RESUMEN
BACKGROUND: Exposures to indoor biological contaminants have been implicated in asthma's aetiology but their effect on lung function is not well quantified. OBJECTIVE: The aim of this cross-sectional study of non-smoking, asthmatic adults in Scotland was to determine the correlation between the results from a standard spirometry test, forced expiratory volume in one-second percent (FEV1 %), and quantitative estimates of some biological exposures. METHODS: A population (n = 55) of non-smoking, adult asthmatics in Scotland was included in this study and each completed a questionnaire that allowed the determination of the Asthma Control Questionnaire scores (ACQ) and St. George's Respiratory Questionnaire scores (SGRQ), as well as corticosteroid use. Spirometry testing was completed and the pre-bronchodilator FEV1 % value calculated. At about the same time, floor dust samples were collected in the living room and in the bedroom. These dust samples were analysed for mould contamination, as described by the Environmental Relative Moldiness Index (ERMI) values and by (1, 3)-ß-D-glucan concentrations, for endotoxin, and for dust mite, cat, and dog allergen concentrations. The asthmatics' FEV1 % values were tested for correlation (Pearson) to questionnaire-based estimates of health. Also, each biological exposure was tested for correlation (Pearson) to the FEV1 % values. RESULTS: FEV1 % results were correlated with ACQ scores (ρ -0.586, P < 0.001), SGRQ scores (ρ -0.313, P = 0.020), and weakly with corticosteroid use (ρ -0.221, P = 0.105). The ERMI values in the homes (average 5.3) were significantly correlated with FEV1 % values (ρ -0.378, P = 0.004). There was no correlation between FEV1 % and concentrations of endotoxin, (1, 3)-ß-D-glucan, or any of the allergens. CONCLUSION AND CLINICAL RELEVANCE: Although these results do not prove that mould exposures caused the deficit in lung function observed in this study, it might be advisable for asthmatics to avoid high ERMI environments.
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Microbiología del Aire , Contaminación del Aire Interior , Asma/epidemiología , Asma/fisiopatología , Volumen Espiratorio Forzado , Hongos , Vivienda , Adulto , Anciano , Alérgenos , Animales , Comorbilidad , Estudios Transversales , Polvo/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escocia/epidemiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Arachidonic acid metabolites are implicated in the pathogenesis of asthma although only limited information is available on the impact of current smoking history on these metabolites. The aim of the study was to examine the effect of smoking status on urinary, sputum, and plasma eicosanoid concentrations and relevant enzyme transcripts in asthma. METHODS: In 108 smokers and never smokers with asthma and 45 healthy controls [smokers and never smokers], we measured urinary tetranor prostaglandin (PG)D2 (PGDM) and leukotriene (LT)E4 , induced sputum fluid LTB4 , LTE4 , PGD2 , and PGE2 , plasma secretory phospholipase A2 (sPLA2 ), and 11ß prostaglandin F2α (11ßPGF2α ), and, in a subgroup with severe asthma, airway leukocyte and epithelial cell mRNA expression levels of arachidonic acid metabolic enzymes. RESULTS: Smokers with asthma had higher urinary LTE4 ; 83 (59, 130) vs 59 (40, 90) pg/mg creatinine, P = 0.008, and PGDM; 60 (35, 100) vs 41 (28, 59) ng/mg creatinine, P = 0.012 concentrations, respectively, and lower sputum PGE2 concentrations 80 (46, 157) vs 192 (91, 301) pg/ml, P = 0.001 than never smokers with asthma. Sputum LTB4 (P = 0.013), and plasma 11ßPGF2α (P = 0.032), concentrations, respectively, were increased in smokers with asthma compared with healthy smokers. Asthma-specific and smoking-related increases (>1.5-fold expression) in arachidonate 15-lipoxygenase and gamma-glutamyltransferase transcripts were demonstrated. CONCLUSIONS: Several arachidonic acid metabolites and enzyme transcripts involving both lipoxygenase and cyclooxygenase pathways are increased in smokers with asthma and differ from never smokers with asthma. Possibly targeting specific lipoxygenase and cyclooxygenase pathways that are activated by asthma and cigarette smoking may optimize therapeutic responses.
