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1.
Acad Emerg Med ; 26(9): 969-981, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31423687

RESUMO

BACKGROUND: Emergency department (ED) patients with uncomplicated atrial fibrillation (AF) of less than 48 hours may be safely managed with rhythm control. Although both chemical-first and electrical-first strategies have been advocated, there are no comparative effectiveness data to guide clinicians. METHODS: At six urban Canadian centers, ED patients ages 18 to 75 with uncomplicated symptomatic AF of less than 48 hours and CHADS2 score of 0 or 1 were randomized using concealed allocation in a 1:1 ratio to one of the following strategies: 1) chemical cardioversion with procainamide infusion, followed by electrical countershock if unsuccessful; or 2) electrical cardioversion, followed by procainamide infusion if unsuccessful. The primary outcome was the proportion of patients discharged within 4 hours of arrival. Secondary outcomes included ED length-of-stay (LOS); prespecified ED-based adverse events; and 30-day ED revisits, hospitalizations, strokes, deaths, and quality of life (QoL). RESULTS: Eighty-four patients were analyzed: 41 in the chemical-first group and 43 in the electrical-first group. Groups were balanced in terms of age, sex, vital signs, and CHADS2 scores. All patients were discharged home, with 83 (99%) in sinus rhythm. In the chemical-first group, 13 of 41 patients (32%) were discharged within 4 hours compared to 29 of 43 patients (67%) in the electrical-first group (p = 0.001). In the chemical-first group, the median ED LOS was 5.1 hours (interquartile range [IQR] = 3.5 to 5.9 hours) compared to 3.5 hours (IQR = 2.4 to 4.6 hours) in the electrical-first group, for a median difference of 1.2 hours (95% confidence interval = 0.4 to 2.0 hours, p < 0.001). No patients experienced stroke or death. All other outcomes, including adverse events, ED revisits, and QoL, were similar. CONCLUSION: In uncomplicated ED AF patients managed with rhythm control, chemical-first and electrical-first strategies both appear to be successful and well tolerated; however, an electrical-first strategy results in a significantly shorter ED LOS.


Assuntos
Antiarrítmicos/administração & dosagem , Fibrilação Atrial/terapia , Cardioversão Elétrica/métodos , Procainamida/administração & dosagem , Adolescente , Adulto , Idoso , Canadá , Serviço Hospitalar de Emergência , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Adulto Jovem
2.
J Vet Cardiol ; 24: 58-63, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31405555

RESUMO

INTRODUCTION: The objective of the present study was to evaluate the pharmacokinetics of a compounded sustained-release procainamide formulation in normal dogs. ANIMALS: Six healthy, purpose-bred mixed-breed dogs participated in the study. METHODS: In phase I, two dogs were administered oral procainamide (30 mg/kg), and plasma was obtained to determine plasma concentration ranges and duration. In phase II, six dogs were administered procainamide (30 mg/kg by mouth every 12 hours) to determine the pharmacokinetics of sustained-release procainamide. Serum procainamide concentration was determined using an immunochemistry assay. RESULTS: No adverse clinical effects were noted in any of the dogs studied. The average maximum serum concentration, average serum concentration, and average minimum serum concentration were 10.17, 7.13, and 3.07 µg/mL, respectively. The average time over a 12-h period during which procainamide concentration exceeded 12 µg/mL was 2.35 h, was between 4 and 12 µg/mL was 7.19 h, and was less than 4 µg/mL was 2.46 h. The average times at maximum concentration and minimum concentration were 18.67 and 12.25 h, respectively. CONCLUSIONS: Administration of sustained-release procainamide twice daily achieved targeted plasma concentrations in most dogs. Evaluation of serum trough concentrations should be considered owing to interanimal variability to confirm that serum concentrations are within the reported therapeutic range for an individual patient.


