Glycine additive enhances sensitivity for N- and O-glycan analysis with hydrophilic interaction chromatography-electrospray ionization-mass spectrometry.

Glycosylation is critical for many biological processes and biotherapeutic development. One of the most powerful approaches for analyzing released glycans is hydrophilic interaction chromatography coupled with electrospray ionization mass spectrometry (HILIC-ESI-MS). The high sensitivity of MS is crucial for detecting low-abundance glycans and elucidating their structures. In this study, we presented a simple solution to boost MS response of procainamide (ProcA) labeled glycans for 2- to over 60-fold by including 1 mM glycine in ammonium formate mobile phases for HILIC-ESI-MS. The glycine additive increased charge states, enhanced ion intensities and signal-to-noise ratios, and improved tandem MS spectral quality of various N- and O-glycans without affecting chromatographic performance. Furthermore, more homogeneous ionization among different ProcA labeled glycans was achieved by using the glycine additive, resulting in more comparable quantitative results relative to fluorescence-based quantification. We demonstrated that ammonium formate caused ion suppression to ProcA labeled glycans, which were likely mitigated by glycine with enhanced ESI ionization. Overall, simple addition of glycine to mobile phases during HILIC-ESI-MS analysis significantly improves MS detection sensitivity and will facilitate future profiling and quantitation of glycans released from N- and O-glycoproteins.

Pharmacokinetic evaluation of a sustained-release compounded procainamide preparation after 24-h (acute) administration in normal dogs.

INTRODUCTION: The objective of the present study was to evaluate the pharmacokinetics of a compounded sustained-release procainamide formulation in normal dogs. ANIMALS: Six healthy, purpose-bred mixed-breed dogs participated in the study. METHODS: In phase I, two dogs were administered oral procainamide (30 mg/kg), and plasma was obtained to determine plasma concentration ranges and duration. In phase II, six dogs were administered procainamide (30 mg/kg by mouth every 12 hours) to determine the pharmacokinetics of sustained-release procainamide. Serum procainamide concentration was determined using an immunochemistry assay. RESULTS: No adverse clinical effects were noted in any of the dogs studied. The average maximum serum concentration, average serum concentration, and average minimum serum concentration were 10.17, 7.13, and 3.07 µg/mL, respectively. The average time over a 12-h period during which procainamide concentration exceeded 12 µg/mL was 2.35 h, was between 4 and 12 µg/mL was 7.19 h, and was less than 4 µg/mL was 2.46 h. The average times at maximum concentration and minimum concentration were 18.67 and 12.25 h, respectively. CONCLUSIONS: Administration of sustained-release procainamide twice daily achieved targeted plasma concentrations in most dogs. Evaluation of serum trough concentrations should be considered owing to interanimal variability to confirm that serum concentrations are within the reported therapeutic range for an individual patient.

A novel, molecularly imprinted polymer sensor made using an oligomeric methyl silsesquioxane-TiO2 composite sol on a glassy carbon electrode for the detection of procainamide hydrochloride.

In this study, we designed a novel molecularly imprinted polymer (MIP), oligomeric methyl silsesquioxane (O-MSSQ)-TiO2 composite sol, which was made using a sol-gel reaction. This polymer has structural rigidity and high surface area of O-MSSQ, as well as high bio-compatibility and relatively good conductivity of the TiO2. Next, a sensitive and selective imprinted electrochemical sensor was successfully constructed for the direct detection of procainamide hydrochloride by molecularly imprinting a film onto the surface of a glassy carbon electrode. Adding TiO2 resulted in a noticeable enhancement in the sensitivity of the MIP sensor. The performance of the O-MSSQ-TiO2 film was discussed, and the optimal conditions for detection were determined. The oxidative peak current increased linearly with the concentration of procainamide hydrochloride in the range of 4.00 × 10(-9)-4.97 × 10(-5) M using differential pulse voltammetry, and the detection limit was 1.30 × 10(-9) M with S/N = 3. Furthermore, the sensor was applied to determine the procainamide hydrochloride content in a human blood serum sample. The recoveries of the sensors varied from 96.77% to 101.35%, indicating that the prepared sensor might be promising for the determination of procainamide hydrochloride in clinical tests. Moreover, the imprinted electrochemical sensor was used to selectively detect procainamide hydrochloride. The analytical application was conducted successfully and yielded accurate and precise results.