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Ácido Araquidónico/metabolismo , Asma/genética , Asma/metabolismo , Fumar , Transcripción Genética , Adulto , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Estudios Transversales , Femenino , Expresión Génica , Humanos , Leucocitos/metabolismo , Leucotrieno E4/sangre , Leucotrieno E4/metabolismo , Leucotrieno E4/orina , Masculino , Persona de Mediana Edad , Prostaglandinas/sangre , Prostaglandinas/orina , ARN Mensajero/genética , Pruebas de Función Respiratoria , Mucosa Respiratoria/metabolismo , Factores de Riesgo , Esputo/metabolismo , Encuestas y CuestionariosRESUMEN
Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13-16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: -0.9 [-12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4, but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.
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Inhibidores de Proteína Activante de 5-Lipoxigenasa/uso terapéutico , Asma/tratamiento farmacológico , Indoles/uso terapéutico , Neutrófilos/metabolismo , Ácidos Pentanoicos/uso terapéutico , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Adulto , Anciano , Asma/fisiopatología , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Indoles/farmacología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Ácidos Pentanoicos/farmacología , Esputo/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480â889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
Asunto(s)
Asma/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Australia , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Metaanálisis como Asunto , Índice de Severidad de la EnfermedadRESUMEN
Macrolide antibiotics were discovered over 50 years ago and following their use as antimicrobials it became apparent that this group of antibiotics also possessed anti-inflammatory properties. Subsequent clinical trials showed benefits of macrolides as long-term adjuncts in the treatment of a spectrum of chronic inflammatory respiratory diseases, particularly diffuse panbronchiolitis, cystic fibrosis, post-transplant bronchiolitis obliterans and more recently chronic obstructive pulmonary disease (COPD). The evidence for efficacy of macrolides in the long-term treatment of chronic asthma and bronchiectasis is less well established. The mechanism(s) of action of macrolides in the treatment of these diseases remains unexplained, but may be due to their antibacterial and/or anti-inflammatory actions, which include reductions in interleukin-8 production, neutrophil migration and/or function. Macrolides have additional potentially beneficial properties including anti-viral actions and an ability to restore corticosteroid sensitivity. The increased prescribing of macrolides for long-term treatment could result in the development of microbial resistance and adverse drug effects. New macrolides have been developed which do not possess any antimicrobial activity and hence lack the ability to produce microbial resistance, but which still retain immunomodulatory effects. Potentially novel macrolides may overcome a significant barrier to the use of this type of drug for the long-term treatment of chronic inflammatory airway diseases.
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Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Macrólidos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedades Respiratorias/tratamiento farmacológico , Antiinflamatorios/efectos adversos , Antiinflamatorios/química , Asma/inmunología , Enfermedad Crónica , Ensayos Clínicos como Asunto , Humanos , Inflamación/inmunología , Macrólidos/efectos adversos , Macrólidos/química , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedades Respiratorias/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: The regulation and function of IgE in healthy individuals and in antigen-naïve animals is not well understood. IL-33 administration increases serum IgE in mice with unknown mechanism. We tested the hypothesis that IL-33 provides an antigen-independent stimulus for IgE production and mast cell degranulation. METHODS: IL-33 was administered to naïve wild-type (WT), nude and ST2(-/-) , IL-4(-/-) , IL4Rα(-/-) and T-or B-cell-specific IL-4Rα(-/-) mice. IgE and cytokines were quantified by ELISA. T- and B-lymphocyte numbers and CD40L expression were determined by flow cytometry. Anaphylaxis was measured by temperature, mast cell degranulation and histamine release. RESULTS: IL-33 enhanced IgE production in naïve WT, T-IL-4Rα(-/-) but not in ST2(-/-) , IL-4(-/-) , IL-4Rα(-/-) or B-cell-specific IL-4Rα(-/-) mice, demonstrating IL-33 specificity and IL-4 dependency. Moreover, IL-4 was required for IL-33-induced B-cell proliferation and T-cell CD40L expression, which promotes IgE production. IL-33-induced IL-4 production was mainly from innate cells including mast cells and eosinophils. IL-33 increased mast cell surface IgE and triggered degranulation and systemic anaphylaxis in allergen-naïve WT but not in IL-4Rα(-/-) mice. CONCLUSION: IL-33 amplifies IgE synthesis and triggers anaphylaxis in naïve mice via IL-4, independent of allergen. IL-33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.
