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Effects of long-term procainamide therapy on immunoglobulin synthesis.

Procainamide is a potent inducer of autoantibodies. In order to evaluate the immunologic effects of this drug in vivo, 23 cardiac disease patients who had received procainamide for at least 6 months and an equal number of matched cardiac disease control subjects were studied, and percentage of circulating T cell subsets, concanavalin A-induced suppressor cell activity, and pokeweed mitogen--stimulated generation of immunoglobulin-secreting cells was quantitated. There was no significant difference between patient and control groups in the percentage of T cell subsets defined by OKT4 and OKT8 monoclonal antibodies or in concanavalin A-induced suppressor cell activity. The numbers of pokeweed mitogen--induced immunoglobulin-secreting cells were markedly decreased in the patient group, as measured by the protein A-augmented reverse hemolytic plaque assay (3,000 +/- 644, mean +/- SEM in patients versus 10,826 +/- 1,529, mean +/- SEM in control subjects, P less than 0.005). Removal of the adherent cell fraction did not improve the hyporesponsiveness. When B and T cell fractions of 6 patients were mixed with normal T and B cell fractions, all of the patients demonstrated diminished B cell responses, and one-half also had diminished T cell responses. Addition of patient adherent cells to a co-culture of normal B cells with deficient patient T cells restored plaque formation to normal levels, suggesting that the T cell defect was correctable by a macrophage-derived factor. The data obtained suggest that procainamide exerts an immuno-suppressive action on both B and T cell function in patients receiving this drug.

Aged↗

Determination of procainamide acetylator status.

Variation in renal function can obscure the measurement of acetylator status for compounds such as procainamide in which appreciable active drug or acetyl metabolite is excreted in urine. Computer simulations and patient studies were used to compare two common metabolite/drug ratio methods and a proposed clearance technique for phenotyping acetylation rate. The calculation of apparent acetylation clearance from steady-state serum concentrations of procainamide and urinary excretion rates of N-acetyl-procainamide provides the most definitive discrimination between fast and slow acetylators.

Acetylation↗

Rapid and micro high-pressure liquid chromatographic method for simultaneous determination of procainamide and N-acetylprocainamide in plasma.

A rapid and simple high-pressure liquid chromatographic method was developed for the simultaneous determination of plasma levels of procainamide and its major metabolite, N-acetonitrile, and the supernate was chromatographed on a cation-exchange column. The assay can be carried out on as little as 20 microliter of plasma and requires only about 7 min for each sample. No interference was found in plasma samples from cardiac patients receiving procainamide. This method is simple, fast, and useful for routine therapeutic monitoring and for pharmacokinetic studies procainamide and its metabolite.

Acetylation↗

Determination of procainamide and N-acetylprocainamide in biological fluids by high-pressure liquid chromatography.

A modification of a high-pressure liquid chromatographic method for the simultaneous determination of procainamide and N-acetylprocainamide in plasma is described. The deficieicies in the specificity of the existing method were overcome by replacing the cation-exchange column and the mobile phase. The recovery and reproducibility of both procainamide and N-acetylprocainamide from human, dog, and rat plasma and urine spiked with either compound were excellent in the concentration range of 0.05--10 microgram/ml for plasma and 0.5--20 microgram/ml for urine. The comparison of this method with a specific extraction method for sets of plasma samples from human subjects and rats receiving N-acetylprocainamide and procainamide, respectively, showed no statistically significant difference.

Acecainide↗

Complexation of procainamide with dextrose.

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.

Chemistry, Pharmaceutical↗

Complexation of procainamide with hydroxide-containing compounds.

The complexation of procainamide with hydroxide-containing compounds, ethanol, fructose, glucose, glycerin, lactose, maltose, propylene glycol, sorbitol, and sucrose, have been studied. Procainamide formed a complex with glucose, lactose, and maltose, all of which contain a hemiacetal group, whereas fructose and sucrose do not. The percent of complex formed was dependent on the pH of the solution, with an optimum range of approximately 4-5.2. As with glucose, the percent of complex formed was directly related to the concentration of lactose in the solution. In dry mixtures, procainamide did not form a complex with glucose or lactose. The complex formed with lactose or maltose could be completely reversed by adding hydrochloric acid. A similar observation with glucose was reported earlier. In the optimum pH range, equilibrium was established in approximately 24 hr, and the process of complexation followed the equation for reversible reactions.

Chemical Phenomena↗

Effects of chronic ethanol ingestion on tissue elimination-phase kinetics of procainamide in rats.

