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PubMed1986

Procainamide toxicity in a patient with acute renal failure.

A patient developed acute renal failure while receiving oral procainamide (PA). This lead to severe PA and N-acetyl procainamide (NAPA) toxicity. Rebound of NAPA plasma levels postdialysis prolonged the toxicity, which was treated with hemodialysis, hemoperfusion, and combined hemodialysis-hemoperfusion. Because of the potential for PA and NAPA toxicity in patients with renal insufficiency, especially in patients with changing renal function due to acute renal failure, it is recommended that the use of PA be curtailed in this population and that another substitute antiarrhythmic agent be used.

Acecainide↗
PubMed1983

Thin-layer chromatographic determination of procainamide and N-acetylprocainamide in human serum and urine at single-dose levels.

Thin-layer chromatographic methods were applied for bioavailability studies of procainamide in serum and urine. Detection of the parent compound and the major metabolite was performed in the ultraviolet range at 275 nm. Using 100-microliter samples, detection limits were 60 ng of procainamide-HCl per ml serum and 7 micrograms/ml urine, and 60 ng of N-acetylprocainamide-HCl per ml serum and 5 micrograms/ml urine. Advantages over previous methods are discussed. From serum and urine data of five volunteers, the bioavailability of procainamide from a 250-mg dragee preparation compared with an intravenous dose was verified. Pharmacokinetic data were computed using one-compartment open models. Results corresponded well with values previously published.

Acecainide↗
PubMed1984

Torsade de pointes induced by N-acetylprocainamide.

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.

Acecainide↗
PubMed1984

Comparative electrophysiologic effects of intravenous and oral procainamide in patients with sustained ventricular arrhythmias.

Thirty-three patients with sustained ventricular arrhythmias underwent electrophysiologic testing after intravenous and again after oral procainamide administration. Two groups were identified: group 1 included 15 patients with concordant serum procainamide concentrations with less than a 3 micrograms/ml difference after intravenous (mean 8.6 +/- 2.7) and oral (mean 8.8 +/- 2.7) procainamide administration, with mean N-acetylprocainamide concentrations of 1.0 +/- 0.6 and 6.2 +/- 2.8 micrograms/ml, respectively. Group 2 included 18 patients with discordant serum procainamide concentrations after intravenous (mean 9.5 +/- 5.9 micrograms/ml) and oral (mean 14.1 +/- 5.2 micrograms/ml) procainamide, with mean N-acetylprocainamide concentrations of 0.9 +/- 0.5 and 10.7 +/- 5.7 micrograms/ml, respectively. In group 1, response to programmed stimulation was the same after intravenous and oral procainamide administration, with no inducible ventricular arrhythmia in 5 of 15 patients. In group 2, 3 of 18 patients had no inducible arrhythmia after intravenous compared with 7 of 18 patients after oral procainamide administration. There was a different response to programmed stimulation after oral compared with intravenous procainamide in 6 of 18 patients in group 2 but in none of 15 patients in group 1 (p = 0.02). The effective procainamide concentration was greater than the ineffective concentration in five of the six patients with a discordant response, and the effective route of administration was oral in five of the six patients. The change in ventricular refractoriness in group 1 was similar after intravenous (28 +/- 23 ms) and oral (29 +/- 19 ms) procainamide, whereas in group 2, refractoriness was increased more after oral (33 +/- 21 ms) than intravenous (20 +/- 17 ms) procainamide administration and paralleled the difference in procainamide concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acecainide↗
PubMed1986

Clinical features and basic mechanisms of quinidine-induced arrhythmias.

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and the morphologically distinctive tachyarrhythmia torsade de pointes. Clinical data from our institution and others have revealed a number of characteristic features: quinidine plasma concentrations are generally low, marked QRS prolongation is absent, hypokalemia is frequent and abrupt heart rate slowing just before the initiation of a paroxysm is almost invariable. The lack of correlation between plasma quinidine concentrations and this adverse drug effect raises the possibility either that external factors (for example, hypokalemia) modulate the response to quinidine in vivo or that one or more unmeasured active metabolites play a role. Therefore, the effect of alterations in extracellular potassium and stimulation rate on the electrophysiologic effects of quinidine were examined in canine Purkinje fibers. It was found that a form of triggered automaticity, early afterdepolarizations, is reliably produced in the presence of quinidine when extracellular potassium is lowered and the stimulation rate is slowed. More recently, the effects of a number of quinidine metabolites, as well as the commonly found impurity dihydroquinidine, were characterized in canine Purkinje fibers in a similar fashion. Although quinidine was the most potent of the substances tested, both dihydroquinidine and 3-hydroxyquinidine prolonged action potential and produced early afterdepolarizations as did quinidine at long cycle lengths. Quinidine-induced torsade de pointes is a potentially lethal adverse drug effect, occurring in 1 to 3% of patients. Hypokalemia and slow heart rates are commonly observed in a clinical setting and, in the tissue bath, quinidine and several of its metabolites induce abnormal automatic behavior when extracellular potassium is lowered and stimulation rate is slowed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acecainide↗
PubMed1987

Effects of N-acetylprocainamide on experimental atrial flutter and atrial electrophysiologic properties in conscious dogs with sterile pericarditis: comparison with the effects of quinidine.