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Degranulación de la Célula , Inmunoglobulina E/biosíntesis , Interleucina-4/inmunología , Interleucinas/inmunología , Interleucinas/farmacología , Mastocitos/fisiología , Anafilaxia/etiología , Anafilaxia/inmunología , Animales , Degranulación de la Célula/inmunología , Citometría de Flujo , Liberación de Histamina , Inmunoglobulina E/efectos de los fármacos , Interleucina-33 , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucinas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones DesnudosRESUMEN
BACKGROUND: Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non-smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. OBJECTIVE: Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. METHODS: Forty-three asthmatics (17 smokers, nine ex-smokers and 17 never-smokers) and 16 healthy volunteers (nine smokers and seven never-smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA-2, CD303), type 1 conventional (cDC) (BDCA-1, CD1c), and type 2 cDC (BDCA-3, CD141)]. RESULTS: Subjects with asthma displayed increases in all DC subtypes compared with normal never-smokers: [type 1 cDCs - asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never-smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs - asthma: 0.04% (0.02, 0.06), normal never-smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs - asthma: 0.32% (0.27, 0.46), normal never-smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never-smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non-asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical trials.gov identifier: NCT00411320)
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Asma/inmunología , Células Dendríticas/inmunología , Fumar , Adulto , Asma/patología , Células Dendríticas/patología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Beclometasona/uso terapéutico , Broncodilatadores/uso terapéutico , Fumar/fisiopatología , Teofilina/uso terapéutico , Administración por Inhalación , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Antiasmáticos/administración & dosificación , Broncodilatadores/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Pruebas de Función Respiratoria , Estadísticas no Paramétricas , Resultado del TratamientoAsunto(s)
Asma/tratamiento farmacológico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Bronquitis/complicaciones , Bronquitis/tratamiento farmacológico , Compuestos de Metilurea/farmacología , Compuestos de Metilurea/uso terapéutico , Eosinofilia Pulmonar/complicaciones , Receptores CCR3/antagonistas & inhibidores , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: The warm, humid environment in modern homes favours the dust mite population, but the effect of improved home ventilation on asthma control has not been established. We tested the hypothesis that a domestic mechanical heat recovery ventilation system (MHRV), in addition to allergen avoidance measures, can improve asthma control by attenuating re-colonization rates. METHODS: We conducted a randomized double-blind placebo-controlled parallel group trial of the installation of MHRV activated in half the homes of 120 adults with asthma, allergic to Dermatophagoides pteronyssinus. All homes had carpets steam cleaned and new bedding and mattress covers at baseline. The primary outcome was morning peak expiratory flow (PEF) at 12 months. RESULTS: At 12 months, the primary end-point; change in mean morning PEF as compared with baseline, did not differ between the MHRV group and the control group (mean difference 13.5 l/min, 95% CI: -2.6 to 29.8, P = 0.10). However, a secondary end-point; evening mean PEF, was significantly improved in the MHRV group (mean difference 24.5 l/min, 95% CI: 8.9-40.1, P = 0.002). Indoor relative humidity was reduced in MHRV homes, but there was no difference between the groups in Der p 1 levels, compared with baseline. CONCLUSIONS: The addition of MHRV to house dust mite eradication strategies did not achieve a reduction in mite allergen levels, but did improve evening PEF.
