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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.

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Propylene glycol (PG) was evaluated as a vehicle for the in vivo percutaneous absorption of the hydrochloride salts of desipramine, nortriptyline, procainamide, and N-acetyl-procainamide. Each drug was administered topically to hairless (hr-1/hr-1) mice in water and in aqueous 10% and 50% PG. Mean drug concentrations in blood, brain, heart, liver, and lung were measured by high-pressure liquid chromatography after either two or three hours of topical absorption. The presence of PG generally enhanced the absorption of each drug, and the degree of enhancement appeared to be related to the percentage of PG in the dosing solution.

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Therapeutical efficacy was clinically evaluated in 21 patients with ventricular cardiac arrhythmias. The drug was given orally with preceded intramuscular dose. Therapeutic effect was verified by the measurements of procainamide and N-acetylprocainamide concentrations in blood serum to determine the minimal effective concentration of the drug required to obtain satisfactory antiarrhythmic effect. Procainamide proved effective in cardiac arrhythmias in 14 patients (66.7%) with statistical significance in the acute myocardial infarctions; blood serum procainamide plus N-acetylprocainamide levels being were below the therapeutical range. The poor correlation of the dose of the drug and respective procainamide, N-acetylprocainamide concentrations in blood was observed. Relationship of the therapeutical effects blood serum level of the drug should be estimated basing of the assays of both procainamide and N-acetylprocainamide .

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Shortly after Dreyfus and his colleagues demonstrated that procainamide was metabolized by acetylation to N-acetylprocainamide (NAPA), Drayer, Reidenberg and Sevy reported that NAPA had antiarrhythmic activity in an animal model. We confirmed these findings and found that plasma levels of NAPA were high enough to warrant consideration in managing patients requiring procainamide therapy. However, the actual impetus for developing NAPA as an antiarrhythmic drug in its own right was provided by the initial studies of NAPA pharmacokinetics in normal subjects. In these studies, we showed that NAPA has an elimination-phase half-life that is more than twice as long as procainamide and suggested that patient compliance and arrhythmia suppression might be improved if NAPA were used to circumvent the inconvenience of the frequent dosing schedule that has been recommended for procainamide. From the standpoint of managing individual patients with NAPA, the pharmacokinetics of this drug continue to provide the scientific basis for designing dose regimens that will have maximal antiarrhythmic efficacy and minimal toxicity. This review summarizes the salient features of NAPA pharmacokinetics and outlines an approach for individualizing therapy with this drug.

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Antiarrhythmic properties of N-acetylprocainamide, an active metabolite of procainamide, were studied in 15 patients who presented with a cardiac arrest or documented sustained ventricular tachycardia. Programmed electrical stimulation studies were performed. All patients tested had inducible ventricular tachycardia by programmed electrical stimulation techniques while off all antiarrhythmic therapy. Patients were then tested on procainamide 1000 mg administered intravenously, and ventricular tachycardia could be provoked in 8 of 10 patients. Twenty-four to 36 hours later, N-acetylprocainamide was administered, intravenously, and programmed stimulation was performed after 20 minutes. N-acetylprocainamide did not significantly change heart rate, mean arterial blood pressure, electrocardiographic intervals, A-H or H-V conduction times. N-acetylprocainamide prevented ventricular tachycardia induction in 6 of 15 patients. The mean serum N-acetylprocainamide levels in the group protected was 15.7 +/- 4 micrograms/ml and 16.2 +/- 4 micrograms/ml in the group not protected. These 6 patients were discharged on N-acetylprocainamide 1.5 grams orally every 8 hours. Three patients have been maintained on chronic N-acetylprocainamide every 8 hours. Three patients have been maintained on chronic N-acetylprocainamide therapy (6 +/- 2 months), two patients had breakthrough ventricular tachycardia on follow-up Holter monitoring and alternative therapy was given. N-acetylprocainamide has antiarrhythmic efficacy in preventing induction of ventricular tachycardia by programmed electrical stimulation in a high risk group of patients. On chronic oral therapy, N-acetylprocainamide appears to be well tolerated with antiarrhythmic efficacy that may be enhanced with further upward dose titration.

