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An elderly man with procainamide hydrochloride-induced lupus syndrome had a circulating anticoagulant against factor XI and a biologic false-positive (BFP) test result for syphilis. This was not associated with hemorrhagic problems. The activity of the circulating anticoagulant and the BFP disappeared within days following discontinuation of procainamide and the administration of corticosteroids.
A time-frequency coherence estimator is developed and applied to study changes in signal characteristics as atrial fibrillation converts to sinus rhythm during administration of procainamide. A coherence spectrogram (CS) using multiple sinusoidal tapers is used in this study to assess phase relations between electrogram recordings at multiple atrial sites of seven patients who received procainamide to terminate atrial fibrillation. CSs are calculated (0 to 60 Hz) with 1 sec time resolution and 6.2 Hz frequency resolution. In agreement with previous studies, CSs generally exhibit low coherence during atrial fibrillation. Conversion to sinus rhythm is concomitant with an increase in coherence and emergence of structured time-frequency topography. Transition from atrial fibrillation to sinus rhythm is associated with a variety of time-frequency dynamics. Both gradual and abrupt increases in coherence coincide with conversion. Results suggest transient electrical organization in the atria during atrial fibrillation not seen in previous low-resolution coherence studies. CSs permit investigation of rhythm organization with unparalleled time and frequency resolution and thus are useful for studying transient changes in cardiac rhythms that may reflect underlying mechanisms.
The USP analysis for procainamide-HCl is titrimetric and relatively nonspecific, capsule and tablet dyes may interfere, and the method is not applicable to coated tablets. In the spectrophotofluorometric method the sample deteriorates when exposed to a xenon source. In the ultraviolet spectrophotometric method reported here, the sample is dispersed in acid medium, possible interferences are extracted in chloroform, base is added, procainamide is extracted in chloroform, the residue is dissolved in sodium hydroxide, the compound is measured by absorption at 272 nm and comparison with a standard. Recoveries of standards added to capsule, tablet, and injection composites ranged from 99.3 to 102%. Twelve collaborators reported duplicate assay results for all 3 dosage forms with per cent standard deviations for 5 samples ranging from 1.01 to 1.27%. The method has been adopted as official first action.
A 61-year-old man developed clinical lupus syndrome with positive antinuclear antibody, positive lupus erythematosus (LE) cell preparation, and diffuse proliferative glomerulonephritis following 26 months of procainamide therapy. He was treated sequentially with prednisone and azathioprine (2 weeks), decreasing doses of prednisone alone (21 months), and no immunosuppressive drugs (10 months). Coincidental with this treatment, the immunopathology of the glomerulonephritis improved dramatically, dramatically, renal function returned almost to normal, and both antinuclear antibody and LE cell preparation became negative. The course of this patient's renal disease contrasts sharply with diffuse proliferative glomerulonephritis of idiopathic systemic lupus, and suggests that this rare complication of procainamide therapy may have a favorable course.
We report an unusual case of a primary colonic bezoar composed of extended-release formulations of nifedipine and procainamide. Although these bezoars are rare, the increasingly frequent application of extended-release delivery systems to other commonly prescribed medications may increase the incidence of such bezoars in vulnerable patients. Clinicians should be aware of this potential problem when prescribing these medications, and have a high index of suspicion when painful or refractory constipation occurs.
Using the technique of immunoblotting, we assessed the ability of sera from 19 patients with drug-induced lupus to bind individual histones and specific histone fragments. The pattern of histone epitopes bound by sera from 9 patients with procainamide-induced lupus was very similar to that described previously in spontaneous systemic lupus erythematosus. In contrast, sera from 10 patients with hydralazine-induced lupus bound a broader array of individual histones and recognized a different set of histone epitopes. We conclude that these 2 drugs induce antihistone antibodies through somewhat different mechanisms, which possibly involve differences in their ability to structurally alter chromatin.
OBJECTIVE: T cells treated with DNA methylation inhibitors overexpress lymphocyte function-associated antigen 1 (LFA-1), which results in autoreactivity, and the autoreactive cells cause a lupus-like disease in vivo, suggesting a mechanism by which some agents may cause drug-induced lupus. This study compared the effects of procainamide (Pca) and hydralazine (Hyd) with those of structural analogs, to determine if the degree of LFA-1 overexpression and T cell autoreactivity correlated with the ability of the agents to induce autoimmunity. METHODS: Cloned murine T helper 2 cells were treated with Pca, N-acetylprocainamide, Hyd, Phthalazine, or hydroxyurea (HU). The treated cells were then compared for LFA-1 overexpression, autoreactivity, and the ability to induce autoimmunity in vivo. RESULTS: Pca and Hyd were more potent than their analogs or HU in all 3 assays. CONCLUSION: The results support a relationship between LFA-1 overexpression, T cell autoreactivity, and autoimmunity, and suggest a mechanism by which Pca and Hyd, but not the analogs, may cause drug-induced lupus.
