fluticasone and Inflammation

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; 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Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Eosinophilic oesophagitis is a unique form of non-IgE-mediated food allergy characterised by oesophageal eosinophilic infiltration. The prevalence of EoE has grown to currently represent the first cause of dysphagia and food impaction in children and young adults. Avoiding food triggers is the only therapy targeting the cause of the disease, but none of the currently available food allergy tests adequately predicts food triggers for EoE. Strategies based on the empirical elimination of food are the most effective and convenient in clinical practice. Proton pump inhibitors constitute an effective first-line therapy in half of patients, through a direct anti-inflammatory effect independent of its action on gastric acid secretion. Topical glucocorticosteroids budesonide and fluticasone reduce eosinophilic inflammation and reverse symptoms. This review includes the most relevant aspects of the epidemiology, diagnosis, treatment and monitoring of eosinophilic oesophagitis.

Topics: Adult; Anti-Inflammatory Agents; Budesonide; Child; Deglutition Disorders; Diet Therapy; Eosinophilic Esophagitis; Evidence-Based Practice; Fluticasone; Humans; Inflammation; Proton Pump Inhibitors; Young Adult

Patients with chronic obstructive pulmonary disease (COPD) are predisposed to atherosclerosis and coronary artery disease, but the underlying mechanisms are unclear. Although there is wide acceptance that atherosclerosis is related to systemic inflammation, the cause(s) and mechanism(s) of pulmonary inflammation in stable COPD remain unknown. Infectious (bacterial and viral) as well as noninfectious agents can cause acute exacerbations in COPD, and they intensify local and systemic inflammation. Although it is not known how systemic inflammation develops in stable COPD, there is good evidence to suggest that it occurs and that the intensity of systemic inflammation is linked to the severity of airflow obstruction. We postulate that systemic inflammation provides the linkage between COPD and atherosclerosis. Inhaled corticosteroids have been shown to improve health outcomes in COPD, but the mechanism by which this occurs is a pivotal and challenging question that has yet to be answered. To prove the concept that inhaled corticosteroids could suppress systemic inflammation (as exemplified by serum C-reactive protein [CRP] levels), a double-blind, placebo-controlled clinical trial was conducted in a group of patients with mild to moderate COPD. We found that withdrawal of inhaled corticosteroids increased serum CRP levels, and that reintroduction of inhaled fluticasone could suppress CRP levels.

Topics: Androstadienes; Anti-Inflammatory Agents; Arteriosclerosis; C-Reactive Protein; Fluticasone; Humans; Inflammation; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Topics: Administration, Inhalation; Androstadienes; Animals; Bronchoconstriction; Bronchodilator Agents; Disease Models, Animal; Fluticasone; Inflammation; Mice; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Respiratory Tract Diseases

The authors describe the scientific rationale for using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist. They discuss the clinical trials demonstrating that using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist provides greater overall asthma control compared with increasing the dose of inhaled corticosteroid. In addition, they review the clinical trials comparing the addition of a leukotriene modifier to an inhaled corticosteroid versus using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist. Discussion also includes descriptions of trials showing reduced exacerbations of asthma when using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist. Finally, the authors provide evidence for the ability to detect deteriorating asthma when using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist, and they provide a comparison of salmeterol and formoterol, two long-acting beta 2-agonists.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchoconstriction; Bronchodilator Agents; Drug Interactions; Drug Therapy, Combination; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans; Inflammation; Salmeterol Xinafoate

Topical corticosteroids are an effective treatment for nasal polyposis and other conditions associated with rhinitis. There is evidence that asthma, otitis media with effusion, and acute sinusitis may all benefit from such therapy. Fluticasone propionate (FP) drops have been shown to reduce polyp size, and to improve nasal inspiratory flow, while avoiding the side-effects of, for example, topical betamethasone therapy. In small children with allergic rhinitis, fluticasone propionate aqueous nasal spray (FPANS) has been shown to be significantly more effective than ketotifen in relieving night and daytime symptoms, and nasal blockage. There is also preliminary evidence of efficacy in obstructive sleep apnoea and acute sinusitis. The advent of FP, with its low propensity to cause systemic side-effects, makes it possible to use topical corticosteroid therapy safely for prolonged periods to treat many inflammatory diseases of the upper respiratory tract.

Topics: Administration, Intranasal; Androstadienes; Anti-Inflammatory Agents; Child, Preschool; Clinical Trials as Topic; Fluticasone; Humans; Inflammation; Respiratory Tract Diseases

Fluticasone propionate is a new corticosteroid based on the androstane nucleus. It is more lipophilic than beclomethasone dipropionate (BDP) and budesonide, and binds more avidly to human lung tissue. It has an absolute affinity (KD) of 0.5 nM for the glucocorticoid receptor and a relative receptor affinity 1.5- and 3.0-times greater than that of beclomethasone-17-monopropionate (17-BMP) and budesonide, respectively. The rate of association with the receptor is faster and the rate of dissociation slower than with standard corticosteroids. As a result, the half-life of the corticosteroid-receptor complex is > 10 h. Fluticasone propionate is also highly selective for the glucocorticoid receptor, with little or no activity at other steroid receptors. Pretreatment with fluticasone propionate significantly inhibits the increase in mast cell numbers in the nasal mucosa of rats chronically exposed to toluene di-isocyanate (TDI), and suppresses TDI-induced mast cell degranulation. It is more potent in vitro than dexamethasone, BDP and budesonide in inhibiting anti-CD3-induced human T-lymphocyte proliferation, in attenuating tumour necrosis factor-alpha-induced endothelial cell adhesion molecule expression, and in increasing secretory leucocyte protease inhibitor levels in airway epithelial cells. It is also more potent and longer-acting than other corticosteroids in inhibiting oedema formation, interleukin-5 (IL-5)-induced blood eosinophilia, and IL-5- or platelet activating factor-stimulated eosinophil accumulation in the lung. Fluticasone propionate therefore has increased intrinsic glucocorticoid potency and high topical anti-inflammatory activity.

Topics: Administration, Topical; Androstadienes; Animals; Anti-Inflammatory Agents; Fluticasone; Glucocorticoids; Humans; Inflammation; Rats; Receptors, Glucocorticoid

Fluticasone furoate/vilanterol trifenatate (FF/VI) is an inhaled therapy for the treatment of asthma, with a prolonged duration of anti-inflammatory and bronchodilatory action. This study investigated the global metabolomic and lipidomic profile following treatment with FF/VI or placebo and assessed whether changes correlated with exhaled nitric oxide levels as a measure of airway inflammation.. This was a single-center, randomized, double-blind, placebo-controlled, two-period, crossover, repeat-dose study. Adults with asthma (forced expiratory volume in 1 s ≥ 60% predicted; fraction of exhaled nitric oxide [FeNO] > 40 parts per billion) received once-daily FF/VI 100 µg/25 µg or placebo for 14 days, followed by a 21-day washout period. Serum samples were taken at pre-dose (T1), and 15 and 21 days (T2 and T3, respectively) post dose in each period. The metabolomic and lipidomic profiles were analyzed by liquid chromatography with tandem mass spectrometry and polar liquid chromatography platforms, and ions were matched to a library of standards for metabolite identification and quantification. FeNO values at each timepoint were evaluated for correlations with the biochemical data.. Of 27 randomized participants (mean age 24.5 years, 63% male), 26 provided serum samples for metabolomic analysis. A total of 1969 metabolites were identified, 1634 of which corresponded to a named structure in a reference library. Treatment-related changes in the metabolome were generally subtle, with a modest increase in metabolite perturbations across timepoints. The percentage of metabolites with significant changes (p < 0.05 for all) (increases↑/decreases↓) versus placebo were: 2.1% (1.1%↑/1.0%↓), 6.7% (0.46%↑/6.2%↓) and 11.8% (0.86%↑/10.9%↓) at T1, T2 and T3, respectively. Treatment with FF/VI reduced FeNO levels by 60%, whereas the systemic intermediates involved in NO biosynthesis remained unaffected. Evidence of systemic anti-inflammatory activity was seen in complex lipid pathways, suggesting reduced phospholipase-A2 activity, but without downstream impact on free fatty acids or inflammatory mediators. Consistent with the pathogenesis of asthma, there was evidence of higher fatty acid β-oxidation and lower glycolysis in the placebo arm; this pattern was reversed in the treatment arm.. Despite the prolonged airway anti-inflammatory action of FF/VI, this was accompanied by only subtle systemic metabolomic and lipidomic changes. Trial registration Prospectively registered on ClinicalTrials.gov registry number NCT02712047.

