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Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18â months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93â mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.
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Introduction: Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown. Materials and methods: The European Respiratory Society (ERS) SHARP Clinical Research Collaboration conducted a three-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on seven end-points: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies. Results: Availability of biologics varied between countries, with 17 out of 28 countries having all five existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, forced expiratory volume in 1â s was used in 46%. Blood eosinophils were an inclusion criterion in all countries for interleukin-5 (IL-5)-targeted and IL-4/IL-13-targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191 out of 263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity. Conclusion: Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation.
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Two subsets of eosinophils have been described: resident eosinophils with homeostatic functions (rEOS) in healthy subjects and in patients with nonallergic eosinophilic asthma, and inflammatory eosinophils (iEOS) in blood and lung samples from patients with allergic asthma. We explored if it would be possible to identify different subsets of eosinophils using flow cytometry and the gating strategy applied to induced sputum. We conducted an observational cross-sectional single-center study of 62 patients with persistent allergic asthma. Inflammatory cells from induced sputum samples were counted by light microscopy and flow cytometry, and cytokine levels in the supernatant were determined. Two subsets of eosinophils were defined that we call E1 (CD66b-high and CD15-high) and E2 (CD66b-low and CD15-low). Of the 62 patients, 24 were eosinophilic, 18 mixed, 10 paucigranulocytic, and 10 neutrophilic. E1 predominated over E2 in the eosinophilic and mixed patients (20.86% vs. 6.27% and 14.42% vs. 4.31%, respectively), while E1 and E2 were similar for neutrophilic and paucigranulocytic patients. E1 correlated with IL-5, fractional exhaled nitric oxide, and blood eosinophils. While eosinophil subsets have been identified for asthma in blood, we have shown that they can also be identified in induced sputum.
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Asma , Eosinófilos , Humanos , Esputo/metabolismo , Interleucina-5 , Estudios Transversales , Recuento de Leucocitos , Asma/metabolismo , Pulmón/metabolismoRESUMEN
Chronic airflow obstruction affects a wide range of airway diseases, the most frequent of which are asthma, COPD, and bronchiectasis; they are clearly identifiable in their extremes, but quite frequently overlap in some of their pathophysiological and clinical characteristics. This has generated the description of new mixed or overlapping disease phenotypes with no clear biological grounds. In this special article, a group of experts provides their perspective and proposes approaching the treatment of chronic airway disease (CAD) through the identification of a series of therapeutic goals (TG) linked to treatable traits (TT) - understood as clinical, physiological, or biological characteristics that are quantifiable using biomarkers. This therapeutic approach needs validating in a clinical trial with the strategy of identification of TG and treatment according to TT for each patient independently of their prior diagnosis.
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Obstrucción de las Vías Aéreas , Asma , Enfermedad Pulmonar Obstructiva Crónica , Asma/diagnóstico , Asma/tratamiento farmacológico , Objetivos , Humanos , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológicoRESUMEN
BACKGROUND: Fuel oil-derived volatile organic compounds (VOCs) inhalation is associated with accidental marine spills. After the Prestige petroleum tanker sank off northern Spain in 2002 and the Deepwater Horizon oil rig catastrophe in 2009, subjects involved in environmental decontamination showed signs of ongoing or residual lung disease up to 5 y after the exposure. OBJECTIVES: We aimed at investigating mechanisms driving persistent respiratory disease by developing an animal model of inhalational exposure to fuel oil-derived VOCs. METHODS: Female Wistar and Brown Norway (BN) rats and C57BL mice were exposed to VOCs produced from fuel oil mimicking the Prestige spill. Exposed animals inhaled the VOCs 2 h daily, 5 d per week, for 3 wk. Airway responsiveness to methacholine (MCh) was assessed, and bronchoalveolar lavage (BAL) and lung tissues were analyzed after the exposure and following a 2-wk washout. RESULTS: Consistent with data from human studies, both strains of rats that inhaled fuel oil-derived VOCs developed airway hyperresponsiveness that persisted after the washout period, in the absence of detectable inflammation in any lung compartment. Histopathology and quantitative morphology revealed the development of peripherally distributed pulmonary emphysema, which persisted after the washout period, associated with increased alveolar septal cell apoptosis, microvascular endothelial damage of the lung parenchyma, and inhibited expression of vascular endothelial growth factor (VEGF). DISCUSSION: In this rat model, fuel oil VOCs inhalation elicited alveolar septal cell apoptosis, likely due to DNA damage. In turn, the development of a peculiar pulmonary emphysema pattern altered lung mechanics and caused persistent noninflammatory airway hyperresponsiveness. Such findings suggest to us that humans might also respond to VOCs through physiopathological pathways different from those chiefly involved in typical cigarette smoke-driven emphysema in chronic obstructive pulmonary disease (COPD). If so, this study could form the basis for a novel disease mechanism for lasting respiratory disease following inhalational exposure to catastrophic fuel oil spills. https://doi.org/10.1289/EHP4178.
