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PubMedDate not supplied

Morphological and histochemical evidence of the protective effect of procainamide hydrochloride on tissue damage induced by repeated administration of low doses of cisplatin.

BACKGROUND: The class 1 antiarrhythmic drug procainamide hydrochloride might protect against acute cisplatin-induced nephrotoxicity and hepatotoxicity in mice and rats. In this report, the protective activity of procainamide hydrochloride against renal and hepatic tissue damage induced by repeated administration of low doses of cisplatin was analyzed morphologically and histochemically. MATERIALS AND METHODS: Light microscopy observations were performed on liver, renal and heart samples obtained from female Wistar rats treated twice a week for 10 weeks with 1 mg/kg cisplatin (cumulative dose: 20 mg/kg), with or without 100 mg/kg procainamide hydrochloride (cumulative dose: 2 g). Samples were then submitted to histochemical stainings [i.e. H & E, periodic acid Schiff (PAS) and Sudan Black]. RESULTS: Light microscopy analysis revealed that the coadministration of cisplatin and procainamide hydrochloride significantly reduced tissue alterations both in the kidneys and liver, while in the heart, neither cisplatin nor the combination of cisplatin and procainamide hydrochloride caused any evident tissue damage. CONCLUSION: The morphological and histochemical data confirm that procainamide hydrochloride is able to protect not only from acute cisplatin-induced toxicities, but also from tissue alterations induced in the liver and kidneys by the administration of repeated low doses of cisplatin.

Animals↗
PubMed1991

Stability of amrinone and digoxin, procainamide hydrochloride, propranolol hydrochloride, sodium bicarbonate, potassium chloride, or verapamil hydrochloride in intravenous admixtures.

The stability of amrinone and digoxin, procainamide hydrochloride, propranolol hydrochloride, sodium bicarbonate, potassium chloride, or verapamil hydrochloride in intravenous admixtures was studied. Admixtures of amrinone and digoxin were studied at one concentration. Amrinone admixtures with propranolol hydrochloride, sodium bicarbonate, potassium chloride, and verapamil hydrochloride were studied at two concentrations. In general, 0.45% sodium chloride injection was used as the diluent; 5% dextrose injection was also used for the procainamide hydrochloride experiments. Duplicate solutions of each test admixture and single-drug control admixture were prepared and stored for four hours at 22-23 degrees C under fluorescent light. Samples were analyzed by visual inspection, tested for pH, and assayed by high-performance liquid chromatography. Admixtures containing amrinone 1.25 or 2.5 mg/mL (as the lactate salt) and sodium bicarbonate 37.5 mg/mL precipitated immediately or within 10 minutes. No changes in pH or visual appearance were noted for amrinone admixtures with procainamide hydrochloride, digoxin, propranolol hydrochloride, potassium chloride, and verapamil hydrochloride. Appreciable degradation of both amrinone and procainamide was observed after four hours when the two were mixed in 5% dextrose. No degradation of amrinone or procainamide was seen when the 5% dextrose was replaced by 0.45% sodium chloride. Amrinone and sodium bicarbonate were incompatible in intravenous admixtures. Amrinone was compatible with digoxin, propranolol hydrochloride, potassium chloride, and verapamil hydrochloride. Amrinone and procainamide were compatible in 0.45% sodium chloride injection but not in 5% dextrose injection.

Amrinone↗
PubMed1988

Procainamide in vivo modulates suppressor T lymphocyte activity.

Autoantibodies to histone and denatured DNA have been found in 80% of patients treated with procainamide. Of these 10 to 20% will eventually develop a Systemic Lupus Erythematosus-like syndrome. Although the mechanism by which procainamide exerts its effect is unknown, in vitro studies suggest that procainamide may inhibit suppressor T cell activity. We have studied the immune function of 18 patients receiving a two hour infusion of procainamide during transvenous catheter electrophysiologic studies. There was no difference between pre and post infusion samples with respect to T and B cell mitogenesis or pokeweed mitogen-induced immunoglobulin secretion. However, in seventeen of eighteen patients, there was a marked decrease in Concanavalin A-inducible suppressor cell activity. This decrease appeared to be related to the amount of procainamide infused as high dose samples showed less suppressor activity than low dose samples. Thus the data show that procainamide, when given in vivo, leads to a rapid and dose dependent decrease in suppressor cell activity.