Topics: Administration, Inhalation; Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Benzyl Alcohols; Chlorobenzenes; Fatty Acids, Nonesterified; Female; Fluticasone; Humans; Inflammation; Inflammation Mediators; Male; Nitric Oxide; Phospholipases; Young Adult

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; 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Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD.In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 µg twice daily), 30-month treatment with fluticasone/salmeterol (500/50 µg twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models.In patients using ICS during GL1 and using ICS 0-50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchi; Bronchodilator Agents; Female; Fluticasone; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Inflammation; Linear Models; Male; Middle Aged; Netherlands; Neutrophils; Pulmonary Disease, Chronic Obstructive; Sputum; Withholding Treatment

Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti-inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry.. Forty-two healthy controls and 20 patients with steroid-naïve asthma before and after treatment with fluticasone propionate (800 μg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) ).. Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/√BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01).. Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma.

Topics: Administration, Inhalation; Adult; Airway Remodeling; Asthma; Biomarkers; Cell Adhesion Molecules; Eosinophils; Female; Fluticasone; Glucocorticoids; Humans; Inflammation; Male; Middle Aged; Respiratory Function Tests; Sputum; Statistics as Topic; Tomography, X-Ray Computed; Treatment Outcome

Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response.. Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage.. Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3% reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0% reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers.. PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents; Azabicyclo Compounds; Benzamides; Bronchial Provocation Tests; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Methylurea Compounds; Middle Aged; Neutrophils; p38 Mitogen-Activated Protein Kinases; Pyridones; Sputum; Young Adult

While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.. 22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.. FP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.. 200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

Topics: Administration, Inhalation; Adolescent; Adult; Airway Remodeling; Androstadienes; Anti-Asthmatic Agents; Asthma; Basement Membrane; Breath Tests; Cytokines; Female; Fluticasone; Humans; Inflammation; Lung; Macrophages, Alveolar; Male; Mannitol; Nitric Oxide; Respiratory Function Tests; Young Adult

Two distinct, stable inflammatory phenotypes have been described in adults with asthma: eosinophilic and non-eosinophilic. Treatment strategies based on these phenotypes have been successful. This study evaluated sputum cytology in children with asthma to classify sputum inflammatory phenotypes and to assess their stability over time.. Sputum induction was performed in 51 children with severe asthma and 28 with mild to moderate asthma. Samples were classified as eosinophilic (>2.5% eosinophils), neutrophilic (>54% neutrophils); mixed granulocytic (>2.5% eosinophils, >54% neutrophils); or paucigranulocytic (≤2.5% eosinophils, ≤54% neutrophils). Sputum induction was repeated every 3 months in children with severe asthma (n=42) over a 1-year period and twice in mild to moderate asthma (n=17) over 3-6 months.. 62 children (78%) had raised levels of inflammatory cells in at least one sputum sample. In the longitudinal analysis 37 of 59 children (63%) demonstrated two or more phenotypes. Variability in sputum inflammatory phenotype was observed in both the severe and the mild to moderate asthma groups. Change in phenotype was not related to change in inhaled corticosteroid (ICS) dose or asthma control, nor was it reflected in a change in exhaled nitric oxide (FE(NO)). 24 children (41%) fulfilled the criteria for non-eosinophilic asthma on one occasion and eosinophilic on another. There were no differences in severity, asthma control, atopy, ICS dose or forced expiratory volume in 1 s between those who were always non-eosinophilic and those always eosinophilic.. Raised levels of inflammatory cells were frequently found in children with asthma of all severities. Sputum inflammatory phenotype was not stable in children with asthma.

Topics: Adolescent; Androstadienes; Asthma; Child; Dose-Response Relationship, Drug; Eosinophilia; Female; Fluticasone; Glucocorticoids; Humans; Inflammation; Longitudinal Studies; Male; Neutrophils; Phenotype; Severity of Illness Index; Sputum; Treatment Outcome

Small airways are an important site of inflammation and obstruction in asthma, which contributes to the severity of airway hyperresponsiveness (AHR) that is usually measured by nebulisation of large-particle stimuli. We investigated whether small and large particle sizes of aerosolised adenosine monophospate (AMP) provoke similar severity of AHR. Additionally, effects of the small-particle inhaled corticosteroid (ICS) ciclesonide and large-particle ICS fluticasone on AHR to large- and small-particle size AMP were assessed. After a 4-week run-in period using open-label fluticasone (100 μg b.i.d.), 37 mild-to-moderate asthmatics underwent provocations with standard-size (3.7 μm), large-particle (9.9 μm) and small-particle (1.06 μm) AMP. Subjects received 4-week ciclesonide (160 μg s.i.d.) or fluticasone (100 μg b.i.d.) treatment (double-blind and double-dummy) followed by large- and small-particle AMP provocation. Small-particle AMP induced a 20% decrease in forced expiratory volume in 1 s (FEV(1)) at a significantly higher dose than large-particle AMP. Ciclesonide and fluticasone had comparable effects on AMP provocations. Not all subjects reached the provocative concentration causing a 20% fall in FEV(1) (PC(20)) at the highest AMP dose. In those who did, ciclesonide improved small-particle AMP PC(20) by 1.74 doubling doses (DD) (p = 0.03), whereas fluticasone did not. Conversely, fluticasone improved large-particle AMP PC(20) significantly (1.32 DD; p = 0.03), whereas ciclesonide did not. Small-particle AMP provocation appears to be a promising tool to assess changes in small airway inflammation. Future adjustments are necessary taking into account the very small particle size used, with large exhaled fractions. In asthmatics reaching a PC(20) with small- and large-particle AMP provocations, ciclesonide improves hyperresponsiveness to small particle size AMP, and fluticasone to large particle size. This warrants further research to target provocations and treatment to specific airway sizes.

Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Androstadienes; Asthma; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Male; Nebulizers and Vaporizers; Nitric Oxide; Particle Size; Spirometry

Topics: Administration, Inhalation; Aged; Androstadienes; Biomarkers; Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Spirometry; Treatment Outcome

Patients with mild asthma may adapt to symptoms that may be neglected at a medical consultation. Despite active airway inflammation, indicating need for treatment symptoms may be poorly perceived and influence on quality of life. The aim was to find out if markers of asthma activity and quality of life are influenced by inhaled steroids in patients who regard themselves as free of symptoms.. Seventy steroid-free patients with mild asthma were treated with inhaled fluticasone (250 microg twice daily) or placebo for 3 months in a randomised, double-blind, study. Spirometry with reversibility test, exhaled nitric oxide (NO), bronchial responsiveness to methacholine and eucapnic dry air hyperventilation and quality of life [(Asthma Quality of Life Questionnaire (AQLQ)] were assessed before and after treatment.. Fluticasone, but not placebo, decreased methacholine responsiveness. Bronchial responsiveness to dry air and exhaled NO levels was significantly lowered by fluticasone compared with placebo. Quality-of-life scores were high already before treatment and were not significantly altered by treatment.. Treatment with an inhaled steroid in mild asthmatics altered bronchial responsiveness and exhaled NO levels but did not improve quality of life. In mild asthma, there is thus a space for improvement with regard to inflammatory parameters in patients who have only minor symptoms that are not influenced by treatment. In a long-term perspective, the indication for treatment of surrogate markers remains, however, unclear.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Androstadienes; Anti-Inflammatory Agents; Asthma; Biomarkers; Breath Tests; Bronchial Hyperreactivity; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Quality of Life; Severity of Illness Index; Spirometry

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Animals; Asthma; Eosinophils; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Neutrophils; Prospective Studies; Sputum; Treatment Outcome

