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At least 73 records · Page 4Linked to original sources
PubMed1992

Effects of antiarrhythmic drugs on phospholipid metabolism in Jurkat T cells. The potassium channel blocker, clofilium, specifically increases phosphatidylserine synthesis.

Five antiarrhythmic drugs (bretylium, clofilium, propranolol, N-acetylprocainamide and amiodarone) were tested for their ability to modify phospholipid metabolism in Jurkat T lymphocytes. The five drugs, decreased in a dose-dependent mode the biosynthesis of both phosphatidylcholine and phosphatidylethanolamine, this effect was essentially due to impairment of either choline or ethanolamine uptake by the cells. The efficiency of the drugs to inhibit phosphatidylcholine and phosphatidylethanolamine synthesis was in the order: clofilium greater than amiodarone much greater than propranolol = bretylium much greater than N-acetylprocainamide. The IC50 varied from 3-5 microM for clofilium to greater than 200 microM for N-acetylprocainamide. In contrast, only clofilium, a voltage-gated K(+)-channel blocker, was able to increase phosphatidylserine synthesis with an EC50 = 50 microM. The effect of clofilium on phosphatidylserine synthesis thus mimics the effect of three other K(+)-channel blockers, quinine, 4-aminopyridine and tetraethylammonium, suggesting close relationships between phosphatidylserine synthesis and K+ channel activity.

Acecainide↗
PubMed1990

CD4+ cells treated with DNA methylation inhibitors induce autologous B cell differentiation.

The DNA methylation inhibitor 5-azacytidine induces autoreactivity in cloned CD4+ T cells, but the functional consequences of this response are unknown. We now report that CD4+ T cells treated with 5-azacytidine respond to autologous antigen-presenting cells and induce autologous B cell differentiation without exogenous antigen or mitogen. This mechanism could play a role in some autoimmune diseases characterized by T cell DNA hypomethylation and polyclonal B cell activation.

Acecainide↗
PubMed1990

Simple in vitro method to characterize antiarrhythmic agents.

A simple, nonmicroelectrode method was developed for the in vitro identification and characterization of potential antiarrhythmic agents. To evaluate the method, standard antiarrhythmic agents from three different classifications (I, III, IV) were tested in isolated right ventricular guinea pig papillary muscles for their effect on developed tension (DT), excitability (EX), and effective refractory period (ERP). ERP was measured with the use of paired field stimuli. Depression or reversal of the force frequency relationship was an index of an agent's effect on DT. A shift in the stimulus strength-duration relationship was an index of an agent's effect on EX. A computer program was developed for data handling and analysis. Disopyramide phosphate (D, 3.0 x 10(-5) M), sotalol (S, 3.0 x 10(-5) M), clofilium phosphate (C, 1.0 x 10(-5) M), and N-acetyl procainamide hydrochloride (N, 3.0 x 10(-5) M) significantly prolonged ERP (+20, +35, +24, +16 ms, respectively), while verapamil (V, 3.0 x 10(-7) M) and the distilled water vehicle (W) did not. D and V significantly decreased DT (-78% and -57% at 1 Hz, respectively) while W, S, C, and N did not. Only D decreased EX. These data correspond well with findings in other models reported in the literature, supporting the use of this simple in vitro method for identification and characterization of potential antiarrhythmic agents.

Acecainide↗
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↗
PubMed1989

Procainamide N-acetyltransferase: modulation by clofibrate and a microsomal form.

1. Detoxification of procainamide by N-acetyltransferase which occurs primarily in the cytoplasmic fraction of the rat liver can be modulated by clofibrate treatment. 2. When the concentration of one of the substrates, procainamide, is 100 microM while the other, acetyl CoA, is 10 or 100 microM, the specific activity is reduced following clofibrate treatment. However, total activity is unchanged because of a 44% increase in cytoplasmic protein. 3. At more physiological levels of the two substrates (10 microM), total enzyme activity is increased from 9.5 +/- 1.5 to 14.0 +/- 1.8 pmol/mg/min, P less than 0.05. 4. A microsomal form of N-acetyltransferase activity is reported which is unaffected by the concentration of acetyl CoA in contrast to the cytoplasmic form.

Acecainide↗
PubMed1987

High-performance liquid chromatographic drug analysis by direct injection of whole blood samples. II. Determination of hydrophilic drugs.

