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At least 19 recordsLinked to original sources
PubMed1989

Pharmacokinetic and pharmacodynamic interaction of N-acetyl procainamide and procainamide in humans.

Procainamide is a sodium channel blocker which prolongs QRS and QTc intervals, yet its major active metabolite, N-acetylprocainamide (NAPA), generally prolongs only QTc and has very different electrophysiologic and antiarrhythmic actions. In greater than 50% of patients receiving chronic treatment with procainamide, plasma concentrations of NAPA exceed those of procainamide. In this study, we examined the hypothesis that NAPA might alter the disposition kinetics or pharmacologic actions of procainamide. Ten patients with frequent ventricular extrasystoles received intravenous (i.v.) infusions of procainamide alone (study day 1), procainamide and NAPA (study day 2), and NAPA alone (study day 3) at least 48 h apart. On study days 1 and 2, procainamide was administered at a constant rate for 4 h. On study days 2 and 3, NAPA was administered as a loading and maintenance infusion designed to reach a target pseudo-equilibrium plasma concentration of 8 micrograms/ml. NAPA increased procainamide elimination half-life (t1/2) from 275 +/- 42 min (mean +/- SD) on day 1 to 340 +/- 74 min on day 2 (p less than 0.01). A significant correlations was noted between the change in procainamide total clearance on day 2 relative to day 1 and the initial procainamide total clearance on day 1 (r = -0.77, p = 0.009). Findings were similar when procainamide fractional urinary excretion was considered (r = -0.89, p = 0.007). NAPA did not alter procainamide-induced QRS prolongation, but potentiated procainamide-induced QTc prolongation. The antiarrhythmic response to procainamide was not significantly altered by NAPA in seven of nine patients. One patient had greater arrhythmia suppression when NAPA and procainamide were combined than when either was administered alone. In one patient, NAPA apparently antagonized procainamide-induced arrhythmia suppression, but this effect was not reproducible. We conclude that accumulation of NAPA during procainamide therapy can alter both procainamide elimination as well as its electrophysiologic actions.

Acecainide↗
PubMed1985

Electropharmacologic testing in sustained ventricular tachycardia associated with coronary heart disease: value of the response to intravenous procainamide in predicting the response to oral procainamide and oral quinidine treatment.

Twenty patients with inducible, sustained ventricular tachycardia (VT) were prospectively evaluated to determine whether the response to intravenous procainamide administration, as assessed by programmed ventricular stimulation, predicted the response to oral procainamide and oral quinidine treatment. Six patients (30%) responded to intravenous procainamide (fewer than 10 beats of inducible VT). Ten of 20 patients (50%) responded to oral quinidine and 5 (25%) responded to oral procainamide. Mean drug serum levels were 11.3 +/- 2.1 micrograms/ml for intravenous procainamide, 5.4 +/- 0.8 micrograms/ml for oral quinidine and 11.7 +/- 3.4 micrograms/ml for oral procainamide. There was no significant difference in serum levels between those who responded and those who did not. Fifteen patients (75%) had a concordant drug response for intravenous and oral procainamide. Ten patients (50%) had a concordant response for intravenous procainamide and oral quinidine. Fifteen patients (75%) had a concordant drug response for oral procainamide and oral quinidine. Thus, in patients with sustained VT, the response to intravenous procainamide does not reliably predict the response to oral quinidine or oral procainamide, and serial day drug testing with these agents is necessary. Furthermore, high-dose quinidine therapy may be more effective in controlling VT in these patients than procainamide.

Administration, Oral↗
PubMed1991

The role of combination therapy with mexiletine and procainamide in patients with inducible sustained ventricular tachycardia refractory to intravenous procainamide.

This study evaluated the role of serial electropharmacological testing on combination therapy with mexiletine and procainamide in 20 patients with inducible sustained ventricular tachycardia (VT) refractory to intravenous procainamide. The clinical arrhythmias were cardiac arrest in five patients, sustained VT in 11 patients, and recurrent syncope of presumably arrhythmic origin in four patients. The mean left ventricular ejection fraction (LVEF) was 0.40 +/- 0.12 (mean +/- SD). All patients had inducible sustained VT at baseline and after administration of intravenous procainamide. All 20 patients underwent electropharmacological testing on combination therapy with mexiletine and procainamide. The mean cycle length of inducible sustained VT was 251 +/- 48 ms at baseline, 324 +/- 81 ms on intravenous procainamide (P less than 0.014 vs baseline), and 365 +/- 82 ms on combination therapy (P less than 0.0001 vs baseline, P = NS vs intravenous procainamide). Combination therapy did not suppress VT inducibility, nor did it make VT more difficult to induce in 19 of 20 patients. The remaining one patient had a partial response (runs of nonsustained VT, longest 10 seconds). Furthermore, combination therapy did not significantly prolong the VT cycle length over and above that observed during testing with intravenous procainamide. Therefore, in patients with inducible sustained VT refractory to procainamide during initial electropharmacological testing, mexiletine in combination with procainamide appears to be of little or no value and serial electropharmacological testing on these drugs is of limited usefulness. Early initiation of alternative therapy may be the preferred clinical option.