Assuntos
Antiarrítmicos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Cães/metabolismo , Procainamida/farmacocinética , Administração Oral , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/sangue , Preparações de Ação Retardada/administração & dosagem , Cães/sangue , Feminino , Masculino , Procainamida/administração & dosagem , Procainamida/sangue , Valores de Referência
4.
Ann Rheum Dis ; 78(4): 504-508, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30793701

RESUMO

OBJECTIVE: Drug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of the pharmacopoeia. Here, we used VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL. METHODS: We analysed all ICSRs classified as 'systemic lupus erythematosus' according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting. RESULTS: A total of 12 166 DIL ICSRs were identified using VigiBase. From those, 8163 ICSRs reporting on 118 suspected drugs with IC025 ≥0 were extracted. The median age at DIL onset was 49 years and the female to male sex ratio was 4.3. The median delay between start of suspected treatment and DIL occurrence was 172 days. DIL was reported as serious adverse event in 55.4%. Among the 118 suspected drugs, 42 had not been previously reported in association with DIL. The drugs associated with the highest number of DIL cases were infliximab, adalimumab, etanercept, procainamide and hydralazine. CONCLUSION: This study enables the identification of 118 drugs associated with DIL. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. TRIAL REGISTRATION NUMBER: NCT03480529.


Assuntos
Lúpus Eritematoso Sistêmico/induzido quimicamente , Adalimumab/efeitos adversos , Adulto , Antirreumáticos/efeitos adversos , Bases de Dados Factuais , Etanercepte/efeitos adversos , Feminino , Humanos , Hidralazina/efeitos adversos , Infliximab/efeitos adversos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Procainamida/efeitos adversos , Estudos Retrospectivos , Organização Mundial da Saúde
5.
JACC Clin Electrophysiol ; 5(2): 212-219, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30784693

RESUMO

OBJECTIVES: This study sought to compare the differences between procainamide and flecainide to stress the His-Purkinje system during electrophysiological study (EPS) in patients with syncope and bundle branch block (BBB). BACKGROUND: Patients with syncope and BBB are at risk of developing atrioventricular block. EPS is recommended including class I drug challenge to unmask His-Purkinje disease in cases with baseline normal His-ventricular interval. There is little data on differences between different class I drugs. METHODS: This was a prospective study of all consecutive patients undergoing EPS for syncope and BBB at a single center (January 1, 2012 to June 30, 2017). Of those patients with negative baseline EPS, 2 cohorts were compared: group A (historical cohort: procainamide) and group B (flecainide). RESULTS: During the study, 271 patients (age 73.9 ± 12.1 years, 64.9% male, QRS duration: 139.4 ± 13.9 ms) underwent EPS. In 166, baseline EPS was negative and class I drug challenge was performed (90 procainamide, 76 flecainide). The final value and percentage increase in the His-ventricular interval (76 ± 16 ms vs. 64 ± 10 ms and 22.5 ± 6.2% vs. 11.8 ± 5.3%; p < 0.001) and diagnostic yield (14.5% vs. 7.8%, p = 0.04) were higher with flecainide. No differences were found in baseline characteristics. During follow-up (25.8 ± 6.3 months), 39 patients (24.8%) with negative EPS (19.2% with flecainide vs. 30.1% with procainamide: relative risk: 5.1; 95% confidence interval: 2.6 to 10.2; p < 0. 001) received a pacemaker. CONCLUSIONS: Flecainide has a higher diagnostic yield than does procainamide in patients with BBB, syncope, and negative baseline EPS due to a greater increase of the His-ventricular interval. Additionally, there is a lesser need for pacemaker implantation in patients in whom the class I drug test using flecainide was negative.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Técnicas Eletrofisiológicas Cardíacas/métodos , Flecainida/farmacologia , Procainamida/farmacologia , Síncope , Idoso , Idoso de 80 Anos ou mais , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Feminino , Flecainida/uso terapêutico , Sistema de Condução Cardíaco/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Procainamida/uso terapêutico , Síncope/diagnóstico , Síncope/fisiopatologia
7.
J Cardiovasc Pharmacol Ther ; 24(3): 288-297, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30497293

RESUMO

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 ∼18% 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.


Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Débito Cardíaco/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Procainamida/administração & dosagem , Sotalol/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Amiodarona/toxicidade , Animais , Antiarrítmicos/toxicidade , Relação Dose-Resposta a Droga , Infusões Intravenosas , Preparação de Coração Isolado , Procainamida/toxicidade , Ratos Sprague-Dawley , Medição de Risco , Sotalol/toxicidade
8.
Curr Opin Rheumatol ; 30(5): 490-497, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29870500