Adult↗
PubMed1988

Stability of milrinone and digoxin, furosemide, procainamide hydrochloride, propranolol hydrochloride, quinidine gluconate, or verapamil hydrochloride in 5% dextrose injection.

The stability of milrinone and digoxin, furosemide, procainamide hydrochloride, propranolol hydrochloride, quinidine gluconate, or verapamil hydrochloride in 5% dextrose injection containing milrinone was studied. Milrinone admixtures with digoxin, furosemide, propranolol hydrochloride, quinidine gluconate, and verapamil hydrochloride were studied at two concentrations. Admixtures of milrinone and procainamide hydrochloride were studied at four concentrations. Duplicate solutions of each admixture and each control were prepared and stored in glass containers for four hours at room temperature (22-23 degrees C), under normal fluorescent lights. The samples were analyzed immediately by visual inspection, tested for pH, and assayed by high-performance liquid chromatography (HPLC). Milrinone 0.35 mg/mL-furosemide 4 mg/mL and milrinone 0.1 mg/mL-furosemide 5 mg/mL admixtures precipitated immediately after preparation and were not studied by HPLC. No changes in pH or visual appearance were observed in the remaining admixtures after storage at room temperature for four hours. Admixtures containing milrinone 0.175 or 0.2 mg/mL and procainamide hydrochloride 1, 2, or 4 mg/mL satisfied the USP standard for procainamide hydrochloride injection USP assay after one hour but failed this test in all cases after four hours. No degradation of milrinone was observed in any of the admixtures containing procainamide hydrochloride. Milrinone and furosemide are incompatible in 5% dextrose injection and should be administered separately. The remaining admixtures were compatible, and all except those containing procainamide hydrochloride were stable for four hours at room temperature.

Digoxin↗
PubMed1985

Conventional and sustained-release procainamide: update on pharmacology and clinical use.

Hemodynamic and electrophysiologic effects of procainamide, the pharmacokinetic properties of conventional and sustained-release forms of the drug, guidelines for its administration and dosage, and contraindications for and adverse effects of its use are outlined. A review of clinical studies of procainamide therapy concludes that in the treatment of ventricular arrhythmia it is comparable to other class IA drugs and generally superior to beta-blockers and to class IB drugs. For atrial arrhythmias, procainamide is usually the drug of choice when intravenous therapy is indicated; for oral prophylaxis, quinidine or the sustained-release form of procainamide is more effective than conventional formulation oral procainamide. Because procainamide is the only class I antiarrhythmic drug currently available that is commonly administered intravenously and orally, it is frequently the drug of choice for patients requiring both immediate and intermediate periods of arrhythmia control. It is often the drug of choice for initial testing with programmed electrical stimulation.

Administration, Oral↗
PubMed1985

Effect of exercise on plasma levels and urinary excretion of sulphadimidine and procainamide.

The pharmacokinetics of sulphadimidine (n = 9) and procainamide (n = 8), drugs which showed typical polymorphic acetylation rate, were studied in healthy volunteers subjected to intense physical exercise and bed rest for 4 hours in a cross-over manner. The exercise and the rest began 3 hours after giving procainamide and 4 hours after the administration of sulphadimidine, when the drug absorption had subsided. In rapid acetylators, the exercise raised both acetylated and non-acetylated sulphadimidine concentrations in serum, compared to rest values. With procainamide the rise was insignificant. In slow acetylators, the exercise revealed a significant difference in the procainamide group but not in sulphadimidine group. The exercise did not influence the acetylation degree of either of the drugs. Neither did it affect the protein binding of sulphadimidine. The urinary excretions of procainamide and acetylprocainamide were reduced by exercise generally more than those of sulphadimidine and acetylsulphadimidine. Endogenous creatinine clearance was reduced to 66%, whereas the renal clearances of sulphadimidine, acetylsulphadimidine and procainamide decreased to 89%, 48% and 16%, respectively. The results agree with our previous findings that physical stress can result in increased serum drug levels. Exercise does not seem to change the acetylation rate nor the protein binding of drugs, but it suppresses their excretion in urine, occasionally even more than what would be expected on the basis of the decrease in the glomerular filtration rate.

Acetylation↗
PubMedDate not supplied

Metabolism of procainamide in the perfused rat liver.

