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PubMed1989

Metabolism of procainamide to the cytotoxic hydroxylamine by neutrophils activated in vitro.

An almost universal side effect of long-term therapy with procainamide is the appearance of serum autoantibodies and less frequently a syndrome resembling lupus erythematosus. Previous studies demonstrated that procainamide-hydroxylamine (PAHA), a metabolite generated by hepatic mixed function oxidases, was highly toxic to dividing cells, but evidence that PAHA could be formed in the circulation was lacking. This study examines the capacity of neutrophils to metabolize procainamide to reactive forms. Neutrophils activated with opsonized zymosan were cytotoxic only if procainamide was present, whereas N-acetyl procainamide, which does not induce autoimmunity, was inert in this bioassay. PAHA was detected by HPLC in the extracellular medium if ascorbic acid was present. Generation of PAHA and cytotoxic procainamide metabolites was inhibited by NaN3 and catalase but not by superoxide dismutase, indicating that H2O2 and myeloperoxidase were involved. Nonactivated neutrophils and neutrophils from patients with chronic granulomatous disease did not generate cytotoxic PAHA, demonstrating that H2O2 was derived from the respiratory burst accompanying neutrophil activation. These conclusions were supported by results of a cell-free system in which neutrophils were replaced by myeloperoxidase and H2O2 or an H2O2 generating system. These studies demonstrate the capacity of neutrophils to mediate metabolism of procainamide and establish the role of myeloperoxidase released during degranulation and H2O2 derived from the respiratory burst in the direct cooxidation of procainamide to PAHA. The profound biologic activity of this metabolite and its possible generation within lymphoid compartments implicate this process in the induction of autoimmunity by procainamide.

Adult↗
PubMed1984

Well-controlled comparative study of the clinical effectiveness of intravenous mexiletine and procainamide on ventricular premature contraction.

In a well-controlled study the clinical efficacy of a single intravenous injection of mexiletine (3 mg/Kg) on ventricular premature contractions was compared with that of procainamide (10 mg/Kg) using continuous electrocardiographic recordings. Of the 56 subjects studied, 55 were analyzed. These consisted of 28 cases in the mexiletine group and 27 in the procainamide group. The backgrounds of both groups were considered to be equivalent. Effectiveness on VPC ("marked and moderate improvement", as judged by the subcommittee) was seen in 88% of the mexiletine group and 84.6% of the procainamide group. This difference was not significant. The duration of efficacy was almost the same in the 2 groups. Overall improvement was the same as improvement in VPC. No significant difference was observed in the incidence of side effects. Five patients in the mexiletine group and 3 in the procainamide group reported side effects. The main side effect was light-headedness in the mexiletine group and a decrease in blood pressure in the procainamide group. A decrease in blood pressure was observed in 1 case in the mexiletine group but this was restored by an intravenous infusion of noradrenaline. Mexiletine had little effect on blood pressure, while procainamide induced a drop in the systolic pressure. This difference was significant. Overall utility ("markedly and moderately useful", as judged by the subcommittee) was seen in 84.0% of the mexiletine group and 84.6% of the procainamide group. There was no significant difference between the 2 groups. From the above results, it is concluded that mexiletine (3 mg/Kg) is as efficacious as procainamide (10 mg/Kg) in the treatment of VPC but that, unlike procainamide, mexiletine has little effect on blood pressure.

Adolescent↗
PubMedDate not supplied

Kinetics of procainamide N-acetylation in the rat in vivo and in the perfused rat liver preparation.

The kinetics of procainamide N-acetylation were studied in the rat in vivo and in vitro. For the in vivo studies, first order kinetics for procainamide and N-acetylprocainamide were found among their respective iv doses of 20, 50, and 70 mg/kg, and 10, 20, and 30 mg/kg. The fraction of total body clearance of procainamide that forms N-acetylprocainamide was found to be 0.22, and very insignificant sequential elimination of N-acetylprocainamide occurred during its formation. By contrast, results from once-through liver perfusion indicated that the steady state hepatic extraction ratio of procainamide was highly dependent on the steady state input concentration delivered under constant hepatic blood flow (10 ml/min). The rate of N-acetylation, however, was a constant percentage of the rate of presentation of procainamide at less than or equal to 80 micrograms/min among the preparations and became apparently saturated at higher rates of input of procainamide. Interestingly, the rate of N-acetylation accounted for an increasing proportion of the rate of loss of procainamide at greater than 80 micrograms/min, and suggested that alternate metabolic routes of procainamide are more easily saturable than N-acetylation. The comparative in vivo and in vitro data suggested that a region of nonlinearity existed during the early periods immediately following iv injection of procainamide into the rat in vivo. Because of rapid distribution, the region of nonlinearity was transient, and was not reflected by area under the curve measurements, which is a time-averaged parameter. Total body clearance, which bears a reciprocal relationship with the area under the curve, hence remained constant and was dose-invariant. The trend of nonlinearity may be more evident on chronic dosing of the drug when accumulation sets in.