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Aceites Combustibles , Exposición por Inhalación , Compuestos Orgánicos Volátiles/toxicidad , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Contaminación por Petróleo , Enfisema Pulmonar , Ratas , Ratas Wistar , Enfermedades Respiratorias , Pruebas de ToxicidadRESUMEN
BACKGROUND: Most patients with nonallergic asthma have normal serum immunoglobulin E (IgE) levels. Recent reports suggest that total and aeroallergen-specific IgE levels in induced sputum may be higher in nonallergic asthmatics than in healthy controls. Our objective is to compare total and dust-mite specific (Der p 1) IgE levels in induced sputum in allergic and nonallergic asthmatics and healthy controls. METHODS: Total and Der p 1-specific IgE were measured in induced sputum (ImmunoCAP immunoassay) from 56 age- and sex-matched asthmatics (21 allergic, 35 nonallergic) and 9 healthy controls. Allergic asthma was defined as asthma with a positive prick test and/or clinically-significant Der p 1-specific serum IgE levels. RESULTS: Patients with allergic asthma presented significantly higher total and Der p 1-specific serum IgE levels. There were no significant between-group differences in total sputum IgE. However, Der p 1-specific sputum IgE levels were significantly higher (p = 0.000) in the allergic asthmatics, but without differences between the controls and nonallergic asthmatics. Serum and sputum IgE levels were significantly correlated, both for total IgE (rho = 0.498; p = 0.000) and Der p 1-specific IgE (rho, 0.621; p = 0001). CONCLUSIONS: Total IgE levels measured in serum and induced sputum are significantly correlated. No significant differences were found between the differents groups in total sputum IgE. Nevertheless, the levels of Der p 1-specific sputum IgE levels were significantly higher in the allergic asthmatics, but without differences between the controls and nonallergic asthmatics. Probably due to the lack of sensitivity of the test used, but with the growing evidence for local allergic reactions better methods are need to explore its presence. The Clinical Trials Identifier for this project is NCT03640936.
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Asma/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina E/metabolismo , Esputo/inmunología , Adulto , Asma/sangre , Asma/complicaciones , Estudios de Casos y Controles , Femenino , Humanos , Hipersensibilidad/sangre , Hipersensibilidad/complicaciones , Inmunoglobulina E/sangre , Masculino , Persona de Mediana EdadRESUMEN
Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6â kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1â s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335â µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344â µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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Antiasmáticos , Asma , Administración por Inhalación , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/epidemiología , Bélgica , Estudios Transversales , Europa (Continente) , Humanos , Hungría , Italia , Países Bajos , Polonia , Sistema de Registros , Estudios Retrospectivos , España , SueciaRESUMEN
BACKGROUND: Emerging data suggest that innate immunity may play a role in asthma, particularly the toll-like receptors (TLRs). Some studies pointed to an involvement of TLRs 2 and 4 in the pathogenesis of allergic asthma, and other studies related TLRs to IgE. However, there are not any studies that have comprehensively evaluated the expression of TLRs 2 and 4 in inflammatory cells, in peripheral blood and induced sputum specimens from asthmatic patients, according to their total serum IgE. METHODS: We studied 44 asthmatic patients (15 with high total serum IgE and 29 with normal total serum IgE). On a single visit, all patients underwent: induced sputum, pulmonary function tests, determination of exhaled nitric oxide fraction, venipuncture for blood analysis and skin prick allergy tests. The induced sputum cellularity was analyzed by flow cytometry, where expression of TLRs 2 and 4 was studied using fluorochrome-conjugated monoclonal antibodies. RESULTS: Asthmatic patients with high total serum IgE showed, a higher percentage of macrophages expressing TLR4 (42.99 % ± 22.49) versus asthmatic patients with normal total serum IgE (28.84 % ± 15.16) (P = 0.048). Furthermore, we observed a correlation (but weak) between the percentage of macrophages expressing TLR4 in induced sputum and the total serum IgE level (R = 0.314; P = 0.040). CONCLUSION: Asthmatic subjects with high total serum IgE show increased macrophage expression of TLR4 in induced sputum. This outcome may result from a link between innate immunity and IgE-mediated, adaptive immune responses in asthma, and point to TLR4 as a potential therapeutic target.