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Alérgenos/análisis , Asma/prevención & control , Pyroglyphidae/inmunología , Ventilación/métodos , Adulto , Alérgenos/inmunología , Animales , Antígenos Dermatofagoides/análisis , Antígenos Dermatofagoides/inmunología , Dermatophagoides pteronyssinus/inmunología , Método Doble Ciego , Femenino , Humanos , Hipersensibilidad/inmunología , Masculino , Persona de Mediana Edad , Ápice del Flujo Espiratorio , Resultado del TratamientoRESUMEN
BACKGROUND: Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function and airway inflammation in atopic adults with asthma. METHODS: 54 adults with atopic asthma were recruited to a double-blind randomised controlled crossover trial comparing the effect of oral atorvastatin 40 mg daily with that of a matched placebo on asthma control and airway inflammation. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included forced expiratory volume in 1 s, asthma control questionnaire score, airway hyper-responsiveness to methacholine, induced sputum cytology and inflammatory biomarkers. RESULTS: At 8 weeks the change in mean morning PEF compared with baseline did not differ substantially between the atorvastatin and placebo treatment periods (mean difference -0.5 l/min, 95% CI -10.6 to 9.6, p = 0.921). Values for other clinical outcomes were similar between the atorvastatin and placebo treatment periods. The absolute sputum macrophage count was reduced after atorvastatin compared with placebo (mean difference -45.0 x 10(4) cells, 95% CI -80.1 to -9.7, p = 0.029), as was the sputum fluid leucotriene B4 (mean difference -88.1 pg/ml, 95% CI -156.4 to -19.9, p = 0.014). CONCLUSION: The addition of atorvastatin to inhaled corticosteroids results in no short-term improvement in asthma control but reduces sputum macrophage counts in mild to moderate atopic asthma. The change in sputum macrophage count suggests potential areas for investigation of statins in other chronic lung diseases.
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Corticoesteroides/administración & dosificación , Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Ácidos Heptanoicos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Pirroles/administración & dosificación , Esputo/citología , Administración por Inhalación , Administración Oral , Adulto , Asma/patología , Asma/fisiopatología , Atorvastatina , Biomarcadores/metabolismo , Enfermedad Crónica , Estudios Cruzados , Método Doble Ciego , Quimioterapia Combinada , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Capacidad Vital/fisiologíaRESUMEN
BACKGROUND: Cigarette smoking in asthma increases the severity and accelerates the decline in lung function. The relative role of symptoms and lung function in determining asthma control in smokers with asthma is not known. AIM OF THE STUDY: The aim of this study was to compare asthma control in smokers vs never-smokers with asthma, using the validated Juniper asthma control questionnaire (ACQ), and assess if any difference was because of a particular symptom or the forced expiratory volume in one second (FEV(1)) value. METHODS: This was a cross-sectional study of 134 asthmatics (74 never-smokers and 60 smokers) with >or=15% reversibility in FEV(1) after salbutamol. All subjects completed the ACQ, recording FEV(1) and asthma symptoms (night awakening, morning symptoms, dyspnoea, wheeze, activity limitation and use of reliever inhaler). RESULTS: Compared with the never-smokers, smokers with asthma had significantly worse median (IQR) total asthma control score [1.6 (1.1-2.3) vs 2.8 (1.7-3.4); (P < 0.0001)] and in each of the six individual symptom question scores (P < 0.001), but no difference in FEV(1) levels (P = 0.908). CONCLUSION: Asthma control is significantly worse in asthmatics who smoke compared with never-smokers, with all symptoms related to asthma control uniformly worse in smokers, independent of FEV(1).
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Antiasmáticos/administración & dosificación , Asma/diagnóstico , Asma/tratamiento farmacológico , Hiperreactividad Bronquial/fisiopatología , Fumar/efectos adversos , Adolescente , Adulto , Anciano , Análisis de Varianza , Asma/epidemiología , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Probabilidad , Pronóstico , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Fumar/epidemiología , Espirometría , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the feasibility of a phase 3 randomised controlled trial (RCT) of a website (Living Well with Asthma) to support self-management. DESIGN AND SETTING: Phase 2, parallel group, RCT, participants recruited from 20 general practices across Glasgow, UK. Randomisation through automated voice response, after baseline data collection, to website access for minimum 12â weeks or usual care. PARTICIPANTS: Adults (age≥16â years) with physician diagnosed, symptomatic asthma (Asthma Control Questionnaire (ACQ) score ≥1). People with unstable asthma or other lung disease were excluded. INTERVENTION: 'Living Well with Asthma' is a desktop/laptop compatible interactive website designed with input from asthma/ behaviour change specialists, and adults with asthma. It aims to support optimal medication management, promote use of action plans, encourage attendance at asthma reviews and increase physical activity. OUTCOME MEASURES: Primary outcomes were recruitment/retention, website use, ACQ and mini-Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes included patient activation, prescribing, adherence, spirometry, lung inflammation and health service contacts after 12â weeks. Blinding postrandomisation was not possible. RESULTS: Recruitment target met. 51 participants randomised (25 intervention group). Age range 16-78â years; 75% female; 28% from most deprived quintile. 45/51 (88%; 20 intervention group) followed up. 19 (76% of the intervention group) used the website, for a mean of 18â min (range 0-49). 17 went beyond the 2 'core' modules. Median number of logins was 1 (IQR 1-2, range 0-7). No significant difference in the prespecified primary efficacy measures of ACQ scores (-0.36; 95% CI -0.96 to 0.23; p=0.225), and mini-AQLQ scores (0.38; -0.13 to 0.89; p=0.136). No adverse events. CONCLUSIONS: Recruitment and retention confirmed feasibility; trends to improved outcomes suggest use of Living Well with Asthma may improve self-management in adults with asthma and merits further development followed by investigation in a phase 3 trial. TRIAL REGISTRATION NUMBER: ISRCTN78556552; Results.