Acecainide↗
PubMed1993

Myocardial uptake and pharmacodynamics of procainamide in patients with coronary heart disease and sustained ventricular tachyarrhythmias.

Little information is available currently regarding the time course of myocardial accumulation and the onset of the electrophysiologic effects of antiarrhythmic drugs in humans. The myocardial uptake and pharmacodynamics of the antiarrhythmic drug, procainamide, were studied during i.v. infusion in nine patients with ventricular tachycardia undergoing electrophysiologic study. Myocardial procainamide uptake was determined by serial measurements of arterial-coronary sinus drug concentration differences and measurement of coronary sinus blood flow during a 50-min procainamide infusion. The myocardial uptake of procainamide was 10 +/- 4% (mean +/- S.D.) of the total dose at 50 min. Coronary sinus procainamide concentrations equilibrated with arterial concentrations within 30 min of the start of the infusion. However, peripheral venous procainamide concentrations did not reach equilibrium with the arterial compartment during the 50-min drug infusion. Changes in the QRS duration, ventricular conduction time, QTc and ventricular refractory periods correlated in a linear fashion with changes in the plasma procainamide concentrations. The slopes of the arterial and coronary sinus concentration-effect relationships were similar and significantly greater than the slopes of the peripheral venous concentration-effect relationships (P < .05). Thus, procainamide equilibrates rapidly, but not instantaneously, in the myocardium. Short-term electrophysiologic effects correlate best with the arterial and coronary sinus drug concentrations. During this period, venous procainamide concentrations do not accurately reflect the myocardial concentration, effects or the eventual steady-state relationships.

Aged↗
PubMed2000

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.

Aged↗
PubMed1976

Hemodialysis for severe procainamide toxicity: clinical and pharmacokinetic observations.

A 67-yr-old woman who ingested approximately 7 gm procainamide developed severe hypotension, renal insufficiency, and life-threatening cardiac toxicity. Hemodialysis doubled the rate of procainamide elimination and increased fourfold the clearance of NAPA, the N-acetylated metabolite of procainamide. Observations of procainamide and N-acetylprocainamide (NAPA) plasma levels during the patient's recovery suggest that lethargy and profound hypotension can be expected when these levels total 60 mug/ml and that severe cardiac toxicity should be anticipated with levels totaling 42 mug/ml or more. Hemodialysis also permitted investigation of the effects of hypotension on the pharmacokinetics of these compounds. The apparent volume of procainamide distribution was reduced from a normal value of 2 L/kg to 0.76 L/kg, and that of NAPA from 1.4 L/kg to 0.63 L/kg. The elimination + 1/2 of procainamide was prolonged from the normal of 3 hr to 10.5 hr, and that of NAPA from 6 to 35.9 hr. Procainamide absorption was also slowed in this clinical setting, causing procainamide plasma levels to continue rising for some time after toxicity was first recognized.

Acetylation↗
PubMed1996

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.

Acecainide↗
PubMed1982

Immune regulatory abnormalities produced by procainamide.

The pathogenesis of procainamide-induced autoantibody production is unknown. To test the effect of procainamide on the immune system, we studied in vitro suppressor cell function and immunoglobulin G (IgG) secretion in 11 patients who developed autoantibodies while taking procainamide. The procainamide group was compared with patients with spontaneous systemic lupus erythematosus (n = 15) and a normal control population (n = 40). Impaired in vitro suppressor cell function was found in 11 of 14 patients with spontaneous systemic lupus erythematosus but in none of the patients taking procainamide. However, total in vitro IgG secretion was significantly increased in the procainamide group with regard to the control and systemic lupus erythematosus groups. There was a direct correlation between the circulating anti-SS DNA antibody titer and in vitro IgG secretion. Furthermore, T cells isolated from the procainamide-treated patients stimulated IgG secretion by normal allogeneic peripheral blood lymphocytes. The added T cells did not affect in vitro suppressor cell function. We postulate that autoantibody production in patients taking procainamide is due to enhanced helper T cell function and not to impaired suppression. However, the development of clinical disease requires the participation of additional genetic or immunologic factors.