Small airways inflammation in asthma has been supposed to contribute to instability of the disease and therapy resistance. This study was designed to determine the validity of measurement of N(epsilon)-(carboxymethyl)lysine (CML) levels in induced sputum and alveolar concentrations of nitric oxide (NO) for the assessment of small airways inflammation in asthma.. The authors measured CML levels in induced sputum and the bronchial flux (Jno) and alveolar concentration (C(alv)) of NO in 37 asthmatic patients and 15 normal controls. After initial analysis, all asthmatics were randomly assigned to receive inhaled fluticasone propionate (FP; 400 microg/day, n = 21) or hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP; 400 microg/day, n = 16) for 12 weeks. And then the determination of exhaled NO level and sputum induction was performed after the treatment period.. CML levels in induced sputum were significantly higher in asthmatics than in normal controls (median [interquartile range], asthmatics: 53.0 [44.8-64.3] microg/ml, normal controls: 22.0 [14.8-28.3] microg/ml; p < .01). Similarly, Jno and C(alv) were also higher in asthmatics. Moreover, CML level was closely correlated with C(alv) but not with Jno in asthmatics (r = .47, p = .005). Jno was significantly correlated with forced expiratory volume in one second/forced vital capacity (FEV(1)/FVC), and CML level and C(alv) were correlated with forced expiratory flow between 25% and 75% of FVC (FEF(25-75)), an index of small airways obstruction. After FP treatment, the decrease in CML level and Calv were very small. In contrast, these levels were markedly decreased after HFA-BDP treatment. Moreover, even after FP or HFA-BDP treatment, CML level was significantly correlated with C(alv).. This novel, noninvasive technique of measurement of CML levels in induced sputum and C(alv) may prove to be important not only in the evaluation of small airways inflammation but also in helping us move toward a better understanding of the roles of the small airways in the pathogenesis of asthma.

Topics: Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Biomarkers; Bronchi; Female; Fluticasone; Humans; Inflammation; Lysine; Male; Middle Aged; Nitric Oxide; Pulmonary Alveoli; Reproducibility of Results; Sputum

The anti-inflammatory effects of salmeterol/fluticasone (SFP), tiotropium/fluticasone (Tio+FP) and tiotropium (Tio) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients. Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study. Subjects (n = 99) were randomised (not double blinded) and received either SFP (100/1,000 microg daily), Tio+FP (18/1,000 microg daily) or Tio (18 microg daily) for 12 weeks. Induced sputum and serum C-reactive protein (CRP) were analysed prior to and at the end of treatment. The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum, compared with treatment with Tio alone. There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels. The reduction in IL-8 showed significant association with the reduction in MMP-9. All treatment groups failed to significantly reduce the numbers of total cells, neutrophils, macrophages and eosinophils in induced sputum; in addition, there were no treatment differences in terms of improvement of forced expiratory volume in one second, forced vital capacity, CRP or quality of life between the three groups. The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fluticasone; Humans; Inflammation; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Sputum; Tiotropium Bromide

T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous.. To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.. Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination.. Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation.. Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

Topics: Administration, Inhalation; Adult; Androstadienes; Asthma; Biomarkers; Bronchi; Bronchodilator Agents; Female; Fluticasone; Genetic Heterogeneity; Humans; Inflammation; Macrophages, Alveolar; Male; Mucins; Phenotype; Pulmonary Fibrosis; Respiratory Mucosa; Th2 Cells; Treatment Outcome

Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD).. To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.. Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847). 2 university medical centers in The Netherlands.. 114 steroid-naive current or former smokers with moderate to severe COPD.. Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.. Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).. 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level.. The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.. ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. .

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchi; Bronchodilator Agents; Cell Count; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Smoking; Sputum; Treatment Outcome

Ozone exposure induces airway neutrophilia and modifies innate immune monocytic cell-surface phenotypes in healthy individuals. High-dose inhaled corticosteroids can reduce O(3)-induced airway inflammation, but their effect on innate immune activation is unknown.. We used a human O(3) inhalation challenge model to examine the effectiveness of clinically relevant doses of inhaled corticosteroids on airway inflammation and markers of innate immune activation in healthy volunteers.. Seventeen O(3)-responsive subjects [>10% increase in the percentage of polymorphonuclear leukocytes (PMNs) in sputum, PMNs per milligram vs. baseline sputum] received placebo, or either a single therapeutic dose (0.5 mg) or a high dose (2 mg) of inhaled fluticasone proprionate (FP) 1 hr before a 3-hr O(3) challenge (0.25 ppm) on three separate occasions at least 2 weeks apart. Lung function, exhaled nitric oxide, sputum, and systemic biomarkers were assessed 1-5 hr after the O(3) challenge. To determine the effect of FP on cellular function, we assessed sputum cells from seven subjects by flow cytometry for cell-surface marker activation.. FP had no effect on O(3)-induced lung function decline. Compared with placebo, 0.5 mg and 2 mg FP reduced O(3)-induced sputum neutrophilia by 18% and 35%, respectively. A similar effect was observed on the airway-specific serum biomarker Clara cell protein 16 (CCP16). Furthermore, FP pretreatment significantly reduced O(3)-induced modification of CD11b, mCD14, CD64, CD16, HLA-DR, and CD86 on sputum monocytes in a dose-dependent manner.. This study confirmed and extended data demonstrating the protective effect of FP against O(3)-induced airway inflammation and immune cell activation.

Topics: Adult; Androstadienes; Anti-Inflammatory Agents; B7-2 Antigen; CD11b Antigen; Dose-Response Relationship, Drug; Double-Blind Method; Female; Flow Cytometry; Fluticasone; HLA-DR Antigens; Humans; Inflammation; Lung; Male; Neutrophils; Ozone; Receptors, IgG; Sputum

Extra-fine hydrofluoroalkane-beclomethasone differs from other inhaled corticosteroids by its fine aerosol characteristics. Therefore, extra-fine hydrofluoroalkane-beclomethasone may be particularly useful for treating peripheral airway inflammation in asthma.. To analyze the anti-inflammatory effects of extra-fine hydrofluoroalkane-beclomethasone vs fluticasone dry powder inhaler (DPI) in asthmatic children by measuring bronchial and alveolar nitric oxide (NO) and inflammatory markers in exhaled breath condensate (EBC).. In a 6-month crossover study, 33 children aged 6 to 12 years with moderate persistent asthma were randomly treated with extra-fine hydrofluoroalkane-beclomethasone (200 microg daily via an Autohaler) and fluticasone DPI (200 microg daily via a Diskus). The primary outcome variables were alveolar NO concentration and bronchial NO flux. The secondary outcome variables were levels of inflammatory markers in EBC, lung function indices, symptoms, exacerbations, and adverse effects. All the variables were recorded at baseline and after each treatment period.. Mean +/- SE alveolar NO concentration and bronchial NO flux were comparable after treatment with hydrofluoroalkane-beclomethasone vs fluticasone DPI (4.7 +/- 0.5 vs 4.3 +/- 0.5 ppb, P = .55, and 1,124.3 +/- 253.6 vs 1,029.1 +/- 195.5 pL/s, P = .70, respectively). In addition, levels of inflammatory markers in EBC, lung function indices, and symptoms did not differ between treatments. Patients used fewer beta2-agonists during the last 2 weeks of hydrofluoroalkane-beclomethasone treatment.. The anti-inflammatory effects of hydrofluoroalkane-beclomethasone are similar to those of fluticasone DPI in children with moderate persistent asthma.