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Asma/prevención & control , Internet/estadística & datos numéricos , Selección de Paciente , Autocuidado , Adolescente , Adulto , Anciano , Antiinflamatorios/administración & dosificación , Asma/tratamiento farmacológico , Asma/fisiopatología , Broncodilatadores/administración & dosificación , Ejercicio Físico , Estudios de Factibilidad , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Proyectos Piloto , Prednisolona/administración & dosificación , Calidad de Vida , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Although about 1% of pregnant women have asthma, it is often underrecognized and suboptimally treated. The course of asthma during pregnancy varies; it improves, remains stable, or worsens in similar proportions of women. The risk of an asthma exacerbation is high immediately postpartum, but the severity of asthma usually returns to the preconception level after delivery and often follows a similar course during subsequent pregnancies. Changes in beta(2)-adrenoceptor responsiveness and changes in airway inflammation induced by high levels of circulating progesterone have been proposed as possible explanations for the effects of pregnancy on asthma. Good control of asthma is essential for maternal and fetal well-being. Acute asthmatic attacks can result in dangerously low fetal oxygenation. Chronically poor control is associated with pregnancy-induced hypertension, preeclampsia, and uterine hemorrhage, as well as greater rates of cesarian section, preterm delivery, intrauterine growth retardation, low birth weight, and congenital malformation. Women with well-controlled asthma during pregnancy, however, have outcomes as good as those in their nonasthmatic counterparts. Inhaled therapies remain the cornerstone of treatment; most appear to be safe in pregnancy.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/fisiopatología , Resultado del Embarazo , Agonistas Adrenérgicos beta/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/complicaciones , Broncodilatadores/uso terapéutico , Árboles de Decisión , Diabetes Gestacional/etiología , Femenino , Humanos , Hipertensión/etiología , Lactante , Mortalidad Infantil , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro , Preeclampsia/etiología , Embarazo , Esteroides , Teofilina/uso terapéutico , Hemorragia Uterina/etiologíaRESUMEN
1. Contractions in human bronchial rings evoked by methacholine (10(-6) M) were reversed by single contractions of alpha-human atrial natriuretic peptide (10(-6) M), salbutamol (10(-6) M), sodium nitroprusside (10(-6) M) or isosorbide dinitrate (4.2 x 10(-5) M) and the extent of the relaxations compared. The activity of combinations of ANP with salbutamol, sodium nitroprusside and isosorbide dinitrate were compared with those for each agonist alone. 2. ANP and salbutamol were equipotent in reversing methacholine-evoked contraction and, in combination these agonists evoked an additive response. ANP and sodium nitroprusside also evoked similar degrees of relaxation and were additive, as were ANP and isosorbide dinitrate; however, with isosorbide dinitrate a higher concentration was required to evoke the same degree of relaxation as ANP, sodium nitroprusside or salbutamol. 3. Cumulative concentration-response curves to methacholine (10(-9)-3 x 10(-4) M) were examined in the presence and absence of the above bronchodilator substances, alone and in combination allowing their abilities to protect against contraction to be compared. ANP (10(-6) M) and salbutamol (10(-6) M) each attenuated subsequent contractions evoked by methacholine, an ability not shared with sodium nitroprusside (10(-6) M) or isosorbide dinitrate (4.2 x 10(-5) M). Indeed at lower concentrations of methacholine (< 3 x 10(-7) M), sodium nitroprusside evoked a paradoxical enhancement of methacholine-evoked contractions. 4. In combination, ANP and salbutamol attenuated contractions evoked by methacholine to a significantly greater degree than that seen with either agonist alone, whilst a combination of ANP and sodium nitroprusside evoked no greater effect than that seen with ANP alone. By contrast, isosorbide dinitrate and ANP together evoked a greater inhibition than ANP alone.5 These results suggest that a combination of agents such as ANP and salbutamol evokes a greater effect than either alone, both in reversing and protecting against methacholine-evoked contractions.Such combinations may be of benefit in the treatment of patients, allowing lower doses of drug to be used. Combinations of ANP and isosorbide dinitrate may likewise be of interest; however, the mechanism underlying the enhancement of ANP responses by isosorbide dinitrate requires further study.
