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At least 145 records · Page 8Linked to original sources
PubMed1987

Interaction of steady-state procainamide with H2-receptor antagonists cimetidine and ranitidine.

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on steady-state procainamide pharmacokinetics. Six healthy men were given 500 mg sustained-release procainamide every 6 h, for a total of 13 doses, on three occasions. Subjects were randomly assigned to three treatments by a Latin-square design: cimetidine 1,200 mg/day, ranitidine 300 mg/day, and no H2-receptor antagonist (control) for 4 days. Cimetidine significantly increased the procainamide area under the serum concentration-time curve by 43%, decreased renal clearance by 36%, and decreased the ratio of systemic clearance of procainamide to bioavailability by 28%. Ranitidine did not significantly alter procainamide steady-state pharmacokinetics.

Acecainide↗
PubMed1993

Procainamide-induced myasthenia-like weakness and dysphagia.

A 64-year-old man with chronic renal insufficiency was hospitalized with dysphagia and inability to keep his head erect 11 months after beginning procainamide hydrochloride (PA) for control of atrial flutter. Evaluation revealed esophageal dysmotility, worsening renal function, and elevated serum PA and N-acetylprocainamide (NAPA) concentrations. No evidence of autoimmune myasthenia gravis was found. PA was discontinued and normalization of PA and NAPA concentrations was associated with a decrease in muscle weakness and resolution of dysphagia. The correlation between clinical findings and serum concentrations of PA and NAPA suggests that drug excess due to impaired clearance was the basis for this unusual adverse drug reaction.

Acecainide↗
PubMed1994

Comparison of three immunoassays for the determination of N-acetylprocainamide. Determination of false elevations by a polyclonal antibody-based method.

The performance of the ROCHE FP NAPA reagent, a newly reformulated monoclonal antibody-based fluorescence polarization immunoassay (FPIA) for N-acetylprocainamide, was compared with two commercially available polyclonal antibody-based immunoassays, the Abbott TDx and Syva EMIT. Although excellent correlation was observed between the ROCHE FP NAPA reagent and the Syva EMIT reagent, a positive bias was observed in the correlation between the ROCHE FP NAPA reagent and the Abbott TDx reagent. The bias in the TDx method was investigated further by the concurrent high-performance liquid chromatography (HPLC) analysis of patient samples. Insignificant differences (p < 0.05) were observed between the HPLC and ROCHE FP values. The TDx system, however, yielded significantly higher (p < 0.0005) results than did HPLC.

Acecainide↗
PubMed1996

Comparison of fluorescence polarization immunoassay with liquid chromatography for quantification of procainamide and N-acetylprocainamide in urine.

The objective of this study was to compare the precision and accuracy of fluorescence polarization immunoassay (FPIA) with high-performance liquid chromatography (HPLC) for measurement of procainamide (PA) and N-acetylprocainamide (NAPA) concentrations in urine. To determine the correlation between FPIA and HPLC, urine PA and NAPA concentrations were assayed using both techniques in samples obtained from study patients receiving PA and in spiked samples. In samples from patients, FPIA-determined PA and NAPA concentrations were 19 +/- 9% lower and 28 +/- 31% higher, respectively, than those determined by HPLC. The slope of the FPIA-HPLC regression lines for PA and NAPA differed significantly from that of the line of unity (the slope that would result if FPIA and HPLC yielded identical concentrations). In spiked samples, FPIA-determined PA and NAPA concentrations were 15 +/- 2% and 11 +/- 2% lower than HPLC-determined concentrations, respectively, and the slopes of the FPIA-HPLC regression lines differed significantly from the line of unity. Therefore, FPIA cannot be recommended as a urine assay method when quantitative assessment of urine PA or NAPA excretion is needed for pharmacokinetic studies.

Acecainide↗
PubMed1998

Effect of age, gender, and race on steady state procainamide pharmacokinetics after administration of procanbid sustained-release tablets.

