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PubMed1986

Studies on the bradycardia induced by aprindine in rabbit sinoatrial node cells.

The effects of aprindine (1 X 10(-7) to 4 X 10(-6) M) were examined on membrane potential and current of rabbit sinoatrial node by means of conventional microelectrode and double microelectrode voltage clamp methods. Aprindine decreased, in a dose-dependent manner, the spontaneously firing frequency, the maximum rate of depolarization and the action potential amplitude, and prolonged the action potential duration at half-amplitude. The slope of the diastolic depolarization was also reduced by the drug. In the voltage clamp experiment, aprindine reduced the slow inward current (Isi), the time-dependent potassium current (Ik) and the hyperpolarization activated current (Ih). The recovery time constant of Isi was prolonged by aprindine, while the kinetics of Ik was not altered. It is indicated that aprindine does not have an effect on a specific conductance or a single current system, but that the drug exerts an inhibitory effect on the electrical activity of sinoatrial node.

Action Potentials↗
PubMed2004

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.

Aged↗
PubMed1975

Effects of aprindine HCL on cardiac tissues.

The effects of aprindine HCL on cardiac tissues were studied in anesthetized, open-chest dogs pretreated with atropine (0.8 mg/kg) and propranolol (1.0 mg/kg). Aprindine (10(-5)-10(-3) g/ml), injected into the sinus node artery, decreased the spontaneous sinus rate; when injected into the atrioventricular nodal artery, aprindine (10(-4) g/ml) prolonged the conduction time and functional refractory period of the atrioventricular node. Intravenous administration of aprindine (1.4, 2.8 and 4.2 mg/kg cumulative dose) prolonged atrial and ventricular conduction time and prolonged the effective refractory period of both tissues. The results from this study indicate that aprindine has a negative dromotropic effect on all cardiac tissue.

Animals↗
PubMedDate not supplied

Experimental study on the electrophysiological effects of the combination of the antiarrhythmic drugs aprindine and verapamil.

The acute electrophysiological effects of the antiarrhythmic drugs aprindine and verapamil, injected intravenously either alone or in combination, were studied in 14 dogs during invasive electrophysiology. The AH and HV intervals during sinus rhythm were significantly prolonged, especially in the aprindine and the aprindine plus verapamil groups. The cycle lengths of the antegrade and retrograde atrio-ventricular block were most prolonged in the combination group. The effective refractory period and the functional refractory period of the atrial tissue, as well as the functional refractory period of the atrio-ventricular node, the effective refractory period of ventricular tissue and the ventriculo-atrial conduction system were most prolonged when the combination of the agents was given. The effective refractory period of the atrio-ventricular node was prolonged in the groups receiving verapamil and verapamil plus aprindine. There was no significant difference in the serum concentration of each agent given alone or in combination. These results suggest that the efficacy of the combination of verapamil and aprindine may be due to additive or synergistic effects of these antiarrhythmic agents.

Animals↗
PubMed1990

[A case of aprindine-induced pneumonitis].

A 73-year-old man had been treated with Aprindine because of paroxysmal atrial fibrillation. On July 13, 1987, five months after the commencement of aprindine administration, he developed dyspnea and low grade fever. His chest X-ray revealed multiple infiltrative shadows in both lung fields. He was treated by various antibiotics, but the infiltrative shadows increased. BALF showed increased percentage of lymphocytes and a decrease in the OKT4/T8 ratio, and the histological findings of TBLB carried out on August 6, 1987, showed alveolitis with Masson bodies. The lymphocyte stimulation test by drugs was positive only for aprindine. After cessation of Aprindine administration, his complaints and laboratory data improved, but his abnormal shadow on chest X-ray did not diminish completely. Open lung biopsy was performed for differential diagnosis of BOOP, on Sep. 14, 1987. The histopathology of specimens of the lung was compatible with drug-induced pneumonitis. The administration of 30 mg of prednisolone was started on Oct. 14, 1987, and the dosage was decreased gradually. The abnormal shadow on chest X-ray improved. To our knowledge, there has been no reported case of Aprindine-induced pneumonitis, and this could be the first report.

Aged↗
PubMed1983

[Comparison of the anti-arrhythmic effects of propafenone and aprindine in the treatment of refractory chronic ventricular arrhythmias. A randomized double-blind crossover study controlled with placebo].

A placebo-controlled, randomized, double-blind, crossover study was performed in 14 patients with chronic, resistant, ventricular arrhythmias in order to evaluate the efficacy and safety of two new antiarrhythmic agents, propafenone and aprindine. After an initial placebo phase, patients received orally either propafenone (600 mg daily) or aprindine (150 mg daily for the first two days and 50 mg every 12 hours successively) for five days. This treatment was followed by a drug-free period (placebo II); patients were then crossed over to the alternative drug. A 24-hour Holter recording was performed during the last 48 hours of the initial placebo phase and on the final day of each phase of the crossover period. Analysis of Holter recordings revealed that the mean hourly PVCs frequency, for the group, was similar during the two control periods. Significant reduction in the mean hourly frequency of PVCs from control levels was observed in 78% of the patients during propafenone therapy and in 42% during aprindine therapy. For the whole group, propafenone induced a significant reduction of the average PVCs/h frequency (p less than 0.05), whereas the aprindine was ineffective. Finally no patient experienced side effects with propafenone, whereas aprindine caused side effects in three patients (dizziness, tremor, ataxy).