Adolescent↗
PubMed1992

Transport of procainamide in a kidney epithelial cell line LLC-PK1.

Transport of procainamide, an anti-arrhythmic drug, was investigated in LLC-PK1 kidney epithelial cell line. The uptake of procainamide by LLC-PK1 monolayers cultured in plastic dishes was temperature-dependent, saturable and inhibited by organic cations such as cimetidine and N-acetylprocainamide. An aminocephalosporin antibiotic, cephalexin, also inhibited procainamide uptake, but an organic anion, p-aminohippurate, did not. The uptake of procainamide was greater at an alkaline external pH than at an acidic pH. In addition, procainamide uptake increased when intracellular pH was decreased and the uptake decreased when the intracellular pH was increased by ammonium chloride treatment, indicating the involvement of an H+/procainamide antiport system in apical membrane. The basolateral to apical flux of procainamide across LLC-PK1 monolayers cultured on permeable supports was 2.5-times larger than the apical to basolateral flux, and only the former process was inhibited by other organic cations. These findings suggest that LLC-PK1 cells can transport procainamide by the organic cation transport system and that procainamide is transported unidirectionally from basolateral to apical side across the cell monolayers.

Animals↗
PubMed1985

IgG antibodies to the histone complex H2A-H2B characterize procainamide-induced lupus.

Patients treated with procainamide and other drugs commonly develop antinuclear antibodies and occasionally symptoms of lupus erythematosus. However, the pathological events which lead to clinical symptoms in some patients but only abnormal serology in others have not been established. The present study examines the incidence, amount, immunoglobulin class, and antigen-binding specificity of anti-histone and anti-denatured DNA (anti-dDNA) antibodies in three groups of patients. These comprised a prospective study of patients treated with procainamide, patients with clinical drug-induced lupus symptoms, and a group undergoing therapy for many years without any symptoms. Procainamide elicited IgG and IgM anti-dDNA antibodies concordantly. Anti-histone IgM antibodies also appeared de novo during this period but IgG anti-histone antibodies were detected less frequently. Asymptomatic patients tended to have an antibody profile consisting of highly elevated anti-dDNA, IgM antibodies reactive with all histones and IgG antibodies specific for only one or two histone classes. In contrast symptomatic patients usually had little anti-dDNA or antibodies to individual histones but had pronounced IgG antibodies to the histone complex H2A-H2B. This unique antibody was characteristics of procainamide-induced lupus and was not detected in patients whose disease was induced by hydralazine. Anti-(H2A-H2B) decreased after procainamide was discontinued, concomitant with subsidence of symptoms. The finding that autoantibodies elicited by procainamide in patients with lupus symptoms have a characteristic immunoglobulin class and specificity may be of pathogenic significance and suggests that patients susceptible to procainamide-induced lupus have a unique immune response. In addition, this information could be of diagnostic value in predicting which procainamide-treated patients will develop overt symptoms of lupus.

Adult↗
PubMed1989

Procainamide hydroxylamine lymphocyte toxicity--I. Evidence for participation by hemoglobin.

A number of lines of evidence suggest that the lupus-like symptoms associated with procainamide therapy may be caused by products of metabolic N-oxidation. In the present study, the perfusion of the isolated rat liver with a hemoglobin-free solution containing procainamide (100 microM) resulted in the rapid appearance of the N-oxidation metabolite procainamide hydroxylamine in the perfusate. Addition of procainamide hydroxylamine in vitro to whole rat blood (1-40 microM) resulted in a concentration-dependent loss of proliferative response among mononuclear cells isolated from the treated blood and cultured with mitogens (phytohemagglutinin, PHA-P: concanavalin A, Con A; and pokeweed mitogen, PWM), as well as a loss of viability. Similar effects on lymphocyte mitogen responsiveness were observed when procainamide hydroxylamine (1-40 microM) was added to rat whole splenic cell populations. Carbon monoxide or ascorbic acid pretreatment inhibited the toxicity of procainamide hydroxylamine to lymphocytes in whole blood, but only carbon monoxide pretreatment inhibited procainamide hydroxylamine-induced methemoglobin formation. These observations are consistent with the participation of hemoglobin in a redox cycle with procainamide hydroxylamine, generating products which are primarily responsible for its cytotoxicity in blood.