Simultaneous quantitation of nicorandil and its denitrated metabolite in plasma by LC-MS/MS: application for a pharmacokinetic study.

A liquid chromatography-electrospray ionization tandem mass spectrometry method was developed and validated for the simultaneous quantitation of nicorandil and its denitrated metabolite, N-(2-hydroxyethyl)-nicotinamide, in rat plasma. After a liquid-liquid extraction step, chromatographic separation was performed on a ShinPack C(18) column with an isocratic mobile phase composed of methanol and 2 mM aqueous ammonium acetate containing 0.03% (v/v) formic acid (33:67 v/v). Procainamide was used as an internal standard (IS). Selected reaction monitoring was performed using the transitions m/z 212 → m/z 135, m/z 166 → m/z 106 and m/z 236 → m/z 163 to quantify nicorandil, its denitrated metabolite and IS, respectively. Calibration curves were constructed over the range of 5-15,000 ng.ml(-1) for both nicorandil and its metabolite. The mean relative standard deviation (RSD%) values for the intra-run precision were 5.4% and 7.3% and for the inter-run precision were 8.5% and 7.3% for nicorandil and its metabolite, respectively. The mean accuracy values were 100% and 95% for nicorandil and its metabolite, respectively. No matrix effect was detected in the samples. The validated method was successfully applied to a pharmacokinetic study after per os administration of nicorandil in rats.

Stacking for nonaqueous capillary electrophoresis.

Nonaqueous capillary electrophoresis (NACE) is a useful mode in CE for separation and quantification of hydrophobic compounds. However, because of the low conductivity of most of the organic solutions, stacking is not used often in this technique and the sample volume is very limited. As a result of the small sample volume, the detection limits are poor. Furthermore, NACE is affected greatly by the presence of salts in the sample. Here, we show that transient isotachophoresis (t-ITP) can be used easily in this type of electrophoresis to enhance the detection limits and also to reverse the deleterious effects of salts in the sample. Several factors, which affect the stacking in this type of electrophoresis, are described. For example, the presence of salts in the organic solvent, type of sample introduction, and the solvent for the terminating ion were all found to have profound effects on the degree of concentration. Furthermore, the separation time can be shortened by t-ITP.

Influence of midazolam on pharmacokinetic parameters of procainamide in rabbits.

The majority of antiarrhythmic drugs have very narrow therapeutic range, and they may cause some side effects at doses used for curing cardiac arrhythmias. These drugs may enter different interactions. Procainamide also may interact with other drugs. Also some other drugs may change pharmacokinetics of procainamide, for example the iv anesthetics influence on pharmacokinetic parameters of procainamide. The aim of the study was to investigate the influence of midazolam on the plasma concentrations and pharmacokinetic parameters of procainamide in rabbits during two hours of observation. Procainamide was administered in rabbits at a dose of 13 mg/kg iv, and midazolam at 0.2 mg/kg iv. Procainamide levels were determined by immunofluorescence polarization method using ABBOTT reagents. Levels of procainamide were determined in the plasma at 5, 10, 15, 30, 45, 60, 90 and 120 min after the administration of procainamide. After administration of midazolam with procainamide, a decrease in plasma concentration of procainamide, together with its increased elimination, was observed.

Comparison of the effects on drug concentrations, electrophysiologic parameters, and termination of atrial fibrillation in dogs when procainamide and ibutilide are delivered into the right atrium versus intravenously.