A simple and precise high performance liquid chromatographic method for the determination of mexiletine in human serum or plasma is described. Following addition of N-propionylprocainamide as internal standard the specimens are extracted, under basic conditions, into methylene chloride. After removal of the aqueous layer the drug is back-extracted into dilute acid, which is then injected directly for analysis. The extraction efficiency is 79% for both mexiletine and internal standard, and the assay is linear to 4 mg/L (twice upper therapeutic concentration). Inter-run coefficients of variation are 3.0% or less. The relative retention time of mexiletine to internal standard averages 1.3. An adaptation of this method is described for an alternate application to the analysis of tocainide, procainamide and N-acetylprocainamide.
Stress thallium-201 myocardial perfusion imaging was performed in a patient with Wolff-Parkinson-White syndrome. Reverse redistribution phenomenon was observed in the absence of coronary artery disease. This seems to be the first report of normalization of this phenomenon in association with reversion of accessory pathway to normal atrioventricular conduction after pretreatment with procainamide.
The question of pH or flow dependence for the renal elimination of procainamide (PCA) was studied under 4 conditions in each of 4 subjects. Each subject received 500 mg of PCA intravenously at weekly intervals while in a state of (1) acid load (NH4Cl) and water deprivation, (2) acid load and water excess, (3) alkali load (NaHCO3) and water deprivation, and (4) alkali load and water excess. Plasma and urine were collected at frequent intervals for PCA and N-acetyl PCA (NAPA) analysis. Urine flow rates varied markedly between the water deprivation and water excess states (approximately 1.2 vs 5 ml/min, respectively), and urine pH varied markedly between the acid and alkali load states (pH = ca 5 vs 8, respectively). Despite this marked variation, there were no significant changes in PCA renal clearance or 24-hr PCA or NAPA excretion. If passive diffusion of PCA were taking place, such flow and pH changes would have caused marked changes in PCA clearance were the pH partition hypothesis true. We therefore conclude that passive diffusion is not an important mechanism in the renal elimination of PCA in man and that there must be tubular secretion. The implication for the clinical use of the drug is that dose adjustments need not be made in response to variations in urine flow and pH.
The kinetics of a measure of pharmcologic effect (prolongation of the QT interval) of procainamide, as well as the kinetics of the plasma concentration, urine excretion, and saliva concentration of the drug were investigated in 14 trials in 4 subjects. A single 500-mg dose was given by rapid intravenous infusion, and frequent subsequent determinations of the above variables were made. A 2-compartment pharmacokinetic model with a third compartment for the saliva was used to fit the plasma, urine, and saliva data simultaneously. Analysis of the data reveals that the kinetics of the drug concentrations in saliva and of the pharmacologic effect are indistinguishable. They both must be considered to be different from those of the drug concentrations in plasma. Thus, in normal individuals under the conditions of this study, saliva concentrations more precisely indicate the time-course of drug at a cardiac site of action, although they do not parallel plasma drug concentrations until 6 hr or more after a rapid intravenous infusion. The following average pharmacokinetic parameters for plasma were found: terminal half-life, 2.9 hr; total clearance, 828 ml/min; renal clearance, 334 ml/min; and steady-state volume of distribution, 180 L. Average distribution pseudoequilbrium half-time (t1/2 alpha) was 5.2 min from an initial volume of distribution of 36.6 L.
The pharmacokinetics of procainamide (PA) and N-acetylprocainamide (NAPA) were compared in 3 normal subjects after simultaneous intraveous injection of PA and NAPA-13C. The distribution kinetics of both compounds were modeled with a 3-compartment mamillary system, and it was found that their steady-state distribution volumes were not significantly different, averaging 1.41 L/kg for PA and 1.46 L/kg for NAPA. However, the intercompartmental clearances of NAPA were slower than those of PA. In these normal subjects, the average elimination t1/2 and total elimination clearance for PA were 2.5 hr and 589.8 ml/min, and for NAPA were 6.2 hr and 233.7 ml/min. Mean renal clearances of PA (346.7 ml/min) and of NAPA (199.5 ml/min) exceeded the usual rate of glomerular filtration, which suggests that both compounds are eliminated in part by renal tubular secretion. All subjects were phenotypic rapid acetylators of isoniazid and converted approximately one fourth of the administered PA dose to NAPA-12C. The fate of 15.4% of the administered PA and 14.5% of the administered NAPA-13C was not determined.
