RESUMEN
Procainamide (PA) is a drug that is used to treat tachycardia in postoperative patients or for long-term maintenance of cardiac arrythmias. Unfortunately, its use has also been associated with agranulocytosis. Here, we have investigated the metabolism of PA by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that PA oxidation by MPO/H 2O 2 would produce a PA cation radical that, in the absence of a biochemical reductant, would lead to the free radical oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H 2O 2 induced the formation of DMPO-MPO, which was inhibited by MPO inhibitors and ascorbate. N-acetyl-PA did not cause DMPO-MPO formation, indicating that the unsubstituted aromatic amine was more oxidizable. PA had a lower calculated ionization potential than N-acetyl-PA. The DMPO adducts of MPO metabolism, as analyzed by electron spin resonance spectroscopy, included a nitrogen-centered radical and a phenyl radical derived from PA, either of which may be involved in the free radical formation on MPO. Furthermore, we also found protein-DMPO adducts in MPO-containing, intact human promyelocytic leukemia cells (HL-60). MPO was affinity-purified from HL-60 cells treated with PA/H 2O 2 and was found to contain DMPO using the anti-DMPO antibody. Mass spectrometry analysis confirmed the identity of the protein as human MPO. These findings were also supported by the detection of protein free radicals with electron spin resonance in the cellular cytosolic lysate. The formation of an MPO protein free radical is believed to be mediated by free radical metabolites of PA, which we characterized by spin trapping. We propose that drug-induced free radical formation on MPO may play a role in the origin of agranulocytosis.
Asunto(s)
Radicales Libres/metabolismo , Granulocitos/patología , Peroxidasa/metabolismo , Procainamida/farmacología , Acecainida/química , Acecainida/farmacología , Ácido Ascórbico/farmacología , Línea Celular Tumoral , Espectroscopía de Resonancia por Spin del Electrón , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Humanos , Peróxido de Hidrógeno/farmacología , Iones/química , Espectrometría de Masas , Estructura Molecular , Peroxidasa/antagonistas & inhibidores , Procainamida/química , Procainamida/metabolismoRESUMEN
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.
Asunto(s)
Benzamidas/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Proteínas Nucleares , Procainamida/análogos & derivados , Linfocitos T/inmunología , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Acecainida/farmacología , Ligando de CD40/metabolismo , Núcleo Celular/metabolismo , Activación Enzimática , Humanos , Interleucina-2/genética , Células Jurkat , FN-kappa B/análisis , FN-kappa B/química , Subunidad p50 de NF-kappa B , Factores de Transcripción NFATC , Procainamida/farmacología , Regiones Promotoras Genéticas , Linfocitos T/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
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.
Asunto(s)
Acecainida/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Canales de Potasio/fisiología , Tráquea/efectos de los fármacos , Animales , Bario/farmacología , Bovinos , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Cloruro de Metacolina/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Péptidos/farmacología , Potasio/farmacología , Bloqueadores de los Canales de Potasio , Procainamida/farmacología , Tráquea/fisiologíaRESUMEN
1. The cardiac anticholinergic effects of procainamide (1 mg kg(-1) min(-1)) and its N-acetylated metabolite (NAPA) at equimolar dose (1.16 mg kg(-1) min(-1)) were studied using in vivo experimental pharmacological and in vitro radioligand binding studies. 2. Procainamide and NAPA progressively reduced vagal stimulation-induced bradycardia in chloralose-anaesthetized dogs. As indicated by the ED50, the vagolytic activity of NAPA is 1.5-2.0 times weaker than that of procainamide. Both drugs increased heart rate, with lowering of mean blood pressure during the second part of procainamide infusion, but not during NAPA infusion. 3. Binding studies on rat heart membranes yielded Ki values that were 1.5 times higher for NAPA than for procainamide. 4. These results show that NAPA exerts a weaker cardiac vagolytic action than procainamide, which is probably linked to a lower ability to bind to cardiac muscarinic receptors.