RESUMO

PURPOSE OF REVIEW: Rapid introduction of newly developed drugs in the absence of clear understanding of the pathophysiologic mechanisms behind drug-induced lupus erythematosus (DILE) can sometimes make DILE difficult to recognize in clinical practice. The purpose of this review is to summarize drugs most recently reported to be involved in DILE and discuss the current landscape of diverse mechanisms involved. RECENT FINDINGS: A large number of proton pump inhibitor (PPI)-induced subacute cutaneous lupus erythematosus cases have been reported, suggesting a shift over time in the spectrum of drugs implicated in DILE. Twenty-two articles comprising 29 DILE case reports published within the last 2 years are summarized in this review, including 12 (41.4%) systemic DILE. Antitumor necrosis factor (anti-TNF) drugs were the most frequently (41.7%) reported to introduce systemic DILE in these cases. Chemotherapeutic drugs were the most common drug class (54.5%) involved in subacute cutaneous lupus erythematosus, with an observed higher incidence in female patients. Enhanced neutrophil extracellular trap (NET) formation induced by procainamide and hydralazine could be a new mechanism contributing to the pathogenesis of DILE. SUMMARY: The list of drugs implicated in triggering DILE is expanding as new drugs with novel mechanisms of action are being developed. It is important to recognize culprit drugs that may induce lupus erythematosus, as discontinuation usually results in improvement of drug-induced manifestations. Characterizing the mechanisms involved might help better understand the cause of idiopathic autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico/induzido quimicamente , Autoimunidade , Predisposição Genética para Doença , Humanos , Hidralazina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Lúpus Eritematoso Cutâneo/induzido quimicamente , Lúpus Eritematoso Cutâneo/genética , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Procainamida/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
9.
Scand Cardiovasc J ; 52(4): 218-226, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29798684

RESUMO

OBJECTIVES: In normal conditions, sudden heart rate acceleration provokes a rapid reduction in ventricular action potential duration (APD). The protracted APD rate adaptation favors early afterdepolarizations and precipitates arrhythmia. Nevertheless, it is uncertain as to whether the rate-dependent changes of ventricular repolarization can be adversely modified by arrhythmogenic drugs (quinidine and procainamide) and hypokalemia, in comparison to the agents with safe therapeutic profile, such as lidocaine. DESIGN: The rate adaptation of QT interval and monophasic APD obtained from the left ventricular (LV) and the right ventricular (RV) epicardium was examined during rapid cardiac pacing applied in isolated, perfused guinea-pig heart preparations. RESULTS: At baseline, an abrupt increase in cardiac activation rate was associated with a substantial reduction of the QT interval and ventricular APD in the first two cardiac cycles, which was followed by a gradual shortening of repolarization over subsequent pacing intervals. The time constants of the fast (τfast) and slow (τslow) components of the APD dynamics determined from a double exponential fit were longer in RV compared to LV chamber. Quinidine, procainamide, and hypokalemia prolonged ventricular repolarization and delayed the rate adaptation of the QT interval and APD in LV and RV, as evidenced by increased τfast and τslow values. In contrast, lidocaine had no effect on the dynamic changes of ventricular repolarization upon heart rate acceleration. CONCLUSIONS: The rate adaptation of ventricular repolarization is delayed by arrhythmogenic interventions, such as quinidine, procainamide, and hypokalemia, but not changed by lidocaine, a clinically safe antiarrhythmic agent.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Hipopotassemia/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Potenciais de Ação , Adaptação Fisiológica , Animais , Antiarrítmicos/toxicidade , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Estimulação Cardíaca Artificial , Feminino , Cobaias , Ventrículos do Coração/fisiopatologia , Hipopotassemia/complicações , Preparação de Coração Isolado , Lidocaína/farmacologia , Procainamida/farmacologia , Quinidina/farmacologia , Fatores de Tempo
11.
Toxicol Lett ; 292: 63-72, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29709425

RESUMO

Understanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes. Preincubation of an excess of cofactors at 37 °C for fifteen minutes in the S9 before introduction of the testing probe, greatly increased the stability of the enzymes. Using this standardised assay, the rates of sulphation (SULT) and glucuronidation (UGT) of 7-hydroxycoumarin, methylation (COMT) of dopamine and N-acetylation (NAT) of procainamide were measured in the ng/mg protein/h (converted to ng/cm2/h) range in eighty-seven individuals. Glutathione conjugation (GST) of 1-chloro-2,4-dinitrobenzene was assessed in a smaller pool of fifty donors; the metabolic rate was much faster and measured over six minutes using a different methodology to express rates in µg/mg protein/min (converted to µg/cm2/min). A comprehensive statistical analysis of these results was carried out, separating donors by age, gender and metabolic rate measured.