The determination of hydrophilic drugs in whole blood by direct injection high-performance liquid chromatography was investigated. A pre-column equipped with an inlet filter of pore size 40 microns and an outlet filter of pore size 2 microns was packed with Butyl Toyopearl 650-M. A whole blood sample was injected directly into the pre-column to trap proteins, hydrophobic compounds and blood cytomembranes, and hydrophilic compounds emerged into an analytical column (Nucleosil 5SA, particle size 5 microns) and were determined after column switching. Proteins in 40 microliters of rabbit whole blood were adsorbed in the pre-column (0.63 ml of wet gel) in 0.4% perchloric acid solution. The recovery of procainamide and N-acetylprocainamide from whole blood was quantitative with good reproducibility (coefficient of variation less than 4%). It was shown that procainamide added to rabbit whole blood was subjected to N-acetylation by N-acetyltransferase in blood cells.

Acecainide↗
PubMed1981

High performance liquid chromatographic analysis of the antiarrhythmic drugs procainamide, disopyramide, quinidine, propranolol and metabolites from serum extracts.

We describe a method for the simultaneous high performance liquid chromatographic determination of several antiarrhythmic drugs and some of their metabolites after extraction from 2.5 mL of spiked pooled sera. The extracts were applied to a C8 reversed phase column. Nine compounds of interest were resolved within the 30 minute run. An initial mobile phase of 80% phosphate (25 mmol/L, pH 3.5), 20% organic (acteonitrile:methanol, 2:3) was maintained for 2 min at which time a linear gradient was used to change the mobile phase to 30% phosphate, 70% organic at 20 min after injection. This composition was maintained from an additional 5 min. Absorbance at 212 nm was used for detection. Peak area ratios of drug to internal standard (N-propionylprocainamide) were used for quantitation. The relative standard deviations (and mean solute concentrations) of daily duplicate determinations for 15 days are: procainamide, 5.1% (5.9 mg/L); N-acetylprocainamide, 9.3% (6.0 mg/L); Mono-N-dealkyldisopyramide, 3.7% (4.1 mg/L); disopyramide, 4.3% (4.0 mg/L); quinidine, 4.5% (6.5 mg/L); and propranolol, 5.1% (0.097 mg/L). Dihydroquinidine and 4-hydroxypropranolol were also resolved but not quantitated.

Acecainide↗
PubMed1997

Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism.

We studied the genotypes of polymorphic N-acetyltransferase (NAT2) in 145 Japanese subjects by the polymerase chain reaction-restriction fragment length polymorphism method. The rapid-type NAT2*4 was expressed at a higher frequency (68.6%) than the slow-type genes with specific point mutations (NAT2*6A, 19.3%; NAT2*7B, 9.7%; NAT2*5B, 2.4%). The frequency of NAT2* genotypes consisted of 44% of a homozygote of NAT2*4, 49% of a heterozygote of NAT2*4 and mutant genes, and 7% of a combination of mutant genes. The metabolic activity for procainamide to N-acetylprocainamide was measured in 11 healthy subjects whose genotype had been determined. Although the acetylation activity substantially varied interindividually, the variability was considerably reduced after classification according to the genotype. The N-acetylprocainamide/procainamide ratio in urinary excretion was 0.60 +/- 0.17 (mean +/- SD) for those with NAT2*4/*4, 0.37 +/- 0.06 for NAT2*4/*6A, 0.40 +/- 0.03 for NAT2*4/*7B, and 0.17 for NAT2*6A/*7B. The results indicated that the NAT2* genotype correlates with acetylation of procainamide.

Acecainide↗
PubMed2001

Role of K+ channels in N-acetylprocainamide-induced relaxation of bovine tracheal smooth muscle.

We examined the relaxant effects of N-acetylprocainamide, the major hepatic metabolite of procainamide, on bovine tracheal smooth muscle, focusing on the possible involvement of K+ channels. N-acetylprocainamide produced a concentration-dependent and full inhibition of the tension development elicited by methacholine (0.3 or 1 microM). The potency of N-acetylprocainamide in diminishing methacholine-elicited tension development was one-half of that of procainamide. By comparison, N-acetylprocainamide inhibited high-K+ (40 mM)-induced contraction more potently than procainamide though both inhibitions were largely reduced when compared to those against methacholine-induced contraction. Iberiotoxin (30 nM), Ba(2+) (1 mM) or a combination of both agents significantly attenuated the relaxant effect of N-acetylprocainamide on methacholine-induced contraction, whereas apamin (100 nM), 4-aminopyridine (300 microM), and glibenclamide (10 microM) did not affect it. These results suggest that N-acetylprocainamide, similar to procainamide, elicits tracheal smooth muscle relaxation mainly through the activation of plasma membrane K+ channels.