INTRODUCTION: We tested the hypothesis that right intra-atrial (i.a.) administration of antiarrhythmic drugs resulted in higher peak serum drug concentrations, greater electrophysiologic effects, and greater efficacy for termination of atrial fibrillation (AF) than intravenous (i.v.) drug delivery. METHODS AND RESULTS: Eight dogs were treated with 9.7 mg/kg procainamide infusion and eight dogs with 0.02 mg/kg ibutilide infusion, injected over 5 minutes. Each dog had both an electrophysiologic (EP) and an AF termination study during i.a. and i.v. drug administration at > or = 2-day intervals (total four studies each). Right atrial pacing capture threshold, right atrial effective refractory period (ERP), right atrial and right ventricular monophasic action potential (MAP) durations at 70% and 90% of repolarization (MAPD70, MAPD90), AH, HV, and QT intervals, QRS width, intra-arterial systolic and diastolic blood pressures, and cardiac output were measured at different time-points. Blood samples were drawn from the coronary sinus and femoral vein for drug level determination. The right atrium was paced at 400-msec cycle length throughout the study. AF was induced by rapid right atrial pacing and maintained by methacholine infusion at 1.5 to 3 microg/kg/min. The sustained AF was allowed to persist for 10 minutes before starting the antiarrhythmic drug infusion. We found no significant difference between the procainamide concentrations in the coronary sinus and femoral vein during i.a. and i.v. drug delivery. The time course and extent of increase in right atrial ERP, MAPD70, MAPD90, and all the other measured EP parameters did not differ between the two routes of drug administration. No significant difference was found in termination of AF between i.v. (5/7 procainamide; 4/8 ibutilide) or i.a. (3/8 procainamide; 3/8 ibutilide) drug delivery or between drugs (8/15 procainamide; 7/16 ibutilide). CONCLUSION: Our data do not support any beneficial effect of i.a. versus i.v. procainamide or ibutilide delivery.

Electropharmacologic effect of a standard dose of intravenous procainamide in patients with sustained ventricular tachycardia.

BACKGROUND: Patients with inducible sustained ventricular tachycardia (VT) sometimes receive intravenous procainamide during electrophysiologic testing. Unfortunately, the responses to intravenous and subsequent oral drug therapy are variable and may be discordant. HYPOTHESIS: It was the aim of this study to determine whether this variability might be explained by heterogeneity in the electropharmacologic response, even in a homogeneous population. METHODS: We studied 42 patients who had spontaneous malignant ventricular arrhythmia and were inducible to sustained monomorphous VT during electrophysiologic testing. Each received 15 mg/kg of intravenous procainamide followed by a 2 mg/min infusion. Serum levels were drawn immediately following programmed stimulation. The mean procainamide level was 6.7 +/- 1.4 mcg/ml with an N-acetyl procainamide level of 1.0 +/- 0.5 mcg/ml. The 14 procainamide responders (5 of whom were noninducible and 9 whose VT cycle length increased > 100 ms) and the 28 nonresponders had similar procainamide and NAPA levels (6.5 +/- 1.4 vs. 6.7 +/- 1.4 mcg/ml). RESULTS: There was no significant difference in baseline clinical parameters, His to ventricular electrogram (HV) interval, effective refractory period, or VT cycle length. Prolongation of the effective refractory period and infra His conduction time occurred to a similar extent in responders and nonresponders. CONCLUSION: We conclude that procainamide has a consistent dose-response relationship with respect to refractoriness and conduction in patients with malignant arrhythmias. However, acute antiarrhythmic efficacy of procainamide cannot be predicted by clinical factors, drug levels, or drug-induced changes in common electrophysiologic parameters.

Involvement of CYP2D6 activity in the N-oxidation of procainamide in man.

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.

Relative binding of therapeutic drugs by sera of seven mammalian species.