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Asma/sangre , Inmunoglobulina E/sangre , Esputo/metabolismo , Receptor Toll-Like 2/sangre , Receptor Toll-Like 4/sangre , Asma/diagnóstico , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Measurement of the fractional exhaled nitric oxide (FeNO) and eosinophils in induced sputum are noninvasive markers for assessing airway inflammation in asthma. The clinical usefulness of the correlation between raised FeNO and sputum eosinophilia is controversial. We aimed to examine dissociation between FeNO and sputum eosinophils in a clinical series of asthma patients and to determine whether dissociation between these noninvasive markers was associated with clinical and inflammatory differences in these patients. METHODS AND FINDINGS: A total of 110 patients with asthma were included in a cross-sectional study. All of them were on maintenance treatment for asthma. All patients underwent the following on the same day: FeNO, induced sputum, spirometry, serum total IgE levels and skin prick test. The level of asthma control was determined by the Asthma control Test Questionnaire. In 46 (41.8%) patients, a discrepancy between FeNO and sputum eosinophil count was observed, of those, 34 (73.9%) had a FeNO <50 ppb and high eosinophil count, and were characterized by having a predominance of nonallergic asthma with bronchial eosinophilic inflammatory phenotype. Also, 12 (26.1%) patients had FeNO ≥50 ppb and sputum eosinophilia within the normal reference values, and were characterized by having a predominance of atopy with a paucigranulocytic inflammatory phenotype. CONCLUSIONS: A high percentage of patients with dissociation between results of FeNO and sputum eosinophils was observed. These patients showed differential clinical and inflammatory features.
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Asma/diagnóstico , Eosinófilos/citología , Óxido Nítrico/metabolismo , Esputo/citología , Adulto , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Pruebas Respiratorias , Espiración , Femenino , Humanos , Inmunoglobulina E/sangre , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , EspirometríaRESUMEN
INTRODUCTION: Recent studies have found variability in asthma inflammatory phenotypes determined by the inflammatory cells in induced sputum (IS). The aim of this study was to determine the frequency and factors affecting inflammatory phenotype variability in IS. METHODS: Retrospective observational study that included 61 asthmatic patients who underwent at least two IS tests over a period of 5 years. They were classified according to their baseline inflammatory phenotype and subsequently grouped according to phenotype variability (persistent eosinophilic, persistent non-eosinophilic and intermittent eosinophilic). Demographic, clinical and functional data and factors potentially influencing IS variability were collected in all cases. RESULTS: Of the 61 patients, 31 (50.8%) had a change with respect to baseline inflammatory phenotype. Of these, 16 (51.6%) were eosinophilic, 5 (16.1%) neutrophilic, 1 (3.2%) mixed and 9 (29.1%) paucigranulocytic. According to phenotype variability, 18 patients (29.5%) were classified as persistent eosinophilic, 17 (27.9%) non-persistent eosinophilic, and 26 (42.6%) intermittent eosinophilic. Smoking and recent asthma exacerbation were significantly associated with increased risk of variability of the IS inflammatory phenotype (OR=6.44; p=.013; 95% CI=1.49-27.80 and OR=5.84; p=.022; 95% CI=1.29-26.37, respectively). CONCLUSION: Half of asthma patients, predominantly those with eosinophilic phenotype, present a change in IS inflammatory phenotype. This variability is associated with smoking and recent asthma exacerbation. Data suggest these factors can modify the classification of IS inflammatory phenotype in clinical practice.