Acecainide↗
PubMed1993

Polymorphic ventricular tachycardia induced by programmed stimulation: response to procainamide.

OBJECTIVES: This study was designed to evaluate the effects of procainamide on polymorphic ventricular tachycardia induced by programmed stimulation and to correlate the responses with heart disease, left ventricular endocardial activation abnormalities and the signal-averaged electrocardiogram (ECG). BACKGROUND: Polymorphic ventricular tachycardia is induced frequently during electrophysiologic studies. In many patients this response is an artifact of programmed stimulation; in others, it appears to be clinically relevant. Previous observations have suggested that in some patients type IA antiarrhythmic agents can change the response to programmed stimulation from polymorphic to uniform ventricular tachycardia. METHODS: Programmed right ventricular stimulation was performed in the absence of antiarrhythmic drugs and after procainamide. Signal-averaged ECGs and left ventricular maps were performed during sinus rhythm in the absence of antiarrhythmic drugs. RESULTS: We evaluated 79 consecutive patients undergoing clinical electrophysiologic studies, in whom polymorphic ventricular tachycardia was the only arrhythmia induced in the absence of antiarrhythmic drugs. After procainamide administration, uniform monomorphic ventricular tachycardia was induced in 24 patients (Group 1), inducible polymorphic ventricular tachycardia persisted in 30 patients (Group 2) and no ventricular tachycardia could be induced in the remaining 25 patients (Group 3). Twenty-three (96%) of 24 patients developing uniform ventricular tachycardia after procainamide administration had coronary artery disease compared with 63% of Group 2 and 48% of Group 3 patients (p = 0.003). Left ventricular aneurysms were also found more frequently (46%) in the patients developing uniform ventricular tachycardia after procainamide than in either Group 2 or Group 3 (13% and 0%, respectively, p < 0.008). Abnormalities of the signal-averaged ECG typically seen in patients with spontaneous reentrant sustained ventricular tachycardia were significantly more frequent in patients who developed inducible uniform ventricular tachycardia after procainamide than in those who did not. Similarly, patients developing uniform ventricular tachycardia after procainamide had more extensive abnormalities of left ventricular endocardial activation revealed by catheter maps during sinus rhythm. CONCLUSIONS: The conversion of inducible polymorphic ventricular tachycardia to uniform ventricular tachycardia after procainamide administration occurs almost exclusively in patients with coronary disease, previous myocardial infarction and abnormal left ventricular function. This response may permit activation mapping of tachycardias, allowing the application of surgical or catheter ablation techniques that would otherwise not be possible in such patients.

Cardiac Pacing, Artificial↗
PubMed1996

Comparative efficacy of intravenous ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing.

This study compares the influence of intravenous ibutilide, a class III antiarrhythmic agent, with procainamide, a class IA antiarrhythmic agent, and with placebo on its ability to terminate atrial flutter using rapid atrial pacing. Fifty-nine episodes of atrial flutter in 54 patients who failed to terminate with an intravenous infusion of ibutilide, procainamide, or placebo alone underwent attempts at pacing termination using a standard protocol of burst atrial overdrive pacing. Atrial flutter cycle length and atrial monophasic action potential duration recorded from the right atrium during atrial flutter were measured at baseline and following infusion of ibutilide, procainamide, or placebo. Both ibutilide and procainamide significantly enhanced (p <0.001) pacing-induced termination of atrial flutter compared with placebo. Pacing converted 2 of 11 patients (18%) who received placebo, 13 of 15 patients (87%) who received ibutilide, and 29 of 33 patients (88%) who received procainamide to sinus rhythm. Ibutilide and procainamide compared with placebo markedly reduced (p <0.001) the incidence of pacing-induced atrial fibrillation. The atrial flutter cycle length was prolonged significantly less (p <0.001), and the atrial monophasic action potential duration was increased significantly more (p <0.001) by ibutilide than by procainamide. Although the electrophysiologic changes induced by these antiarrhythmic agents contributed to facilitating pacing-induced termination, neither tachycardia cycle length nor action potential duration were useful predictors of the ability of pacing to terminate atrial flutter. In conclusion, despite differing electrophysiologic effects, the use of intravenous ibutilide or procainamide enhances the termination of atrial flutter by atrial overdrive pacing.