Procainamide hydrochloride is a Class 1A antiarrhythmic agent administered intravenously or orally for treatment of symptomatic ventricular premature depolarizations (VPD), nonsustained ventricular tachycardia, and life-threatening ventricular arrhythmias. A new sustained-release formulation, Procanbid, which allows for twice-daily dosing was recently approved for marketing in the United States. This paper describes the population pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), the major metabolite, in healthy volunteers and patients with VPD by combining Cmax, tmax, Cmin, and AUC(0-12) values at steady state from six multiple-dose studies in which one 1000-mg or two 500-mg Procanbid tablets were administered. Means of parameters by race and gender were inspected for trends likely to be of clinical relevance. Procainamide and NAPA pharmacokinetic parameters observed after administration of Procanbid tablets were similar in blacks and whites, and in men and women. However, differences in body size should be considered when determining the Procanbid dose for women. Participant age had significant impact on NAPA pharmacokinetics in this study population and should be considered in dose selection. Age effects on procainamide were not detected in the study population, which was heavily weighted toward younger subjects, but are anticipated in the older population of patients for which procainamide is indicated. Procanbid formulation performance was not altered by patient demographics.

Acecainide↗
PubMed1979

Procainamide-induced lupus erythematosus-like syndrome in relation to acetylator phenotype and plasma levels of procainamide.

To investigate the relationship between acetylator phenotype and the development of procainamide (PA)-induced systemic lupus erythematosus (SLE-like syndrome, 28 patients with chronic ventricular arrhythmias treated with PA were followed for one year. The therapy was guided by plasma monitoring in all patients in order to obtain the proposed therapeutic plasma level of PA. Nine patients (30%), both slow and rapid acetylators, developed the SLE-like syndrome within one year. PA plasma levels were similar in both slow and rapid acetylators and there was no difference in total dose or duration of therapy before development of the syndrome. Thus, the acetylator phenotype is probably of no or minor predictive importance when PA therapy is guided by plasma monitoring. On the other hand, the antinuclear antibodies appeared significantly more rapidly in patients developing the syndrome and could possible be used as an indicator of the risk. The results support the hypothesis that the primary amino group structure of PA may be of importance in the induction of the SLE-like syndrome.

Acecainide↗
PubMed1981

Classification of cardioactive drugs in vivo by using programmed electrical stimulation in combination with monophasic action potential recordings at different pacing rates.

The effect of antiarrhythmic drugs on myocardial refractoriness may be due to changes either in Vmax of phase 0 or the phase of repolarization of the AP or both. By using programmed electrical stimulation in combination with MAP recordings at different pacing rates in the intact dog heart, it was possible to classify and to a certain extent to elucidate the mode of action of various cardioactive drugs in vivo.

Acebutolol↗
PubMed1994

The pharmacokinetics and pharmacodynamics of procainamide in horses after intravenous administration.

Six horses were administered either 15 or 20 mg/kg body weight (b.w.) procainamide (PA) as an intravenous (i.v.) dose over 10 min. The plasma concentrations of PA and N-acetylprocainamide (NAPA) as well as the pharmacodynamic effect (prolongation of the QT interval) were monitored. The PA plasma concentrations could be described by a one-compartment model with a t1/2 of 3.49 +/- 0.61 h. The total body clearance of PA was 0.395 +/- 0.090 l/hr/kg and the volume of distribution was 1.93 +/- 0.27 l/kg. As observed after PA administration, NAPA (an active metabolite) had a t1/2 longer than PA of 6.31 +/- 1.49 h. Peak NAPA concentrations (1.91 +/- 0.51 micrograms/ml) occurred at 5.2 h after the PA i.v. dose. The ratio of area under the curves for NAPA to PA was 0.46 +/- 0.15 which is similar to that expected in humans classified as slow acetylators. Percentage change in the QT interval was examined with respect to PA and PA + NAPA plasma concentrations. For PA, % delta QT = 41.2 log (PA) - 13.26 and correlations (r) ranged from 0.77 to 0.91 among the horses. In the case of PA+ NAPA, % delta QT = 57.3 log (PA + NAPA) - 31.83 and ranged from 0.77 to 0.90. No evidence of toxicity was noted with respect to changes in the PR interval.

Acecainide↗
PubMed1982

The electropharmacology of acute drug testing using pacemakers.

Acute drug testing in patients is useful to select prophylactic treatment for life-threatening or intractable tachycardias. This is generally done by induction of tachycardias with pacing. Acute studies that depend on temporary insertion of pacing electrodes do not determine efficacy in the same sense as longer term clinical drug trials because of the biased population referred for testing with pacemakers. However, the pharmacologic activity of compounds can be tested in terms of electrical functions such as conductivity and refractoriness not merely of the heart in general, but also of the arrhythmogenic focus. Such data can be directly applied to patients with similar arrhythmias, obviating the confusion often caused by interspecies and disease differences.