Topics: Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Biomarkers; Breath Tests; Child; Cross-Over Studies; Dinoprost; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocarbons, Fluorinated; Hydrogen Peroxide; Inflammation; Interleukins; Male; Nitrates; Nitric Oxide; Nitrites; Prospective Studies; Treatment Outcome; Vital Capacity

A subset of patients with chronic obstructive pulmonary disease (COPD) may respond more favorably to inhaled corticosteroids (ICS), but no simple method is currently utilized to predict the presence or absence of ICS responses in patients with COPD.We evaluated the ability of exhaled nitric oxide (FENO) and serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], and interleukin-8 [IL-8]) to independently predict spirometric responses to ICS in patients with COPD.. Among 60 ex-smokers with severe COPD (mean FEV1 1.07 L, 36% of predicted), we conducted a single-arm, open-label study. Participants spent four weeks free of any ICS, followed by four weeks of ICS use (fluticasone propionate 500 mcg twice daily). FENO, CRP, IL-6, IL-8, and pre-bronchodilator spirometry were measured immediately before and after the four weeks of ICS use.. Baseline FENO, CRP, IL-6, and IL-8 showed no correlations to FEV1 responses to ICS. ICS responders (increase in FEV1 > or = 200 mL after four weeks of ICS) did have significantly higher baseline FENO levels compared with non-responders (46.5 parts per billion [ppb] vs. 25 ppb, p = 0.028). The receiver operating characteristic curve for FENO to discriminate responders from non-responders had an area under curve of 0.72. Baseline serum inflammatory markers did not differ between responders and non-responders.. In ex-smokers with severe COPD, a measure of local pulmonary inflammation, FENO, may be more closely associated with FEV1 responses to four weeks of ICS than are standard markers of systemic inflammation, serum CRP, IL-6, and IL-8.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Biomarkers; Bronchodilator Agents; C-Reactive Protein; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Nitric Oxide; Prospective Studies; Pulmonary Disease, Chronic Obstructive; ROC Curve; Salmeterol Xinafoate; Severity of Illness Index; Spirometry

Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer and cardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduce exacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown. The Advair Biomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting beta2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease.. After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily), followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting beta2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500 micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), or placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada. Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predicted or less. Patients will be excluded if they have any known chronic systemic infections, inflammatory conditions, history of previous solid organ transplantation, myocardial infarction, or cerebrovascular accident within the past 3 months prior to study enrollment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function.. If inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Adult; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

This study was performed to determine the clinical characteristics of asthmatics with bronchial hyperresponsiveness (BHR) that could not be normalized by 6 months of treatment with a moderate dose of an inhaled corticosteroid (ICS).. Thirty-four symptomatic patients with mild to moderate asthma, who had never received any ICS, were treated with 200 mug of inhaled fluticasone propionate twice a day for 6 months. Spirometry, BHR to methacholine, exhaled nitric oxide (NO) and eosinophils in induced sputum were examined before and 2 and 6 months after beginning treatment.. FEV1 was increased and bronchial responsiveness, exhaled NO and sputum eosinophilia were significantly decreased 2 and 6 months after starting ICS treatment. Bronchial responsiveness was further decreased at 6 months together with a further increase in FEV1. In 13 patients, BHR was not normalized despite the 6 months of treatment. This group showed a higher prevalence of males, those with a smoking history and airflow limitation, a higher eosinophil count in the sputum following 6 months of treatment and a longer history of asthma. Multiple, stepwise, linear regression analysis showed that sputum eosinophilia and lower FEV1/FVC following 6 months of treatment and a longer history of asthma were significant independent determinants for BHR after 6 months of ICS treatment.. These findings suggest that the resistance to a moderate dose of ICS for BHR in asthmatics may be significantly associated with remained airflow limitation, eosinophilic airway inflammation resistive to moderate dose of ICS, and delayed introduction of ICS therapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Male; Methacholine Chloride; Middle Aged; Nitric Oxide; Respiratory Function Tests

We previously showed that H1-antihistamines may shift the PC20 (provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%) threshold to adenosine monophosphate (AMP) challenge but may paradoxically prolong recovery.. To measure AMP recovery using a constant predetermined AMP PC20 and to evaluate whether fexofenadine use confers add-on effects to treatment with either fluticasone propionate alone or combined fluticasone propionate-salmeterol.. Fourteen atopic patients with mild-to-moderate asthma (forced expiratory volume in 1 second of 76%) completed a double-blind, randomized, crossover study consisting of 3-week treatment blocks of either fluticasone propionate-salmeterol, 250 microg twice daily, or fluticasone propionate alone, 250 microg twice daily, in conjunction with either fexofenadine, 180 mg once daily, or matched placebo. Recovery after a predetermined AMP PC20 challenge was measured (primary outcome), along with exhaled nitric oxide levels, plasma eosinophil cationic protein levels, peripheral eosinophil counts, pulmonary function, diary card outcomes, and quality of life (all secondary outcomes).. There were no differences in any of the primary or secondary outcomes when fexofenadine was added to treatment with either fluticasone propionate-salmeterol or fluticasone propionate alone. The mean AMP recovery time was 25.0 vs 23.4 minutes for fexofenadine and placebo, respectively, as add-on to fluticasone-salmeterol and 22.5 vs 23.9 minutes, respectively, as add-on to fluticasone alone.. Fexofenadine did not affect recovery to a fixed dose of AMP challenge or any other surrogate inflammatory markers when given as add-on therapy to corticosteroid-treatedatopic asthmatic patients.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Albuterol; Androstadienes; Anti-Allergic Agents; Asthma; Biomarkers; Bronchial Provocation Tests; Drug Therapy, Combination; Eosinophil Cationic Protein; Eosinophils; Female; Fluticasone; Humans; Hypersensitivity, Immediate; Inflammation; Male; Nitric Oxide; Respiratory Function Tests; Salmeterol Xinafoate; Terfenadine; Treatment Outcome

The tulobuterol transdermal therapeutic system (TTS) is the world's first commercially available transdermal preparation of tulobuterol, a beta-2 stimulant, that can maintain effective blood tulobuterol levels for 24 hours when applied once daily. In the present study, a total of 36 adult patients with mildly persistent (Step 2) or moderately persistent (Step 3) bronchial asthma 19 who were using inhalational steroids and 17 who were not used tulobuterol TTS for one year and underwent measurement of peak expiratory flow (PEF) once daily. Peripheral eosinophil count, serum eosinophil cationic protein (ECP) level and airway responsiveness (Dmin) were evaluated at 6 months and 1 year after the start of the study. PEF exhibited significant improvements at 6 months and 1 year in patients treated with or without inhalational steroids, while serum ECP was improved significantly only in the patients on inhalational steroids. Patients not using inhalational steroids exhibited no significant exacerbation of Dmin at either 6 months or 1 year: One-year treatment with tulobuterol TTS did not appear to cause tachyphylaxis. The significant improvements in Dmin at 6 months and 1 year in the patients using inhalational steroids suggested that inhalational steroids offer beneficial effects in controlling airway inflammation. Tulobuterol TTS is considered quite beneficial in improving quality of life (QOL) in patients with bronchial asthma because its incidence of adverse effects including palpitations and shivering is significantly lower than those of oral preparations, because of its remarkable improvement of pulmonary function and symptoms of airway obstruction without increasing airway responsiveness even after repeated use, and because it is simple to use and offers excellent clinical efficacy.

Topics: Administration, Cutaneous; Administration, Inhalation; Adrenergic beta-Agonists; Aged; Androstadienes; Asthma; Beclomethasone; Bronchial Hyperreactivity; Delayed-Action Preparations; Drug Therapy, Combination; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Peak Expiratory Flow Rate; Quality of Life; Severity of Illness Index; Terbutaline; Time Factors; Treatment Outcome

Systemic inflammation is present in chronic obstructive pulmonary disease (COPD), which has been linked to cardiovascular morbidity and mortality. We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD. We recruited 41 patients with mild to moderate COPD. After 4 weeks during which inhaled corticosteroids were discontinued, patients were assigned to fluticasone (500 mcg twice a day), oral prednisone (30 mg/day), or placebo over 2 weeks, followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day. Withdrawal of inhaled corticosteroids increased baseline C-reactive protein (CRP) levels by 71% (95% confidence interval [CI], 16-152%). Two weeks with inhaled fluticasone reduced CRP levels by 50% (95% CI, 9-73%); prednisone reduced it by 63% (95% CI, 29-81%). No significant changes were observed with the placebo. An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline (a 29% reduction; 95% CI, 7-46%). Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD.

Topics: Administration, Inhalation; Administration, Oral; Aged; Aged, 80 and over; Androstadienes; Anti-Inflammatory Agents; Biomarkers; C-Reactive Protein; Chemokine CCL2; Double-Blind Method; Drug Administration Schedule; Female; Fluticasone; Follow-Up Studies; Forced Expiratory Volume; Humans; Inflammation; Interleukin-6; Linear Models; Male; Middle Aged; Prednisone; Pulmonary Disease, Chronic Obstructive; Treatment Outcome

We conducted a randomized, double-blind, parallel-group study to assess the effect of 6 weeks treatment with low-dose (100 microg twice a day) or high-dose (500 microg twice a day) inhaled fluticasone propionate (FP) on the vascular component of airway remodeling in 30 patients with mild to moderate asthma. We also studied the effect on the inflammatory cells and the basement membrane thickness, and we compared findings from bronchial biopsies taken in patients with asthma with those in eight control subjects. Bronchial responsiveness to methacholine and asthma symptom score were measured before and after treatments. Eight patients in the low-dose FP group and eight patients in high-dose FP group completed the study. At baseline, patients with asthma showed an increase in the number of vessels and in vascular area as compared with control subjects. In the subjects with asthma, number of vessels correlated with vascular area (p < 0.01) and with number of mast cells (p < 0.01). Bronchial responsiveness to methacholine, asthma symptom score, and inflammatory cells decreased significantly after both low- and high-dose FP (p < 0.05). However, the number of vessels, the vascular area, and the basement membrane thickness decreased only after high-dose FP (p < 0.05). In conclusion, this study shows that in patients with mild to moderate asthma, high dose of inhaled FP given over 6 weeks can significantly affect airway remodeling by reducing both submucosal vascularity and basement membrane thickness.