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Asma/genética , Asma/inmunología , Eosinófilos , Neutrófilos , Esputo/citología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: To determine the general and specific utility in diagnosis and/or treatment of induced sputum (IS) inflammatory cell counts in routine clinical practice. METHODS: Retrospective study of 171 patients referred for clinical sputum induction over a 1-year period in the pulmonology department of a referral hospital. Independent observers established whether the information provided by IS inflammatory cell count was useful for making diagnostic and therapeutic decisions. RESULTS: The most frequent reasons for determination of IS inflammatory cell count were: asthma 103 (59.20%); uncontrolled asthma 34 (19.54%); chronic cough 19 (10.9%), and gastroesophageal reflux 15 (8.6%). In 115 patients (67.3%) it was generally useful for diagnosis and/or treatment; in 98 patients (57.3%) it provided diagnostic information and in 85 patients (49.7%) it assisted in therapeutic decision-making. In asthma, uncontrolled asthma, chronic cough and gastroesophageal reflux, the results were useful in 71.8%, 67.6%, 47.4% and 60%, respectively. CONCLUSION: The information provided by IS inflammatory cell count is extremely useful in clinical practice, especially in asthma and chronic cough. These results may justify the inclusion of the IS technique in pulmonology departments and asthma units of referral centers.
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Asma/patología , Tos/patología , Reflujo Gastroesofágico/patología , Recuento de Leucocitos , Solución Salina Hipertónica/farmacología , Salivación/efectos de los fármacos , Esputo/citología , Adulto , Anciano , Asma/tratamiento farmacológico , Toma de Decisiones Clínicas , Femenino , Departamentos de Hospitales , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVE: Transbronchial lung biopsy (TBLB) is required for evaluation in selected patients with interstitial lung disease (ILD). The diagnostic yield of histopathologic assessment is variable and is influenced by factors such as the size of samples and the presence of crush artefacts left by conventional biopsy forceps. We compared the diagnostic yield and safety of TBLB with cryoprobe sampling versus conventional forceps sampling. METHODS: This randomized clinical trial analysed data for 77 patients undergoing TBLB for evaluation of ILD; patients were assigned to either a conventional-forceps group or a cryoprobe group. Two pathologists assessed the tissue samples and agreed on histopathologic diagnoses. We also compared the duration of procedures, complications and sample-quality variables. RESULTS: The most frequent diagnosis observed in the cryoprobe group was non-specific interstitial pneumonia. Histopathologic diagnoses were identified in more cases in the cryoprobe group (74.4%) than in the conventional-forceps group (34.1%) (P < 0.001), and the diagnostic yield was higher in the cryoprobe group (51.3% vs 29.1% in the conventional forceps group; P = 0.038). A larger mean area of tissue was harvested by cryoprobe (14.7 ± 11 mm(2) ) than by conventional forceps (3.3 ± 4.1 mm(2)) (P < 0.001). More grade 2 bleeding (not statistically significant) occurred in the cryoprobe group (56.4%) than in the conventional-forceps group (34.2%). No differences in other complications were observed. CONCLUSIONS: TBLB by cryoprobe is safe and potentially useful in the diagnosis of ILD. Larger multisite randomized trials are required to confirm the potential benefits of this procedure. Clinical trial registration at ClinicalTrials.gov: NCT01064609.