N-acetylprocainamide (NAPA) is said to have class III antiarrhythmic drug properties. The effects of NAPA (25 mg/kg intravenously) on sustained, stable, reentrant atrial flutter induced in 12 conscious dogs using a sterile pericarditis model were studied and compared with the effects of quinidine (5 mg/kg intravenously) given on a different day in 10 of the same 12 dogs. The effects of these drugs on atrial excitability, the atrial effective refractory period and intraatrial conduction time measured during rapid atrial pacing performed during sinus rhythm were also compared. The mean NAPA and quinidine serum levels were 17.7 and 7.1 micrograms/ml, respectively. Both NAPA and quinidine immediately prolonged the atrial flutter cycle length in all dogs, from 118 +/- 15 to 141 +/- 18 ms and from 119 +/- 17 to 153 +/- 21 ms, respectively (both p less than 0.001), and then terminated atrial flutter in 11 of the 12 NAPA studies and in 6 of the 10 quinidine studies. Neither drug affected atrial excitability. Both NAPA and quinidine increased the atrial effective refractory period significantly, from 138 +/- 17 to 168 +/- 20 ms (p less than 0.001) and from 136 +/- 14 to 148 +/- 16 ms (p less than 0.01), respectively. NAPA did not change intraatrial conduction time measured during atrial pacing at 150 beats/min, but during atrial pacing at 300 beats/min, it prolonged it from 51 +/- 9 to 54 +/- 10 ms (p less than 0.05), and at 400 beats/min, from 52 +/- 10 to 64 +/- 13 ms (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acecainide↗
PubMed2001

Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.

Acecainide↗
PubMed2005

High-throughput solution-based medicinal library screening against human serum albumin.

High-throughput screening of combinatorial libraries has evolved from studying large diverse libraries to analyzing small, structurally similar, focused libraries. This paradigm shift has generated a need for rapid screening technologies to screen both diverse and focused libraries in a simple, efficient, and inexpensive manner. We have proactively addressed these needs by developing a high-throughput, solution-based method combining size exclusion (SEC), two-dimensional liquid chromatography (2-D LC), and mass spectrometry (MS) for determining the relative binding of drug candidates in small, focused medicinal libraries against human serum albumin (HSA). Two types of libraries were used to evaluate the performance of the system. The first consisted of five diverse ligands with a wide range of hydrophobicities and whose association constants to HSA cover 3 orders of magnitude. A beta-lactam library composed of structurally similar compounds was used to further confirm the validity of the methodology. The ability to distinguish site-specific interactions of drugs competing for individual domains of the HSA receptor is also demonstrated. Comparison of chromatographic profiles of the library components before and after incubation with the receptor using multiple reaction monitoring allowed a ranking of the ligands according to their relative binding affinities. The observed rankings correlate closely with literature values of the association constants between the respective ligands and HSA. This simple, rugged methodology can screen a wide spectrum of chemical entities from combinatorial mixtures in less than 6 min.

Acecainide↗
PubMed1996

Application of computer-assisted radiotelemetry in the pharmacokinetic and pharmacodynamic modeling of procainamide and N-acetylprocainamide.

The cardiovascular pharmacodynamics (PD) of procainamide and N-acetylprocainamide have not been well characterized in small rodents without the presence of anesthesia or restraint. This study was undertaken to examine the pharmacokinetics (PK) and PD relationship of procainamide and N-acetylprocainamide by use of electrocardiogram (ECG) telemetry in unrestrained rats. Male Sprague Dawley rats received the following treatments: vehicle, procainamide 50 and 100 mg/kg and N-acetylprocainamide 50 and 100 mg/kg via intraperitoneal (i.p.) administration. Blood samples were collected over 8 h and subsequently analyzed. PD measurements (PQ, QS, QR, QT, RR, and HR) were collected prior to dosing and over a 24 h period. Mean PK parameters after the 50 mg/kg dose were as follows: Cls/Fprocainamide = 86.42 mL min-1 kg-1, Cls/FN-acetylprocainamide = 36.62 mL min-1 kg-1, Vdprocainamide = 10.42 L/kg, and VdN-acetylprocainamide = 5.91 L/kg. The relationship between concentration (procainamide or N-acetylprocainamide) and effect (percent change QT interval) was best described by an Emax model for procainamide (EC50 = 445 ng/mL; Emax = 30.09%). These results approximate ECG changes noted in procainamide clinical studies, suggesting that telemetry can be used as a predictive tool of efficacy. Furthermore, the proposed PK-PD model describes the electrophysiological effects associated with procainamide.

Acecainide↗
PubMed1988

Metabolite formation pharmacokinetics: rate and extent of metabolite formation determined by deconvolution.