The relative binding of acetaminophen, lidocaine, phenobarbital, procainamide, quinidine, and theophylline to sera of seven mammalian species was studied. Pooled commercial sera from cow, goat, horse, human, pig, rabbit, and sheep were supplemented with 5 and 10 mM concentrations of each drug. For each serum, each drug, and each drug concentration, equilibrium dialysis was performed in duplicate against phosphate buffer (pH 7.4, 0.1 M, 4 degrees C). Percent drug bound to serum was calculated. Phenobarbital demonstrated more than 20% binding to goat, horse, human, and sheep serum at both 5 and 10 mM concentrations; more than 20% binding to bovine serum at a concentration of 10 mM; and more than 20% binding to pig and rabbit serum at 5 mM. Quinidine (studied only at 5mM concentration) bound more than 20% to cow, goat, horse, human, pig, and rabbit serum. In contrast, procainamide at both the 5 and 10 mM concentrations showed no binding to cow, horse, pig, rabbit, or sheep serum. Acetaminophen (studied only at 5 mM concentration), lidocaine, and theophylline demonstrated less than 20% binding to each serum. Acetaminophen at 5 mM did not bind to human serum, and lidocaine at 10 mM did not bind to horse or pig serum. Although some interspecies variation in drug binding to the seven sera was noted, the overall magnitude of binding of each drug to each serum was, for the most part, similar. Phenobarbital and quinidine showed stronger (> 20%) binding; procainamide showed negligible binding; and acetaminophen, lidocaine, and theophylline demonstrated intermediate (< 20%) binding.

Serum procainamide analysis based on acetonitrile stacking by capillary electrophoresis.

Stacking methods are important in capillary electrophoresis (CE) to overcome the poor detection limits. Cationic drugs are difficult to stack because they tend to interact with the capillary wall. As an example of the stacking of the cationic compounds, procainamide, an anti-arrhythmic drug, is analyzed in serum by CE using an acetonitrile treatment. Serum was deproteinized with acetonitrile containing quinine as an internal standard. About 12% of the capillary volume was filled with sample and separated using an electrophoresis buffer composed of triethanolamine, 2-(N-cyclohexylamino)ethanesulfonic acid (CHES) and 20% isopropanol, pH 8.2. Both the triethanolamine and the CHES were critical for the stacking. The addition of isopropanol improved the plate number for the procainamide and decreased the interfering compounds. Procainamide, its metabolite N-acetyl procainamide, and quinine were separated in about 7 min. The CE compared well with an immunoassay method.

Conversion of atrial fibrillation to sinus rhythm using acute intravenous procainamide infusion.

The efficacy and safety of intravenous procainamide in the conversion of atrial fibrillation was investigated. A total of 114 patients without severe heart failure were randomized to receive either intravenous procainamide (1 g over 30 minutes, followed by an infusion of 2 mg/min over 1 hour) or placebo in a double-blind trial. Digoxin (0.5 mg intravenously) was administered to all patients who had not previously been receiving digoxin. Treatment was considered successful if sinus rhythm was restored within 1 hour after starting the infusion. Conversion to sinus rhythm was achieved in 29 (50.9%) of the 57 patients treated with procainamide and in 16 (28.1%) of the 57 who received placebo (P approximately 0.012). When the duration of the atrial fibrillation was < or = 48 hours, conversion to sinus rhythm was achieved in 29 (69%) of the 42 patients receiving procainamide and in 16 (38.1%) of those receiving placebo (P approximately 0.004). None of the patients with atrial fibrillation lasting > or = 48 hours converted to sinus rhythm in either group. Another factor that played a role in the restoration of sinus rhythm was the size of the left atrium: the smaller the left atrium, the larger the success rate. The results of the study suggest that intravenous procainamide is an effective and safe means for the rapid termination of atrial fibrillation of recent onset and that its success rate is inversely related to the size of the left atrium. However, the drug is ineffective in the conversion of atrial fibrillation lasting more than 48 hours.

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.

Comparison of right atrial and peripheral procainamide infusion levels in patients with spontaneous or induced atrial fibrillation.