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The kinetics of N-acetylprocainamide (NAPA) were studied in 5 patients (all men, mean age = 62) with coronary artery disease and ventricular arrhythmias during loading infusions of 0.22-0.45 mg/kg/min, prolonged (19-48 hrs) intravenous infusions 2.5-5.2 mg/min, and in 4 of the patients, during subsequent oral doses 1.5-3 g every 8 hrs. Serum, concentrations of NAPA were determined by high-performance liquid chromatography. The individual concentration-time profiles could, with one exception, be described by a two-compartment, open, kinetic model with apparent first-order elimination. The kinetic variables were: initial distribution volume (Vc) 0.20 +/- 0.11 l/kg (mean +/- SD); steady-state distribution volume (Vss) 1.58 +/- 0.55 l/kg; distributional clearance (Cle) 133 +/- 23 ml/(kg X hr); absorption rate constant (Ka) 0.354 +/- 0.173 hr-1; and fraction of dose reaching systemic circulation (F) 1.00 +/- 0.14. The data for one patient who had received increasing oral dosages of 1.5, 2, 2.5 and 3 g every 8 hours resulted in systematic underprediction of observed concentrations at the two highest oral dosing rates. This suggests the possibility of some degree of nonlinearity or time-dependent change in the kinetic behavior of NAPA. Only low concentrations of procainamide, less than 1 mg/L, were found at the end of the infusions.

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The pharmacokinetics of N-acetylprocainamide, administered orally or intravenously, were studied in 3-, 6-, and 12-month-old rats using a two-way crossover study design. At 3, 6, and 12 months of age, the half-life values of N-acetylprocainamide were 1.66, 1.82, and 2.29 hr, respectively; the apparent volumes of distribution were 4.75, 3.35, and 1.98 liter/kg, respectively. The elimination rate constant, clearance, and absolute bioavailability of the drug (determined by AUC measurements and the amounts excreted unchanged in the urine) decreased significantly with age. The rate of absorption remained unchanged. The amounts of N-acetylprocainamide in the liver and kidneys were significantly higher in the 12-month-old animals. These results clearly demonstrate a significant alteration with age in the bioavailability, distribution, and elimination of N-acetylprocainamide in rats. In long-term toxicity studies of this and other drugs that show age-dependent pharmacokinetics, an adjustment in the chronically administered dose is essential.

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To define electrophysiologic properties and antiarrhythmic mechanisms of N-acetylprocainamide (NAPA), we studied 16 patients with symptomatic ventricular dysrhythmias. Electrophysiologic studies were performed before and after intravenous infusion of NAPA at 20 mg/kg over 20 minutes, achieving plasma concentrations of 24 +/- 3.2 to 35.5 +/- 4.5 micrograms/ml. NAPA did not significantly change sinus cycle length or atrioventricular (AV) conduction times (PA, AH, HV, and QRS), but it lengthened the QTc interval (p less than 0.001) during sinus rhythm. Programmed atrial stimulation revealed that NAPA had no discernible effects on AV nodal conduction; however, it exerted depressive effects on the His-Purkinje system in 9 of 16 patients. In 7 of 16 patients who manifested frequent ventricular premature beats (VPBs), NAPA abolished VPBs in only three of them; NAPA induced progressive prolongation of the premature coupling interval before complete abolition of VPBs. In 8 of 16 patients who had inducible repetitive ventricular response (RVR) because of reentry within the His-Purkinje system, NAPA narrowed or abolished the RVR zone in 3 patients and slowed the RVR rate with widening of the RVR zone in the remaining 5 patients. In 2 of 16 patients with slow ventricular tachycardia (VT), NAPA had no antiarrhythmic effects. By contrast, in the other 2 of 16 patients in whom sustained VT could be reproducibly elicited with programmed ventricular stimulation, NAPA slowed the rate of VT and suppressed VT inducibility. We conclude that electrophysiologic properties of NAPA are slightly different from those of procainamide and that NAPA is not uniformly effective for suppressing ventricular dysrhythmias, but its antiarrhythmic mechanisms are similar to those of procainamide.