Acecainide↗
PubMed1997

Direct determination of procainamide and N-acetylprocainamide by capillary zone electrophoresis in pharmaceutical formulations and urine.

In this work a new sensitive capillary zone electrophoresis method for the direct determination of procainamide (PA) and N-acetylprocainamide (NAPA) in pharmaceutical formulations and urine samples without any extraction and/or preconcentration steps has been developed. The determination was carried out in a fused-silica capillary of 43.5 cm (35.9 cm length to the detector) x 0.75 micron J.D. Phosphate 0.05 M buffer was used as the background electrolyte and 10 kV separation voltage was applied. The separation of PA and NAPA is possible in a wide range of pH from 1.7 to 9.7. However, in order to avoid the effect of the urine matrix, it is optimal to work at pH 7.7. The determination of PA and NAPA takes less than 5 min while high resolution is achieved. The detection limits obtained, 1.235 micrograms/ml and 0.359 microgram/ml for PA and NAPA respectively, are lower than those for GC method normally reported.

Acecainide↗
PubMed2001

N-substituted benzamides inhibit nuclear factor-kappaB and nuclear factor of activated T cells activity while inducing activator protein 1 activity in T lymphocytes.

N-substituted benzamides are compounds that have recently been reported to inhibit nuclear factor-kappaB (NF-kappaB) activity and induce apoptosis in a pre-B cell line. In this study, we focused on the effects of N-substituted benzamides on transcriptional regulation in Jurkat T cells. We used a model system where the cells can be stimulated either through TCR/CD28 or by treatment of the cells with PMA and ionomycin to induce transcription factors typical for T lymphocyte activation. Treatment of the Jurkat cells with procainamide did not influence the transcription factor profile of stimulated cells, while treatment with a derivative having an acetyl group in position 4 of the aromatic ring inhibited NF-kappaB and nuclear factor of activated T cells (NFAT) activity. Declopramide, which contains a chloride in position 3 of the aromatic ring, was inactive in this system, whereas also the acetylated derivative of this compound inhibited NF-kappaB and NFAT activity. In contrast, the transcriptional activity and nuclear expression of activator protein 1 induced by TCR/CD28 stimulation or PMA and ionomycin treatment was enhanced by the acetylated variants of the N-substituted benzamides. Finally, we investigated the effect of N-substituted benzamides on intact promoters for two genes central in immune regulation; the CD40 ligand (CD40L) and IL-2 promoters. The transcriptional activity of the CD40L promoter as well as surface expression of the CD40L induced by signaling through TCR/CD28 was inhibited by addition of acetylated N-substituted benzamides, while the transcriptional activity of the IL-2 promoter was enhanced. Taken together, these data indicate that derivatives of N-substituted benzamides are potential drug candidates for quantitative as well as qualitative modulation of immune functions.

Acecainide↗
PubMed1992

Combined high-efficiency hemodialysis and charcoal hemoperfusion in severe N-acetylprocainamide intoxication.

Several extracorporeal techniques have been used to remove N-acetylprocainamide (NAPA), the major metabolite of procainamide, in patients intoxicated with this substance. We report a patient with life-threatening NAPA intoxication who was rapidly and successfully treated with combined high-efficiency hemodialysis and charcoal hemoperfusion. The hemodialyzer and hemoperfusion cartridge were placed in series such that the patient's blood was dialyzed before reaching the cartridge. Overall clearance of NAPA was 153 mL/min, with clearance due to hemodialysis averaging 102 mL/min and that due to hemoperfusion averaging 88 mL/min. Thus, addition of the hemoperfusion cartridge into the extracorporeal circuit resulted in a 50% increase in clearance over that obtainable by high-efficiency hemodialysis alone. In comparison to other modalities, this technique is more effective than either hemodialysis or charcoal hemoperfusion alone and can achieve a more rapid reduction of serum NAPA levels than that observed with slow continuous hemofiltration or hemodiafiltration.

Acecainide↗
PubMed1984

Use of procainamide in chronic ambulatory peritoneal dialysis: report of a case.

A patient on chronic ambulatory peritoneal dialysis (CAPD) was treated with procainamide for control of ventricular arrhythmias. A procainamide half-life of 11.5 hours was observed, with a dialysis clearance of 6.5 mL/min. The N-acetylprocainamide (NAPA) dialysis clearance was 5.3 mL/min. The CAPD clearance of procainamide and its active metabolite, NAPA, is much lower than that reported for hemodialysis. Procainamide therapy should be initiated with reduced dosages in patients with renal failure.

Acecainide↗