Adult↗
PubMed2000

Reduction of cisplatin nephrotoxicity by procainamide: does the formation of a cisplatin-procainamide complex play a role?

Procainamide protects mice bearing P388 leukemic cells against the toxicity of cisplatin without diminishing antitumor activity. The mechanism of action of procainamide protection was investigated both in vitro and in vivo. HPLC studies showed that procainamide forms a complex with cisplatin in vitro that has a UV spectrum similar to that of DPR, a triamine platinum complex that contains procaine as ligand. We report here the effect of the reaction product of cisplatin and procainamide on both cisplatin-induced DNA interstrand cross-links (ISCLs) and on the total DNA platination of isolated DNA. Total DNA platination in vitro of isolated DNA was increased by 113% (P <.01) and 17% (P <.05) after incubation times of 1.75 and 6 h, respectively, compared with products from the reaction of cisplatin with water. Furthermore, the reaction product of cisplatin and procainamide was bound to DNA to a significantly greater extent than was cisplatin itself. ISCLs were decreased by 41% when this drug combination was incubated with DNA for 1.75 h, but no changes were observed after incubation for 6 h. We also examined the influence of the time interval between administration of cisplatin and procainamide on normal kidney injury, the renal distribution and urinary excretion of platinum, and the formation of cisplatin-DNA adducts in renal tissue of Sprague-Dawley rats after i.p. administration of 7.5 mg/kg cisplatin either with or without procainamide. The plasma concentrations of urea and creatinine and kidney histology demonstrated that procainamide provided effective protection in vivo in the rat when administered either simultaneously or at 0.5 and 1 h before or after cisplatin. The protection was accompanied by both higher renal levels of platinum and cisplatin-DNA adducts and by an increase in the formation of ISCLs. Moreover, a dose-dependent reduction of urinary excretion and concentration of platinum was also observed. We propose that procainamide, after accumulation in the kidney, may coordinate with cisplatin to form a less toxic DPR-like complex that renders rats less susceptible to cisplatin-induced toxicity.

Animals↗
PubMedDate not supplied

[Verification of therapeutic levels of procainamide and N-acetyl- procainamide in ventricular arrhythmia].

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 .

Acecainide↗
PubMed1987

Mandibular and parotid salivary excretion of procainamide and N-acetylprocainamide after intravenous administration of procainamide to rats.

Flow rate, protein level and pH of mandibular and parotid saliva samples in rats were almost stabilized 2 h after induction of salivation with pilocarpine (9.0 mg h-1 kg-1). Salivary excretion profiles of procainamide, 50 mg kg-1 i.v., and its metabolite N-acetylprocainamide (NAPA) were then investigated. Plasma and salivary procainamide levels declined bi-exponentially with time almost in parallel. Salivary procainamide levels (Y) from both types of gland were correlated with the plasma level (X) over a wide concentration range [Y = 0.108X + 1.96 (r = 0.795) for mandibular and Y = 0.917X (r = 0.974) for parotid glands]. The mean saliva to plasma concentration ratio (S/P ratio) was significantly higher in parotid (0.974 +/- 0.243) than in mandibular (0.284 +/- 0.119) saliva samples. Similar correlations and S/P ratios were observed for NAPA. Procainamide and NAPA mean S/P ratios for saliva from both glands were fairly consistent with the calculated value according to the pH-partition hypothesis.

Acecainide↗
PubMed1989

[A new anti-arrhythmia drug. II. Comparative studies of the effects of a new acyl derivative of procainamide, procainamide and N-acetylprocainamide on blood pressure and the electrocardiogram in rabbits].

In the recent years a remarkable number of new antiarrhythmic drugs have been introduced, but their side effects limit the application. Procainamide (PA) and N-acetylprocainamide (Acekainide, NAPA) display many undesired side effects, too. It was assumed that N-propionyl-procainamide, having antiarrhythmic activity, might display less unfavourable effects on arterial blood pressure, heart rate and heart conduction system in rabbits, because of blockade of the primary aromatic amine group. The obtained results were subjected to statistical analysis. It has been stated that N-propionylprocainamide decreases the arterial blood pressure in rabbits to a lesser extent than procainamide. Moreover, in contrast with the latter compound, N-propionylprocainamide accelerates the heart rate, but does not influence the atrio-ventricular conduction, and does not prolong the ventricular refraction time. Antiarrhythmic activity of N-propionylprocainamide, not being inferior to that of procainamide and N-acetylprocainamide, and lesser side effects of N-propionylprocainamide indicate for advisability of further studies of this compound.