Topics: Administration, Inhalation; Administration, Topical; Adolescent; Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Basement Membrane; Biopsy; Bronchi; Bronchoconstrictor Agents; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Glucocorticoids; Humans; Inflammation; Male; Methacholine Chloride; Time Factors

The aim of the study was to investigate the effect of addition of montelukast to inhaled fluticasone propionate (FP) therapy, compared with FP therapy alone (100 microg twice a day) on airway immunopathology in individuals with mild asthma. Twenty-eight subjects received FP (100 microg twice a day) or FP (100 microg twice a day) plus montelukast (10 mg at night) for 8 weeks and were then crossed over to the alternate treatment for a further 8 weeks. Physiological measurements and bronchial biopsies were obtained at +/- 2 days before treatment and +/- 2 days at the end of each treatment period. A two-period crossover analysis was performed and the mean and SE were calculated. There was no significant difference in percent predicted FEV1 (p = 0.51) or PC20 mg/ml (p = 0.81) between the two treatment regimes after 8 weeks of therapy. There was no difference in the efficacy of either treatment in decreasing T cell (p = 0.97), CD45RO+ (p = 0.37), mast cell (p = 0.37), or activated eosinophils (p = 0.55) numbers in bronchial biopsies. There was no significant difference in the percentage area stained for IFN-gamma (p = 0.76) or interleukin-4 (p = 0.61) between treatments. Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP plus montelukast was not significantly different from the reduction observed with FP alone in individuals with mild asthma.

Topics: Acetates; Administration, Inhalation; Administration, Topical; Adult; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biopsy; Bronchi; Bronchodilator Agents; Cross-Over Studies; Cyclopropanes; Data Interpretation, Statistical; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Immunohistochemistry; Inflammation; Interferon-gamma; Interleukin-4; Leukotriene Antagonists; Male; Middle Aged; Placebos; Quinolines; Sulfides; Time Factors

The clinical benefit of combining long-acting beta(2)-agonists with inhaled corticosteroids rather than doubling the dose of corticosteroid has been well-documented. However, there are concerns that this might result in a masking of underlying airway inflammation.. The aim of this study was to test the hypothesis that the addition of the long-acting beta(2)-agonist salmeterol (SALM) to a low dose of the inhaled corticosteroid fluticasone propionate (FP) has a steroid-sparing effect and does not result in a worsening of bronchial inflammation compared to doubling the dose of inhaled corticosteroid.. Fifty-six asthmatic subjects, previously not well-controlled on inhaled corticosteroids, were randomized to receive 3 months of treatment with inhaled FP 500 microg twice a day (FP 1000) or FP 200 microg twice a day plus SALM 50 microg twice a day (FP 400 + SALM). Fluticasone propionate 200 microg twice a day served as the control (FP400). Bronchial mucosal biopsy specimens, bronchial washings (BW), and bronchoalveolar lavage were obtained before and after treatment. The primary end points for the study were submucosal mast cell and eosinophil counts.. There was a significant improvement in FEV(1) in the FP400 + SALM group compared to both the FP400 and FP1000 groups. This was accompanied by a significant improvement in peak expiratory flow in the FP400 + SALM group in both the morning and evening compared to the FP1000 group. There were no significant between treatment differences in the change in the number of submucosal mast cells or eosinophils. However, in the FP400 + SALM group there was a significant decrease in submucosal mast cells after 12 weeks of treatment. The addition of SALM to FP was not associated with any increases in airway inflammation in the biopsy specimens, bronchoalveolar lavage, or bronchial washings.. These findings confirm that addition of SALM to FP has clinical benefits but does not mask or exacerbate airway inflammation and suggest that long-acting beta(2)-adrenoceptor agonists might influence mast cell numbers.

Topics: Administration, Inhalation; Adult; Albuterol; Androstadienes; Asthma; Biopsy; Bronchi; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Lung; Male; Middle Aged; Salmeterol Xinafoate

Topics: Albuterol; Androstadienes; Asthma; Cross-Over Studies; Drug Therapy, Combination; Fluticasone; Humans; Inflammation; Lung; Muscle, Smooth; Salmeterol Xinafoate

Although corticosteroid therapy for asthma improves lung function and reduces airway inflammation, the relation between these two events is unclear. This article investigates associations between changes in bronchial inflammation and lung function during high-dose inhaled corticosteroid therapy for asthma.. Nine subjects with atopic asthma received high-dose inhaled fluticasone propionate (FP), 2,000 microg/d for 8 weeks. Fiberoptic bronchoscopy with endobronchial biopsies, spirometry, and histamine provocation challenge were performed on each subject at baseline, after 2 weeks, and again after 8 weeks of therapy. Spearman rank correlation coefficients between changes in parameters of bronchial inflammation and lung function were computed.. As expected, significant down-regulation of airway inflammation and improvements in lung function were observed after both short-term and long-term therapy with high-dose inhaled FP. During corticosteroid therapy, changes in lymphocyte and macrophage numbers in bronchial biopsy specimens were closely correlated. Changes in EG1+ eosinophils were associated with changes in EG2+ eosinophils after 8 weeks of therapy. Although changes in airway inflammation and changes in lung function were not closely associated after 2 weeks of therapy, changes in eosinophils (EG1) in bronchial biopsy specimens correlated with changes in bronchodilator response (r = 0.77, p = 0.016) after 8 weeks of therapy.. In patients with atopic asthma, changes in bronchial eosinophils and lung function during steroid therapy are closely related but do not occur simultaneously.

Topics: Administration, Inhalation; Administration, Topical; Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Biopsy; Bronchi; Bronchial Provocation Tests; Bronchodilator Agents; Bronchoscopy; Cell Count; Double-Blind Method; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Histamine; Humans; Hypersensitivity, Immediate; Inflammation; Lymphocytes; Macrophages; Male; Middle Aged; Skin Tests; Spirometry

It has been suggested in cross-sectional studies that provocation with adenosine 5'-monophosphate (AMP) more closely reflects the inflammatory process in asthma than does provocation with methacholine or histamine. We investigated whether the steroid-induced improvement in the provocative concentration of AMP producing a 20% decline in FEV1 (PC20 AMP) is more closely associated with the concomitant reduction in airway inflammation than is the improvement in PC20 methacholine. In 120 asthmatic patients, we measured PC20 methacholine and PC20 AMP as well as sputum induction and nitric oxide (NO) in exhaled air before and after 2 weeks of treatment with corticosteroids. Improvement in PC20 AMP was solely related to reduction in airway inflammation (i.e., change in the number of sputum eosinophils, lymphocytes, epithelial cells, and concentration of NO in exhaled air). In contrast, improvement in PC20 methacholine was related to both reduction in airway inflammation (i.e., change in the number of sputum eosinophils and lymphocytes) and increase in FEV1 %predicted. The total explained variance of the improvement in bronchial hyperresponsiveness was greater for AMP than for methacholine (36% versus 22%, respectively). We conclude that PC20 AMP is more sensitive to changes in acute airway inflammation than is PC20 methacholine, further reinforcing the notion that PC20 AMP can be a useful tool for monitoring the effects of antiinflammatory therapy.

