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European Journal of Clinical... Mar 1976The acetylation of procainamide and sulfadimidine has been measured simultaneously in plasma and urine in 20 healthy human volunteers by a specific G.L.C. method, after... (Comparative Study)
Comparative Study
The acetylation of procainamide and sulfadimidine has been measured simultaneously in plasma and urine in 20 healthy human volunteers by a specific G.L.C. method, after single and multiple oral dral doses of procainamide retard tablets. A distinct bimodality (9 rapid and 11 slow acetylators) was apparent from the concentrations of procainamide and N-acetylprocainamide both in urine and plasma, which was in complete agreement with data about sulfadimidine acetylation. The influence of acetylator phenotype on the relative concentrations of procainamide and N-acetylprocainamide in plasma as cn 5 additional healthy subjects after a single oral dose of procainamide. The present results show that acetylator phenotype can now be determined using procainamide as the test substance, and for this purpose multiple doses offer hardly any advantage over a single dose of the drug. However, because the separation between rapid and slow acetylators is less pronounced for procainamide than for sulfadimidine, precise criteria must be established for the conditions of the test, and the influence of diseases, such as renal insufficiency, should be taken into consideration.
Topics: Acetylation; Adult; Drug Administration Schedule; Female; Humans; Male; Phenotype; Procainamide; Sulfamethazine; Time Factors
PubMed: 971707
DOI: 10.1007/BF00606561 -
The Journal of Clinical Investigation Apr 1989An almost universal side effect of long-term therapy with procainamide is the appearance of serum autoantibodies and less frequently a syndrome resembling lupus...
An almost universal side effect of long-term therapy with procainamide is the appearance of serum autoantibodies and less frequently a syndrome resembling lupus erythematosus. Previous studies demonstrated that procainamide-hydroxylamine (PAHA), a metabolite generated by hepatic mixed function oxidases, was highly toxic to dividing cells, but evidence that PAHA could be formed in the circulation was lacking. This study examines the capacity of neutrophils to metabolize procainamide to reactive forms. Neutrophils activated with opsonized zymosan were cytotoxic only if procainamide was present, whereas N-acetyl procainamide, which does not induce autoimmunity, was inert in this bioassay. PAHA was detected by HPLC in the extracellular medium if ascorbic acid was present. Generation of PAHA and cytotoxic procainamide metabolites was inhibited by NaN3 and catalase but not by superoxide dismutase, indicating that H2O2 and myeloperoxidase were involved. Nonactivated neutrophils and neutrophils from patients with chronic granulomatous disease did not generate cytotoxic PAHA, demonstrating that H2O2 was derived from the respiratory burst accompanying neutrophil activation. These conclusions were supported by results of a cell-free system in which neutrophils were replaced by myeloperoxidase and H2O2 or an H2O2 generating system. These studies demonstrate the capacity of neutrophils to mediate metabolism of procainamide and establish the role of myeloperoxidase released during degranulation and H2O2 derived from the respiratory burst in the direct cooxidation of procainamide to PAHA. The profound biologic activity of this metabolite and its possible generation within lymphoid compartments implicate this process in the induction of autoimmunity by procainamide.
Topics: Adult; B-Lymphocytes; Biotransformation; Cell Line; Chromatography, High Pressure Liquid; Female; Humans; Hydrogen Peroxide; Hypochlorous Acid; Male; Neutrophils; Oxygen Consumption; Phagocytosis; Procainamide
PubMed: 2539397
DOI: 10.1172/JCI114020 -
Circulation Jul 1985We evaluated the efficacy of a single oral dose of procainamide to terminate paroxysmal tachycardia, when procainamide was taken shortly after onset of tachycardia, a...