As part of a new effort to develop an implantable drug infusion/pacing system to treat atrial fibrillation, this study examined the effects of rapid intracardiac procainamide infusion in humans with pacing-induced atrial fibrillation. Twenty patients with atrial fibrillation for > 5 minutes during an EP study received 500 mg of procainamide either via a peripheral venous infusion (n = 5) or directly in the right atrium (n = 15). Peak coronary sinus and femoral vein procainamide blood levels (mean +/- SEM) during 10, 5, and 3.3 minute central infusions were 17.0 +/- 4.1, 25.1 +/- 4.5, 45.6 +/- 5.1 and 11.3 +/- 3.2, 17.1 +/- 6.4, 18.7 +/- 5.0, respectively. In contrast, peak coronary sinus and femoral procainamide levels following the 5 minute intravenous infusion were 17.7 +/- 5.1 and 9.3 +/- 2.1. Changes in QT, QTc, QRS, and RI intervals were similar at each infusion rate. Systolic blood pressures (BP) decreased more with higher procainamide infusion rates but similar when comparing intravenous versus central drug administration at the same rate. The mean +/- SEM decreases in blood pressure with the 10, 5, and 3.3 min procainamide infusions were 12f5, 20f11, and 39f14, respectively. Conversion to sinus rhythm was not a primary endpoint given the often transient nature of acute atrial fibrillation in this setting. We conclude that significantly higher femoral vein and coronary sinus procainamide levels can be achieved by central rather than peripheral drug infusion. These data support that concept that rapid central infusion of anti-arrhythmic therapy can result in high intracardiac levels of antifibrillatory agents for the treatment of paroxysmal atrial fibrillation.

Improved high-performance liquid chromatographic assay for the determination of procainamide and its N-acetylated metabolite in plasma: application to a single-dose pharmacokinetic study.

An improved high-performance liquid chromatographic assay for the determination of procainamide and N-acetylprocainamide (NAPA) at concentrations observed up to 32 h after a single oral dose administration of procainamide to human subjects is reported. Following liquid-liquid extraction of plasma samples, procainamide, NAPA, and the internal standard (N-propionylprocainamide) are separated on a reversed-phase C8 column with retention times of 4.0, 6.7, and 13.2 min, respectively. The ultraviolet detection limit (wavelength, 280 nm) of procainamide and NAPA is 2 ng/mL (signal-to-noise ratio, 3:1), and the quantitation limit is 4 ng/mL (signal-to-noise ratio, 5:1). Intra- and interday coefficients of variation are less than 8% in the range of 20-500 ng/mL.

Evaluation of an open-loop, computer-based infusion system designed to achieve a series of constant, targeted plasma procainamide concentrations in patients undergoing electrophysiologic testing.

STUDY OBJECTIVE: To evaluate the performance of a computer-based procainamide infusion system in patients undergoing electrophysiologic testing. DESIGN: Prospective case series. SETTING: Electrophysiology laboratory in a university hospital. PATIENTS: Thirty-four patients with inducible sustained ventricular tachycardia. INTERVENTIONS: Intravenous infusion of procainamide to achieve and maintain targeted plasma concentrations. MEASUREMENTS AND MAIN RESULTS: System performance was assessed by comparing targeted and observed plasma concentrations. The population median absolute performance error (size of typical miss) was 12.6% (95% CI 11.2-14.1%). The population median performance error (system bias) was not significantly different from zero. A small but statistically significant improvement in performance over time was observed (population absolute performance error divergence -0.125%/min). Population wobble (overall system stability) was 7.6% (95% CI 6.8-8.3%). Population-based estimates of central compartment volume and volume of distribution at steady state were significantly higher and lower, respectively, than estimates used by the infusion system. CONCLUSION: The computer-based infusion system is capable of achieving and maintaining a series of targeted procainamide concentrations in patients undergoing electrophysiologic testing.

Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism.