Topics: Adenosine Monophosphate; Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Male; Methacholine Chloride; Multivariate Analysis; Prednisone

Although both inhaled and oral corticosteroids have anti-inflammatory effects causing improvement in clinical symptoms and spirometry in the treatment of asthma, the role of corticosteroids in the management of chronic obstructive pulmonary disease (COPD) is controversial.. To evaluate the effects of inhaled corticosteroids on sputum neutrophilia in clinically stable COPD patients.. In total, 18 patients were enrolled in the study. During 2 months, 9 patients in group A inhaled fluticasone propionate (FP) 500 microg 3 times daily. In group B 9 patients received placebo. All of the patients continued to inhale both salbutamol and ipratropium bromide. In 9 patients, sustained-released theophylline was also administered. Blood samples, spirometric tests, blood gas analyses, and either spontaneous or induced sputum cultures were evaluated on entry into the study, after a 2 months of treatment and following the 6-week washout period.. After the 2-month FP treatment, no significant changes in the number of peripheral blood neutrophils, blood gas and spirometry data were observed in both groups. In group A, the total cell number and the number of neutrophils decreased from a mean of 3. 4 +/- 1.3 x 10(6) cells/g and 0.6 +/- 0.3 x 10(6) neutrophils/g on entry into study to 1.9 +/- 0.6 x 10(6) cells/g and 0.02 +/- 0.01 x 10(6) neutrophils/g after 8-week treatment with FP, returning to 3.3 +/- 1.1 x 10(6) cells/g and 0.5 +/- 0.3 x 10(6) neutrophils/g following the washout period. The percentages of neutrophils were 55. 6 and 77.9% in groups A and B after 2 months of FP treatment. There was no significant change in group B values during the study.. These data suggest that neutrophilic inflammation in sputum may be decreased by inhaled corticosteroids in clinically stable COPD patients.

Topics: Administration, Inhalation; Aged; Androstadienes; Anti-Inflammatory Agents; Blood Gas Analysis; Female; Fluticasone; Humans; Inflammation; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Spirometry; Sputum

The addition of long-acting beta(2) agonists to inhaled corticosteroid (ICS) therapy in symptomatic patients with asthma improves clinical status more than increasing the dose of ICS. It has been suggested that these benefits could be at the cost of an increase in airway inflammation, but few histopathological studies have been performed in the relevant group. In a double-blind, parallel-group, placebo-controlled study, we randomly assigned 50 symptomatic patients with asthma who were receiving ICS (range, 100 -500 microgram/d) to 12 wk of supplementary treatment with salmeterol (50 microgram twice daily) or fluticasone (100 microgram twice daily) or placebo. Bronchial biopsies and BAL were obtained from 45 patients before and after treatment and analyzed. After treatment with salmeterol there was no deterioration of airway inflammation as assessed by mast cells, lymphocytes, or macrophages in BAL or biopsies, but rather a significant fall in EG1-positive eosinophils in the lamina propria (from a median 18.3 to 7.6 cells/mm, p = 0.01), which was not seen after treatment with fluticasone. The only cellular effect of added fluticasone was a decrease in BAL lymphocyte activation. There was a concurrent improvement in clinical status, more marked with salmeterol than with increased ICS. Thus, adding salmeterol to ICS is not associated with increased "allergic" airway inflammation, but conversely with a complementary antieosinophil effect.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biopsy, Needle; Bronchi; Bronchoalveolar Lavage Fluid; Double-Blind Method; Eosinophils; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Lymphocytes; Macrophages; Mast Cells; Peak Expiratory Flow Rate; Salmeterol Xinafoate

Inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease (COPD), despite lack of proven efficacy. Because COPD involves airway inflammation and probable protease-antiprotease imbalance, we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms. Thirteen patients with COPD were treated with fluticasone propionate (500 microg twice a day) for 4 wk, delivered via MDI and spacer, in a double-blind crossover study. There was no clinical benefit in terms of lung function or symptom scores, and induced sputum inflammatory cells, percentage neutrophils, and IL-8 levels were unchanged. Sputum supernatant elastase activity, matrix metalloproteinase (MMP)-1, MMP-9, and the antiproteases secretory leukoprotease inhibitor (SLPI) and tissue inhibitor of metalloproteinase (TIMP)-1 were similarly unaffected by treatment. These results add to previous evidence that inhaled steroids have no anti-inflammatory action in stable COPD. Furthermore, inhaled steroids do not appear to redress the protease-antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction.

Topics: Administration, Inhalation; Administration, Topical; Adult; Aerosols; Aged; Androstadienes; Anti-Inflammatory Agents; Cross-Over Studies; Cytokines; Double-Blind Method; Endopeptidases; Female; Fluticasone; Glucocorticoids; Humans; Inflammation; Interleukin-8; Lung Diseases, Obstructive; Male; Matrix Metalloproteinases; Middle Aged; Pancreatic Elastase; Proteinase Inhibitory Proteins, Secretory; Proteins; Secretory Leukocyte Peptidase Inhibitor; Serine Proteinase Inhibitors; Sputum; Tissue Inhibitor of Metalloproteinase-1

Although corticosteroid therapy might be clinically beneficial for bronchiectasis, very little is known of its effects on the inflammatory and infective markers in bronchiectasis. We have therefore performed a double-blind, placebo-controlled study to evaluate the effects of a 4-wk administration of inhaled fluticasone in bronchiectasis. Twenty-four patients (12 female; mean age 51 yr) were randomized into receiving either inhaled fluticasone (500 microgram twice daily) via the Accuhaler device (n = 12) or placebo. At each visit, spirometry, 24-h sputum volume, sputum leukocyte density, bacterial densities, and concentrations of interleukin (IL)-1beta, IL-8, tumor necrosis factor-alpha (TNF-alpha), and leukotriene B4 (LTB4) were determined. There was a significant (p < 0.05) decrease in sputum leukocyte density and IL-1beta, IL-8, and LTB4 after fluticasone treatment. The fluticasone group had one and the placebo group three episodes of exacerbation. There were no significant changes in spirometry (p > 0.05) or any reported adverse reactions in either group. The results of this study show that high-dose fluticasone is effective in reducing the sputum inflammatory indices in bronchiectasis. Large-scale and long-term studies are indicated to evaluate the effects of inhaled steroid therapy on the inflammatory components in bronchiectasis.

Topics: Administration, Inhalation; Administration, Topical; Adult; Androstadienes; Anti-Inflammatory Agents; Bronchiectasis; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Interleukin-1; Interleukin-8; Leukocyte Count; Leukotriene B4; Male; Middle Aged; Nebulizers and Vaporizers; Peak Expiratory Flow Rate; Placebos; Pseudomonas aeruginosa; Sputum; Tumor Necrosis Factor-alpha; Vital Capacity

Controlling lung inflammation may be the key to improving morbidity and mortality in cystic fibrosis.. To assess the effects of inhaled corticosteroids on lung inflammation in cystic fibrosis.. Double blind placebo controlled randomised sequence crossover trial. Fluticasone propionate (400 micrograms/day) was given as a dry powder inhaler for six weeks with a four week washout period before crossover.. Sputum inflammatory markers (interleukin-8, tumour necrosis factor-alpha (TNF-alpha) and neutrophil elastase-both free and bound to alpha 1-antiprotease), sputum interleukin-10, lung function, and symptomatology.. Twenty three children from a regional cystic fibrosis centre were enrolled into the study, with mean age 10.3 years (range 7 to 17 years) and mean baseline forced expiratory volume in one second (FEV1) of 64% (range 21% to 102%) predicted for sex and height. One patient was excluded for non-compliance to the study protocol.. No significant benefit was shown for the use of fluticasone propionate in any of the outcomes. For sputum interleukin-8 there was an estimated true treatment median difference of 142 pg/ml (95% confidence interval (CI) 8 to 2866 pg/ml) in favour of placebo; while for maximal expiratory flow at 25% (MEF25%) remaining forced vital capacity predicted for sex and height there was a 15 percentage points (pp) (95% CI 4 to 26 pp) mean treatment difference in favour of placebo. Sputum interleukin-10 was undetected in any samples and unaffected by fluticasone propionate. Neither atopic status, baseline FEV1, nor concomitant DNase therapy had any effect on response to treatment.. Lack of benefit from fluticasone propionate was most likely due to failure of the drug to penetrate the viscid mucus lining the airways. It is suggested a large multicentre trial with higher doses given for a longer time by a different delivery system is required to assess efficacy.