We evaluated the efficacy of a single oral dose of procainamide to terminate paroxysmal tachycardia, when procainamide was taken shortly after onset of tachycardia, a regimen we have termed "periodic procainamide." In 12 patients (mean age 15 years) with non-life-threatening tachycardia (orthodromic reciprocating tachycardia, 8/12; ventricular tachycardia, 3/12; atrial flutter, 1/12) in whom intravenously administered procainamide (15 mg/kg at 1 mg/kg/min) terminated tachycardia, efficacy of a single oral dose of procainamide (25 mg/kg) to terminate tachycardia was tested during electrophysiologic study. After oral administration of procainamide, tachycardia was terminated and could not be reinitiated in 11 of 12 patients (9/12 less than 75 min, 2/12 greater than 120 min after administration). Time of tachycardia termination approximately coincided with the time of peak serum concentration of procainamide after the single oral dose. Delayed response or failure of procainamide to terminate tachycardia was associated with delayed and diminished peak serum procainamide concentration. After evaluation, 10 responders were instructed to take a single dose of procainamide when tachycardia occurred. During a mean follow-up of 9 months (range 2 to 17) seven of 10 patients had an opportunity to use periodic procainamide on one to more than 100 occasions; four of 10 patients have not had recurrence of tachycardia. Tachycardia was successfully terminated in six of seven patients using the periodic regimen and could not be terminated on the first out-of-hospital use in one of seven patients. Success of periodic procainamide was predicted during evaluation by rapid termination of tachycardia after oral administration.
Topics: Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Male; Metabolic Clearance Rate; Periodicity; Procainamide; Tachycardia, Paroxysmal
PubMed: 4006125
DOI: 10.1161/01.cir.72.1.147 -
Journal of Pharmaceutical Sciences Sep 1982The percent of procainamide complexed with dextrose was determined to be directly related to the concentration per mole fraction of dextrose in the solution. The...
The percent of procainamide complexed with dextrose was determined to be directly related to the concentration per mole fraction of dextrose in the solution. The complexation process was reversible and did not proceed at lower pH (approximately 1.5). The rate of formation of complex was dependent on the initial pH value of the solution and the pH decreased as the concentration of the complex increased. The increase in the concentration of procainamide did not change the equilibrium concentration of the complex. The addition of sodium chloride or edetate disodium did not alter the rate of formation of the complex or its equilibrium concentration. The addition of hydrochloric acid prevented the formation of the complex and on adding hydrochloric acid after the formation of the complex, procainamide was completely freed.
Topics: Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Glucose; Hydrogen-Ion Concentration; Procainamide
PubMed: 7131286
DOI: 10.1002/jps.2600710910 -
Clinical Pharmacokinetics 1984Routine clinical pharmacokinetic data collected from patients receiving procainamide were analysed to estimate population pharmacokinetic parameters. 116 plasma...
Routine clinical pharmacokinetic data collected from patients receiving procainamide were analysed to estimate population pharmacokinetic parameters. 116 plasma concentration determinations for procainamide and 14 timed urine collections for the drug and its major metabolite N-acetylprocainamide (NAPA) were obtained from 39 patients, mostly males. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. Estimates of the influence of weight, height, renal function, and the presence of congestive heart failure (CHF) on the renal clearance (CLR), acetylation clearance (CLA), miscellaneous metabolic clearance (CLO), and volume of distribution (Vd) of procainamide were obtained. The mean (SE) CLR, CLA, CLO and Vd for procainamide in a 70kg patient with normal renal function were estimated to be 14.4 (2.3) L/h, 10.1 (1.7) L/h, 1.2 (1.3) L/h, and 136.0 (20.0) L, respectively. These pharmacokinetic parameters vary linearly with bodyweight; height adds no information if weight is known. The presence of CHF has no significant effect on either CLO or Vd, but reduces CLA and CLR by 11% (p less than 0.01). Even after adjustments for CHF, renal function and weight, the total clearance and Vd of procainamide vary unpredictably among individuals, with a coefficient of variation between 30 and 40%, and less than 50%, respectively.
Topics: Arrhythmias, Cardiac; Female; Heart Failure; Humans; Kinetics; Male; Middle Aged; Models, Biological; Procainamide
PubMed: 6509861
DOI: 10.2165/00003088-198409060-00004 -
Kidney International Dec 1977Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of...
Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.
Topics: Adult; Female; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Nephrectomy; Procainamide; Time Factors
PubMed: 609192
DOI: 10.1038/ki.1977.133 -
Journal of Pharmaceutical Sciences Aug 1988We examined the effect of amiodarone on the disposition of procainamide in the rat to determine the mechanism of a reported interaction between amiodarone and...
