serious side effects as cholestatic jaundice and agranulocytosis remains low enough, aprindine should prove to be a useful addition to currently available antiarrhythmic drugs.

Administration, Oral↗
PubMed1978

Prolongation of cardiac conduction times by intravenous aprindine in man.

The acute electrophysiologic effects of intravenous aprindine were evaluated in 48 patients to assess the effect on conduction times and refractoriness in patients with severe cardiac disease and arrhythmias. The patients had not responded to conventional antiarrhythmic medications or had been unable to tolerate effective doses of conventional medications because of side effects. Eleven patients had an abnormal H-V interval, 9 had prolonged QRS duration and 22 had evidence of severe left ventricular dysfunction. Aprindine prolonged conduction transiently in the atria, the atrioventricular (A-V) node, the His-Purkinje system and the ventricles. The refractory times of the atria, the A-V node and the ventricles increased insignificantly, both functionally and statistically. Atrioventricular block did not develop in any patient, and side effects were minor. Thus, aprindine can be safely administered intravenously (10 to 15 mg/min) to severely ill patients with arrhythmias that are refractory to other medications even in the presence of underlying conduction system and myocardial disease.

Adult↗
PubMed1982

Aprindine-induced polymorphous ventricular tachycardia.

Five cases of aprindine-induced polymorphous ventricular tachycardia (torsade de pointes) are presented. In four cases, polymorphous ventricular tachycardia appeared after the oral administration of 400 mg of aprindine. One patient had mild hypokalemia at the time of polymorphous ventricular tachycardia so that a direct cause and effect relation between the drug and the tachycardia cannot be established. All five patients manifested Q-T prolongation and recurrent syncope due to polymorphous ventricular tachycardia. In all five, polymorphous ventricular tachycardia subsided once administration of aprindine was discontinued.

Aged↗
PubMed2005

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

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

Animals↗
PubMed1976

Intracellular electrophysiological alterations in canine cardiac conducting tissue induced by aprindine and lignocaine.

The effects of aprindine and lignocaine (lidocaine USP) were compared on intracellularly recorded potentials from normal canine conducting tisues. Only aprindine produced marked depression of the maximum rate of rise (Vmax) of action potentials elicited at normal cycle lengths (1000 ms). Both compounds, however, produced enhanced depression of Vmax at short cycle lengths or at short S1-S2 coupling intervals at normal membrane resting potential. Both lignocaine and aprindine shorten the action potential duration (APD) and effective refractory period (ERP) but increase the EPR/APD ratio. These effects are easily reversible upon perfusion with drug-free solution only in the case of lignocaine.

Action Potentials↗
PubMed1984

Mechanism of aprindine induced agranulocytosis: direct toxicity on CFU-C and CFU-GEMM.

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.

Aged↗
PubMed1976

Suppression of ouabain-induced ventricular rhythms with aprindine HCl. A comparison with other antiarrhythmic agents.

Three groups of dogs were given ouabain (mean 60 mug/kg) until an accelerated ventricular escape (AVE) and repetitive ventricular response (RVR) followed cessation of pacing. In a group of six control dogs, the AVE and RVR were found to occur at stable escape intervals for periods of at least three hours. A second group of dogs received various antiarrhythmic agents in an attempt to suppress the AVE and RVR. Quinidine, diphenylhydration, lidocaine, procainamide, and propranolol, were successful in only 0 to 33% of trials. Potassium canrenoate, 12 mg/kg was unsuccessful in three dogs. Verapamil, by bolus, suppressed RVR in 41% and AVE in 21% of trials. KCl, infused until AVE and RVR were suppressed, was successful when the mean serum potassium rose from 3.8 mEq/L to 7.2 mEq/L. Aprindine, 2.86 mg/kg, suppressed AVE and RVR in 14 of 14 dogs. In the third group of dogs, verapamil was infused continuously and suppressed RVR and AVE at a mean cumulative dose of 2.93 mg/kg. Calcium chloride reversed aprindine and verapamil-induced suppression of RVR and AVE. This study demonstrates that RVR and AVE resist suppression by available antiarrhythmic agents in clinically-used doses. Only aprindine was 100% successful at doses used in man. The ionic pathogenesis of RVR and AVE is unknown, but some data suggest the slow current may play an important role.

Animals↗