Asunto(s)
Acecainida/farmacología , Antiarrítmicos/farmacología , Antagonistas Colinérgicos/farmacología , Corazón/efectos de los fármacos , Procainamida/farmacología , Receptores Colinérgicos/efectos de los fármacos , Acetilación , Animales , Antiarrítmicos/metabolismo , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Bradicardia/inducido químicamente , Antagonistas Colinérgicos/metabolismo , Perros , Femenino , Corazón/inervación , Masculino , Miocardio/metabolismo , Sistema Nervioso/efectos de los fármacos , Procainamida/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores Muscarínicos/efectos de los fármacos , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiologíaRESUMEN
The cardiovascular pharmacodynamics (PD) of procainamide and N-acetylprocainamide have not been well characterized in small rodents without the presence of anesthesia or restraint. This study was undertaken to examine the pharmacokinetics (PK) and PD relationship of procainamide and N-acetylprocainamide by use of electrocardiogram (ECG) telemetry in unrestrained rats. Male Sprague Dawley rats received the following treatments: vehicle, procainamide 50 and 100 mg/kg and N-acetylprocainamide 50 and 100 mg/kg via intraperitoneal (i.p.) administration. Blood samples were collected over 8 h and subsequently analyzed. PD measurements (PQ, QS, QR, QT, RR, and HR) were collected prior to dosing and over a 24 h period. Mean PK parameters after the 50 mg/kg dose were as follows: Cls/Fprocainamide = 86.42 mL min-1 kg-1, Cls/FN-acetylprocainamide = 36.62 mL min-1 kg-1, Vdprocainamide = 10.42 L/kg, and VdN-acetylprocainamide = 5.91 L/kg. The relationship between concentration (procainamide or N-acetylprocainamide) and effect (percent change QT interval) was best described by an Emax model for procainamide (EC50 = 445 ng/mL; Emax = 30.09%). These results approximate ECG changes noted in procainamide clinical studies, suggesting that telemetry can be used as a predictive tool of efficacy. Furthermore, the proposed PK-PD model describes the electrophysiological effects associated with procainamide.
Asunto(s)
Acecainida/farmacología , Acecainida/farmacocinética , Antiarrítmicos/farmacología , Antiarrítmicos/farmacocinética , Procainamida/farmacología , Procainamida/farmacocinética , Animales , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/metabolismo , Electrocardiografía/efectos de los fármacos , Electrocardiografía/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Telemetría/métodosRESUMEN
Ischemic zone refractoriness and conduction delay respond differently to infarct healing and, hypothetically, may exert discordant influences on the electrophysiologic action of different classes of antiarrhythmic drugs. This study evaluated the influence of infarct healing on the electrophysiologic effects of procainamide (PA) and N-acetylprocainamide (NAPA) in a sedated, closed-chest canine model with a healing anterior wall myocardial infarction, indwelling myocardial electrodes and inducible sustained ventricular tachyarrhythmias (VT). Infarct zone refractory periods, conduction times and the inducibility of VT were tested at base line and during infusion of PA or NAPA in a crossover study design at 1, 4 and 8 weeks of infarct healing. Data were presented as the percent magnitude of change from base line induced by drug. The magnitude of change during PA infusion in infarct zone refractory periods, but not conduction times, decreased during infarct healing (P < .001). The magnitude of change in refractory period and conduction time during NAPA was not significantly altered by the stage of myocardial infarction healing. At week 1, PA prevented inducible VT in 9 of 14 animals vs. 3 of 15 during NAPA infusion (P < .05). At weeks 4 and 8 there was no significant difference in VT suppression between PA and NAPA. We conclude that the stage of infarct healing can selectively influence the response of the infarct zone to the effects of PA, but not NAPA. This discordant effect may be class-specific. These data may have important implications for the management of lethal ventricular arrhythmias soon after myocardial infarction.
Asunto(s)
Acecainida/farmacología , Corazón/efectos de los fármacos , Infarto del Miocardio/fisiopatología , Procainamida/farmacología , Animales , Perros , Electrofisiología , Corazón/fisiopatología , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , Periodo Refractario Electrofisiológico/efectos de los fármacosRESUMEN
The prescription drugs procainamide (PA) and hydralazine (HYD) are associated with the induction of autoimmunity and a clinical syndrome called drug-induced lupus. Since PA- and HYD-induced autoantibodies are directed primarily against histones and histones are prime acceptors of poly (ADP-ribose) (PADPR), we have investigated the effects of PA and HYD on the activity of poly (ADP-ribose) polymerase (PADPRP). Control substances, with structures similar to PA and HYD but not known to induce lupus, included N-acetylprocainamide (NAPA) and the amino acids phenylalanine, tryptophan and proline, and their amide derivatives. Wil-2 cells were incubated in 0.5-50 microM PA, NAPA and HYD, which included therapeutic concentrations of these drugs. The mean enhancement of incorporation of [3H]-nicotinamide adenine dinucleotide (NAD) into PADPR was 1.84 (P = 0.005) with PA, with HYD 1.48 (P = 0.029), and with NAPA 1.38 (P = 0.036). This increase was suppressed by 3-aminobenzamide, an inhibitor of PADPRP activity. Little or no increase in [3H]-NAD incorporation was observed with equivalent concentrations of phenylalanine, phenylalaninamide or tryptophan. However, a 1.29-fold increase was noted with 0.5 microM tryptophanamide, a 1.26-fold increase with 0.5 microM prolinamide and a 1.4-fold increase with 50 microM proline. PA increased PADPRP activity in B- and T-cell lines but not in promyelocytic leukemia or epithelial cell lines. Since poly (ADP-ribosylation) is important in the cellular response to various agents, the increased ADP-ribosylation of intracellular molecules may be a key event in the induction of autoantibodies.
