RESUMEN
Non-bilayer phospholipid arrangements are three-dimensional structures that can form when anionic phospholipids with an intermediate form of the tubular hexagonal phase II (H(II)), such as phosphatidic acid, phosphatidylserine or cardiolipin, are present in a bilayer of lipids. The drugs chlorpromazine and procainamide, which trigger a lupus-like disease in humans, can induce the formation of non-bilayer phospholipid arrangements, and we have previously shown that liposomes with non-bilayer arrangements induced by these drugs cause an autoimmune disease resembling human lupus in mice. Here we show that liposomes with non-bilayer phospholipid arrangements induced by Mn²âº cause a similar disease in mice. We extensively characterize the physical properties and immunological reactivity of liposomes made of the zwitterionic lipid phosphatidylcholine and a H(II)-preferring lipid, in the absence or presence of Mn²âº, chlorpromazine or procainamide. We use an hapten inhibition assay to define the epitope recognized by sera of mice with the disease, and by a monoclonal antibody that binds specifically to non-bilayer phospholipid arrangements, and we report that phosphorylcholine and glycerolphosphorylcholine, which form part of the polar region of phosphatidylcholine, are the only haptens that block the binding of the tested antibodies to non-bilayer arrangements. We propose a model in which the negatively charged H(II)-preferring lipids form an inverted micelle by electrostatic interactions with the positive charge of Mn²âº, chlorpromazine or procainamide; the inverted micelle is inserted into the bilayer of phosphatidylcholine, whose polar regions are exposed and become targets for antibody production. This model may be relevant in the pathogenesis of human lupus.
Asunto(s)
Lupus Eritematoso Sistémico/metabolismo , Liposomas Unilamelares/metabolismo , Animales , Anticuerpos/sangre , Anticuerpos/metabolismo , Anticuerpos Monoclonales/metabolismo , Cardiolipinas/química , Cardiolipinas/inmunología , Bovinos , Clorpromazina/toxicidad , Glomérulos Renales/patología , Lupus Eritematoso Sistémico/inducido químicamente , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Manganeso/toxicidad , Ratones , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Ácidos Fosfatidicos/química , Ácidos Fosfatidicos/inmunología , Fosfatidilcolinas/química , Fosfatidilcolinas/inmunología , Fosfatidilserinas/química , Fosfatidilserinas/inmunología , Procainamida/toxicidad , Piel/patología , Liposomas Unilamelares/química , Liposomas Unilamelares/inmunologíaRESUMEN
Drug-induced lupus is a serious side effect of certain medications, but the chemical features that confer this property and the underlying pathogenesis are puzzling. Prototypes of all six therapeutic classes of lupus-inducing drugs were highly cytotoxic only in the presence of activated neutrophils. Removal of extracellular hydrogen peroxide before, but not after, exposure of the drug to activated neutrophils prevented cytotoxicity. Neutrophil-dependent cytotoxicity required the enzymatic action of myeloperoxidase, resulting in the chemical transformation of the drug to a reactive product. The capacity of drugs to serve as myeloperoxidase substrates in vitro was associated with the ability to induce lupus in vivo.