Acecainide↗
PubMed1985

Torsades de pointes due to n-acetylprocainamide.

A 66-year-old female with chronic renal failure received five doses of procainamide and developed marked QT interval prolongation and recurrent episodes of torsades de pointes, which were temporally related to high serum n-acetylprocainamide (NAPA) levels and not to procainamide levels. Repeated hemodialysis was effective in lowering NAPA levels. Torsades de pointes is a potential hazard of NAPA accumulation during procainamide administration to patients with renal insufficiency.

Acecainide↗
PubMed1984

Procainamide: clinical pharmacology and efficacy against ventricular arrhythmias.

Procainamide (PA) has been a mainstay of treatment against acute and chronic supraventricular and ventricular arrhythmias for more than 30 years. PA's clinical pharmacology has been studied extensively and its bioavailability (75-95%); volume of distribution (1.5-2.5 liters per kg), plasma protein-binding (15-25%), half-time for elimination (3-7 hours), and metabolism are known. PA's efficacy against acute ventricular arrhythmias and chronic stable VPDs is associated with plasma drug concentrations of 4 to 10 micrograms per ml; but much higher plasma concentrations may be required against sustained ventricular arrhythmias. From 30 to 60% of a PA dose is excreted as the metabolite, N-acetylprocainamide (NAPA), and PA's metabolism is determined genetically (fast or slow acetylation phenotype). Studies in patients with VPDs indicate that NAPA is also antiarrhythmic, although the contribution of NAPA to the antiarrhythmic effect after PA is not known. Studies in patients with the systemic lupus-like syndrome from PA show that NAPA is not associated with this. Investigations comparing efficacy and adverse effects of PA with those of new antiarrhythmic agents available for clinical trials are indicated in the future.

Acecainide↗
PubMed1985

Circadian changes in procainamide and N-acetylprocainamide kinetics in the rat.

The aim of this study was to investigate the possible influence of the time of administration on procainamide and N-acetylprocainamide (NAPA) kinetics in the rat. A single 50 mg kg-1 i.p. dose of procainamide was given to Wistar AF SPF adult male rats maintained under controlled environmental conditions (LD: 06.00h-18.00h) at four different fixed times i.e. 10.00, 16.00, 22.00 and 04.00h. Procainamide and NAPA plasma levels were determined by an immunoenzymatic method. Our data showed significant 24 h variation of the following pharmacokinetic parameters: highest elimination half-lives at 10.00h (t1/2 beta = 0.736 +/- 0.020h) for procainamide and at 04.00h (t1/2 beta = 3.55 +/- 0.08h) for NAPA (P less than 0.001); highest apparent volume of distribution at 04.00h for procainamide (Vd = 2.35 +/- 0.17 litre) (P less than 0.05); highest ratio AUC NAPA/AUC procainamide at 04.00h (1.039 +/- 0.056) (P less than 0.001). Procainamide clearance and Cmax and AUC for procainamide and NAPA were not significantly dependent on time of day. These data indicate a 24 h variation in the metabolism of procainamide which is converted to NAPA, the N-acetylation being greatest at 04.00h.

Acecainide↗
PubMed1986

Effect of acute renal failure on the disposition and elimination of [3H]N-acetyl procainamide ethobromide in the rat.

The effect of glycerol-induced acute renal failure (ARF) on the disposition and elimination of the organic cation [3H]N-acetyl procainamide ethobromide (APAEB) was investigated in the rat. In rats with ARF the plasma clearance, rate constant for the terminal portion of the plasma concentration-time curve and apparent volume of distribution were all decreased (P less than 0.01). Furthermore, the renal clearance of APAEB and the percentage dose excreted in urine were reduced by 85 and 74%, respectively. Decreased renal excretion probably accounted for the altered kinetics of APAEB in ARF because ligation of the renal pedicles of control rats produced changes in the kinetics of APAEB that were similar to those seen in animals with ARF. No change in either the hepatic content of APAEB or its biliary excretion were detected in rats with ARF. Similarly, the hepatic handling of ouabain and taurocholic acid was previously found to be unaltered in ARF; but by contrast, the hepatic uptake and initial biliary excretion of bromosulphophthalein and indocyanine green were decreased (Bowmer & Yates 1984, Br. J. Pharmacol. 83: 773-782). Together these studies indicate that there is a selective impairment of hepato-biliary transport in ARF.