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Despite widespread marketing of a sustained release preparation of procainamide hydrochloride (PROCAN-SR, Parke-Davis), published literature demonstrating its efficacy in maintaining uniform serum drug levels over a 6-hour dosing interval is derived from only normal healthy volunteers. Thirty-three patients with ischemic heart disease, ages 30-88 years, were administered 1-4g/24 hours (mean dose 34 mg/kg/day) of PROCAN-SR in 4 equally divided doses on a Q6H schedule. After achievement of steady-state equilibrium drug concentration, procainamide and N-acetylprocainamide levels were determined by high-performance liquid chromatography on sera obtained from blood samples drawn 2, 3.5 and 5 hours after an oral dose. Mean maximal procainamide and N-acetylprocainamide serum concentrations were 4.6 +/- 1.8 microgram/ml and 4.2 +/- 2.1 micrograms/ml respectively. Mean minimal concentrations were 3.5 +/- 1.7 microgram/ml and 3.6 +/- 2.0 micrograms/ml respectively. The mean change in drug concentration was small (1.1 microgram/ml procainamide and 0.6 microgram/ml N-acetylprocainamide) with procainamide and N-acetylprocainamide concentrations varying only by 27 and 15 percent respectively. These data demonstrate in a population of patients with ischemic heart disease, that Q6H dosing with a sustained release procainamide hydrochloride preparation (PROCAN-SR, Parke-Davis) is associated with only a small acceptable variation between maximal and minimal serum procainamide and N-acetylprocainamide concentrations. This preparation should, therefore, offer greater patient convenience and compliance without sacrificing antiarrhythmic efficacy.

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Kinetics of and clinical responses to N-acetylprocainamide (NAPA) were evaluated in 10 patients with chronic ventricular arrhythmias who had not responded to usual doses of currently available antiarrhythmic drugs. Kinetic data analysis was by measured NAPA concentrations (n = 149) collected during repeated dosing. Response was evaluated with serial 24-hr ambulatory ECGs. An a priori kinetic model based on earlier studies predicted NAPA concentrations well (r = 0.94, SEE = 3.6 mg/l). The capability for defining patient-specific estimates for drug disposition with six or seven serum concentrations measured at the outset of therapy was subsequently confirmed with larger data sets from the same patients. Mean values for elimination rate (0.082 hr -1 +/- 0.017) and volume of distribution (1.25 l/kg +/- 0.28) were of the same order as in earlier single-dose studies. A substantial degree of interpatient and intrapatient variability in the absorption rate for NAPA was observed. NAPA was not found to be clinically effective in any of the 10 patients, although two patients demonstrated a greater than 70% reduction in frequency of premature ventricular contractions. There were adverse effects in all patients, which frequently required dose reduction or cessation of therapy. In this group of patients with resistant arrhythmias, NAPA was no more effective than baseline therapy, and adverse effects often limited complete evaluation. The kinetic analysis demonstrated the feasibility of a strategy for developing patient-specific kinetic models that may have applications to other antiarrhythmic drugs.

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In six normal subjects and 6 patients with primary cardiomyopathy, left ventricular performance was evaluated at rest and during isometric handgrip exercise after 4 days of oral N-acetylprocainamide (NAPA) at each of the three dosage levels (3, 4, 5, and 6 gm/day). Changes in heart rate, blood pressure, and echocardiographic performance indices were noted during isometric exercise, but no effect of NAPA could be demonstrated. In five additional patients with ventricular dysrhythmias due to cardiac diseases, NAPA was given by vein until dysrhythmias were controlled and then a maintenance infusion was continued for 48 hr. Continuous ECG recordings showed excellent dysrhythmia control in four of the five patients, but no effect of NAPA on heart rate, blood pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, or cardiac output was demonstrated, either at the peak of initial infusion (serm NAPA 27 +/- 6.7 microgramsm/ml) or at steady state during the maintenance infusion (16 +/- 4.5 microgramm/ml). We conclude that NAPA by vein and mouth in clinically appropriate doses should be safe in patients with the reduced left ventricular performance due to cardiac disease.