Asunto(s)
Albuterol/farmacología , Factor Natriurético Atrial/farmacología , Bronquios/efectos de los fármacos , Dinitrato de Isosorbide/farmacología , Músculo Liso/efectos de los fármacos , Nitroprusiato/farmacología , Broncodilatadores/farmacología , Sinergismo Farmacológico , Humanos , Técnicas In Vitro , Cloruro de Metacolina/antagonistas & inhibidores , Cloruro de Metacolina/farmacología , Contracción Muscular/efectos de los fármacosRESUMEN
1. This study examined the activity and mechanisms of action of urodilatin in bovine bronchi. For comparison, the ability of urodilatin to evoke bronchodilatation or protect against subsequent challenge was compared to that of the closely related peptide alpha-human atrial natriuretic peptide (ANP). 2. Urodilatin reversed methacholine-evoked contraction in a concentration-dependent manner in bovine bronchi. In the absence of any attempt to prevent degradation by neutral endopeptidases, urodilatin was more potent than ANP in this tissue. 3. The bronchodilator properties of urodilatin were significantly augmented by the neutral endopeptidase inhibitor, phosphoramidon (3.68 x 10(-5) M). This provides evidence for at least partial degradation of urodilatin by neutral endopeptidases. With phosphoramidon present, urodilatin and ANP were equipotent. 4. In the presence of phosphoramidon (3.68 x 10(-5) M), pre-incubation with urodilatin (10(-6) M) had a protective effect against subsequent methacholine-induced contraction. This action of urodilatin was quantitatively similar to that of ANP in the presence of this endopeptidase inhibitor. 5. The actions of urodilatin appear to involve ATP-sensitive K+ channels since tolbutamide (10(-6) - 10(-5) M) significantly attenuated the relaxations induced by this peptide. 6. Small conductance Ca(2+)-activated K+ channels seem likewise to be implicated in the actions of urodilatin since blockade of these channels with apamin (10(-7) - 10(-6) M) resulted in a marked attenuation of urodilatin-evoked responses. 7. The presence of charybdotoxin (10-9 M-10-M) had no significant effect on subsequent responses tourodilatin suggesting that large conductance Ca2+-activated K+ channels are not involved in the relaxations evoked by this peptide.8. In the presence of phosphoramidon (3.68 x 10-5 M), urodilatin (10-6 M) evoked elevation of cyclic GMP levels within bovine bronchial tissue. Levels of cyclic GMP increased significantly within 5-10 s in response to this peptide and preceded the initiation of relaxant responses. Maximum increases in cyclic GMP levels were reached within 5 min; the time required for maximal relaxation evoked by this peptide.9. In conclusion, urodilatin, like ANP reversed and protected against, subsequent methacholine-induced bronchoconstriction; an action enhanced by the presence of phosphoramidon (3.68 x 1O-5 M).Associated with these actions of urodilatin was a rise in cyclic GMP levels as well as the opening of ATP-sensitive K+ and small conductance Ca2+-activated K+ channels.