Adult↗
PubMed1981

Pharmacokinetic study of aprindine and moxaprindine in dogs.

Moxaprindine and aprindine were each administered to a group of six dogs at a single dose of 5.5 mg/kg by intravenous injection and at the same dose 14 days later by oral route. In each series the sequence of route of administration was randomized. In a second experiment, 8 to 12 weeks later, the dogs were treated for 5 successive days with the same drug at the dose of 5.5 mg/kg twice daily. Moxaprindine and aprindine are similar in several of their pharmacokinetic characteristics. Their plasma levels are suitably explained by a two-compartment open model. No significant differences are found between their respective terminal plasma half-lives nor their k12, k21 and kel values; on multiple dosing, the steady state is reached within 3 days with both drugs. However, the plasma levels of moxaprindine are twice as high as those of aprindine. Consequently the distribution volume of moxaprindine is half as small as that of aprindine. Moxaprindine is 95.3% protein bound at 1 microgram/ml and 93.6% at 2 microgram/ml; the corresponding values for aprindine are 98.3% and 98.1%. These differences may be of clinical significance as regards therapeutic effectiveness and safety of these two substances.

Administration, Oral↗
PubMed1980

[Effects of aprindine on the electromechanical coupling of the myocardium and smooth muscle].

The effect of aprindine on myocardial and smooth muscle preparations activity were studied. Aprindine exerts a marked inhibition of the rate and contractility of guinea pig isolated atria and counteracts the inotropic effect induced by calcium. On the isolated guinea-pig left atrium electrically driven, apridine was found to exert negative inotropic effect both at low and high rates of stimulation, without depressing the "post-stimulation" potentiation. In spontaneously active guinea-pig taenia coli aprindine induces stimulation and regularization of the mechanical and electrical activity; on the other hand, aprindine is able to inhibit the contraction induced by acetylcholine, and this inhibition is counteracted by increasing concentration of calcium. Aprindine exerts no influence on the electrical membrane resistence of the guinea-pig taenia coli.

Acetylcholine↗
PubMed1975

Absorption, half-life, and toxicity of oral aprindine in patients with acute myocardial infarction.

Plasma concentrations of aprindine were used to assess its absorption, toxicity and disappearance rate after oral administration to patients within 24 hours of admission to a coronary care unit. Despite high oral doses, absorption was so slow that in half the patients effective plasma levels (exceeding 0.70 mug/ml) were not found during the first 12 hours of treatment. Therefore the oral route should not be used to treat cases of acute myocardial infarction with severe ventricular dysrhythmias. Clinical tolerance was good; there was one episode of delirium tremens in a chronic alcoholic (aprindine plasma concentration: 3 mug/ml); no case of tremor or cerebellar syndrome was observed. Disappearance of aprindine from plasma was slow, by far exceeding the half-lives found in healthy volunteers, and ranging from 20 to over 100 h. The variability of biological half-life in individual patients makes plasma level determiniations necessary whenever aprindine is to be administered for a long period.

Administration, Oral↗
PubMed1980

Studies with aprindine.

Aprindine is a very effective antiarrhythmic agent with a narrow therapeutic-toxic ratio. It has been used successfully in treating patients who have both supraventricular and ventricular tachyarrhythmias. Aprindine slows conduction in all cardiac fibers and suppresses digitalis-induced after-depolarizations. Voltage-clamp studies indicate that aprindine, in higher doses, suppresses the slow inward current in frog atria. In the dog subjected to coronary artery occlusion, aprindine may be arrhythmogenic, antiarrhythmic, or have no effect on the development of arrhythmias, depending on the temporal relationship between time of administration and time of occlusion.

Agranulocytosis↗
PubMed1991

Effects of aprindine on monophasic action potentials.

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.

Action Potentials↗
PubMed1977

Development of a radioimmunoassay for aprindine.

We have developed a radioimmunoassay for aprindine, a new antiarrhythmic drug used in the treatment of ventricular disorders. The antibodies were produced by immunization of New-zealand rabbits with aprindine coupled to human serum albumin. Their biochemical characteristics have been determined. Tritiated aprindine was used as radioactive competitor. The cross-reactivity with several metabolites of aprindine was studied too. Finally, the results obtained by RIA in plasma and tissues of dogs were compared to those obtained by gas-chromatography.

Animals↗
PubMed1985

Torsade des pointes and aprindine.