The effects of chronic ethanol ingestion on the pharmacokinetics of procainamide in various tissues were studied. Ethanol-treated rats received ethanol at 4 g/kg/day for an initial 7 days and then at 8 g/kg/day for the subsequent 21 days; control rats received isocaloric sucrose. After a single intravenous dose, the semilogarithmic procainamide concentration-time profiles observed in hearts and kidneys of both groups of rats were similar to the previously reported biexponential profiles of procainamide concentration in blood. This finding indicates a rapid distribution equilibrium of drug in both blood and these highly perfused tissues. The profiles of drug concentration in thigh muscle and fat of both groups of rats exhibited a drug-uptake phase during the initial 25-min period followed by a monoexponential decline in drug concentration. For all tissues, the slopes (beta values) of the curves of the drug concentration versus time were calculated on the basis of elimination-phase data, except for fat of control rats where the predominant elimination phase was not discernible. The beta values in hearts and thigh muscles of ethanol-treated rats were significantly higher than those in the corresponding tissues of control rats. These results are evaluated in light of previously reported effects of the same ethanol treatment on the distribution pharmacokinetics and the steady-state partition coefficients of the drug in these tissues. Possible mechanisms are proposed to account for these effects on the basis of the known diverse effects of chronic ethanol ingestion on the cellular compositions of individual organs and tissues.

Animals↗

Mexiletine: double-blind comparison with procainamide in PVC suppression and open-label sequential comparison with amiodarone in life-threatening ventricular arrhythmias.

The antiarrhythmic effects of mexiletine (n = 14) were compared to procainamide (n = 16) by a double-blind parallel protocol in 30 patients (group I) with frequent premature ventricular contractions (PVCs) (greater than 20/hr), and to amiodarone by an open-label sequential approach in 25 patients (mean left ventricular ejection fraction of 32.6 +/- 13.4%) with life-threatening ventricular arrhythmias (group II) resistant to two or more conventional agents. The predetermined end point of therapy in group I patients was met in 6 of 14 (43%) given mexiletine, with 7 (50%) requiring drug discontinuation for severe gastrointestinal or central nervous system side effects and only 3 of 16 patients (19%) given procainamide, with 5 (31%) developing limiting side effects. Increases in dose led to a higher efficacy rate for PVC suppression with a corresponding increase in side effects with mexiletine; with procainamide, the higher dose was not associated with greater PVC suppression. In group II patients, mexiletine was effective in 4 (16%), with one patient discontinuing the drug during long-term therapy; mexiletine was ineffective in 16 (64%) and early side effects developed in 5 (20%). Patients not responding to or not tolerating mexiletine were given amiodarone; 20 of 21 (95%) responded with arrhythmia control after the loading dose. During a mean follow-up period of 2 years, sudden death occurred in two patients, death from heart failure in two, and death from subarachnoid hemorrhage in one patient; 15 (75%) patients are alive and free of arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Constrictive pericarditis in procainamide-induced lupus erythematosus syndrome.

A rare case of constrictive pericarditis in procainamide-induced lupus erythematosus syndrome is reported. After 6 months of procainamids therapy fever, pleuritic chest pain, arthralgia and muscle soreness developed in a 47 year old man. These symptoms were soon followed by the onset of acute pericarditis and rapidly accumulating massive pericardial effusion. After withdrawal of procainamide therapy and administration of corticosteroids in large doses, there was marked subjective improvement and rapid reduction in pericardial effusion. However, constrictive pericarditis with massive leg edema and ascites developed 6 weeks after admission as corticosteroid therapy was gradually discontinued. These manifestations subsided after pericardiectomy was performed.

Humans↗

Comparative cost-effectiveness analysis of quinidine, procainamide and mexiletine.

Quinidine and procainamide have the potential for major organ toxicity, whereas mexiletine has been reported to have little risk of organ toxicity, serious proarrhythmia or congestive heart failure, but a relatively high incidence of nuisance side effects. In light of the potential adverse effects of all antiarrhythmic agents as highlighted by the Cardiac Arrhythmia Suppression Trial, the relative cost-effectiveness of these 3 agents was assessed. Based on a review of greater than 1,000 published reports, studies included in the analysis examined greater than or equal to 1 of these agents in adults, with adequate efficacy or safety data, or both. The majority of studies assessed patients with symptomatic or malignant arrhythmias, or both. Data were analyzed using a decision analysis/cost-effectiveness model. Probabilities were averaged using techniques of meta-analysis. Costs were obtained from a university medical center cost-accounting system and from expected follow-up visits to university clinics. Thirty-seven separate side effects were included in the analysis. In terms of overall cost, 12 months of mexiletine would engender $875, quinidine $1,239 and procainamide $1,911 of expenses. Mexiletine dominates the older agents in terms of cost per successful drug response, a result that holds over a wide range of efficacy and safety data. Analyses demonstrated no increase in all-cause mortality for quinidine and mexiletine over placebo, but a trend toward higher mortality with procainamide. The results suggest that mexiletine is a cost-saving alternative therapy for ventricular arrhythmias when adverse reactions are considered in addition to pharmaceutical costs and treatment efficacy.