We studied the genotypes of polymorphic N-acetyltransferase (NAT2) in 145 Japanese subjects by the polymerase chain reaction-restriction fragment length polymorphism method. The rapid-type NAT2*4 was expressed at a higher frequency (68.6%) than the slow-type genes with specific point mutations (NAT2*6A, 19.3%; NAT2*7B, 9.7%; NAT2*5B, 2.4%). The frequency of NAT2* genotypes consisted of 44% of a homozygote of NAT2*4, 49% of a heterozygote of NAT2*4 and mutant genes, and 7% of a combination of mutant genes. The metabolic activity for procainamide to N-acetylprocainamide was measured in 11 healthy subjects whose genotype had been determined. Although the acetylation activity substantially varied interindividually, the variability was considerably reduced after classification according to the genotype. The N-acetylprocainamide/procainamide ratio in urinary excretion was 0.60 +/- 0.17 (mean +/- SD) for those with NAT2*4/*4, 0.37 +/- 0.06 for NAT2*4/*6A, 0.40 +/- 0.03 for NAT2*4/*7B, and 0.17 for NAT2*6A/*7B. The results indicated that the NAT2* genotype correlates with acetylation of procainamide.

Effects of procainamide on the excitable gap composition in a canine model of atrial flutter.

The effects of increasing concentrations of procainamide on the composition of the excitable gap were determined in a canine model of atrial flutter. Using the model of a Y-shaped lesion in the right atrium, reentry around the tricuspid valve was induced by burst pacing in 10 open-chest chloralose-anesthetized dogs. Diastole was scanned with a single premature stimulus and the relationship between the coupling interval of the premature beat and the return cycle length (CL) determined a reset-response curve that described the excitable gap. This was repeated up to the maximum flutter CL while infusing procainamide (30 mg/kg) over 1 h. Procainamide progressively prolonged the flutter CL from 131 +/- 21 (+/-SD) to 188 +/- 46 ms (p < 0.01) and the effective refractory period from 96 +/- 19 to 149 +/- 47 ms (p < 0.01). At peak plasma levels of 77 +/- 33 mumol/L the drug terminated flutter only in two dogs. Neither the duration (35 +/- 10 to 39 +/- 13 ms) nor the composition of the excitable gap changed on drug. A fully excitable portion (7 +/- 3 ms or 20 +/- 11% of the excitable gap) persisted on procainamide (7 +/- 3 ms or 19 +/- 9% of the excitable gap). It was concluded that procainamide prolongs the atrial flutter CL and the effective refractory period but does not change either the duration or composition of the excitable gap even at plasma concentrations that significantly exceed those recommended in man.

Pharmacokinetic and pharmacodynamic comparisons of twice daily and four times daily formulations of procainamide in patients with frequent ventricular premature depolarization.

A study was conducted to evaluate the pharmacokinetics of procainamide and its active metabolite, N-acetylprocainamide (NAPA), as a function of dose and formulation and to characterize the relationship between ventricular premature depolarization (VPD) rate and plasma concentrations of procainamide and NAPA. A subset of patients (n = 43) with frequent VPD who were enrolled in a double-blind, multicenter, activity trial were assigned in randomized fashion to receive 1 of 4 dose levels (placebo or 1,000, 2,000, or 4,000 mg/day procainamide) and to receive Procanbid (Parke-Davis) tablets every 12 hours or Procan SR (Parke-Davis) tablets every 6 hours during the first week of a blinded crossover phase. Patients crossed over to the alternative formulation after one week. Maximum and steady-state average concentrations of procainamide and NAPA after administration of Procanbid tablets were equivalent to those after administration of an equivalent daily dose of Procan SR tablets. Corresponding trough concentrations of procainamide were lower after administration of Procanbid tablets than after administration of Procan SR tablets. Both formulations produced disproportionate increases in procainamide concentrations with increasing dose; concentrations of NAPA increased in proportion to dose. Assessment of the relationship between VPD rate and drug concentration in plasma indicated no substantive difference between the two formulations. It was concluded that administration of Procanbid tablets every 12 hours is essentially equivalent to administration of procainamide extended-release tablets (Procan SR) every 6 hours with respect to pharmacokinetics of procainamide and NAPA and to VPD suppression.