Aprindine was given orally to an 88-year-old patient with atrial fibrillation and ventricular premature depolarizations. The premature beats disappeared and sinus rhythm was restored on the third day of treatment. While on aprindine the QT interval was prolonged and the U wave became very prominent. The aprindine was stopped but 36 hr following the last oral dose, ventricular arrhythmia appeared with the characters of torsade des pointes. Three such episodes occurred within 24 hr. It is suggested that aprindine both eliminated the premature depolarizations and rendered the myocardium vulnerable by prolonging the QT interval. On discontinuing the medicament the premature beats reappeared while the myocardium was still vulnerable, so that torsade des pointes resulted.

Aged↗
PubMed1992

Aprindine-induced hepatic granulomata.

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.

Aprindine↗
PubMed1985

The utility of aprindine blood levels in the management of ventricular arrhythmias.

Sixty-four patients with a history of ventricular tachycardia and ventricular fibrillation refractory to conventional therapy received aprindine to abolish recurrent episodes of symptomatic ventricular tachycardia. Fifty-six patients became asymptomatic and were followed up for a mean period of 23 months. Aprindine dose was adjusted to minimize adverse reactions but still control arrhythmia. Survival analysis was performed for the group with aprindine levels greater than 1.5 micrograms/ml and the group with levels of 1.5 micrograms/ml or less. At the end of the study, 65% of the patients with a high level were alive and asymptomatic as compared with only 35% of the patients with a low level (p less than 0.036). In patients at risk of recurrent sudden cardiac death, high aprindine levels maintained after abolition of symptomatic ventricular tachycardia were associated with improved survival.

Aprindine↗
PubMed1977

Cardiovascular and antiarrhythmic effects of aprindine (AC1802) during partial occlusion of a coronary artery in the pig.

The effect of intravenously administered aprindine (AC1802) as a prophylactic agent against ventricular arrhythmias was studied in pigs. During the first 30 min of ischaemia 5 of the 22 untreated animals died because of ventricular fibrillation against 1 of the 23 animals pretreated with aprindine (P=0.09). Ventricular tachycardias were observed in 10 untreated animals and in none of the aprindine group (P=0.0002). The incidence of other arrhythmias was significantly less in the aprindine group compared with the untreated group (P less than 0.02).

Animals↗
PubMed1993

Antiarrhythmic effects of combined application of class I antiarrhythmic drugs; addition of low-dose mexiletine-enhanced antiarrhythmic effects of disopyramide and aprindine in various-rate canine ventricular tachycardias.

We examined the possible beneficial effects of combined application of class I drugs using digitalis-induced and two-stage coronary ligation-induced canine ventricular arrhythmia models. Combination treatment with disopyramide (0.3 mg/kg/min for 10 min) and mexiletine (0.3 mg/kg/min for 5 min) enhanced the antiarrhythmic effect of a single treatment of disopyramide (0.3 mg/kg/min for 10 min). Combination treatment with aprindine (0.1 mg/kg/min for 10 min) and mexiletine (0.3 mg/kg/min for 5 min) enhanced antiarrhythmic effects of a single treatment of aprindine (0.1 mg/kg/min for 10 min) on digitalis and 24-h two-stage coronary ligation-induced arrhythmia models, but in the 48-h two-stage coronary ligation-induced arrhythmia model, a slow ventricular tachycardia (VT) model, addition of mexiletine to aprindine caused no enhancement of antiarrhythmic effects. The results support those of a previous electrophysiologic study of combination treatment with class I drugs in which disopyramide and mexiletine acted additively but aprindine and mexiletine did not act additively when the ventricular preparation was driven at slow rates. Total heart rate (HR) and mean blood pressure (MAP) were not influenced by additional application of mexiletine.

Animals↗
PubMed1985

Effects on rabbit cardiac potentials of aprindine and indecainide, a new antiarrhythmic agent, in normoxia and hypoxia.

Intracellular potentials were recorded from rabbit atria, cardiac Purkinje cells and papillary muscles before and after exposure to various concentrations of indecainide. The effects of aprindine also were studied in the atrial preparations. Both drugs depressed the maximum rate of depolarization (MRD) in a dose-related manner, indecainide being approximately ten times more potent than aprindine. Aprindine caused a dose-related bradycardia, but indecainide had no significant effect on sinus node frequency. Indecainide had a dose-related negatively inotropic effect in normal, half-normal and twice-normal extracellular calcium concentrations. Indecainide shortened action potential duration (APD) in atrium and Purkinje cells but prolonged APD to 50% repolarization in ventricular muscle. The actions of indecainide were extremely persistent. No significant recovery of MRD was observed after pauses in stimulation of up to 16 s. Indecainide had no effect on effective refractory period (ERP) measured by interpolated premature stimuli. Indecainide is therefore categorized as a Class 1c antiarrhythmic agent. The effects of both aprindine and indecainide on MRD were increased in hypoxic atria. Conduction velocity in hypoxic atria exposed to indecainide was greater than in controls, however, suggesting the possibility of improved cell-to-cell coupling.

Action Potentials↗