We examined the effect of amiodarone on the disposition of procainamide in the rat to determine the mechanism of a reported interaction between amiodarone and procainamide and to determine the effect of amiodarone on drug acetylation. Animals received a 5-d pretreatment with amiodarone hydrochloride (100 mg/kg) or diluent prior to the intravenous administration of 50 mg/kg of procainamide hydrochloride. The plasma clearance, volume of distribution, and half-life of procainamide did not significantly differ between the two groups. The urinary recovery of N-acetylprocainamide was increased by 31% (p less than 0.01) in amiodarone pretreated animals. However, there was no change in the partial clearance of procainamide to N-acetylprocainamide. Neither the renal clearance of procainamide nor N-acetylprocainamide was altered by amiodarone pretreatment. These data suggest that amiodarone interacts with procainamide by reduction of an alternate pathway of elimination, possibly oxidative metabolism.
Topics: Administration, Oral; Amiodarone; Animals; Drug Interactions; Half-Life; Male; Procainamide; Rats; Rats, Inbred Strains
PubMed: 3210153
DOI: 10.1002/jps.2600770804 -
Clinical and Investigative Medicine.... 1979
Topics: Acetylation; Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Biological Availability; Female; Humans; Infusions, Parenteral; Kidney Failure, Chronic; Male; Middle Aged; Procainamide; Renal Dialysis; Tablets
PubMed: 509808
DOI: No ID Found -
Journal of Pharmaceutical and... 1990As a result of the implication of N-oxidized procainamide metabolites in drug-related lupus (DRL), the electrochemical behaviour of these compounds was investigated and...
As a result of the implication of N-oxidized procainamide metabolites in drug-related lupus (DRL), the electrochemical behaviour of these compounds was investigated and a coulometric synthesis of the nitroso derivative developed using a previously described carbon packed bed bulk electrolysis flow cell. The electrochemical characterization of the parent p-substituted aromatic amine and the N-oxidized derivatives was achieved through systematic comparison with previously well described aromatic amine and nitro systems using cyclic voltammetry and liquid chromatography with electrochemical detection (LC-EC). Chromatographically assisted hydrodynamic voltammetry indicated current limiting plateau potentials of 0.45 and -0.2 V versus Ag/AgCl, respectively, for synthetically prepared procainamide hydroxylamine and electrolytically prepared nitrosoprocainamide. Reaction characterization and binding behaviour is described for each of the procainamide metabolites following in vitro incubations with cysteine, glutathione, ascorbic acid and mouse haemoglobin.
Topics: Chromatography, High Pressure Liquid; Electrochemistry; Mass Spectrometry; Oxidation-Reduction; Procainamide
PubMed: 2094415
DOI: 10.1016/0731-7085(90)80021-g -
American Journal of Hospital Pharmacy Dec 1988The stability of procainamide hydrochloride in neutralized 5% dextrose injection was studied. Sixty-four admixtures were prepared by adding either 2 mL (for 0.4%...
The stability of procainamide hydrochloride in neutralized 5% dextrose injection was studied. Sixty-four admixtures were prepared by adding either 2 mL (for 0.4% admixtures) or 4 mL (for 0.8% admixtures) of procainamide hydrochloride to 250 mL of 5% dextrose injection in plastic containers. The pH of 32 of these admixtures (16 of each type) was adjusted to 7.5. These 32 admixtures represented the neutralized group, and the remaining 32 represented the control group. The admixtures were stored at either 23-25 degrees C (room temperature) or 5 degrees C (refrigeration) for 24 hours. Procainamide hydrochloride concentrations in each sample were determined by high-performance liquid chromatography immediately after the admixtures were prepared and at various intervals during storage. Procainamide concentrations decreased over time in 5% dextrose injection. The decrease was significantly less for admixtures in neutralized 5% dextrose injection, those stored under refrigeration, and those with an 0.8% concentration of drug. Decreases in procainamide hydrochloride concentrations in the control admixtures might have been caused by procainamide-dextrose complexation. Initial concentrations of procainamide hydrochloride in 5% dextrose injection can be adequately maintained over a 24-hour storage period by neutralizing the 5% dextrose injection or storing the admixture at 5 degrees C. However, because it is impractical to maintain the necessary temperature condition during a 24-hour infusion, neutralization might be the most viable alternative when extended stability of procainamide hydrochloride in 5% dextrose injection is required.
Topics: Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Drug Stability; Glucose; Injections; Procainamide; Temperature; Time Factors
PubMed: 3228104
DOI: No ID Found