Acecainide↗
PubMed1980

[Steady-state plasma and saliva concentrations of procainamide and N-acetyl-procainamide after a sustained release preparation].

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.

Acecainide↗
PubMed1977

Analysis for procainamide and N-acetyl procainamide in plasma or serum by high-performance liquid chromatography.

A high-performance liquid chromatography method is presented for simultaneous analysis for procainamide and N-acetyl procainamide in plasma or serum. The procedure involves internal-standard addition, organic extraction, and separation on a reverse-phase column. The detection limit for procainamide is 0.1 mg/liter and the calibration plot is linear to at least 30 mg/liter. Comparison with a colorimetric assay for procainamide gave a correlation coefficient of 0.989. We checked for interference by a large series of appropriate drugs, and found none, nor did icteric or lipemic sera present problems.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Improved semi-automated analysis of procainamide and N-acetyl procainamide utilizing a totally volatile mobile phase.

A semi-automated technique has been devised for the analysis of the antirhythmic drugs, procainamide (PA) and N-acetyl procainamide (NAPA) from human serum. Reverse-phase high-performance liquid chromatographic (HPLC) separations were performed by means of an autoinjector system in combination with microBondapak C18 column. A mobile phase containing only volatile buffers (e.g., triethylamine-acetic acid or N-ethyl morpholine-acetic acid) at apparent pH 5.3 was necessitated to prevent the buildup of salt residues on the valves and fittings within the autoinjector and high pressure pump. For HPLC analysis of these drugs, the within-run precision, as estimated by coefficient of variation analysis, was less than 9%. Comparable precision was shown for day-to-day variation in analysis. No interference was noted from 20 other substances, metabolites or drugs that might be present in the sera extracts. This semi automated procedure has been utilized successfully to quantitate over 200 patient sera on a bach or emergency basis.

Acecainide↗
PubMed1986

Prediction of steady-state trough serum procainamide concentrations after administration of a sustained-release procainamide preparation.

Four methods of predicting steady-state trough serum procainamide concentrations (SPC) were compared in 15 patients receiving sustained-release procainamide (Procan-SR) therapy. All methods were based on a one-compartment pharmacokinetic model. Method 1 utilized nine initial measured SPC and individualized pharmacokinetic parameters for prediction of the steady-state SPC. Method 2 utilized three SPC and individualized pharmacokinetic parameters. Method 3 utilized two SPC and an individualized apparent elimination rate constant plus other average pharmacokinetic parameters. Method 4 utilized all averaged pharmacokinetic parameters (required no initial SPC). The predicted and measured SPCs for each method were analyzed by linear regression. Regression equations and correlation coefficients (r) for Methods 1, 2, 3, and 4 were as follows: predicted SPC = 0.72 measured SPC + 1.60 (r = 0.86), predicted SPC = 0.67 measured SPC + 1.74 (r = 0.82), predicted SPC = 0.13 measured SPC + 2.57 (r = 0.58), and predicted SPC = 0.15 measured SPC + 2.47 (r = 0.52), respectively. The precision, as measured by the mean squared prediction error (95% confidence interval) for Methods 1, 2, 3, and 4 was 1.44 (0.61, 2.27), 1.75 (0.93, 2.57), 2.81 (1.3, 4.49), and 3.68 (1.12, 6.26), respectively. (Eighty-five percent of the predictions were within +/- 1.5 micrograms/ml of the measured SPC by Methods 1 and 2, as compared with 69% by Methods 3 and 4.) Bias, as measured by the mean prediction error (95% confidence interval) for Methods 1, 2, 3, and 4 were -0.44 (-0.90, 0.03), -0.34 (-0.87, 0.18), -0.43 (-1.09, 0.24), and -0.98 (-1.66, -0.31).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1981

Identification of desethyl procainamide in patients: a new metabolite of procainamide.