We have previously produced evidence that procainamide forms a reactive metabolite. This study of the metabolism of procainamide in a perfused rat liver was aimed at providing clues to the identity of this reactive metabolite. Several metabolites were found that had not been previously described and three of these were identified. Probably the most significant of these metabolites is the phenol, N-acetyl-3-hydroxyprocainamide. This phenol could have been formed from either a hydroxylamine or an arene oxide intermediate and either of these could represent a reactive metabolite. In contrast to the metabolism of procainamide, the phenol metabolite, N-acetyl-3-hydroxyprocainamide, is not formed in significant quantities from N-acetylprocainamide. This implies that oxidation of procainamide to 3-hydroxyprocainamide precedes acetylation to give N-acetyl-3-hydroxyprocainamide. As N-acetylation of procainamide decreases both its toxicity and the formation of the oxidative phenol metabolite, among the hypotheses to be explored is relationship between the formation of the phenol metabolite and the toxicity of procainamide. The other metabolites that were identified were N-acetylprocainamide N-oxide and N-acetyl-4-aminohippuric acid.

Acecainide↗
PubMed1978

The effect of hydralazine and other drugs on the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase.

The objectives of this study were to investigate 1) the tissue distribution of procainamide acetylase activity in the rat and 2) the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase and 3) to determine the effect of drugs thought to be similarly acetylated on procainamide acetylation. The cytosol fraction (100,000 X g) of tissue homogenates served as the source of N-acetyltransferase. Of the tissues studied the liver possessed the greatest acetylase activity followed by the kidney, lung, intestine and spleen. The apparent procainamide Michalis constant (Km) for liver and kidney was 2.03 X 10(-4) and 2.09 X 10(-4) M in the presence of 4.2 X 10(-4) M acetyl CoA. The liver Km for procainamide with "infinite" acetylCoA concentration was 4.36 X 10(-3) M. The liver Km for acetyl CoA in the presence of "infinite" PA concentration was 2.44 X 10(-3) M. Hydralazine, para-aminobenzoic acid, isoniazid, and sulfapyridine competitively inhibited procainamide acetylation by liver and kidney N-acetyltransferase.

Acetylation↗
PubMed1993

Stability of procainamide hydrochloride syrups compounded from capsules.

The stability of procainamide hydrochloride in two oral syrups, one prepared with sucrose and the other with maltitol, was studied. A syrup containing powder from 500-mg procainamide hydrochloride capsules, simple sucrose syrup, and other additives was prepared; the theoretical initial concentration of procainamide hydrochloride was 50 mg/mL. Three samples each were stored at 40, 50, 60, and 70 degrees C. Drug concentration was measured with high-performance liquid chromatography at times ranging from 2 to 107 days. In a second study, a syrup containing powder from 500-mg procainamide hydrochloride capsules, a maltitol-based syrup vehicle, and other additives was prepared; the theoretical initial drug concentration was 50 mg/mL. Three samples each were stored at 40, 50, 60, and 70 degrees C. Drug concentration was measured at times ranging from 7 to 187 days. For the sucrose-based syrup, there was apparent first-order degradation of procainamide hydrochloride at all temperatures. An Arrhenius plot was used to calculate a shelf life of the syrup of 456 days at 25 degrees C. Most samples turned brown over time, and pH values were constant. For the maltitol-based syrup, drug degradation appeared to be biphasic; an initial period during which concentrations remained at nearly 100% was followed by apparent first-order degradation. Arrhenius plotting gave a shelf life of 97 days at 25 degrees C. Most samples turned brown over time, and pHs remained constant. Arrhenius plots indicated that in a maltitol-based oral syrup, procainamide hydrochloride was more stable than in a sucrose-based syrup when the storage temperature was above 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsules↗
PubMed1997

A metabolite of the lupus-inducing drug procainamide prevents anergy induction in T cell clones.