Assuntos
Variação Biológica da População , Dinitroclorobenzeno/metabolismo , Dopamina/metabolismo , Procainamida/metabolismo , Pele/enzimologia , Umbeliferonas/metabolismo , Acetilação , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criopreservação , Estabilidade Enzimática , Feminino , Glucuronídeos/metabolismo , Glutationa/análogos & derivados , Glutationa/metabolismo , Humanos , Cinética , Modelos Lineares , Masculino , Desintoxicação Metabólica Fase II , Metilação , Pessoa de Meia-Idade , Fatores Sexuais , Sulfatos/metabolismo , Adulto Jovem
13.
Aquat Toxicol ; 197: 143-152, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29494946

RESUMO

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 µm diameter) influences the toxicity of the pharmaceuticals procainamide and doxycycline to the marine microalga Tetraselmis chuii. Bioassays (96 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 41.5 mg/l, whereas chlorophyll was significantly reduced at 0.9 and 2.1 mg/l of microplastics, but not at higher concentrations. The 96 h EC50 (growth rate and chlorophyll, respectively) determined for the other bioassays were: 104 and 143 mg/l for procainamide alone; 125 and 31 mg/l for procainamide in the presence of microplastics; 22 and 14 mg/l for doxycycline alone; 11 and 7 mg/l for doxycycline in the presence of microplastics. Significant differences (p < 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.


Assuntos
Organismos Aquáticos/metabolismo , Clorófitas/metabolismo , Doxiciclina/toxicidade , Microalgas/metabolismo , Plásticos/toxicidade , Procainamida/toxicidade , Antibacterianos/toxicidade , Organismos Aquáticos/efeitos dos fármacos , Clorófitas/efeitos dos fármacos , Microalgas/efeitos dos fármacos , Microalgas/crescimento & desenvolvimento , Preparações Farmacêuticas , Poluentes Químicos da Água/toxicidade
14.
PLoS One ; 13(1): e0191514, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29352276

RESUMO

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.


Assuntos
Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Fenômenos Eletrofisiológicos , Feminino , Flecainida/efeitos adversos , Cobaias , Técnicas In Vitro , Perfusão , Fenetilaminas/efeitos adversos , Procainamida/efeitos adversos , Quinidina/efeitos adversos , Sulfonamidas/efeitos adversos
15.
Hum Exp Toxicol ; 37(6): 647-662, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28741378

RESUMO

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.


Assuntos
Autoimunidade/efeitos dos fármacos , Procainamida/toxicidade , Linfócitos T/efeitos dos fármacos , Animais , Antiarrítmicos/toxicidade , Anticorpos Antinucleares/sangue , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Citocinas/sangue , Masculino , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Baço/patologia , Linfócitos T/imunologia
16.
Arthritis Rheumatol ; 70(3): 468-474, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29121457

RESUMO

OBJECTIVE: Aberrant neutrophil extracellular trap (NET) formation has been implicated as a mechanism to induce autoreactivity in individuals at risk of autoimmune diseases. The objective of this study was to assess whether medications implicated in cases of drug-induced autoimmunity (hydralazine and procainamide) and medications less commonly associated with drug-induced autoimmunity (minocycline and clozapine) induce NET formation and/or prevent NET degradation. METHODS: Human neutrophils were incubated with the drugs of interest and resultant NET formation was quantified by fluorescent microscopy. The ability of these drugs to interfere with NET degradation by serum nuclei was assessed. Pathways of drug-induced NET formation were studied with pharmacologic inhibitors of reactive oxygen species (ROS), peptidylarginine deiminases (PADs), and muscarinic receptors, and by assessment of intracellular calcium levels by flow cytometry. To determine if NET protein cargo varies by drug stimulus and/or neutrophil source, proteomic analysis of NET lysates induced by specific medications was compared using neutrophils from healthy donors and from patients with autoimmune diseases. RESULTS: Hydralazine and procainamide significantly induced NET formation while minocycline and clozapine did not. None of the medications significantly impaired NET degradation. NETosis induced by these drugs required NADPH oxidase and PAD4 activation. Procainamide triggered NETs via muscarinic receptor engagement on neutrophils, while hydralazine modulated calcium release from intracellular stores. Differences in protein cargo, particularly histone content, were observed in NETs induced by hydralazine and procainamide. CONCLUSION: Medications commonly implicated in drug-induced autoimmunity trigger NET formation displaying distinct protein cargo, via common and specific pathways. NETosis may play a role in the pathogenesis of drug-induced autoimmunity.