Asunto(s)
Muerte Celular/efectos de los fármacos , Lupus Eritematoso Sistémico/inducido químicamente , Activación Neutrófila , Neutrófilos/metabolismo , Peroxidasa/metabolismo , Animales , Bioensayo , Biotransformación , Clorpromazina/análogos & derivados , Clorpromazina/metabolismo , Clorpromazina/toxicidad , Humanos , Hidralazina/análogos & derivados , Hidralazina/metabolismo , Hidralazina/toxicidad , Peróxido de Hidrógeno/metabolismo , Isoniazida/análogos & derivados , Isoniazida/metabolismo , Isoniazida/toxicidad , Ratones , Neutrófilos/enzimología , Procainamida/análogos & derivados , Procainamida/metabolismo , Procainamida/toxicidad , Propiltiouracilo/análogos & derivados , Propiltiouracilo/metabolismo , Propiltiouracilo/toxicidad , Quinidina/análogos & derivados , Quinidina/metabolismo , Quinidina/toxicidad , Células Tumorales CultivadasRESUMEN
INTRODUCTION: Direct comparison of the effects of antiarrhythmic agents on myocardial performance may be useful in choosing between medications in critically ill patients. Studies directly comparing multiple antiarrhythmic medications are lacking. The use of an experimental heart preparation permits examination of myocardial performance under constant loading conditions. METHODS: Hearts of Sprague Dawley rats (n = 35, 402-507 g) were explanted and cannulated in working heart model with fixed preload and afterload. Each heart was then exposed to a 3-hour infusion of procainamide (20 µg/kg/min), esmolol (100 or 200 µg/kg/min), amiodarone (10 or 20 mg/kg/d), sotalol (80 mg/m2/d), or placebo infusions (n = 5 per dose). Cardiac output, contractility (dP/dTmax), diastolic performance (dP/dTmin), and heart rate were compared between groups over time by linear mixed modeling. RESULTS: Compared with placebo, sotalol decreased contractility by an average of 24% ( P < .001) over the infusion period, as did amiodarone (low dose by 13%, P = .029; high dose by 14%, P = .013). Compared with placebo, mean cardiac output was significantly lower in animals treated with sotalol (by 22%, P = .016) and esmolol 200 µg/kg/min (by 23%, P = .012). Over time, amiodarone decreased cardiac output (20 mg/kg/d, ß = -89 [-144, -33] µL/min2 decrease, P = .002) and also worsened diastolic function, decreasing dP/dTmin by â¼18% and 22% ( P = .032 and P = .011, low and high doses, respectively). Procainamide did not have a significant effect on any measures of systolic or diastolic performance. CONCLUSIONS: In isolated hearts, amiodarone and sotalol depressed myocardial contractility, cardiac output, and diastolic function. However, procainamide did not negatively affect myocardial performance and represents a favorable agent in settings of therapeutic equivalence.
Asunto(s)
Amiodarona/administración & dosificación , Antiarrítmicos/administración & dosificación , Gasto Cardíaco/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Procainamida/administración & dosificación , Sotalol/administración & dosificación , Función Ventricular Izquierda/efectos de los fármacos , Amiodarona/toxicidad , Animales , Antiarrítmicos/toxicidad , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , Preparación de Corazón Aislado , Procainamida/toxicidad , Ratas Sprague-Dawley , Medición de Riesgo , Sotalol/toxicidadRESUMEN
Drug-induced autoimmunity (DIA) refers to a group of adverse drug reactions, and they remain unpredictable largely due to the limited understanding of the mechanisms involved. There is evidence that procainamide can cause autoimmune reactions in humans but the mechanisms involved remain unclear. To examine the cellular and genetic factors involved in the procainamide-induced autoimmune response, we compared rats that are genetically T-helper (Th)2-predisposed (Brown Norway (BN)), Th1-predisposed (Lewis (LEW)) or not genetically predisposed (Sprague Dawley (SD)). We revealed significant differences in response to autoimmunity induced by procainamide among three strains rats, BN was the most sensitive one, SD exhibited less sensitive, while LEW resistance to procainamide. Much more pronounced of Th2-type responses and more complex differentially expressed genes involved in immune regulation and response in BN might contribute to its susceptibleness to DIA. Moreover, similar immune mechanisms were found between BN and SD, which suggesting that these changes would serve as the potential bridge biomarkers to predict DIA among species. This study may also benefit to further understand the toxicological mechanism of drug-induced autoimmune reactions.