Asunto(s)
Factor Natriurético Atrial/farmacología , Bronquios/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Animales , Apamina/farmacología , Bovinos , GMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Glicopéptidos/farmacología , Técnicas In Vitro , Cloruro de Metacolina/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Tolbutamida/farmacologíaRESUMEN
1. In this study, mechanical responses to endothelin-1 and endothelin-3 were examined in bovine bronchial smooth muscle. In addition, the involvement of phosphatidylinositol 4,5-bisphosphate hydrolysis (PIP2) in the responses to these peptides was assessed by measurement of inositol (1,4,5) trisphosphate (I(1,4,5)P3) production using a specific mass assay. 2. ET-1 evoked contractions of bovine bronchi which were concentration-dependent and initiated at between 10(-9) M and 10(-8) M. ET-1-evoked responses were unaffected by slight elevation of tone with potassium chloride (3 x 10(-2) M), methacholine (10(-6) M) or U46619 (10(-7) M). 3. Contractions to ET-1 were not altered by pre-incubation with atropine (10(-5) M), indomethacin (10(-5) M), nifedipine (10(-5) M), phosphoramidon (3.67 x 10(-5) M) or by removal of the epithelium. 4. ET-3 evoked small contractions which were not concentration-dependent. In the presence of phosphoramidon (3.67 x 10(-5) M) however, concentration-dependent contractions were obtained to ET-3 which were unaffected by atropine (10(-5) M) or by removal of the epithelium, but were significantly attenuated by indomethacin (10(-5) M). Nifedipine (10(-5) M) virtually abolished this response. 5. Both ET-1 and ET-3 (in the presence of phosphoramidon)-evoked contractions were significantly enhanced by the presence of the phorbol ester phorbol 12,13-dibutyrate (10(-8) M). Neither ET-1-, nor ET-3-mediated responses were antagonized by the protein kinase C (PKC) inhibitor, Ro 31-8220 (3 x 10(-9) - 3 x 10(-8) M). 6. ET-1 (3 x 10(-7) M) evoked a biphasic rise in levels of I(1,4,5)P3 which was unaltered by preincubation with atropine, whilst ET-3 (10(-10) - 3 x 10(-7) M) failed to alter levels of I(1,4,5)P3 at any time point examined, even in the presence of phosphoramidon (3.67 x 10(-5) M). 7. These results suggest that, in bovine bronchial smooth muscle, ET-l does not evoke contraction via cyclo-oxygenase metabolites, does not evoke release of the neurotransmitter substance acetylcholine, or require calcium influx via dihydropyridine-sensitive channels. ET-1 evokes 1(1,4,5)P3 production, but stimulation of protein kinase C may not be critical for the associated contraction. In contrast,ET-3-evoked contractions are partly mediated by cyclo-oxygenase metabolites. ET-3 does not stimulate PIP2 hydrolysis, nor activate PKC, but may, either directly or as a requirement of intermediates released in response to ET-3, rely upon extracellular calcium.
Asunto(s)
Bronquios/efectos de los fármacos , Endotelinas/farmacología , Músculo Liso/efectos de los fármacos , Animales , Bronquios/fisiología , Bovinos , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiologíaRESUMEN
Inhaled topical lidocaine, used to produce anesthesia of the respiratory tract prior to bronchoscopy, may cause bronchoconstriction in asthmatic patients. We investigated whether the degree of histamine airway responsiveness would predict the development and extent of lidocaine-induced bronchoconstriction in 20 asthmatic patients. The provocation concentration of histamine producing a 20 percent fall in FEV1 (PC20) was measured. On a separate day, challenge with 6 ml 4 percent lidocaine (Xylocaine 4 percent topical) was performed. There was no correlation between the response to lidocaine and the histamine PC20. Five patients (25 percent) showed a fall in FEV1 of greater than 15 percent (max 42.1 percent). Three responders were rechallenged double-blind with the commercial 4 percent lidocaine preparation and with a 4 percent preservative-free lidocaine solution. There was no difference in the response to these two solutions. These results demonstrate that inhaled topical lidocaine induces bronchoconstriction in a significant proportion of patients with asthma. This response is not related to airway histamine responsiveness or to the preservative in the lidocaine preparation.