A fluorometric procedure for procainamide hydrochloride was developed, and it offers improvements in ease, speed, and sensitivity over the official method. The new procedure is based on the reaction with fluorescamine in aqueous medium at pH 7.5 to form a fluorophore, with activation and emission wavelengths of 400 and 485 nm, respectively. The fluorescence is linear (r = 0.999) over the 0. 04-1 mug/ml concentration range and is stable for at least 2 hr. Recovery data appeared to be accurate, quantitative, and reproducible. The overall recovery was 99.8% with a standard deviation of +/-1.14 (n = 5). The method was successfully applied to commercially available dosage forms.
A rapid, specific, high-pressure liquid chromatographic method for the determination of procainamide and its N-acetyl derivative in plasma was developed. The procedure is fast enough (15 min from receipt of blood to reporting value) to be used for emergency determinations. The sensitivity, precision, and accuracy are sufficient for routine monitoring of therapeutic levels in patients. The assay is specific enough to be valid in the presence of a number of drugs and dietary substances present in clinical samples.
A sensitive, specific, high-performance liquid chromatographic procedure is described for the simultaneous determination of procainamide and its metabolite, N-acetylprocainamide, in plasma. Basic plasma (2.0 ml), containing pheniramine maleate as an internal standard, is partitioned with methylene dichloride. The organic extract is concentrated to between 0.3 and 0.5 ml, and 100-microliter aliquots are chromatographed on a microparticulate silica gel column using 0.1% acetic acid-20% 0.1 M ammonium acetate in acetonitrile as the mobile phase. With a fixed-wavelength (254-nm) UV detector, both compounds can be quantitated in the 0.1-8.0-microgram/ml of plasma range.
A simple, rapid colorimetric method is described which determines procainamide in commercially available, injectable solutions. It is based on complexing the drug with cupric ion and then measuring the absorption at 380 nm. The reaction is fast and the metal-drug ratio in the complex is 1:1. The pH optimum for maximum reaction is 4.0-4.5 which is maintained by an acetate buffer. Linear standard curves were obtained from 1.52 to 6.06 mg/mL. Analysis of 29 commercial samples resulted in an average of 97.3% of the label claim.
We report a reversed-phase high-performance liquid chromatography method for the determination of procainamide (PA) and three of its metabolites, n-acetylprocainamide (NAPA), deethylprocainamide (DEPA), and deethyl-n-acetylprocainamide (DENAPA), in serum and urine. (p-Amino)-n-(2-dipropylaminoethyl)-benzamide was the internal standard. A phenyl column (1.0-mL/min flow rate) and a mobile phase consisting of 0.075 M acetate buffer (pH 4.3):acetonitrile (20:3) resulted in a total chromatography time of 21.6 min. The optimum detector wavelength was 270 nm. Maximum linear concentrations were 37.8, 34.2, 20.0, and 16.3 mg/L for DEPA, DENAPA, PA, and NAPA, respectively. Minimum detectable concentrations were 0.05 mg/L or less for all four compounds. One-tenth milliliter of sample was extracted into methylene chloride:2-propyl alcohol (9:1). Extraction efficiencies were independent of concentration or biological fluid for each compound. Standard curves were linear and best-fit by dividing the curve into two portions and/or using weighted linear regression. Within-day and day-to-day precison were excellent. No interfering substances were observed in the serum or urine of normal subjects with the exception of caffeine, which was resolved by alteration of the mobile phase. Advantages of this method include a small sample volume, low minimum detectable concentrations, and an order of elution which enhances the detectability of the deethyl metabolites. Urinary excretion of DEPA and DENAPA accounted for an average of only 0.58 and 0.53%, respectively, of PA doses administered intravenously to six normal volunteers.
Procainamide (PA), a cardiac anti-arrhythmic agent, was applied in vitro to the rat neuromuscular junction and its effect on neuromuscular transmission was investigated using intracellular microelectrode recording techniques. Clinically relevant doses of PA produced a dose-dependent decrease in the amplitude of spontaneous miniature end-plate potentials (MEPPs) and a marked increase in the half-decay time without altering MEPP frequency or resting membrane potential. The amplitude of impulse-evoked end-plate potentials was also reduced in a similar dose-dependent manner, with a marked prolongation of the decaying phase. Direct quantal analysis using magnesium-blocked preparations showed that the drug also caused a reduction in the mean number of acetylcholine quanta released per nerve impulse. This presynaptic inhibitory effect of the drug, however, contributed less to the overall blocking action than did the postsynaptic effect. The junctional effects of the drug were completely reversible, with all affected parameters returning to the control levels after washout of PA with control solution. These direct inhibitory actions on neuromuscular transmission could account for the clinical exacerbations associated with the administration of PA to patients with myasthenia gravis and other neuromuscular diseases.