Relationship between serum aprindine concentration and neurologic side effects in Japanese.

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 was <1 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 were >1 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.

Chronic administration of aprindine during maintenance hemodialysis.

Aprindine was administered for 12 months to 8 hemodialysis patients suffering from arrhythmias. The serum aprindine concentration ranged from 0.3 to 0.6 microgram/ml, and did not increase with time during the 1-year treatment period. The PQ interval was temporarily prolonged in the first and second months, but the QRS and QT intervals were not changed by chronic aprindine treatment. The changes of the PQ interval in the second month of treatment were directly correlated with the serum aprindine concentration. No alterations of the ECG findings were observed when aprindine was discontinued. The cardiothoracic ratio (chest radiography) and laboratory findings were also not influenced by either aprindine treatment or its withdrawal. In conclusion, aprindine may be safely administered for at least 1 year to arrhythmia patients on maintenance hemodialysis.

Determination of aprindine in human plasma using reversed phase HPLC.

A rapid, simple, accurate method is presented for the determination of aprindine in human plasma. Liquid-liquid extraction of aprindine was carried out using diethyl ether. Amiodarone was applied as an internal standard. The samples were chromatographed on LiChrosorb RP-18 (10 microns) column and the mobile phase was methanol/acetonitrile/phosphate buffer pH 2.5 (80:15:5). The detection was carried at 254 nm. The method was tested for linearity (range from 0.5 to 2.5 micrograms/ml), recovery (ca. 90%) and precision (CV = 3.7%).

Determination of amiodarone in tablets and plasma by high-performance liquid chromatography.

A method is described for measuring amiodarone in human plasma and tablets using a LiChrosorb RP-18 column, a mobile phase methanol-acetonitrile-phosphate buffer pH 2.6 (80:15:5, v/v) and UV detection at 254 nm. Another antiarrhythmic drug - aprindine was used as an internal standard (i.s.).

Chromatographic analysis (TLC) aprindine and nadoxolol in human plasma.

Aprindine and nadoxolol extracted from plasma were separated by TLC method on silica gel by ascending technique on 5 x 20 cm and 2.5 x 7.5 cm microscopic slides and also by horizontal development, using suitable mobile phases. The substances were identified by reaction with Kiefer reagent (up to the amount 100 ng of aprindine and 300 ng of nadoxolol).

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.

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.

Combination therapy with aprindine and verapamil for paroxysmal supraventricular tachycardia as assessed by transesophageal atrial pacing.

UNLABELLED: 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).

[Effects of intravenous aprindine on hemodynamics in patients with cardiac dysfunction and its pharmacodynamics in patients with premature ventricular contractions].

The effects of aprindine, 100 mg iv, on hemodynamics, and the relationship between its inhibitory effect on PVC and its levels in the blood were determined in patients with diminished cardiac function. PVC was inhibited in 7 of 13 patients (54%), compared with a 50% inhibition rate in controls. The levels of aprindine in the blood after intravenous administration, rapidly decreased from 1.78 +/- 1.09 micrograms/ml immediately after administration, to 0.80 +/- 0.25 micrograms/ml after 15 min, to 0.65 +/- 0.23 micrograms/ml after 30 min and to 0.56 +/- 0.19 micrograms/ml after 1 hour. The duration of blood levels of 0.55 +/- 0.35 micrograms/ml, which are the levels presumed to be effective, was one hour after administration. The mean elimination half-life of aprindine was 18.9 +/- 8.4 hours. Aprindine produced relatively little effect on hemodynamics in patients with moderate to severe heart failure, but when its effects in individual cases were studied, it was found that aprindine elicited such changes as reduction in cardiac index, stroke volume index and stroke work index, and elevation in pulmonary arterial diastolic pressure. These findings suggest that care should be exercised in aprindine therapy in patients with diminished cardiac function. At least there should be monitoring of blood pressure and heart rate at appropriate times after intravenous administration.

[Clinical effects and plasma concentration levels of aprindine hydrochloride in patients with tachyarrhythmias].

Aprindine hydrochloride (aprindine) was administered orally in 17 Japanese patients with supraventricular or ventricular tachyarrhythmias, and the clinical effects and plasma concentration levels were evaluated. The antiarrhythmic effects were defined using Holter ECG recordings. Aprindine was administered orally with a daily dose of 40 mg for 2 weeks in all cases, and aprindine, 60 mg daily, was administered for the next 2 weeks in patients who did not show sufficient antiarrhythmic effects with 40 mg of the drug. Aprindine was effective in 9 of 17 patients, and the mean plasma concentration level reached 0.6 micrograms/ml 2 weeks after the administration was started. Effective results were seen in 2 of the 4 patients receiving a daily dose of 60 mg, and the mean plasma concentration level reached 1.0 microgram/ml 2 weeks after the administration was started. Transient mild elevations of liver transaminases were observed in one patient and mild transient anemia was observed in another. These abnormal data disappeared although the drug administration was continued. In conclusion, the administration of a relatively small dose of aprindine and, consequently, low plasma concentration levels, are effective for cardiac tachyarrhythmias in Japanese patients.