Topics: Administration, Inhalation; Adolescent; Androstadienes; Anti-Inflammatory Agents; Biomarkers; Child; Cross-Over Studies; Cystic Fibrosis; Double-Blind Method; Female; Fluticasone; Humans; Inflammation; Interleukin-10; Interleukin-8; Leukocyte Elastase; Lung; Male; Neutrophils; Sputum; Treatment Outcome; Tumor Necrosis Factor-alpha

Mast cell degranulation, and the subsequent recruitment of infiltrating inflammatory cells, such as eosinophils, into the nasal mucosa has long been considered the most important model to explain allergic rhinitis. Several studies show a decrease in the number of eosinophils and possibly also mast cells during local corticosteroid treatment. Over the last decade, a new model to explain allergic inflammation has evolved. In this model, Langerhans' cells and T-cells play an important role. Langerhans' cells possess a high affinity receptor for IgE. In patients with allergic rhinitis, allergen provocation results in stimulation of T-cells by the IgE-positive Langerhans' cells. The T-cells produce a number of cytokines which stimulate IgE production as well as the inflammatory reaction. The number of T-cells is not usually influenced by corticosteroid treatment; however, the function of the T-cells, shown by the spectrum of cytokines produced, is clearly influenced. The cells that are most dramatically affected by local corticosteroid treatment are the Langerhans' cells, which completely disappear during treatment. This decrease suggests that there is a reduction in antigen presentation. The subsequent decrease in T-cell stimulation may result in a reduction of the reactions that are dependent on T-cell-derived mediators.

Topics: Administration, Topical; Aerosols; Androstadienes; Anti-Inflammatory Agents; Antigen-Presenting Cells; Double-Blind Method; Eosinophils; Fluticasone; Glucocorticoids; Humans; Inflammation; Mast Cells; Nasal Mucosa; Rhinitis, Allergic, Perennial; T-Lymphocytes

MP-AzeFlu (intranasal fluticasone and azelastine) has been widely studied and has demonstrated efficacy in Allergic rhinitis with a superior effect compared to these drugs administered individually; however, the mechanism by which MP-AzeFlu produces this improved clinical effect has not yet been fully explained. In this study, we investigated the effect of MP-AzeFlu and fluticasone propionate (FP) on arachidonic acid metabolism as measured by changes in regulation of cyclooxygenase (COX) isoforms, prostaglandin (PG) D

Topics: Cyclooxygenase 2; Dinoprostone; Fluticasone; Humans; Inflammation; Mucous Membrane; RNA, Messenger

Asthma is a heterogeneous disease in which the complexity of the breathing pattern reduces as the severity of the disease increases. Since the pathophysiological basis of reduced breathing pattern complexity in asthma is unclear, in this study, we investigated the effect of reducing inflammation using an inhaled corticosteroid (fluticasone propionate) on the breathing pattern of a rat model of asthma. Detrended fluctuation analysis, sample entropy, and cross-sample entropy analysis of both inter-breath interval and respiratory volume time series showed that early treatment with inhaled corticosteroids not only diminishes lung inflammation and airway hyper-responsiveness, but also has a protective effect against the reduction of breathing pattern complexity due to asthma. However, late treatment had a partial effect on asthma-induced respiratory pattern changes. Since inflammation is a key factor in shifting breathing dynamics away from normal fluctuations, these findings further emphasize the importance of early treatment of asthma with corticosteroids.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Animals; Asthma; Fluticasone; Inflammation; Pneumonia; Rats; Respiration

The objectives of this study were to quantify lymphocytes and eosinophils in the mucosa of the duodenum and rectum in asthmatic horses.. 8 healthy and 10 asthmatic horses.. Asthmatic horses were evaluated in a symptomatic (after 6 weeks of exposure to moldy hay) and asymptomatic status (3 and 7 months after being fed alfalfa pellets [n = 4] or treated with inhaled fluticasone [6]). Duodenal and rectal biopsies were endoscopically (n = 4 to 6) taken in each horse. Eosinophils were counted on slides stained with hematoxylin, eosin, phloxine, and saffron, and immunohistochemistry was used to evaluate T and B lymphocytes using CD3 and CD20, respectively.. The duodenal and rectal epithelium of asthmatic and control horses contained exclusively T lymphocytes (CD3). Symptomatic asthmatic horses, compared to controls, had a significantly higher number of T lymphocytes (CD3) in the duodenal epithelium (P = .016) and the adjacent lamina propria of the villi (P = .04). Compared to symptomatic asthmatic horses, the fluticasone-treated group had significantly fewer T lymphocytes in the total lamina propria of the rectal mucosa (P < .01).. Taken together, these results suggest that asthmatic horses have greater infiltration of T lymphocytes in the duodenal and rectal mucosa, indicating a certain degree of inflammation, which could be due to a systemic inflammatory effect and/or a local effect of ingested hay allergens in asthmatic horses. Systemic markers of inflammation have not been investigated to better qualify if the infiltration noted is due to a local and/or systemic effect.

Topics: Animals; Asthma; Duodenum; Fluticasone; Horse Diseases; Horses; Inflammation; Intestinal Mucosa; Lymphocytes; Rectum; T-Lymphocytes

Asthma and inflammatory airway diseases restrict airflow in the lung, compromising gas exchange and lung function. Inhaled corticosteroids (ICSs) can reduce inflammation, control symptoms, and improve lung function; however, a growing number of patients with severe asthma do not benefit from ICS. Using bronchial airway epithelial brushings from patients with severe asthma or primary human cells, we delineated a corticosteroid-driven fibroblast growth factor (FGF)-dependent inflammatory axis, with FGF-responsive fibroblasts promoting downstream granulocyte colony-stimulating factor (G-CSF) production, hyaluronan secretion, and neutrophilic inflammation. Allergen challenge studies in mice demonstrate that the ICS, fluticasone propionate, inhibited type 2-driven eosinophilia but induced a concomitant increase in FGFs, G-CSF, hyaluronan, and neutrophil infiltration. We developed a model of steroid-induced neutrophilic inflammation mediated, in part, by induction of an FGF-dependent epithelial-mesenchymal axis, which may explain why some individuals do not benefit from ICS. In further proof-of-concept experiments, we found that combination therapy with pan-FGF receptor inhibitors and corticosteroids prevented both eosinophilic and steroid-induced neutrophilic inflammation. Together, these results establish FGFs as therapeutic targets for severe asthma patients who do not benefit from ICS.

Topics: Adrenal Cortex Hormones; Animals; Asthma; Fibroblast Growth Factors; Fluticasone; Granulocyte Colony-Stimulating Factor; Humans; Hyaluronic Acid; Inflammation; Mice

Ovarian chronic inflammation has been created and extended in the laying hen mainly via increasing laying frequency and microbial infection, especially during the late stage of production period. This study was aimed to evaluate glucocorticoid (GC) Fluticasone as an anti-inflammatory agent on the gene expression of the ovarian pro-and anti-inflammatory mediators (follicular cyclooxygenases COX 1, 2, and cytokines), inflammatory responses of the immune system, ovarian functions (ovulation rate and follicular growths), and hormones in the commercial-aged laying hens. White Leghorn hens aged 92-weeks were used for four weeks to be supplemented by 2 ppm Fluticasone as an optimum dose obtained in a pre-trial base on ovulation rate. As compared to control, Fluticasone resulted in a significant decrease in the mRNA expression of COX-1 and pro-and anti-inflammatory cytokines, and increase in COX-2 mRNA expression and heterophil to lymphocyte ratio (P < 0.001). A significant reduction was observed in the ovulation rate, follicular size (P < 0.001), ovarian hormones, immunoglobulins, body weight, and food consummation (P ≤ 0.05) by administering GC Fluticasone. Although a relative anti-inflammatory improvement was created by Fluticasone in the ovarian condition, the administration of this glucocorticoid resulted in a considerable reduction in ovarian hormones and functions of commercial aged laying hens.