Asunto(s)
Autoinmunidad/efectos de los fármacos , Procainamida/toxicidad , Linfocitos T/efectos de los fármacos , Animales , Antiarrítmicos/toxicidad , Anticuerpos Antinucleares/sangre , Autoinmunidad/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Citocinas/sangre , Masculino , Ratas Endogámicas BN , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Bazo/patología , Linfocitos T/inmunologíaRESUMEN
Microplastics and pharmaceuticals are considered ubiquitous and emergent pollutants of high concern but the knowledge on their effects on primary producers is still limited, especially those caused by mixtures. Thus, the goal of the present study was to investigate if the presence of microplastics (1-5⯵m diameter) influences the toxicity of the pharmaceuticals procainamide and doxycycline to the marine microalga Tetraselmis chuii. Bioassays (96â¯h) to investigate the toxicity of those substances individually and in mixtures (i.e. microplastics-procainamide mixtures and microplastics-doxycycline mixtures) were carried out. Effect criteria were the average specific growth rate (growth rate) and chlorophyll a concentration (chlorophyll). EC10, EC20 and EC50 were determined. Microplastics alone had no significant effects on growth rate up to 41.5â¯mg/l, whereas chlorophyll was significantly reduced at 0.9 and 2.1â¯mg/l of microplastics, but not at higher concentrations. The 96â¯h EC50 (growth rate and chlorophyll, respectively) determined for the other bioassays were: 104 and 143â¯mg/l for procainamide alone; 125 and 31â¯mg/l for procainamide in the presence of microplastics; 22 and 14â¯mg/l for doxycycline alone; 11 and 7â¯mg/l for doxycycline in the presence of microplastics. Significant differences (pâ¯<â¯0.001) between the toxicity curves of each pharmaceutical alone and in mixture with microplastics were found for procainamide (chlorophyll), and doxycycline (both parameters). Thus, both pharmaceuticals were toxic to T. chuii in the low ppm range, and microplastics-pharmaceutical mixtures were more toxic than the pharmaceuticals alone. Very high decreases of doxycycline concentrations in test media were found, indicating degradation of the antibiotic. Thus, although the biological results are expressed in relation to doxycycline concentration, the effects were likely caused by a mixture of the parental compound and its degradation products. The concentrations of microplastics and pharmaceuticals tested (low ppm range) are higher than those expected to be found in waters of the most part of marine ecosystems (ppt or ppb ranges). However, considering the widespread contamination by microplastics and pharmaceuticals, the concentrations already found in waters, sediments and/or organism of heavily polluted areas, the long-term exposure (over generations) of wild populations to such substances in polluted ecosystems and the possibilities of bioaccumulation and toxicological interactions, these findings are of concern and further research on microplastics-pharmaceuticals toxicological interactions is needed.
Asunto(s)
Organismos Acuáticos/metabolismo , Chlorophyta/metabolismo , Doxiciclina/toxicidad , Microalgas/metabolismo , Plásticos/toxicidad , Procainamida/toxicidad , Antibacterianos/toxicidad , Organismos Acuáticos/efectos de los fármacos , Chlorophyta/efectos de los fármacos , Microalgas/efectos de los fármacos , Microalgas/crecimiento & desarrollo , Preparaciones Farmacéuticas , Contaminantes Químicos del Agua/toxicidadRESUMEN
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.
Asunto(s)
Neutrófilos/metabolismo , Fagocitosis , Procainamida/análogos & derivados , Procainamida/metabolismo , Adulto , Linfocitos B/metabolismo , Biotransformación , Línea Celular , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Peróxido de Hidrógeno , Ácido Hipocloroso , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Consumo de Oxígeno/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Procainamida/toxicidadRESUMEN
A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.