Asunto(s)
Hidralazina/farmacología , Poli Adenosina Difosfato Ribosa/metabolismo , Procainamida/farmacología , Acecainida/farmacología , Línea Celular Transformada , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Células Tumorales CultivadasRESUMEN
The study objective was to characterize the electrophysiologic interactions of procainamide (PA) and its metabolite, N-acetylprocainamide (NAPA), in canine Purkinje fibers. Cell (N = 43) action potentials were measured in Tyrode's solution (K+ = 4.0 mM, 36 degrees C) at a basic cycle length of 1,000 ms using standard microelectrode techniques. Six PA concentrations (0.020-0.32 mM) and six NAPA concentrations (0.010-0.24 mM) were studied alone and in combination. PA caused concentration-dependent decreases in Vmax and APD50 but did not alter APD90, ERP, or RMP. NAPA caused a small but not significant concentration-dependent decrease in Vmax, no change in RMP, and significant concentration-dependent increases in APD50, APD90, and ERP. Low NAPA concentrations increased, intermediate concentrations did not affect, and high NAPA concentrations again increased PA's effect on Vmax. PA-NAPA combinations resulted in concentration-dependent changes in APD50 that were intermediate between the effects of PA or NAPA alone. PA did not significantly alter NAPA's effects on APD90 at NAPA concentrations less than or equal to 0.040 mM, while it antagonized NAPA's effect at higher concentrations. The effects of PA-NAPA combinations on ERP were generally similar to their effects on APD90. The electrophysiologic effects of PA-NAPA combinations in normal canine Purkinje fibers are complex functions of the relative and absolute concentrations of the two compounds.
Asunto(s)
Acecainida/farmacología , Procainamida/farmacología , Ramos Subendocárdicos/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Perros , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electrofisiología , Técnicas In Vitro , Procainamida/metabolismo , Ramos Subendocárdicos/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antiarrítmicos/farmacología , Fosfolípidos/metabolismo , Linfocitos T/metabolismo , Acecainida/farmacología , Amiodarona/farmacología , Compuestos de Bretilio/farmacología , Carboxiliasas/metabolismo , Colina/metabolismo , Descarboxilación , Relación Dosis-Respuesta a Droga , Etanolamina , Etanolaminas/metabolismo , Humanos , Fosfatidilcolinas/biosíntesis , Fosfatidiletanolaminas/biosíntesis , Fosfatidilserinas/biosíntesis , Propranolol/farmacología , Compuestos de Amonio Cuaternario/farmacología , Linfocitos T/efectos de los fármacosRESUMEN
According to mathematical models of antiarrhythmic drug-receptor interactions, lidocaine binds preferentially to the sodium channel when the membrane is depolarized (i.e., the "inactivated" channel state). Therefore, the effect of lidocaine on conduction should be greater when the action potential duration is prolonged. To test this prediction in vivo we evaluated the rate-dependent effects of lidocaine on His-Purkinje conduction in the intact newborn canine heart. Lidocaine's effect was assessed alone and then when given in combination with N-acetylprocainamide, a Class III antiarrhythmic agent. Utilizing intracardiac electrical stimulation and electrogram recording techniques, changes in the steady-state His-Purkinje conduction time during atrial pacing at increasingly rapid cycle lengths, changes in the conduction time of pacing trains delivered directly to the His bundle and changes in conduction time during His bundle extra stimulation were measured. After bilateral sectioning of the vagi and the administration of propranolol (1.0 mg/kg i.v.), His-Purkinje conduction was assessed in newborn canines (ages 5-15 days) under the following conditions: 1) control (n = 18); 2) after an i.v. infusion of lidocaine HCl (serum concentration 3.7 +/- 0.8 micrograms/ml) (n = 12); and 3) after the combined administration of lidocaine and N-acetylprocainamide (serum concentration, 26.4 +/- 6.3 micrograms/ml) (n = 12). Rate-dependent changes in His-Purkinje conduction time were observed in the newborn in response to lidocaine at rapid paced cycle lengths. These changes were significantly amplified by the coadministration of N-acetylprocainamide. Furthermore, the time constant of recovery from rate-dependent conduction delay, determined during His bundle extra stimulation, was 45 msec, which is notably shorter than values reported for lidocaine in the adult.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Acecainida/farmacología , Animales Recién Nacidos/fisiología , Sistema de Conducción Cardíaco/efectos de los fármacos , Corazón/efectos de los fármacos , Lidocaína/farmacología , Envejecimiento/fisiología , Animales , Función Atrial , Fascículo Atrioventricular/efectos de los fármacos , Fascículo Atrioventricular/fisiología , Perros , Sinergismo Farmacológico , Corazón/fisiología , Atrios Cardíacos/efectos de los fármacos , Lidocaína/farmacocinética , Ramos Subendocárdicos/efectos de los fármacosRESUMEN