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The kinetic behavior of N-acetylprocainamide (NAPA) was studied after single and repeated oral doses in six healthy subjects and five patients with cardiomyopathy. Renal clearance (CLR) of NAPA was lower in patients than in normal subjects after an initial 1-gm dose (1.3 +/- 0.4 [x +1- SD] and 2.7 +/- 0.4 ml . min-1 . kg-1, P less than or equal to 0.001) and a final 2 gm dose (1.6 +/- 0.4 and 2.6 +/- 0.5 ml . min-1 . kg-1, P less than or equal to 0.01) even though there was no difference between measured creatinine clearance (ClCR) 80.8 +/- 23.6 and 93.2 +/- 19.3 ml . min-1 [1.73 M2]-1). The decrease in the ratio of NAPA ClR to ClCR (R) could not be accounted for by age alone. A published regression formula overestimated the R ratio for patients (1.65 +/- 0.09 and 1.25 +/- 0.17, P less then 0.025), but accurately predicted the R ratio for healthy subjects (2.10 +/- 0.04 and 1.99 +/- 0.54). Mean steady-state concentration (normalized for daily dose per unit of body mass) after 2 gm every 8 hr for at least 3 days was higher for patients (P less than or equal to 0.05). Comparing the parameters for all subjects after the initial 1-gm dose to those after the last 2-gm dose with paired data, oral clearance was somewhat lower after the last dose (3.7 +/- 1.0 and 3.1 +/- 1.0 ml . min-1 . kg-1, P less than or equal to 0.01). In spite of this, before and 2 hr after dose steady-state NAPA serum concentration were generally proportional to dose over the concentration range studied. Net deacetylation of NAPA to procainamide in both groups was minimal.

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Pharmacokinetic analysis of plasma concentration of acetyl procainamide ethobromide (APAEB) after single injection of 1.5, 8.8 and 20 mumol/300 g rat of APAEB showed that its elimination from plasma followed saturation kinetics. The existence of saturable step in transport of APAEB from blood to bile was also evident from the data of the biliary excretion at three dose levels. The data of the biliary excretion were well fitted to two compartment model with two saturable processes at the hepatic uptake and the biliary excretion. The Michaelis-Menten parameters were calculated according to that model. The model was also applicable to the data of biliary excretion obtained by constant infusion of APAEB Simulation of liver and plasma content gave a good agreement to the experimental data. All these results indicate that the pharmacokinetics of APAEB is satisfactorily represented by the proposed model.

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The purpose of this study was to determine the bioavailability of N-Acetylprocainamide (NAPA) from mixed diet in rats. Six groups of 8 male Charles River CD rats received NAPA-HCl as follows: Group I, an intravenous dose (mean 21 mg) of 14C-labelled drug. Group II, in a solution given by oral gavage with and without feed (50 mg) in a two-way crossover fashion. Groups III-VI, incorporated in diet (42-68 mg). Urine and feces were collected for 48 hours and assayed for NAPA and procainamide by a specific HPLC method. On the average, 73% of the drug was eliminated unchanged in urine. Only a small percentage (3-4%) of the intact drug was recovered in feces after intravenous or oral administration. There were no detectable levels of procainamide in urine and feces. The absolute bioavailability of NAPA from oral solution with and without feed was 87 and 90%, respectively, and from the mixed diet was 84-92%. There was no statistically significant difference between the bioavailability of NAPA from solution in fasted and fed rats or from NAPA-mixed diet, indicating that the absorption of the drug in rats was not affected by food. The relative bioavailability of the drug from mixed diet ranged from 94-103%.

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With ordinary procainamide tablets a dosing interval of 3-4 hours must be chosen to achieve therapeutically useful plasma concentrations during the entire interval. The concentrations of procainamide and its N-acetylated metabolite, NAPA, have been studied in the plasma of 10 normal volunteers and 11 patients who were given a new sustained release preparation at 8 hour intervals. Blood samples were taken between two doses on the fourth day of treatment. Procainamide showed levels within the accepted therapeutic range during the entire dosing interval. A dose of 4.5 g per day per 70 kg body-weight is necessary in order to achieve adequate levels. NAPA concentrations did not fluctuate during the dosing interval and mean steady-state concentrations were influenced predominantly by the degree of renal function. Saliva to plasma concentration ratio, measured in four patients, showed huge inter- and intraindividual variability. Therefore, saliva concentrations measurements of procainamide and NAPA are of little clinical use.

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N-Acetylprocainamide (NAPA) disposition kinetics was studied in eight patients with coronary artery disease. NAPA was given over a 45-min period by intravenous infusion, and blood samples were drawn at specified times for 24 hr. NAPA plasma levels were determined by a specific high-pressure liquid chromatography (HPLC) procedure and the concentration-time data were fit to a three-compartment model. Mean (+/- SD) values for the elimination half-life, the total body clearance, and the steady-state volume of distribution were 9.53 +/- 3.22 hr, 1.98 +/- 0.40 ml/min/kg, and 1.30 +/- 0.18 1/kg. There was moderate intersubject variability in disposition. The data reported here differ from those reported for normal subjects.

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