Asunto(s)
Autoinmunidad , Tolerancia Inmunológica/efectos de los fármacos , Lupus Eritematoso Sistémico/inducido químicamente , Lupus Eritematoso Sistémico/inmunología , Procainamida/análogos & derivados , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Traslado Adoptivo , Animales , Anticuerpos Antinucleares/biosíntesis , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Celular/efectos de los fármacos , Técnicas In Vitro , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos MRL lpr , Ratones Endogámicos NZB , Procainamida/toxicidad , Timo/efectos de los fármacos , Timo/inmunologíaRESUMEN
To treat patients with ventricular arrhythmias properly, one must characterize the arrhythmia, define the underlying heart disease and look for and treat reversible causes. When arrhythmias are suitable for pharmacologic suppression, it is necessary to predefine therapeutic goals, then carefully document that the drug accomplishes these goals. Knowledge of a drug's metabolism, excretion, active metabolites and plasma protein binding is often required for full understanding of its clinical effect. Pharmacokinetic principles require that antiarrhythmic drugs be given on a rigid schedule and that plasma drug levels be frequently determined. Use of compartment models and the principle of superposition can enable one to achieve and maintain therapeutic drug concentrations while avoiding toxic side effects. The drugs commonly used to treat arrhythmias, lidocaine, propranolol, procainamide, diphenylhydantoin and quinidine, as well as some newer agents, have specific pharmacokinetics and toxic effects that must be understood.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Antiarrítmicos/farmacología , Antiarrítmicos/toxicidad , Arritmias Cardíacas/etiología , Quimioterapia Combinada , Humanos , Cinética , Lidocaína/metabolismo , Lidocaína/farmacología , Lidocaína/toxicidad , Modelos Biológicos , Procainamida/metabolismo , Procainamida/farmacología , Procainamida/toxicidad , Propranolol/metabolismo , Propranolol/farmacología , Propranolol/toxicidad , Quinidina/metabolismo , Quinidina/farmacología , Quinidina/toxicidadRESUMEN
The role of human granulocytes in the promotion of procainamide (PA) toxicity in vitro has been studied and one of the agents responsible for DNA strand scission and cell death in human target cells has been characterized. Crude peripheral blood mononuclear cells (cPBMNs) isolated by density centrifugation, and the lymphocyte cell lines--CCRF-HSB2 and WIL-2NS--were exposed to PA, and DNA strand breaks were quantified by fluorescent analysis of DNA unwinding. Therapeutic plasma concentrations of PA (0-50 microM) caused dose-dependent cytotoxicity, determined by dye exclusion, and strand breaks in cPBMNs incubated for 3 and 1.5 hr at 37 degrees, respectively. Using 50 microM PA a five-fold increase in DNA strand breaks was observed after 1.5 hr, with significant induction of strand breaks also being observed for 10 and 25 microM concentrations. Toxicity was much reduced in lymphocyte cell lines (maximal killing = 3.0% at 50 microM PA compared with 13.2% in cPBMNs). A similar decrease in toxicity was observed where N-acetyl procainamide (NAPA) was substituted for PA (less than 50% of strand breaks at all concentrations). Further investigations showed that the presence of a contaminating granulocyte population in the cPBMN fraction was responsible for the induction of PA toxicity. Incubation of a highly enriched granulocyte population with PA for 1 hr prior to exposure to purified peripheral blood mononuclear cells (pPBMNs) led to the complete restoration of the toxic effects. The resulting cyto- and genotoxicity were not significantly different to levels observed in cPBMNs. Significantly, incubation of granulocytes with NAPA did not induce toxicity in target pPBMNs. Ultrafiltration of granulocyte supernatants led to the identification of two toxic fractions of < 3000 and > 30,000 Da. Temporal studies showed that the toxicity associated with the < 3000 Da fraction appeared during the first 10-15 min incubation with PA whereas the > 30,000 Da fraction did not display significant toxicity until the 40-60 min period. Further assessment of the nature of these agents indicated that the 30,000 Da fraction was a protein. SDS-PAGE analysis showed an inducible 17,800 Da species appearing in granulocyte supernatants after 40 min incubation with PA. Dot blot analysis indicated that tumour necrosis factor alpha (TNF alpha) was present in the > 30,000 Da fraction. Evidence that TNF alpha was the high-molecular weight species responsible for PA-induced toxicity was obtained from neutralization assays employing an anti-TNF alpha antibody.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Granulocitos/efectos de los fármacos , Procainamida/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Granulocitos/metabolismo , HumanosAsunto(s)
Enfermedades Autoinmunes/inducido químicamente , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Autoinmunidad , Tiomalato Sódico de Oro/metabolismo , Tiomalato Sódico de Oro/toxicidad , Ratones , Neutrófilos/fisiología , Procainamida/metabolismo , Procainamida/toxicidad , Propiltiouracilo/metabolismo , Propiltiouracilo/toxicidadRESUMEN
Procaine and procainamide were covalently bound to acryloyl monomers and polymers. The dose-response and time-action parameters of the cardiac antiarrhythmic protection afforded by the prototype drugs and their acryloyl derivatives against chloroform-hypoxia-induced cardiac arrhythmias in unanesthetized mice and epinephrine-induced arrhythmias in alpha-chloralose anesthetized cats were determined. Similarly, the pharmacological parameters which characterized their acute toxic responses in unanesthetized male albino mice were also determined. The similar pharmacological spectra of their activity and the parallelism of their lethal dose-response curves indicate that the active constituents of the polymer derivatives are the local anesthetic moieties. Compared to the prototype drugs, the polymer derivatives were more potent on a molar basis and their pharmacological effects were prolonged. The increased potency and duration of action reinforce the idea that the local anesthetic moieties are pharmacologically active while still bound to the polymer backbones.