The electrophysiologic effects of N-acetylprocainamide (NAPA), a metabolite of procainamide reported to exert significant Class III antiarrhythmic effects in the adult heart, were evaluated in 12 neonatal mongrel canines (ages 7-14 days). Following transvascular placement of quadripolar electrical catheters in the right atrium and ventricle, and a tripolar catheter in the region of the His bundle, electrophysiologic assessments were made of sinus and AV nodal function and atrial and ventricular refractoriness utilizing intracardiac stimulation and recording techniques following cumulative intravenous doses of 20 and 40 mg/kg of NAPA (serum concentrations 13.1 +/- 1.9 and 25.6 +/- 3.4 micrograms/ml). NAPA resulted in an overall increase in sinus cycle length of 18%. No changes were observed in the paced cycle length resulting in AV nodal Wenckebach. Consistent with NAPA's reported Class III action, NAPA increased the effective and functional refractory periods of the ventricle by 35 and 34%, respectively (p less than 0.001). Even larger increases were observed in atrial refractoriness (effective 75%, functional 57%, p less than 0.001). In separate experiments (n = 6), the effects of intravenous NAPA (40 mg/kg) on the duration of the monophasic action potential recorded from the neonatal atrium and ventricle were determined. NAPA increased APD90 of the atrium by approximately 50% and that of the ventricle by 60%, thus confirming a significant effect on myocardial repolarization in the neonate.
Asunto(s)
Acecainida/farmacología , Animales Recién Nacidos/fisiología , Corazón/efectos de los fármacos , Acecainida/sangre , Potenciales de Acción/efectos de los fármacos , Animales , Función Atrial , Presión Sanguínea/efectos de los fármacos , Fascículo Atrioventricular/efectos de los fármacos , Fascículo Atrioventricular/fisiología , Perros , Relación Dosis-Respuesta a Droga , Corazón/fisiología , Atrios Cardíacos/efectos de los fármacos , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ramos Subendocárdicos/efectos de los fármacos , Ramos Subendocárdicos/fisiología , Factores de Tiempo , Función VentricularRESUMEN
The change of electrically induced VFT was chosen as index of effect in anesthetized rabbits for study of pharmacodynamics of PA and NAPA. We analyzed the pharmacokinetic properties of PA and NAPA and elucidated their effect kinetics with a pharmacokinetic-pharmacodynamic (PK/PD) model in view of different transfer qualities. A linear-addition effect model was used to describe the relationship between the effect and the amount of drug and its metabolite in the effect compartment. PA was found to be eliminated faster than NAPA and distributed more extensively in rabbits. The effect per unit concentration of PA was shown to be larger than that of NAPA.
Asunto(s)
Acecainida/farmacocinética , Procainamida/farmacocinética , Fibrilación Ventricular/fisiopatología , Acecainida/farmacología , Animales , Femenino , Modelos Lineales , Masculino , Matemática , Procainamida/farmacología , Conejos , Fibrilación Ventricular/metabolismoRESUMEN
The pharmacokinetic and pharmacodynamic profiles of procainamide (PA) and its major metabolite, acetylprocainamide (NAPA), were analyzed by extended combined pharmacokinetic and pharmacodynamic model in rabbits. The pharmacodynamic parameters Keo, S, Ce(50), Emax for PA were 0.023 +/- 0.005 min-1, 3.9 +/- 1.1, 3.6 +/- 0.9 micrograms.ml-1, 37 +/- 10 ms respectively and for NAPA were 0.061 +/- 0.017 min-1, 2.2 +/- 0.4, 6.2 +/- 1.7 micrograms.ml-1, 53.6 +/- 2.5 ms. Following PA iv to rabbit both PA and NAPA were involved in the QTc prolongation of the initial period, but the later action was mainly associated with NAPA. Differences of pharmacokinetic and pharmacodynamic parameters between PA and NAPA were found.