A two-step analytic procedure to determine the rate and extent of metabolite production following administration of the parent compound is described. The procedure provides the rate and extent of metabolite production as a function of time by application of the general model independent approach of deconvolution. The metabolite unit impulse response function is obtained by implicit deconvolution of the metabolite data with a truncated constant-rate metabolite input function. Then the obtained unit impulse response function is used in an analytic deconvolution with metabolite data following administration of the parent compound to obtain the rate and extent of metabolite production. The input function is also deconvolved with metabolite data to obtain the unit impulse response function appropriate for prediction of metabolite levels given a selected input of parent compound. The expected profile following administration of the consecutive infusions of parent drug is shown for both parent and metabolite. The rationale for selection of deconvolution methods is discussed. The approach is applied to data for procainamide and N-acetylprocainamide from three human subjects. The results indicate that from 27 to 39% of the procainamide was converted to N-acetylprocainamide in these subjects.

Acecainide↗
PubMed1989

Effect of the immunomodulator tilorone on the in vivo acetylation of procainamide in the rat.

Interferon and interferon inducers have been found to inhibit cytochrome P-450-dependent metabolism in animals and man. The effect of these agents on the acetylation of drugs has not been previously reported. Since these agents stimulate the reticuloendothelial system, together with the abundance of N-acetyltransferase in the reticuloendothelial system, it was hypothesized that these immunomodulators may affect drug acetylation. To test this hypothesis, the effect of tilorone (a synthetic interferon inducer) on the in vivo acetylation of procainamide was examined in the rat. Pretreatment with tilorone hydrochloride (50 mg/kg) 48 hr prior to the administration of procainamide hydrochloride (50 mg/kg) resulted in a 32% increase in the urinary recovery of N-acetylprocainamide and a 35% increase in the metabolic clearance of procainamide to N-acetylprocainamide. These data indicate that interferon inducers increase the N-acetylation of drugs in vivo.

Acecainide↗
PubMed1980

Intravenous N-acetylprocainamide disposition kinetics in coronary artery disease.

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.

Acecainide↗
PubMed1980

Kinetics of N-acetylprocainamide deacetylation.

The kinetics of N-acetylprocainamide (NAPA) deacetylation to procainamide (PA) were determined in a normal subject using NAPA-13C, labeled in the acetyl group. The deacetylation clearance of NAPA (ClD) was found to be 6.5 ml/min whereas total NAPA elimination clearance was 231 ml/min, so that 2.8% of the administered NAPA-13C was metabolized by deacetylation. This estimated of ClD was shown to be representative of the rate of NAPA deacetylation in four patients on long-term NAPA therapy. Steady-state [PA]/[NAPA] ratios averaged 0.024, but would be expected to rise to 0.057 if functionally anephric patients were treated with NAPA. Despite reports that patients with the PA-induced systemic lupus erythematosus-like reaction have had symptomatic and immunologic remission when switched to NAPA, the demonstration that NAPA is deacetylated to PA indicates that the apparently greater immunologic safety of NAPA may be relative rather than absolute.

Acecainide↗
PubMed1980

Aging and renal clearance of procainamide and acetylprocainamide.

Thirty-two patients had blood and urine collected simultaneously for measurement of procainamide, acetylprocainamide, and creatinine. The ratios of drug clearance to creatinine clearance were calculated for each. The procainamide:creatinine clearance ratio averaged 2.9 +/- 1.6 (SD) and fell as age of the patients rose (r = 0.5, p < 0.01). The acetylprocainamide:creatinine clearance ratio averaged 1.7 +/- 0.8 and also fell with age. The combination of decline in overall renal function with age with this decrease in the rate of renal tubular secretion of these drugs led to a progressive age-related rise in the steady-state serum level of procainamide (r = 0.56, p < 0.01) and acetylprocainamide (r = 0.36, p < 0.1) achieved by any dose of procainamide. Thus, the dosage of procainamide must be individualized for both overall renal function (GFR) and the age-related variations in renal tubular secretion that are of most note in children and the elderly.

Acecainide↗
PubMed1981

N-Acetyl-procainamide kinetics in the elderly.

Plasma and saliva N-acetyl-procainamide (NAPA) concentrations were measured by high-power liquid chromatography (HPLC) after intravenous infusion of 750 mg to 14 elderly patients (x age = 69 yr). The plasma NAPA disappearance curve can best be described by a two-compartment body model. Mean total body clearance was 10.6 1/hr, Vdss 125.8 1, and terminal half-life (t 1/2) 8.8 hr. A nonrenal clearance of 2.72 1/hr was calculated, that is, 19% of the expected total body clearance with normal kidney function. Saliva concentrations show huge inter- and intraindividual variability and are probably not usable for NAPA monitoring in older patients.

Acecainide↗
PubMed1982

N-Acetylprocainamide kinetics and clinical response during repeated dosing.

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.

Acecainide↗