Ambulatory Care↗

Comparative effects of lidocaine and procainamide on acutely impaired hemodynamics.

Controversy exists regarding the relative safety of intravenously administered lidocaine and procainamide to patients with acutely impaired hemodynamics. Accordingly, their effects were studied in 15 such patients, 14 with acute myocardial infarction and one with cardiomyopathy and severe congestive heart failure. All had elevated levels of pulmonary capillary wedge pressure (greater than 15 mm Hg) and/or low cardiac index (less than 2.5 liters/min/m2). Patients were given lidocaine, a 100 mg bolus followed by a 3 mg/min infusion and, after at least a 30 minute recovery period, procainamide, a 100 mg bolus over 2 minutes followed by a 20 mg/min infusion for 20 to 25 minutes. Hemodynamic measurements were compared early and late in the infusion of each drug. Small, clinically insignificant differences were observed in the hemodynamic responses to the drugs, and no clinically significant deterioration occurred with either. Conventional therapeutic doses of intravenous procainamide can be administered by this regimen, to patients with acute myocardial infarction complicated by cardiac failure or low cardiac output, without producing deleterious hemodynamic effects.

Acute Disease↗

Procainamide-induced antinuclear antibodies in beagle dogs.

Procainamide produces a high incidence of autoimmune reactions in humans. To establish an animal model, we treated three groups of beagle dogs with increasing doses of procainamide HCl (100 to 200 mg/kg) for 11 to 14 months. Sera were examined before and during treatment for antinuclear antibodies (ANA) at a 1:10 dilution by an indirect immunofluorescence assay. The first group of six dogs, which were 1 year old and born in our colony, remained generally negative for ANA. In the second group of four dogs, which were of the same origin but were 3 to 6 years old, two developed ANA after 4 months of treatment. The third group of four dogs were 3 to 6 years old and had been born in the FDA colony to parents originating from another source. These dogs developed ANA after 1 to 2 months and remained generally positive throughout the 11 months of treatment. Dogs of the control groups remained negative except for one that was ANA-positive on several occasions. Three of the ANA-positive treated dogs and the ANA-positive control dog had circulating immune complexes. Serum procainamide concentrations were comparable in dogs of each group; acetylprocainamide was not detected. No alterations were found in serum proteins or in the hemograms, and no clinical signs were seen. The data suggest that age plays a contributory role in the development of this autoimmune response in the dog.

Aging↗

Drug-specific immune responses induced by procainamide, hydralazine and isoniazid in guinea-pigs.

The drug-induced graft vs host reaction (GVHR) hypothesis requires, as its first step, specific T-cell immune responses to the drug-modified self. Procainamide, isoniazid and hydralazine are known to provoke various allergic reactions including GVHR-like adverse effects in man. We now report that drug-specific immune responses can easily be induced by these drugs in guinea-pigs. Twenty-five milligrams of each of these drugs and penicillin G, which is known to make covalent bonds with proteins and to also induce drug-specific immune responses, were mixed with complete Freund's adjuvant (CFA) and subcutaneously (s.c.) injected twice at an interval of 2 weeks into female Hartley guinea-pigs. The antibodies to these drugs were assessed by means of an enzyme-linked immunosorbent assay (ELISA). Two weeks after the last injection, all animals treated with isoniazid, hydralazine and penicillin G produced high titers of antibodies to these drugs. Antibodies to procainamide were also detected, although their antibody titers were low. The specificity of the antibodies produced were tested by the inhibition of ELISA and concentration-dependent inhibition was observed. Delayed type hypersensitivity (DTH) reactions were also observed in the animals treated with procainamide, isoniazid and hydralazine 2 weeks after the last injection. These results suggest that the allergic reactions observed in clinical use are related to the inducing potential of drug-specific immune responses in an animal system. Therefore, immunization of guinea-pigs with test drugs and CFA may give useful information for predicting the occurrence of allergic reactions in man.

Animals↗

Electrochemical investigations of immunologically reactive procainamide metabolites.