Aged↗
PubMed1984

Effect of procainamide on myocardial contractile function and digoxin inotropy.

The effect of procainamide and digoxin, singly and together, on peak active force and rate of force development of isolated right ventricular papillary muscles from adult cats was examined. Procainamide (1.5 X 10(-5) M) increased force and rate of force development in each muscle with further increments in performance up to 2.4 X 10(-4) M in most muscles. The maximal increases in force (+/- SEM) averaged 75 +/- 13% above control values. Essentially no response to procainamide was observed when basal levels of contractile state were increased by increasing stimulus frequency or calcium concentrations of the bathing solution. Propranolol (10(-6) M) markedly reduced and verapamil (10(-7) M) abolished the inotropic effect of procainamide. Exposing muscles to procainamide (1.5 or 3 X 10(-5) M) before or after the administration of digoxin (2 or 4 X 10(-7) M) did not alter the inotropic action of either drug. Thus, procainamide in concentrations that are in the therapeutic range in human patients has potent positive inotropic effects that may be masked at high levels of contractile state. This action of procainamide appears to be due to an effect on calcium channels, which in part may be due to beta-adrenergic receptor stimulation. These concentrations of procainamide do not alter the inotropic response to digoxin.

Animals↗
PubMed1986

Coronary venous retroinfusion of procainamide: a new approach for the management of spontaneous and inducible sustained ventricular tachycardia during myocardial infarction.

The efficacy of retrograde coronary venous delivery of procainamide for the management of spontaneous and inducible sustained ventricular tachycardia was evaluated and compared with systemic intravenous procainamide administration in 22 conscious dogs with permanent left anterior descending coronary artery occlusion. Selective retrograde injection of procainamide was achieved through an autoinflatable balloon catheter placed in the great cardiac vein, with the tip positioned in the vicinity of the site of left anterior descending coronary occlusion. Great cardiac vein retroinfusion of procainamide was significantly (p less than 0.05) more effective than systemic intravenous injection against spontaneous ventricular tachycardia 1 day after coronary artery occlusion (13 dogs) and against electrically induced sustained ventricular tachycardia in the 3 to 12 day postocclusion period (9 dogs). Significantly lower doses of procainamide were used with retroinfusion as compared with systemic administration, that is, 19.6 +/- 8.8 versus 35 +/- 0 mg/kg body weight during spontaneous tachycardia and 13.4 +/- 4.1 versus 32.1 +/- 2 mg/kg during induced tachycardia (p less than 0.01). Retroinfusion of saline solution through the great cardiac vein had no effect on either type of tachycardia. Myocardial tissue procainamide levels measured in infarcted and ischemic zones of the left anterior ventricular wall were 9 to 100 times higher after great cardiac vein retroinfusion than after systemic injection. Great cardiac vein dye injection studies demonstrated a preferential distribution in left ventricular regions supplied by the occluded coronary artery. It is concluded that regional coronary venous procainamide retroinfusion in dogs with myocardial infarction is more effective than systemic intravenous injection against both spontaneous and inducible sustained ventricular tachycardia. The greater efficacy of great cardiac vein treatment appears to be primarily related to selectively increased delivery of procainamide to ischemic myocardial sites.

Animals↗
PubMedDate not supplied

N-Chlorination and oxidation of procainamide by myeloperoxidase: toxicological implications.