Therapeutic treatment with procainamide is occasionally associated with the development of drug-induced lupus. This syndrome has become the prototype for an aseptic systemic autoimmune disease caused by a known environmental agent, but the underlying mechanisms remain puzzling. We explored the possibility that lupus-inducing drugs affect processes involved in T cell tolerance to self-Ag. An in vitro model of anergy using established T cell clones was used to determine whether procainamide or one of its metabolites could prevent development of T cell nonresponsiveness to cognate Ag. Addition of procainamide-hydroxylamine, but not procainamide or its further oxidation products during anergy induction by CD3 engagement, caused a dose-dependent recovery of the capacity of T cells to proliferate and secrete IFN-gamma upon subsequent Ag challenge. Resistance to anergy induction required 2 h of exposure to procainamide-hydroxylamine, and this state remained for 8 h, suggesting that uptake of the drug caused a reversible interference in signaling pathways involved in establishing anergy. We suggest that prevention of anergy induction by procainamide-hydroxylamine may also take place in vivo during establishment of T cell tolerance to self-Ag, thereby allowing the production of autoreactive T cells.

Animals↗
PubMed1997

High prevalence of antiphospholipid antibodies in patients taking procainamide.

OBJECTIVE: To determine whether antiphospholipid antibodies (aPL) are more prevalent in cardiac patients taking procainamide than in a control population of similar elderly cardiac patients and to determine whether these antibodies react in an ELISA in which the primary antigen is beta 2-glycoprotein I (beta 2-GPI). METHODS: aPL and antibodies to beta 2-GPI were measured in 66 patients taking procainamide from a Veterans Administration Medical Center population and a control group of 30 similar cardiac patients not taking procainamide. RESULTS: 21% of the patients taking procainamide and no control patients were found to have moderate to high aPL. There were similar results in an assay that measured anti-beta 2-GPI in the absence of exogenous phospholipids. aPL were associated with antinuclear antibodies and antihistone antibodies but not with diabetes or clinical manifestations of drug related lupus. There was no increase in cholesterol or past thrombotic history associated with aPL, but there was a frequent history of noncardiac thrombosis in patients taking procainamide (25.7%). CONCLUSION: The predictive significance of procainamide induced aPL remains unknown but beta 2-GPI dependent aPL may be of some concern in this elderly population already at high risk for thrombosis.

Adult↗
PubMedDate not supplied

Development of antibodies to ribonucleoprotein following short-term therapy with procainamide.

An autoimmune response to certain nuclear antigens frequently develops in patients receiving prolonged therapy with procainamide. In order to define events involved in the initiation of this immune response, patients with myocardial infarction were studied early after starting procainamide and at later times. Polynucleotide antibodies and circulating polynucleotide antigens were sought by sensitive assay techniques in the sera of these patients. Very high titers of antiribonucleoprotein developed selectively in the majority of these patients after short-term therapy with procainamide. Such antibodies were infrequent in the long-term therapy group, most of whose members exhibited anti-single-strand DNA and were symptomatic with overt procainamide-induced lupus. Patients with acute myocardial infarction who did not receive procainamide did not develop anti-polynucleotide antibodies, but rather had high levels of free ribonucleoprotein antigen in their serum. Various interpretations of these data are discussed.

Aged↗
PubMed1981

The implications of procainamide metabolism to its induction of lupus.

The principal metabolic pathway of procainamide leads to formation of the less toxic N-acetyl-procainamide and the rapid acetylator phenotype is associated with a lower incidence of procainamide-induced lupus. Another metabolic pathway forms a reactive metabolite which causes revertants in the Ames test and covalently binds to microsomal protein. A study of the metabolism of procainamide revealed three metabolites that have not been previously described. A comparison of the metabolites of N-acetylprocainamide with those of procainamide suggests possibilities for the identity of the reactive metabolite. The hypotheses to be discussed explore the relationships between the formation of a reactive metabolite and the induction of lupus.

Acecainide↗
PubMed1998

Propafenone versus procainamide for conversion of atrial fibrillation to sinus rhythm.