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Biopsia/métodos , Broncoscopía/instrumentación , Criopreservación/instrumentación , Técnicas Histológicas/instrumentación , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/patología , Anciano , Biopsia/efectos adversos , Biopsia/instrumentación , Broncoscopía/efectos adversos , Broncoscopía/métodos , Criopreservación/métodos , Femenino , Hemorragia/epidemiología , Hemorragia/etiología , Técnicas Histológicas/métodos , Humanos , Incidencia , Pulmón/patología , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Reproducibilidad de los Resultados , Instrumentos QuirúrgicosRESUMEN
BACKGROUND: The measurement of fractional nitric oxide concentration in exhaled breath (FeNO), a noninvasive indicator of airway inflammation, remains controversial as a tool to assess asthma control. Guidelines currently limit asthma control assessment to symptom and spirometry based appraisals such as the Asthma Control Questionnaire-7 (ACQ-7). We aimed at determining whether adding FeNO to ACQ-7 improves current asthma clinical control assessment, through enhanced detection of not well controlled asthma. METHODS: Asthmatic subjects, classified as not well controlled as per ACQ-7 on regular clinical practice, were included in a prospective, multicenter fashion, and had their maintenance treatment adjusted on visit 1. On follow-up (visit 2) four weeks later, the subjects were reevaluated as controlled or not well controlled using ACQ-7 versus a combination of FeNO and ACQ-7. RESULTS: Out of 381 subjects enrolled, 225 (59.1%) had not well controlled asthma on visit 2 as determined by ACQ-7, and 264 (69.3%) as per combined FeNO and ACQ-7. The combination of FeNO to ACQ-7 increased by 14.8% the detection of not well controlled asthma following maintenance therapy adjustment. CONCLUSIONS: The addition of FeNO to ACQ-7 increased the detectability of not well controlled asthma upon adjustment of maintenance therapy. Adding a measure of airway inflammation to usual symptom and spirometry based scores increases the efficacy of current asthma clinical control assessment.
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Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Óxido Nítrico/análisis , Encuestas y Cuestionarios , Adulto , Asma/fisiopatología , Pruebas Respiratorias/métodos , Espiración , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Estudios Prospectivos , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
One of the largest oil spill disasters in recent times was the accident of the oil tanker Prestige in front of the Galician coast in 2002. Thousands of people participated in the cleanup of the contaminated areas, being exposed to a complex mixture of toxic substances. Acute and prolonged respiratory symptoms and genotoxic effects were reported, although environmental exposure measurements were restricted to current determinations, such that attribution of effects observed to oil exposure is difficult to establish. The aim of this study was to analyze peripheral blood leukocytes (PBL) harvested from a rat model of subchronic exposure to a fuel oil with similar characteristics to that spilled by the Prestige tanker, in order to determine potential genotoxic effects under strictly controlled, in vivo exposure. Wistar Han and Brown Norway rats were exposed to the oil for 3 wk, and micronucleus test (MN) and comet assay, standard and modified with 8-oxoguanine DNA glycosylase (OGG1) enzyme, were employed to assess genotoxicity 72 h and 15 d after the last exposure. In addition, the potential effects of oil exposure on DNA repair capacity were determined by means of mutagen sensitivity assay. Results obtained from this study showed that inhalation oil exposure induced DNA damage in both Brown Norway and Wistar Han rats, especially in those animals evaluated 15 d after exposure. Although alterations in the DNA repair responses were noted, the sensitivity to oil substances varied depending on rat strain. Data support previous positive genotoxicity results reported in humans exposed to Prestige oil during cleanup tasks.
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Contaminantes Atmosféricos/toxicidad , Daño del ADN , Reparación del ADN/efectos de los fármacos , Aceites Combustibles/toxicidad , Exposición por Inhalación , Mutágenos/toxicidad , Animales , Cámaras de Exposición Atmosférica , Ensayo Cometa , Restauración y Remediación Ambiental , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Pruebas de Micronúcleos , Mutágenos/administración & dosificación , Contaminación por Petróleo/efectos adversos , Ratas , Ratas Endogámicas BN , Ratas Wistar , España , Especificidad de la Especie , Factores de Tiempo , Pruebas de Toxicidad SubcrónicaRESUMEN
Dehydroepiandrosterone (DHEA) prevents chronic hypoxia-induced pulmonary hypertension and associated right ventricle dysfunction in rats. In this animal model, reoxygenation following hypoxia reverses pulmonary hypertension but not right ventricle dysfunction. We thus studied the effect of DHEA on the right ventricle after reoxygenation, i.e. after a normoxic recovery phase secondary to chronic hypoxia in rats. Right ventricle function was assessed in vivo by Doppler echocardiography and in vitro by the isolated perfused heart technique in three groups of animals: control, recovery (21 days of hypoxia followed by 21 days of normoxia) and recovery DHEA (30 mg · kg(-1) every 2 days during the recovery phase). Right ventricle tissue was assessed by optical and electron microscopy. DHEA abolished right ventricle diastolic dysfunction, as the echographic E wave remained close to that of controls (mean ± SD 76.5 ± 2.4 and 79.7 ± 1.7 cm · s(-1), respectively), whereas it was diminished to 40.3 ± 3.7 in the recovery group. DHEA also abolished right ventricle systolic dysfunction, as shown by the inhibition of the increase in the slope of the pressure-volume curve in isolated heart. The DHEA effect was related to cardiac myocytes proliferation. In conclusion, DHEA prevents right ventricle dysfunction in this animal model by preventing cardiomyocyte alteration.