Desethyl procainamide (PADE) was identified in the urine of a patient treated with procainamide (PA) by high-performance liquid chromatography followed by solid-probe mass spectrometry. PADE prevented ventricular fibrillation in chloroform-asphyxiated mice but PA was 1.5 times more potent than PADE with respect to dose and 1.7 times more potent with respect to plasma concentration measured after administration of antiarrhythmic ED50 doses of the two compounds. N-acetylprocainamide was found to be 1.8 times more potent than desethyl N-acetylprocainamide with respect to dose and 2.9 times more potent with respect to plasma concentration. Measurements of PA, PADE, N-acetylprocainamide and desethyl-N-acetylprocainamide concentrations in 10 patients receiving long-term PA therapy suggest that only PA and N-acetylprocainamide concentrations make important contributions to observed therapeutic responses.

Acecainide↗
PubMed1996

Procainamide-induced agranulocytosis differs serologically and clinically from procainamide-induced lupus.

Agranulocytosis is a well recognized but uncommon complication of procainamide (PA) therapy, whereas a lupus-like syndrome occurs in approximately 20% of patients treated chronically with PA. In order to gain insight into the immunopathogenic relationships among these conditions, we compared the humoral immune abnormalities in these patient groups as well as in asymptomatic PA-treated patients. A relatively uniform profile of IgM but not IgG autoantibody reactivity with a set of chromatin-related antigens was observed in eight elderly men who developed agranulocytosis after treatment with PA. In contrast PA-induced lupus patients had predominant reactivity with [(H2A-H2B)-DNA] in both IgM and IgG classes. Five of eight patients with agranulocytosis had elevated levels of neutrophil-reactive IgG which appeared to be due to immune complexes based on Fc gamma receptor blocking studies. However, 12 of 15 patients with PA-induced lupus, none of whom had neutropenia, had similar levels of neutrophil-reactive IgG, suggesting that this reactivity was not causally related to agranulocytosis. Agranulocytosis developed after less than 3 months treatment with PA in six of eight patients. This time course was similar to that seen in 77 PA-induced agranulocytosis patients reported in the literature plus 127 patients reported to the U.S. Food and Drug Administration in whom 90% developed agranulocytosis within 3 months of starting PA. In contrast, the mode duration of treatment with PA before lupus-like symptoms develop is 10-12 months. These findings, together with the different profiles of autoantibodies and clinical presentations, suggest that agranulocytosis arises from a different mechanism than that underlying PA-induced lupus.

Aged↗
PubMed1979

Procainamide-induced lupus erythematosus-like syndrome in relation to acetylator phenotype and plasma levels of procainamide.

To investigate the relationship between acetylator phenotype and the development of procainamide (PA)-induced systemic lupus erythematosus (SLE-like syndrome, 28 patients with chronic ventricular arrhythmias treated with PA were followed for one year. The therapy was guided by plasma monitoring in all patients in order to obtain the proposed therapeutic plasma level of PA. Nine patients (30%), both slow and rapid acetylators, developed the SLE-like syndrome within one year. PA plasma levels were similar in both slow and rapid acetylators and there was no difference in total dose or duration of therapy before development of the syndrome. Thus, the acetylator phenotype is probably of no or minor predictive importance when PA therapy is guided by plasma monitoring. On the other hand, the antinuclear antibodies appeared significantly more rapidly in patients developing the syndrome and could possible be used as an indicator of the risk. The results support the hypothesis that the primary amino group structure of PA may be of importance in the induction of the SLE-like syndrome.

Acecainide↗
PubMed1996

Monitoring of procainamide and N-acetylprocainamide concentration in saliva after oral administration of procainamide.

The aim of this study was to evaluate saliva as a potential monitoring medium for procainamide (PA) and its metabolite, N-acetylprocainamide (NAPA). Saliva concentrations of PA and NAPA were determined both in single and repeated oral administration of PA in four healthy subjects. PA and NAPA were detected both in serum and saliva after 500 mg of single oral administration of PA. After single oral administration, serum and saliva concentrations of PA and NAPA reached peak levels at about 1 h and declined thereafter. The mean half-lives of PA were 2.35 h in serum and 1.28 h in saliva. The mean half-lives of NAPA were 5.29 h in serum and 5.01 h in saliva. In this study, PA and NAPA concentrations in saliva were nearly twice as high as those in serum upon chronic oral administration as well as those in a single oral dose of PA. Significant correlation coefficients were observed between serum and saliva concentrations of PA (r = 0.78, p < 0.001, n = 21) and NAPA (r = 0.76, p > 0.001, n = 21) in single oral administration of PA. Significant correlation coefficients were also observed between serum and saliva concentrations of PA (r = 0.89, p < 0.001, n = 17) and NAPA (r = 0.87, p > 0.001, n = 19) after repeated oral administration of PA. The saliva-to-serum ratios of PA and NAPA maintained nearly constant at 1 h after oral administration. It would appear from this study that saliva is a suitable medium for monitoring PA and NAPA concentration regarding acetylator status.

Journal Article↗