Asunto(s)
Acecainida/farmacocinética , Procainamida/farmacocinética , Acecainida/farmacología , Animales , Cromatografía en Capa Delgada , Femenino , Masculino , Modelos Estadísticos , Procainamida/farmacología , ConejosRESUMEN
The effects of N-acetylprocainamide (NAPA) and sotalol on membrane current systems of guinea-pig ventricular myocytes were examined and compared with those of quinidine using patch-clamp techniques. All of the drugs prolonged the action potential duration (i.e. Class III effect) in isolated guinea-pig papillary muscles. In isolated ventricular cells. NAPA (300 microM) and sotalol (100 microM) produced a decrease in the delayed outward potassium current (IK) concomitantly with a slight decrease in the calcium current (ICa), which was similar to quinidine (10 microM). NAPA also slightly depressed the inward rectifier potassium current (IKrect). Thus, NAPA and sotalol both inhibited IK, and this action appears to be mainly responsible for their Class III effect.
Asunto(s)
Acecainida/farmacología , Canales Iónicos/efectos de los fármacos , Miocardio/metabolismo , Sotalol/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Estimulación Eléctrica , Femenino , Cobayas , Corazón/efectos de los fármacos , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Miocardio/citología , Músculos Papilares/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Quinidina/farmacologíaRESUMEN
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.
Asunto(s)
Azacitidina/farmacología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Acecainida/farmacología , Formación de Anticuerpos/fisiología , Células Presentadoras de Antígenos/inmunología , Antígenos CD/biosíntesis , Antígenos de Diferenciación/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , ADN/efectos de los fármacos , Antígenos de Histocompatibilidad/biosíntesis , Humanos , Hidroxiurea/farmacología , Integrina beta1 , Antígenos Comunes de Leucocito , Metilación , Procainamida/farmacologíaRESUMEN
Acecainide (N-acetylprocainamide), the N-acetylated metabolite of procainamide, is a Class III antiarrhythmic agent. It can be given either intravenously or orally, and is eliminated primarily by renal excretion. In a small number of noncomparative and placebo-controlled short term therapeutic trials acecainide markedly reduced premature ventricular beats and prevented induction of ventricular tachycardia in more than 70% of patients following intravenous administration and in about 50% after oral administration. Acecainide was effective in about one-quarter of patients refractory to other antiarrhythmic drugs. Interpretation of its effectiveness following long term oral therapy is complicated by the limited number of patients, and patients discontinuing due to adverse effects or lack of efficacy. However, about 40% of the small number treated for extended periods were controlled for periods of 6 months to 3 to 4 years. Comparative studies with other antiarrhythmic drugs have not been undertaken apart from a small study in atrial flutter where acecainide was better than quinidine plus digoxin. Thus, although further clinical experience is required before the relative place of acecainide in therapy can be determined, the drug nevertheless appears to offer advantages over procainamide, particularly with respect to the reduced formation of antinuclear antibodies.
Asunto(s)
Acecainida/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Procainamida/análogos & derivados , Acecainida/efectos adversos , Acecainida/farmacocinética , Acecainida/uso terapéutico , HumanosRESUMEN
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.
Asunto(s)
Antiarrítmicos/farmacología , Acecainida/farmacología , Animales , Disopiramida/farmacología , Estimulación Eléctrica , Cobayas , Técnicas In Vitro , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Periodo Refractario Electrofisiológico/efectos de los fármacos , Sotalol/farmacología , Verapamilo/farmacologíaRESUMEN
We analyzed the effects of procainamide (PROC), hydralazine (HYD), N-acetylprocainamide (NAPA), and L-canavanine (CAN) on circular supercoiled plasmids as models for chromosomal loop domains. The supercoil-dependent B-Z equilibrium in recombinant plasmids was used as an indicator of structural changes induced in circular DNA. Two-dimensional gel electrophoresis showed that PROC and HYD strongly inhibited supercoil-induced Z-DNA formation, whereas NAPA caused less pronounced changes in the B-Z equilibrium, and CAN had no effect. Gel retardation assays showed that the binding of a Z-DNA-specific autoimmune antibody to a Z-DNA-containing plasmid was strongly perturbed by HYD, but not influenced by CAN. Both PROC and NAPA showed moderate inhibition of antibody binding. Our results demonstrate the different potentials of these 4 drugs to interact with DNA and to alter the tertiary topology of DNA domains. It is conceivable that the in vivo capacity of PROC and HYD to induce antinuclear antibodies may be related to their ability to influence structural features in chromosomal DNA domains or nucleosomes, thus liberating antigenic structural epitopes in DNA and/or DNA-associated proteins.