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Deshidroepiandrosterona/farmacología , Hipoxia/terapia , Oxígeno/metabolismo , Disfunción Ventricular Derecha/terapia , Animales , Apoptosis , Proteína de Unión a CREB/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Ecocardiografía Doppler/métodos , Masculino , Microscopía/métodos , Microscopía Electrónica/métodos , Mitocondrias/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Perfusión , Ratas , Ratas WistarRESUMEN
Asthma is characterized by inflammation and remodeling of the airways, giving rise to airway obstruction and symptoms of wheezing, chest tightness, cough and dyspnea. Most of these observations arise from the study of samples obtained from the central airways by distinct methods. However, it is currently accepted that this inflammatory process occurs not only in the central airway but also in the small airway and even in the pulmonary parenchyma of all asthmatic patients, even those with mild asthma. CD4+ lymphocytes, activated eosinophils and IL-5 mRNA expression are present in a greater quantity in the small airways. Also present is remodeling, with an increase in submucosal thickness, the muscular layer and adventitia. This inflammatory process causes a disconnection between the pulmonary parenchyma and the airway, giving rise to obstruction of the small airway, which is currently considered to be predominant in asthmatic patients. Likewise, studies of experimental asthma in animals support the substantial role of the distal airway. Recognition that asthma affects the entire airway could be clinically important and lead to the distal lung being considered as a target in any effective therapeutic strategy. However, longitudinal studies are required to evaluate the impact of distal airway inflammation and its treatment in asthma.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/fisiopatología , Bronquios/patología , Modelos Animales de Enfermedad , Obstrucción de las Vías Aéreas/etiología , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Animales , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/metabolismo , Asma/patología , Hiperreactividad Bronquial/etiología , Bronquiolos/patología , Técnicas de Diagnóstico del Sistema Respiratorio , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Inflamación , Metaloproteinasas de la Matriz/metabolismo , Alveolos Pulmonares/patología , Eosinofilia Pulmonar/etiología , Especificidad de la EspecieAsunto(s)
Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Resistencia a Medicamentos/fisiología , Glucocorticoides/farmacología , Receptores de Glucocorticoides/metabolismo , Transporte Activo de Núcleo Celular , Antiasmáticos/farmacocinética , Antiasmáticos/uso terapéutico , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Asma/etiología , Asma/patología , Asma Inducida por Aspirina/tratamiento farmacológico , Asma Inducida por Aspirina/patología , Budesonida/farmacología , Núcleo Celular/metabolismo , Células Cultivadas/efectos de los fármacos , Dexametasona/farmacología , Descubrimiento de Drogas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapéutico , Humanos , Hipersensibilidad Inmediata/complicaciones , Mucosa Nasal/patología , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/patología , Receptores de Glucocorticoides/agonistasRESUMEN
Current guidelines for the management of chronic obstructive pulmonary disease (COPD) establish that bronchodilator medications are central to the symptomatic treatment of the disease. Regular treatment with long-acting bronchodilators is recommended as more effective and convenient than short-acting bronchodilators, because the long-acting agents provide greater bronchodilator efficacy and symptomatic relief, increased tolerance to exercise, and improved rate of exacerbations and quality of life test scores. Dosing regimens requiring less frequent dosing also provide improved treatment compliance. Indacaterol is a novel once-daily ultra-long-acting ß(2)-agonist bronchodilator now approved in the European Union for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD, to be administered as 150 or 300 microg once-daily dose by means of a single-dose dry powder inhaler. This review focuses on providing a clinical practice-oriented synopsis of the data generated from the randomized trials during the clinical development of indacaterol, published as of the time of writing. Indacaterol has been shown to provide effective 24-h bronchodilation and a fast onset of action, with an efficacy at least comparable or superior to current bronchodilator therapy standards and with a favourable safety and tolerability profile within the ß(2)-agonist drug class.