Asunto(s)
Resinas Acrílicas/farmacología , Procainamida/análogos & derivados , Procainamida/farmacología , Procaína/análogos & derivados , Procaína/farmacología , Resinas Acrílicas/toxicidad , Animales , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/tratamiento farmacológico , Gatos , Relación Dosis-Respuesta a Droga , Femenino , Cinética , Dosificación Letal Mediana , Masculino , Ratones , Procainamida/toxicidad , Procaína/toxicidadRESUMEN
The popliteal lymph node assay (PLNA) was proposed for the preclinical prediction of xenobiotics-induced autoimmune reactions in humans. Among the substances so far tested in this model, procainamide and isoniazid gave negative PLNA responses despite reports of lupus syndromes in man. To confirm the hypothesis that a metabolite instead of the parent molecule is involved, rats were pretreated with phenobarbital or beta-naphthoflavone, then injected with procainamide or isoniazid. In additional groups of animals, procainamide or isoniazid were injected together with S9-mix following various incubation times. Pretreated rats had a positive PLNA response when injected with procainamide, whereas preincubation with S9-mix resulted in a positive response to isoniazid. These results further support the validity of the PLNA.
Asunto(s)
Benzoflavonas/farmacología , Isoniazida/toxicidad , Extractos Hepáticos/farmacología , Ganglios Linfáticos/efectos de los fármacos , Fenobarbital/farmacología , Procainamida/toxicidad , Animales , Enfermedades Autoinmunes/inducido químicamente , Biotransformación , Evaluación Preclínica de Medicamentos , Inducción Enzimática , Femenino , Isoniazida/farmacocinética , Rodilla , Masculino , Modelos Biológicos , Procainamida/farmacocinética , Ratas , Ratas Endogámicas BN , Ratas Sprague-Dawley , Factores de Tiempo , beta-naftoflavonaRESUMEN
Outbred (namely Wistar and Sprague-Dawley) and inbred (Wistar-Furth, Lewis, Fisher 344 and Brown-Norway) strains of rats were screened for their responses to reference compounds in the popliteal lymph node (PLN) assay. Streptozotocin and diphenylhydantoin gave positive responses as evidenced by increased weight and cellularity indices in all strains used whereas procainamide, isoniazid and barbital consistently gave negative responses. Although these findings overall are in agreement with previous investigations involving these compounds, the lack of marked interstrain differences in PLN responses argues against a strong immunogenetically controlled mechanism as could be assumed in presumably auto-immune reactions. The question is raised whether drug-induced side-effects predicted by the PLN assay are basically non-autoimmune as suggested by clinical and immunological findings in man.
Asunto(s)
Ganglios Linfáticos/efectos de los fármacos , Animales , Barbital/toxicidad , Femenino , Miembro Posterior , Isoniazida/toxicidad , Masculino , Fenitoína/toxicidad , Procainamida/toxicidad , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , Ratas Wistar , Especificidad de la Especie , Estreptozocina/toxicidadRESUMEN
Several compounds derived from benzamidines and nicotinic pyridinic amidines with a structure similar to that of procainamide, exhibit notable antiarrhythmic properties after injection into animals. The diffusion rate of these different compounds through a solid lipidic artificial membrane was studied with Dibbern's apparatus. A statistical relation was established between the diffusion rate and the principal pharmacological parameters obtained after intraperitoneal injection (toxicity and anthiarrhythmic activity). Essential structural elements seem to determine a better bioavailability than procainamide: character of the substitution (in para) of the benzenic cycle; length of the lateral chain.