Assuntos
Autoimunidade/efeitos dos fármacos , Armadilhas Extracelulares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Antiarrítmicos/efeitos adversos , Antiarrítmicos/imunologia , Antibacterianos/efeitos adversos , Antibacterianos/imunologia , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/imunologia , Antipsicóticos/efeitos adversos , Antipsicóticos/imunologia , Autoimunidade/imunologia , Clozapina/efeitos adversos , Clozapina/imunologia , Armadilhas Extracelulares/imunologia , Citometria de Fluxo , Humanos , Hidralazina/efeitos adversos , Hidralazina/imunologia , Microscopia de Fluorescência , Minociclina/efeitos adversos , Minociclina/imunologia , Neutrófilos/imunologia , Procainamida/efeitos adversos , Procainamida/imunologia , Proteômica , Transdução de Sinais/efeitos dos fármacos
17.
Anal Bioanal Chem ; 410(1): 131-143, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29098336

RESUMO

Glycosaminoglycans (GAGs) are a family of linear heteropolysaccharides made up of repeating disaccharide units that are found on the surface and extracellular matrix of animal cells. They are known to play a critical role in a wide range of cellular processes including proliferation, differentiation and invasion. To elucidate the mechanism of action of these molecules, it is essential to quantify their disaccharide composition. Analytical methods that have been reported involve either chemical or enzymatic depolymerisation of GAGs followed by separation of non-derivatised (native) or derivatised disaccharide subunits and detection by either UV/fluorescence or MS. However, the measurement of these disaccharides is challenging due to their hydrophilic and labile nature. Here we report a pre-column LC-MS method for the quantification of GAG disaccharide subunits. Heparan sulphate (HS) was extracted from cell lines using a combination of molecular weight cutoff and anion exchange spin filters and digested using a mixture of heparinases I, II and III. The resulting subunits were derivatised with procainamide, separated using hydrophilic interaction liquid chromatography and detected using electrospray ionisation operated in positive ion mode. Eight HS disaccharides were separated and detected together with an internal standard. The limit of detection was found to be in the range 0.6-4.9 ng/mL. Analysis of HS extracted from all cell lines tested in this study revealed a significant variation in their composition with the most abundant disaccharide being the non-sulphated ∆UA-GlcNAc. Some structural functional relationships are discussed demonstrating the viability of the pre-column method for studying GAG biology. Graphical abstract Extraction and HILIC UPLC-MS analysis of procainamide-labelled heparan sulphate disaccharides.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dissacarídeos/análise , Glicosaminoglicanos/química , Heparitina Sulfato/análise , Procainamida/química , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas/métodos
18.
Talanta ; 168: 307-312, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28391859

RESUMO

In the current study, liquid-liquid extraction, using deep eutectic solvent (DES) as a "green" extraction solvent, was coupled with a stepwise injection system for the first time. The suggested approach was applied for the development of spectrofluorimetric method for procainamide determination. The method is based on aspiration of saliva sample and DES (choline chloride with glycerol at a 1:2M ratio) solution into the mixing chamber of a flow system, followed by injection of acetonitrile into the mixed DES-sample solution. The extraction process and final phase separation were then promoted by air-bubbling. After phase separation, the DES phase, containing the extracted procainamide, was transported to a spectrofluorimetric detector. The excitation and emission wavelengths were set at 280nm and 347nm, respectively. The calibration plot was linear in the range of 5×10-6 to 5×10-5molL-1. The limit of detection, calculated as 3σ of a blank test (n=10), was found to be 1.5×10-6molL-1. The developed method was successfully applied for the determination of procainamide in human saliva samples, and the analytical results agreed rather well with the results obtained by the reference HPLC-UV method.