Acecainide↗
PubMed1987

Mandibular and parotid salivary excretion of procainamide and N-acetylprocainamide after intravenous administration of procainamide to rats.

Flow rate, protein level and pH of mandibular and parotid saliva samples in rats were almost stabilized 2 h after induction of salivation with pilocarpine (9.0 mg h-1 kg-1). Salivary excretion profiles of procainamide, 50 mg kg-1 i.v., and its metabolite N-acetylprocainamide (NAPA) were then investigated. Plasma and salivary procainamide levels declined bi-exponentially with time almost in parallel. Salivary procainamide levels (Y) from both types of gland were correlated with the plasma level (X) over a wide concentration range [Y = 0.108X + 1.96 (r = 0.795) for mandibular and Y = 0.917X (r = 0.974) for parotid glands]. The mean saliva to plasma concentration ratio (S/P ratio) was significantly higher in parotid (0.974 +/- 0.243) than in mandibular (0.284 +/- 0.119) saliva samples. Similar correlations and S/P ratios were observed for NAPA. Procainamide and NAPA mean S/P ratios for saliva from both glands were fairly consistent with the calculated value according to the pH-partition hypothesis.

Acecainide↗
PubMed1989

Rapid assessment of rate and antiarrhythmic drug effect on the myocardium using asymmetric biphasic pulse stimulation.

An asymmetric biphasic pulse which stimulates the heart and neutralizes the poststimulation polarization at the electrode-myocardial interface permitting the recording of the evoked endocardial response (EER) up to approximately 1 ms poststimulation with the same electrode used for stimulation is described. Using this mode of cardiac stimulation in 20 dogs the effects on the EER of increasing heart rate and antiarrhythmic drugs, procainamide (PA) and N-acetylprocainamide (NAPA), were studied. EERs were recorded during bipolar and unipolar pacing rates of 120, 150, and 200/min before and during a five step PA or NAPA infusion which resulted in progressively increasing PA and NAPA plasma concentrations (Cps), 1.7-32.5 mg/l for PA and 8.1-116.1 mg/l for NAPA. The effects of progressively increasing heart rates were: The T wave amplitude and QS area increased with increases in rate; during pacing at 120, 150, and 200/min, the T wave amplitudes were 7.6 +/- 2.3, 8.2 +/- 2.1, and 9.8 +/- 2.5 mV and the QS areas were 905 +/- 204, 995 +/- 199, and 1101 +/- 231 mVms. The QT interval and QST area decreased with increases in rate; during pacing at 120, 150, and 200/min, the QT intervals were 265 +/- 61, 249 +/- 57, and 226 +/- 52 ms and the QST areas were 288 +/- 198, 221 +/- 154, and 154 +/- 52 mVms. The effects of the antiarrhythmic drugs, PA and NAPA, on the EER were: PA prolonged both the QS duration and QT interval at low Cp (type Ia antiarrhythmic drug property); at a therapeutic PA Cp of 15.0 +/- 0.2 mg/l and a heart rate of 120/min the percent increase of the QS duration was 12 +/- 4% (P = 0.001) and that of the QT interval was 20 +/- 6% (P less than 0.001). The prolongation of the QS duration by PA was rate dependent, the faster the rate the greater the prolongation. NAPA prolonged the QT interval at low Cp, while the QS duration was not significantly effected at low or therapeutic Cps (type III antiarrhythmic drug property); at a therapeutic NAPA Cp of 15.9 +/- 1.6 mg/l and a heart rate of 120/min the percent increase of the QS duration was 1 +/- 1% (NS) and that of the QT interval was 13 +/- 9% (P = 0.018). Our results show that the use of an asymmetric biphasic pulse allows for pacing and recording of an EER, QS and T waves, with a single electrode.(ABSTRACT TRUNCATED AT 400 WORDS)

Acecainide↗
PubMed2005

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma.

Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.

Acecainide↗
PubMed2005

Levofloxacin and ciprofloxacin decrease procainamide and N-acetylprocainamide renal clearances.

Ten healthy adults participated in a randomized, crossover drug interaction study testing procainamide only, procainamide plus levofloxacin, and procainamide plus ciprofloxacin. During levofloxacin therapy, most procainamide and N-acetylprocainamide (NAPA) pharmacokinetic parameters, including decreased renal clearances and renal clearance/creatinine clearance ratios, changed (P < 0.05). During ciprofloxacin treatment, only procainamide and NAPA renal clearances decreased significantly.

Acecainide↗