Asunto(s)
Antiarrítmicos/síntesis química , Procainamida/análogos & derivados , Procainamida/farmacología , Absorción , Animales , Antiarrítmicos/farmacocinética , Antiarrítmicos/toxicidad , Disponibilidad Biológica , Difusión , Dosificación Letal Mediana , Membranas Artificiales , Ratones , Procainamida/farmacocinética , Procainamida/toxicidadRESUMEN
Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.
Asunto(s)
Antiarrítmicos/toxicidad , Arritmias Cardíacas/inducido químicamente , Lidocaína/toxicidad , Procainamida/toxicidad , Potenciales de Acción/efectos de los fármacos , Animales , Antiarrítmicos/farmacología , Arritmias Cardíacas/fisiopatología , Electrocardiografía , Femenino , Cobayas , Lidocaína/farmacología , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Procainamida/farmacología , Taquicardia Ventricular/inducido químicamente , Taquicardia Ventricular/fisiopatología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/toxicidadAsunto(s)
Procainamida/metabolismo , Administración Oral , Arritmias Cardíacas/tratamiento farmacológico , Nitrógeno de la Urea Sanguínea , Semivida , Humanos , Inyecciones Intramusculares , Inyecciones Intravenosas , Absorción Intestinal , Cinética , Procainamida/administración & dosificación , Procainamida/sangre , Procainamida/uso terapéutico , Procainamida/toxicidadRESUMEN
Free radical processes are proposed to play a crucial role in the development of procainamide adverse effects. Therefore, selenium, as a potent antioxidant, may modified procainamide toxicity. To test this hypothesis plasma and liver thiobarbituric acid-reacting substances (TBARS), plasma antioxidant activity (AOA), erythrocyte and liver superoxide dismutase (SOD), catalase, as well as selenium-dependent glutathione peroxidase (Se-GPX) were determined in the following four groups of rats: selenium-treated (Se), procainamide-treated (P), procainamide and selenium-treated (P + Se), and control (C). Morphological studies of leukocytes [tested for lupus erythematosus (LE) cells] and liver were also made. Atypical, i.e. enlarged and swollen, leukocytes resulting from procainamide and selenium treatment were observed. These changes were found in four out of five rats in the Se group, eight out of ten in the P group, and in seven out of ten in the P + Se group. LE-like cells were observed in two rats in the P + Se group. A statistically significant decrease in plasma and liver TBARS by 20% and 36%, respectively, increased activity of SOD by 20%, catalase by 48% and Se-GPX by 15% in erythrocytes, and decreased activity of liver SOD by 17% and catalase by 22% were found in the P + Se group as compared to the P group. These results indicated that selenium exerted antioxidant effects on the procainamide-treated rats. However, selenium did not prevent the development of disturbances in leukocyte morphology, on the contrary, it possibly promoted the conversion of leukocytes to LE cells.
Asunto(s)
Procainamida/toxicidad , Selenio/farmacología , Animales , Antioxidantes/análisis , Femenino , Radicales Libres , Peroxidación de Lípido , Ratas , Ratas Wistar , LevadurasRESUMEN
To elucidate the mechanisms of the arrhythmogenic and antifibrillatory action of procainamide, 24 episodes of polymorphous ventricular tachycardia were analyzed. They were induced electrically in 12 canine hearts before and after the administration of 40 mg/kg of procainamide. The isochronal maps of the epicardial activation sequence were successfully constructed by 40 simultaneously recorded bipolar electrograms in 14 of 17 episodes after procainamide. The isochronal maps showed a possible macroreentrant circuit in 12 episodes, and in four of them the functional block was noticed to have disappeared before the termination of tachycardia. This study suggests that procainamide predisposes the ventricle to reentrant tachyarrhythmias and that the dimension of the reentrant circuit induced is too large to be fragmented into multiple reentries, which results in the prevention of the development of ventricular fibrillation.