Asunto(s)
Acecainida/farmacología , Canavanina/farmacología , ADN Superhelicoidal/efectos de los fármacos , Hidralazina/farmacología , Lupus Eritematoso Sistémico/inducido químicamente , Procainamida/análogos & derivados , Procainamida/farmacología , Animales , Anticuerpos/inmunología , ADN Superhelicoidal/inmunología , ADN Superhelicoidal/ultraestructura , Electroforesis en Gel de Agar , Escherichia coli , PlásmidosRESUMEN
The pharmacokinetic and pharmacodynamic profiles of N-acetyl procainamide were analyzed by integrated PK-PD model following intravenous infusion to rabbits. No significant differences between the PK parameters estimated from iv administration and intravenous infusion were found. However, two of the PD parameters were shown to be significantly different. The values of Emax, Keo, S, EC50 were found to be 120 +/- 13.2 ms, 0.0182 +/- 0.007 min-1, 2.26 +/- 0.93, 6.31 +/- 0.71 microgram/ml respectively following intravenous infusion; the corresponding values following iv administration were 53.6 +/- 2.5 ms, 0.061 +/- 0.017 min-1, 2.19 +/- 0.39, 6.21 +/- 1.74 micrograms/ml respectively.
Asunto(s)
Acecainida/farmacocinética , Acecainida/farmacología , Animales , Femenino , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Matemática , ConejosRESUMEN
An asymmetric biphasic pulse which stimulates the heart and neutralizes the poststimulation polarization at the electrode-myocardial interface permitting the recording of the evoked endocardial response (EER) up to approximately 1 ms poststimulation with the same electrode used for stimulation is described. Using this mode of cardiac stimulation in 20 dogs the effects on the EER of increasing heart rate and antiarrhythmic drugs, procainamide (PA) and N-acetylprocainamide (NAPA), were studied. EERs were recorded during bipolar and unipolar pacing rates of 120, 150, and 200/min before and during a five step PA or NAPA infusion which resulted in progressively increasing PA and NAPA plasma concentrations (Cps), 1.7-32.5 mg/l for PA and 8.1-116.1 mg/l for NAPA. The effects of progressively increasing heart rates were: The T wave amplitude and QS area increased with increases in rate; during pacing at 120, 150, and 200/min, the T wave amplitudes were 7.6 +/- 2.3, 8.2 +/- 2.1, and 9.8 +/- 2.5 mV and the QS areas were 905 +/- 204, 995 +/- 199, and 1101 +/- 231 mVms. The QT interval and QST area decreased with increases in rate; during pacing at 120, 150, and 200/min, the QT intervals were 265 +/- 61, 249 +/- 57, and 226 +/- 52 ms and the QST areas were 288 +/- 198, 221 +/- 154, and 154 +/- 52 mVms. The effects of the antiarrhythmic drugs, PA and NAPA, on the EER were: PA prolonged both the QS duration and QT interval at low Cp (type Ia antiarrhythmic drug property); at a therapeutic PA Cp of 15.0 +/- 0.2 mg/l and a heart rate of 120/min the percent increase of the QS duration was 12 +/- 4% (P = 0.001) and that of the QT interval was 20 +/- 6% (P less than 0.001). The prolongation of the QS duration by PA was rate dependent, the faster the rate the greater the prolongation. NAPA prolonged the QT interval at low Cp, while the QS duration was not significantly effected at low or therapeutic Cps (type III antiarrhythmic drug property); at a therapeutic NAPA Cp of 15.9 +/- 1.6 mg/l and a heart rate of 120/min the percent increase of the QS duration was 1 +/- 1% (NS) and that of the QT interval was 13 +/- 9% (P = 0.018). Our results show that the use of an asymmetric biphasic pulse allows for pacing and recording of an EER, QS and T waves, with a single electrode.(ABSTRACT TRUNCATED AT 400 WORDS)