Asunto(s)
Anestesia Local , Asma/diagnóstico , Espasmo Bronquial/inducido químicamente , Broncoscopía , Lidocaína/toxicidad , Administración por Inhalación , Adulto , Bronquios/fisiopatología , Pruebas de Provocación Bronquial , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Histamina , Humanos , Masculino , Parabenos/toxicidad , Conservadores Farmacéuticos/toxicidadRESUMEN
STUDY OBJECTIVE: We have previously described activation of the renin-angiotensin system (RAS) in acute severe asthma and have also reported activation of the RAS in normal subjects by single doses of nebulized beta 2-agonists. In the present study, we have examined the effect of single and multiple doses of nebulized albuterol on the activity of the RAS in mild asthma. DESIGN: Eight patients with mild asthma were studied. The effect of single and multiple doses of nebulized albuterol (5 mg) on the activity of the RAS was compared with that of placebo using a randomized, double-blind crossover study design. Nebulized drugs were administered at time 0 and 30 min. MEASUREMENTS: Plasma renin, angiotensin II (Ang II), and serum potassium levels were measured at baseline following a short rest, and thereafter at intervals up to 150 min. RESULTS: Renin levels increased after both the single (S) and double (D) nebulized doses of albuterol and were significantly greater than placebo at 30 min after S, and at 45 and 120 min after D. Plasma Ang II level also increased after S and D and was significantly greater than placebo at 30 and 45 min after S, and at 30 min and all timepoints thereafter following D. In addition, the effect of D was significantly greater than S at 45 min. CONCLUSIONS: These results confirm that there is activation of the RAS in asthmatic subjects by single doses of nebulized beta 2-agonists and that repeated dosing with nebulized albuterol has further, additive effects on plasma Ang II levels. It therefore seems likely that these agents are contributing to activation of the RAS in acute asthma, although the exact clinical significance of these transient changes in plasma Ang II levels in asthma is at present unclear.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Albuterol/farmacología , Asma/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Agonistas Adrenérgicos beta/administración & dosificación , Aerosoles , Albuterol/administración & dosificación , Angiotensina II/sangre , Estudios Cruzados , Método Doble Ciego , Humanos , Potasio/sangre , Renina/sangreRESUMEN
STUDY OBJECTIVES: Cigarette smoking is common in asthmatic patients, and we investigated the impact of cigarette smoking on airway inflammation in asthma. DESIGN: Single-center observational study of airway inflammation in asthmatic and healthy smokers and nonsmokers. SETTING: Asthma research unit in a university hospital. PATIENTS OR PARTICIPANTS: Sixty-seven asthmatic and 30 nonasthmatic subjects classified as smokers or nonsmokers. Asthmatics had chronic, stable asthma and were not receiving inhaled or oral steroids at the time of the study. INTERVENTIONS: We examined induced-sputum cell counts and levels of interleukin (IL)-8 and eosinophilic cationic protein (ECP). Bronchial hyperreactivity was assessed using methacholine challenge. MEASUREMENTS AND RESULTS: Asthmatic smokers had higher total sputum cell counts than nonsmoking asthmatics and both smoking and nonsmoking healthy subjects. Smoking was associated with sputum neutrophilia in both asthmatics and nonasthmatics (median, 47% and 41%, respectively) compared with nonsmokers (median, 23% and 22%, respectively), and sputum IL-8 was increased in smokers compared with nonsmokers, both in subjects with asthma (median, 945 pg/mL vs 660 pg/mL, respectively) and in healthy subjects (median, 1,310 pg/mL vs 561 pg/mL, respectively). Sputum eosinophils and ECP levels were higher in both nonsmoking and smoking asthmatics than in healthy nonsmokers. In smoking asthmatics, lung function (FEV(1) percent predicted) was negatively related to both sputum IL-8 (r = - 0.52) and sputum neutrophil proportion (r = - 0.38), and sputum IL-8 correlated positively with smoking pack-years (r = 0.57) and percent neutrophil count (r = 0.51). CONCLUSIONS: In addition to the eosinophilic airway inflammation observed in patients with asthma, smoking induces neutrophilic airway inflammation; a relationship is apparent between smoking history, airway inflammation, and lung function in smoking asthmatics.