In previous studies we had shown that procainamide is metabolized to reactive metabolites by activated leukocytes, and evidence pointed to involvement of myeloperoxidase (MPO). In this study we examine the metabolism of procainamide by MPO/H2O2, in the presence and absence of chloride ion. In the absence of chloride ion, the metabolism was very similar to that seen with activated leukocytes. The major metabolite was formed by oxidation of the arylamine group to a hydroxylamine. In the presence of chloride ion, a much greater degree of metabolism occurred, and the major product (40% of the starting procainamide) was a reactive species that could not be isolated. This metabolite spontaneously rearranged to 3-chloroprocainamide, and from its mass spectrum and chemical reactions, we deduce its structure to be N-chloroprocainamide. The N-chloroprocainamide metabolite reacted very rapidly with reducing agents, such as ascorbate, and also reacted with protein such as albumin, the major product in both cases being procainamide. This metabolite also chlorinated phenylbutazone. When radiolabeled procainamide was oxidized by MPO/H2O2 in the presence of albumin, covalent binding of the radiolabel to albumin occurred, and binding was greater under conditions in which N-chloroprocainamide was formed. It is probable that the failure to observe N-chloroprocainamide, when procainamide is oxidized by activated leukocytes, is due to its rapid reaction with the cells. We propose that modification of neutrophils (or neutrophil precursors in the bone marrow) by these reactive metabolites is responsible for procainamide-induced agranulocytosis. In a similar manner, procainamide-induced lupus could be due to modification of monocytes by monocyte-generated reactive metabolites.

Albumins↗
PubMed1987

Food-induced gastric retention and absorption of sustained-release procainamide.

The relationship between variations in the gastric residence time and the absorption of procainamide from a waxed matrix, sustained-release tablet was evaluated in a repeated-measures study conducted in eight healthy men. Subjects received sustained-release procainamide together with a Heidelberg capsule, alone and with food. Blood and urine samples were collected for up to 24 hours before and after gastric emptying of the Heidelberg capsule for procainamide and N-acetylprocainamide concentration determinations. The gastric residence time of the Heidelberg capsule was prolonged by food (median 3.5 [range 1.5 to 10.0] vs. 1.0 [range 0.5 to 2.5] hours; P less than 0.02). No significant differences (median [range]; fasting vs. fed) in procainamide lag time (0.5 [0.5 to 1.0] vs. 0.5 [0.5 to 1.5] hours) or time at which peak procainamide plasma concentrations occurred (2.9 [1.0 to 4.3] vs. 2.8 [2.0 to 6.0] hours) were evident with feeding. Slight increases in procainamide AUC and peak concentrations occurred with feeding. No alteration in the extent of urinary excretion of procainamide or N-acetylprocainamide occurred with feeding. Thus food did not influence the absorption of sustained-release procainamide despite apparent prolonged gastric retention.

Acecainide↗
PubMed2002

Intrapericardial therapeutics: a pharmacodynamic and pharmacokinetic comparison between pericardial and intravenous procainamide delivery.

INTRODUCTION: Procainamide delivery into the pericardial space may produce a greater and more prolonged electrophysiologic effect, particularly in thin superficial atrial tissue, compared with intravenous delivery. METHODS AND RESULTS: Swine were randomized to sequential procainamide doses delivered intravenously (n = 6) or into the pericardial space (n = 7). The cumulative pericardial doses were 0.5, 1.5, and 3.5 mg/kg, and the intravenous doses were 2, 10, and 26 mg/kg. Pericardial procainamide prolonged right atrial effective refractory period from baseline by 22% (P < 0.01) but only at the 3.5 mg/kg cumulative dose. This dose slowed interatrial conduction time by 14% (P < 0.05) and raised atrial fibrillation threshold by 70 mA (P < 0.05). Pericardial procainamide had minimal effect on ventricular electrophysiology. Similar results occurred with a single 2 mg/kg pericardial dose in a closed chest model. Intravenous 10 and 26 mg/kg cumulative doses prolonged atrial effective refractory period from baseline by 24% and 18% (P < 0.01), respectively. The 26 mg/kg cumulative intravenous dose slowed interatrial and atrial-ventricular conduction times by 27% and 17%, respectively (P < 0.05), raised atrial fibrillation threshold, and slowed ventricular conduction time by 29% (P < 0.05). Pericardial procainamide produced pericardial fluid concentrations ranging from 250 to 1,500 microg/mL, but plasma concentrations were <1 microg/mL. Intravenous procainamide doses produced pericardial fluid concentrations similar to plasma trough concentrations 0 to 12 microg/mL. CONCLUSION: The single 2 mg/kg and 3.5 mg/kg cumulative pericardial procainamide doses prolonged atrial refractoriness and raised atrial fibrillation threshold similar to the 26 mg/kg cumulative intravenous dose, but the duration of effect was similar between delivery methods. Pericardial procainamide did not affect global or endocardial ventricular electrophysiology nor was it associated with ventricular proarrhythmia.

Action Potentials↗