Assuntos
Antiarrítmicos/análise , Extração Líquido-Líquido/métodos , Procainamida/análise , Saliva/química , Solventes/química , Espectrometria de Fluorescência/métodos , Adolescente , Adulto , Feminino , Humanos , Limite de Detecção , Masculino , Adulto Jovem
19.
Talanta ; 167: 709-713, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28340783

RESUMO

A fully automated sugaring-out assisted liquid-liquid extraction procedure was suggested. The procedure was based on the separation of the acetonitrile phase, containing a target analyte from the homogeneous sample solution after injection of sugaring-out reagent (glucose) into a mixing chamber of the flow system. Air bubbling was used to promote the extraction process and phase separation. After the fast phase separation in the mixing chamber, the acetonitrile phase containing the target analyte was transferred to an HPLC-UV system. Under the optimal conditions, the detector response of procainamide was linear in the concentration range of 6×10-7-4×10-5molL-1. The limit of detection, calculated from a blank test based on 3σ, was 2×10-7molL-1. The proposed method was successfully applied for the determination of procainamide in human urine samples and the analytical results agreed fairly well with the results obtained by reference CE method.


Assuntos
Acetonitrilos/química , Automação , Cromatografia Líquida de Alta Pressão/métodos , Glucose/química , Extração Líquido-Líquido/métodos , Procainamida/urina , Adolescente , Adulto , Feminino , Voluntários Saudáveis , Humanos , Limite de Detecção , Masculino , Raios Ultravioleta , Adulto Jovem
20.
J Pharm Biomed Anal ; 139: 54-64, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28273651

RESUMO

Malignant melanoma is the most aggressive form of skin cancer. The early detection of primary melanoma tumors and metastases using non-invasive PET imaging determines the outcome of this disease. Previous studies have shown that benzamide derivatives (e.g. procainamide) conjugated with PET radionuclides specifically bind to melanin pigment of melanoma tumors. 68Ga chelating agents can have high influence on physiological properties of 68Ga labeled bioactive molecules, as was experienced during the application of HBED-CC on PSMA ligand. The aim of this study was to assess this concept in the case of the melanin specific procaindamide (PCA) and to compare the melanin specificity of 68Ga-labeled PCA using HBED-CC and NODAGA chelators under in vitro and in vivo conditions. Procainamide (PCA) was conjugated with HBED-CC and NODAGA chelators and was labeled with Ga-68. The melanin specificity of 68Ga-HBED-CC-PCA and 68Ga-NODAGA-PCA was investigated in vitro and in vivo using amelanotic (MELUR and A375) and melanin containing (B16-F10) melanoma cell lines. Tumor-bearing mice were prepared by subcutaneous injection of B16-F10, MELUR and A375 melanoma cells into C57BL/6 and SCID mice. 21±2days after tumor cell inoculation and 90min after intravenous injection of the 68Ga-labelledlabeled radiopharmacons whole body PET/MRI scans were performed. 68Ga-NODAGA-PCA and 68Ga-HBED-CC-PCA were produced with excellent radiochemical purity (98%). In vitro experiments demonstrated that after 30 and 90min incubation time 68Ga-NODAGA-PCA uptake of B16-F10 cells was significantly (p≤0.01) higher than the 68Ga-HBED-CC-conjugated PCA accumulation in the same cell line. Furthermore, significant difference (p≤0.01 and 0.05) was found between the uptake of melanin negative and positive cell lines using 68Ga-NODAGA-PCA and 68Ga-HBED-CC-PCA. In vivo PET/MRI studies using tumor models revealed significantly (p≤0.01) higher 68Ga-NODAGA-PCA uptake (SUVmean: 0.46±0.05, SUVmax: 1.96±0.25,T/M ratio: 40.7±4.23) in B16-F10 tumors in contrast to 68Ga-HBED-CC-PCA where the SUVmean, SUVmax and T/M ratio were 0.13±0.01, 0.56±0.11 and 11.43±1.24, respectively. Melanin specific PCA conjugated with NODAGA chelator showed higher specific binding properties than conjugated with HBED-CC. The chemical properties of the bifunctional chelators used for 68Ga-labeling of PCA determine the biological behaviour of the probes. Due to the high specificity and sensitivity 68Ga-labeled PCA molecules are promising radiotracers in melanoma imaging.


Assuntos
Acetatos/metabolismo , Ácido Edético/análogos & derivados , Radioisótopos de Gálio/metabolismo , Compostos Heterocíclicos com 1 Anel/metabolismo , Melanoma Experimental/metabolismo , Procainamida/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Ácido Edético/metabolismo , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Melanoma Experimental/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Tomografia por Emissão de Pósitrons/métodos , Neoplasias Cutâneas/diagnóstico por imagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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