Rapid and sensitive determination of aprindine in serum by gas chromatography using a surface ionization detector.

A rapid and highly sensitive method for the determination in serum of aprindine, an antiarrhythmic drug, was developed employing gas chromatography with a surface ionization detector. No interfering peak from endogenous substances appeared when an organic phase was directly injected into the system after single extraction from a serum sample. A standard curve obtained was linear up to the serum level of 6 micrograms/ml, and the limit of sensitivity was 16 pg. The method described is applicable to routine therapeutic monitoring of serum concentrations of aprindine.

Therapeutic effectiveness and plasma levels of single or combination use of class I antiarrhythmic agents for ventricular arrhythmias.

The efficacy of disopyramide (DP), mexiletine (MX), aprindine (AP) and cibenzoline (CZ) on ventricular arrhythmias was compared (single drug therapy). In addition, the efficacy of the combination therapy of DP with MX was also studied (combination therapy). One hundred of the 106 patients completed the protocol of the single drug therapy. Fifty percent or more reduction in the frequency of ventricular premature contractions (VPCs) was obtained in 24 of 43 patients (56%) with DP, in 24 of 44 (55%) with MX, in 18 of 29 (62%) with AP and 10 of 18 (56%) with CZ. AP was comparatively more effective than the other drugs tested. DP was significantly effective on VPCs with organic heart disease as compared to idiopathic VPCs (p less than 0.05), while the other 3 drugs did not have such a tendency. With MX therapy, 10 of the 12 patients with fast VT rate (greater than or equal to 150 beats/min) showed a significant effect while only 4 of the 12 patients with non-fast VT rate (greater than or equal to 100 and 150 beats/min) had a significant one (p less than 0.05). On the other hand, DP, AP and CZ showed almost the same efficacy at any cycle length of VT. Six patients withdrew from the study, 4 because of digestive troubles with MX therapy, 1 because of micturition disturbances with DP and 1 because of skin rash with AP. The average therapeutic plasma levels of DP, MX, AP and CZ were 1.76 +/- 0.54 microgram/ml, 1.08 +/- 0.41 microgram/ml, 0.85 +/- 0.43 microgram/ml and 268.2 +/- 123.3 ng/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Effective plasma concentrations of aprindine in canine ventricular arrhythmias.

Antiarrhythmic effects of aprindine were examined using three canine ventricular arrhythmia models (induced by digitalis, adrenaline, and two-stage coronary ligation), and the minimum effective plasma concentration of aprindine was determined for each arrhythmia model. Aprindine suppressed all three arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, and 24-h and 48-h coronary ligation were 0.8 +/- 0.4, 1.0 +/- 0.4, 1.6 +/- 0.3, and 3.1 +/- 0.5 micrograms/ml, respectively (mean +/- SD, n = 6-7). The minimum effective plasma concentrations of aprindine for digitalis- and adrenaline-induced arrhythmias were significantly lower than those for coronary ligation-induced arrhythmias. Oral aprindine was also effective in suppressing both the 24- and 48-h coronary ligation-induced arrhythmias. Aprindine had a hypotensive effect when it was given intravenously, but this effect was not observed when it was given orally. The correlations between the aprindine plasma concentrations and the antiarrhythmic effects were not very strong and indicated individual variations in sensitivity to aprindine.

[Detection of aprindine and its metabolites in plasma and urine]. / Nachweis von Aprindin und seinen Metaboliten in Plasma und Urin.

In 36 patients with cardiac arrhythmias (predominantly ventricular premature beats), who were on oral aprindine long-term therapy with 50 to 400 mg daily, plasma levels were measured by gas chromatography after 3.5 hours of the last administration. There was a general dependency of plasma levels on the given dose, however, with considerable overlapping in individual values. In 24 patients the arrhythmias ceased, in six patients there was a clear, in two a moderate improvement. There was no clear therapeutic effect in four patients who were treated with a daily dose of 50 and 100 mg, respectively. Among the 36 patients, three who had plasma levels exceeding 2 micrograms/ml developed tremor and dizziness. After dose-reduction these side effects disappeared. The present results suggest that therapeutic plasma levels of aprindine are in the range of 1.0 to 1.75 micrograms/ml. A plasma level of 2 micrograms/ml should not be exceeded because of the possibility of side-effects. In six healthy males time-concentration curves of aprindine and its metabolites in plasma and urine were measured by gas chromatography. From the results a two-compartment model may be applied, the half-life of elimination was calculated to be 37 hours (plasma) and 31 hours (urine). With respect to the metabolites, in plasma only des-ethyl-aprindine (DEAP), in urine DEAP, hydroxy-, des-phenyl- and des-indanyl-aprindine could be found. Unlike aprindine, the DEAP-concentration curve in plasma showed a very slight decrease until the end of the 96-hour period of determination.