BACKGROUND AND HYPOTHESIS: Antiarrhythmic drugs are widely used for treatment of atrial fibrillation (AF) and restoration of sinus rhythm. This prospective, randomized, and controlled study compared the efficiency and safety of propafenone versus procainamide for the treatment of acute AF. METHODS: In all, 117 patients (55 women, 62 men, mean age 64.2 +/- 13 years, median 63 years) who presented with AF were included in the study. Exclusion criteria were signs or symptoms of heart failure on physical examination, recent myocardial infarction or cardiac surgery, cardiogenic shock, or hypotension. Forty-one patients spontaneously recovered sinus rhythm; the remaining 76 patients were randomized to receive propafenone or procainamide. Propafenone was given at a dose of 2 mg/kg body weight intravenously (i.v.) over 30 min. Patients randomized to receive procainamide received a bolus of 100 mg i.v. administered every 5 min up to a maximum dose of 1 g. The clinical characteristics of the two groups were comparable. RESULTS: The number of patients who recovered sinus rhythm after the treatment was larger in the procainamide-treated group (Group 1) (69.5%) than in the propafenone-treated group (Group 2) (48.7%); p < 0.05. The time required for cardioversion was significantly lower in Group 1 (mean 4.1 +/- 1.3 h), than in Group 2 patients (mean 7.3 +/- 2.6 h) (p < 0.01). CONCLUSION: In the present study, procainamide was more effective than propafenone for the treatment of AF of short duration.

Aged↗
PubMed1991

Effect of probenecid on the pharmacokinetics and pharmacodynamics of procainamide.

Renal tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 +/- 95 mL/min without probenecid vs. 478 +/- 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed.

Adult↗
PubMed1996

Disposition of procainamide in patients with chronic congestive heart failure receiving medical therapy.

Dosage reduction of procainamide has been recommended in patients with congestive heart failure (CHF). However, these recommendations are based primarily on studies with unmatched control groups, suboptimal blood sampling, and in patients not receiving angiotensin-converting enzyme (ACE) inhibitors. These agents increase renal blood flow, which theoretically may offset alterations in drug disposition in patients with CHF. The pharmacokinetics of procainamide in patients with chronic CHF and in matched controls were compared. A single intravenous dose of 750 mg of procainamide was administered to 9 patients with chronic New York Heart Association (NYHA) class II or III CHF (mean +/- SD left ventricular ejection fraction 22 +/- 9%) receiving medical therapy and 7 control subjects matched for age and gender. Blood and urine samples were collected at intervals over a period of 48 and 72 hours, respectively. Patients with CHF and control subjects were demographically similar, with the exception of concomitant medications, including ACE inhibitors (8/9 versus 1/7, respectively). There were no significant differences between patients with CHF and control subjects in mean +/- SD peak serum concentrations (Cmax), area under the serum concentration-time curve (AUC0-infinity), total clearance, renal clearance, half-life (t1/2), or volume of distribution (Vd) of procainamide. Similarly, there were no significant differences between patients with CHF and control subjects in the mean +/- SD Cmax, AUC0-infinity, renal clearance, or t1/2 of N-acetylprocainamide (NAPA). Procainamide dosage reduction may not be necessary in patients with chronic stable CHF who are receiving medical therapy.

Adult↗
PubMed1981

Pharmacokinetics of procainamide and N-acetylprocainamide in rats.

The pharmacokinetics of distribution and elimination of procainamide and its major metabolite, N-actylprocainamide, were studied in rats. Eight rats were selected randomly, and each received intravenously 14C-labeled procainamide hydrochloride (75 mg/kg) or 14C-labeled N-acetylprocainamide hydrochloride (86 mg/kg) according to a two-way crossover design. Serial blood samples were withdrawn for 8 hr, and cumulative urine and feces were collected for 48 hr. The plasma concentration-time relationships of procainamide and N-acetylprocainamide were characterized by one- and two-compartment open models, respectively. A pseudo-three-compartment model was necessary to characterize the time course of N-acetylprocainamide in plasma formed after administration of procainamide. The biological half-lives of procainamide and N-acetylprocainamide averaged 0.66 and 2.1 hr, respectively. The urinary excretion profiles of these drugs and the ratio of their biological half-lives in rats were similar to those in humans.

Acecainide↗
PubMed1979

Significance of the acetylation phenotype and the therapeutic effect of procainamide.

In order to estimate the relative anti-arrhythmic effect of procainamide and N-acetyl-procainamide, 18 randomly selected, patients with arrhythmia were divided into two groups; the first was treated with Pronestyl in the first half of the investigation period, followed by Duretter in the second half, and the second group began with Duretter and terminated with Pronestyl. The concentrations of procainamide and N-acetylprocainamide were measured twice a day during the steady state part of each treatment period. The acetylation phenotype of the patients was determined with sulfadimidine, and compared with the relative serum concentrations of procainamide and N-acetylprocainamide. N-acetylprocainamide was found to antagonize the action of procainamide.

Acetylation↗