Pharmacokinetics of n-propyl-ajmaline-bitartrate in elderly patients with ventricular ectopic activity.

11 patients (9m, 2f, median age 59 years) with ventricular ectopic activity of at least Lown grade III received 20 mg N-Propyl-ajmaline-bitartrate (N-PAB) p.o. Plasma concentrations of N-PAB were determined with HPLC from blood samples within 26 hours after administration. An open two-compartment model was used. In 8 patients with normal function of the liver and the kidneys, the median clearance of N-PAB was 6.86 ml/min/kg and the median volume of distribution was 1.56 l/kg. Two patients had a clearly diminished clearance of 1.58 ml/min/kg without obvious impairment of liver or renal function. One patient with chronic glomerulonephritis (plasma creatinine 3.4 mg/dl) had a N-PAB clearance of 2.79 ml/min/kg. None of the Spearman rank correlation coefficients between the pharmacokinetic parameters of N-PAB with age, plasma albumin/globulin-quotient, plasma creatinine and cholin-esterase were significant. All calculated parameters were in the range determined in young subjects. It is concluded that physiological changes with age do not lead to significant changes of the pharmacokinetics of N-PAB. On the other hand in patients with increased levels of plasma creatinine a diminished clearance of N-PAB can be expected. It is also possible that patients without an obvious impairment of liver or renal function may have diminished N-PAB clearance.

[Dose-effect relation of N-prajmalium bitartrate with control of plasma levels]. / Dosis-Wirkungs-Beziehung von N-Prajmaliumbitartrat unter Plasmaspiegelkontrolle.

15 patients with ventricular ectopic beats classified to at least Lown class III with more than 100 ventricular ectopic beats in one hour were treated with N-prajmalium bitartrate (NPAB) in increasing dosages. The first dosage of 4 X 5 mg/d has been increased by 5 mg in three steps of three days to a level of 4 X 20 mg/d. A resting ECG, the systolic time intervals and a 24 h ECG were registered before treatment and after every dose. The median PQ time increased from 170 msec to 200 msec, the increase becoming significant (p less than 0.05) with a dose of 4 X 5 mg/d NPAB and above. Frequency, QRS and the frequency-corrected QT time did not change significantly. At a dose of 4 X 10 mg/d NPAB the increase of the quotient pre-ejection period to ejection time PEP/LVET became significant, increasing continuously from 0.35 to 0.48. Six of the 15 patients showed a significant reduction of ventricular ectopic beats, couplets and salvoes. In two patients the antiarrhythmic effect was significant at 4 X 5 mg/d. With an increasing dose from 4 X 10 mg/d each responder showed a significant reduction of ventricular ectopy. The lowest effective plasma concentrations ranged from 15 to 213 ng/ml with a median value of 58 ng/ml and an upper quartile of 94 ng/ml. There was no significant difference in plasma concentrations between responders and non-responders.

Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation.

In order to determine whether the metabolism of the antiarrhythmic drug N-propylajmaline is under the same genetic control as sparteine metabolism, the pharmacokinetics of this antiarrhythmic drug were studied in a groups of six extensive and four poor metabolizers of sparteine. Pronounced differences in terminal half-life, total plasma clearance, metabolic clearance and urinary excretion of N-propylajmaline were observed between extensive and poor metabolizers. A close relationship between the total clearance and metabolic clearance of N-propylajmaline and sparteine could be demonstrated. Clinically available N-propylajmaline is a 55% to 45% mixture of the i- and n-diastereomers. The extensive metabolizers exhibited stereoselective metabolism; the i-diastereomer was preferentially metabolized. Poor metabolizers were characterized by a loss of this stereoselective metabolism. Five subjects were treated for 7 days with a daily N-propylajmaline dosage of either 60 mg or 20 mg. Since a close relationship between the clearance of N-propylajmaline and the metabolic ratio of sparteine had been observed after single dosing the metabolic ratio of sparteine was used to predict N-propylajmaline steady-state plasma concentrations during multiple dosing. Only in two extensive metabolizers with a metabolic ratio less than 0.4 predicted and observed, steady-state plasma concentrations were in good agreement. In the other three subjects observed steady-state plasma concentrations were appreciably higher than predicted. In these three subjects metabolic N-propylajmaline clearance decreased indicating saturation N-propylajmaline metabolism during multiple dosing. The data indicate that N-propylajmaline metabolism is subject to a genetic polymorphism controlled by the sparteine/debrisoquine gene locus.

Effects of oral prajmaline bitartrate on exercise test responses in patients with coronary artery disease.

The safety, tolerability and haemodynamic effects of oral prajmaline bitartrate were assessed in a double-blind, randomized, placebo-controlled, crossover trial in 21 patients with stable angina pectoris and coronary artery disease. No serious side-effects occurred. Prajmaline bitartrate produced no statistically significant changes in resting heart rate or systolic blood pressure or in work capacity on the treadmill, or in heart rate or systolic blood pressure at maximum exercise compared to placebo values. No new arrhythmias or conduction abnormalities were produced in any patient. We conclude that oral prajmaline bitartrate is well tolerated and can be given safely to patients with coronary artery disease without producing deleterious haemodynamic effects or changes in exercise capacity.

[Pharmacokinetics and biotransformation of N-propylajmaline hydrogen tartrate in man]. / Pharmakokinetik und Biotransformation von N-Propyl-ajmalin-hydrogentartrat beim Menschen.

10 and 20 mg of N-Propyl-ajmalin-hydrogentartrate (N-PAB, Neo-Gilurytmal) were administered i.v. and orally respectively to healthy volunteers. In the study 14C-labelled N-PAB was used. The pharmacokinetics and the metabolic behaviour was examined. A fast and complete absorption of the compound could be observed. The bioavailability was 78%. The terminal plasma elimination half-life (beta-phase) was in the range of 4 to 6 hours. A total of 33% of the administered radioactivity was excreted via the kidney. 35 to 48% of the radioactivity found in urine was unchanged N-PAB. The excretion-kinetics of the three main metabolites as well as of the parent compound were determined. The possible presence of non-metabolizers is suggested.