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.

Chromatography, High Pressure Liquid↗

Use of procainamide with rapid atrial pacing for successful conversion of atrial flutter to sinus rhythm.

Rapid atrial pacing is a useful technique and often the therapy of choice to terminate atrial flutter in patients. However, interruption of atrial flutter by rapid atrial pacing may not always produce sinus rhythm, but rather may result in atrial fibrillation. Twelve patients with spontaneous atrial flutter that had been present for greater than 24 h were studied to assess the efficacy of atrial pacing, alone and in combination with procainamide, to convert atrial flutter to normal sinus rhythm. Rapid atrial pacing for greater than or equal to 15 s from selected atrial sites at selected pacing rates were performed during atrial flutter. The initial pacing rate was always at a cycle length 10 ms shorter than the atrial flutter cycle length. If atrial flutter persisted after cessation of pacing, it was repeated at progressively shorter cycle lengths until either a rate of 400 beats/min was achieved or atrial fibrillation was induced. In two patients, atrial flutter was converted to sinus rhythm with pacing alone. Three patients developed sustained atrial fibrillation as a result of the rapid atrial pacing, this rhythm ultimately reverting back to atrial flutter in two. Ten patients received procainamide and 9 of the 10 had lengthening of the atrial flutter cycle length by a mean of 68 ms (1 patient continued to have atrial fibrillation). Then, using the same atrial pacing protocol, high right atrial pacing alone at a mean cycle length of 227 ms interrupted atrial flutter in all these patients, returning their rhythm to sinus rhythm. It is concluded that intravenous procainamide effectively augments the efficacy of rapid atrial pacing to convert atrial flutter to sinus rhythm.

Adolescent↗

Contrasting effects of verapamil and procainamide on rate-dependent bundle branch block: pharmacologic evidence for the role of depressed sodium channel responses.

The mechanisms responsible for intermittent bundle branch block are still under debate. The role of the time-dependent behavior of the slow calcium channel has recently been emphasized. To test this hypothesis and ascertain the possible involvement of the fast sodium channel, the effects of the slow calcium channel blocker verapamil and the fast sodium channel blocker procainamide were compared in 10 patients with intermittent bundle branch block. All 10 patients showed bundle branch block during spontaneous sinus rhythm. Maneuvers to slow cardiac rate (that is, carotid sinus massage, Valsalva maneuver) were performed to identify normal conduction as well as phase 4 bundle branch block. Thus, the ranges of diastolic intervals (RR) resulting in phase 3 (tachycardia-dependent) bundle branch block, phase 4 (bradycardia-dependent) bundle branch block and normal conduction were measured in two control studies performed before intravenous administration of verapamil (control 1) and procainamide (control 2) and at the peak effect of both drugs. In the control studies, all 10 patients showed phase 3 bundle branch block, whereas phase 4 bundle branch block occurred in only 4 patients. The ranges of phase 3 bundle branch block, phase 4 bundle branch block and normal conduction were very similar in control studies 1 and 2. The phase 3 bundle branch block range was slightly shortened by verapamil (983 +/- 83.5 ms in control 1; 930 +/- 69.4 ms at the peak effect of verapamil), whereas phase 4 bundle branch block remained unchanged. In contrast, conduction was systematically worsened by procainamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Procainamide therapy, physical performance and energy expenditure in the Schwartz-Jampel syndrome.

The effects of procainamide administration were assessed in a 5-yr-old boy with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Without procainamide the resting metabolic rate was found to be significantly higher than in an age-matched control group. With a serum level of 3.8 mg l-1 procainamide a reduction of the resting metabolic rate of 22% was observed, and times needed to climb stairs and to re-open eyes after forceful contraction (blepharospasm) were significantly reduced.

Child, Preschool↗

Usefulness of procainamide challenge for electrophysiologic arrhythmia risk stratification.

Among 58 consecutive patients who underwent electrophysiologic testing for risk assessment and who subsequently received a third-generation implantable cardioverter-defibrillator, 39 had ventricular tachycardia induced in the baseline state and 19 had ventricular tachycardia induced only after administration of intravenous procainamide, increasing the yield of electrophysiologic risk assessment by 49%. At follow-up, ventricular arrhythmias requiring implantable cardioverter-defibrillator termination occurred in 14 of 39 patients inducible in the baseline state and in 7 of 19 patients inducible only with intravenous procainamide. The provocative use of intravenous procainamide during electrophysiologic risk assessment increases the detection rate for risk of sustained ventricular arrhythmias with no loss of positive predictive value.

Aged↗