Topics: Animals; Anti-Inflammatory Agents; Chickens; Female; Fluticasone; Hormones; Immune System; Inflammation; Ovary; Ovulation

Allergic asthma, typically controlled with inhaled corticosteroids (ICS), is the leading chronic health condition for youth under 18 years of age. During this peri-adolescent period, significant brain maturation occurs. Prior studies indicate that both chronic inflammation and corticosteroid medications increase risk for developing an internalizing disorder like anxiety.. To determine if chronic ICS treatments exacerbate or alleviate anxiety symptoms associated with developmental allergic asthma, we used a mouse model to isolate the influence of ICS (fluticasone propionate, FLU) vs. airway inflammation (induced with house dust mite extract, HDM).. During development, male and female BALB/cJ mice were repeatedly exposed to HDM or saline plus one of four FLU doses (none/vehicle, low, moderate, or high). In adulthood, we assessed lung inflammation, circulating and excreted corticosteroids, anxiety-like behavior, and gene expression in stress and emotion regulation brain regions.. FLU treatment decreased body weight and anxiety-like behavior and increased fecal corticosterone metabolite concentrations and Crhr2 gene expression in ventral hippocampus. FLU effects were only observed in saline/non-HDM-exposed mice, and the FLU doses used did not significantly decrease HDM-induced airway inflammation. Females had greater serum and fecal corticosterone concentrations, less anxiety-like behavior, and lower Crhr1 gene expression in ventral hippocampus and prefrontal cortex than males.. These findings suggest that steroid medications for youth with allergic asthma may not exacerbate anxiety-related symptoms, and that they should be avoided in children/adolescents without a health condition. The results are informative to future work on the use of corticosteroid medications during childhood or adolescent development.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aging; Allergens; Animals; Anxiety; Asthma; Disease Models, Animal; Female; Fluticasone; Humans; Inflammation; Male; Mice; Mice, Inbred BALB C; Pyroglyphidae

This work aimed to elaborate an optimised fluticasone propionate (FP)-loaded solid lipid nanoparticles (SLNs) to enhance FP effectiveness for topical inflammatory remediation. The influences of drug amount, lipid, and surfactant ratios, on drug release pattern and stability were investigated utilising Box-Behnken design. Elaboration, characterisation, and pharmacodynamic evaluation in comparison with the marketed formulation (Cutivate® cream, 0.05%

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Dinoprostone; Drug Compounding; Drug Liberation; Drug Stability; Fluticasone; Foot; Inflammation; Lipids; Male; Nanoparticles; Particle Size; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Topics: Animals; Antithrombins; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Chemokine CXCL1; Dabigatran; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fluticasone; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Mice, Inbred Strains; Osteopontin; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

Topical steroids are the primary medical therapy for eosinophilic esophagitis (EoE). Current steroid formulations are used off-label and designed for airway delivery. It is known that the efficacy of topical steroids depends on drug-mucosal contact time, which is related to its formulation. The purpose of this study is to examine the effectiveness of fluticasone administered by means of an orally administered powder formulation. We conducted a retrospective analysis of patients diagnosed with EoE based on current guidelines and who were treated with orally administered fluticasone powder. The primary outcome was histologic response (peak eosinophil density (eos/hpf)). Secondary outcomes included patient-reported symptoms (EoEQ) and endoscopic features measured by a validated instrument (EoE endoscopic reference score, EREFS). Forty patients were treated with fluticasone powder with doses of 500 to 1000 mcg b.i.d. A significant difference was found between pre- and posttreatment levels of eosinophilia (P < 0.0001). Seventy-five percent of patients achieved peak densities of <15 eos/hpf. Improvement was also demonstrated in dysphagia symptoms (P = 0.031) and endoscopic findings of furrows (P = 0.0001) and exudates (P = 0.0001). Oral fluticasone powder induced significant improvement in histopathology, symptoms, and endoscopic features of inflammation in adults with EoE. It offers an easy-to-administer formulation of a topical steroid that circumvents concerns with esophageal delivery of commonly used, aerosolized inhaler preparations.

Topics: Adult; Anti-Inflammatory Agents; Eosinophilic Esophagitis; Esophagus; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Powders; Retrospective Studies; Treatment Outcome

Patients with more severe chronic obstructive pulmonary disease frequently experience exacerbations and it is estimated that up to 50% of these exacerbations are associated with bacterial infections. The mainstay treatment for these infection-related exacerbations constitutes the administration of glucocorticoids, alone or in combination with antibiotics. A recent line of evidence demonstrates that many hormones including the steroid beclomethasone can also directly affect bacterial growth, virulence, and antibiotic resistance. The effect of these regimens on the release of potentially virulent and toxic membrane vesicles (MVs) is at present unclear. In this study, we determined the effect of several pharmacological agents on MVs release by and bacterial growth of common respiratory pathogens. We found that neither the release of MVs nor the bacterial growth was affected by the glucocorticoids budesonide and fluticasone. The macrolide antibiotic azithromycin only inhibited the growth of Moraxella catarrhalis but no effects were observed on bacterial MV release at a concentration that is achieved locally in the epithelial lining on administration. The macrophage pro-inflammatory response to MVs was significantly reduced after treatment with budesonide and fluticasone but not by azithromycin treatment. Our findings suggest that these glucocorticoids may have a positive effect on infection-related inflammation although the bacterial growth and MV release remained unaffected.

Topics: Anti-Bacterial Agents; Azithromycin; Bacteria; Bacterial Infections; Beclomethasone; Budesonide; Cell Line; Cell-Derived Microparticles; Fluticasone; Glucocorticoids; Humans; Inflammation; Macrophages

Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) <0.05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold-change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C-X-C motif) ligand (CXCL) 11 (

Topics: Airway Remodeling; Anti-Inflammatory Agents; Antigens; Bronchi; Bronchoscopy; Chronic Disease; Cough; Cytokines; Cytoskeletal Proteins; Female; Fluticasone; Gene Expression Profiling; Humans; Immunity, Innate; Inflammation; Male; Middle Aged; Myocytes, Smooth Muscle; Pilot Projects; Poly C

Most attempts to achieve sustained drug delivery to pulmonary tissues using nanoparticles have focused on mucoadhesive particles (MAP). However, MAP become trapped in the luminal mucus layer and, as a result, are largely eliminated from the respiratory tract by mucociliary escalator and expiratory clearance, which undermines their sustained release potential. Recent studies have shown that mucus-penetrating particles (MPP) engineered to diffuse through mucus can avoid rapid mucociliary clearance in vivo and persist in the lung longer. Nonetheless, it has not been confirmed that MPP encapsulating small molecules can sustain drug release in the lung longer than MAP of similar size and core composition. As a proof of concept, we encapsulated fluticasone propionate (FP) into poly(lactide)-based MPP and MAP (both ∼ 200 nm diameter, ∼ 30-35% drug loading) and evaluated their pulmonary residence by measuring FP levels in mouse lungs over 24h following intratracheal instillation. Furthermore, we evaluated the duration of action of FP MPP in a rat lung inflammation model compared to that of a non-encapsulated FP control. In rodents, pulmonary delivery of FP formulated as MPP provided a 60% higher local exposure compared to MAP and extended the single dose efficacy by at least 16 h compared to non-encapsulated FP.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Delayed-Action Preparations; Drug Delivery Systems; Female; Fluticasone; Humans; Inflammation; Lipopolysaccharides; Lung; Lung Diseases; Male; Mice; Mucus; Nanoparticles; Polyesters; Rats, Inbred Lew

Hecogenin is a steroidal sapogenin plays important role in treatment of variety of inflammatory diseases. We have investigated the anti-inflammatory effects of Hecogenin (50 µg/animal) (HG), Fluticasone (50 µg/animal) (FC) and Hecogenin+Fluticasone (HG+FC) combination (25 µg/animal, each) on various inflammatory models. The anti-inflammatory effect of HG, FC and HG+FC combination was studied on % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase assay, serum pro-inflammatory cytokines, colon weight to length ratio, macroscopic lesions, adhesion score, diarrhoea score and histopathological analysis of ear and colon tissue on Cotton pellets induced granuloma in rats, Croton oil induced ear edema in mice and TNBS induced granuloma in rats. Topical administration of HG and its combination with FC showed significant decrease (p<0.001) in the % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase level, serum pro-inflammatory cytokines levels, colon weigh to length ratio as compared with Cotton pellets treated with acetone groups and Croton oil treated animals. Further histopathological analysis of ear tissue showed significant decrease in dermal thickness and epidermal hyperplasia and colon tissue showed reduction of edema, infiltration of inflammatory cells and normalization of crypt structure compared to DC animals. Thus, the findings of present study suggest the possible role of HG in the treatment of inflammation by reducing the dose of FC in combination with HG.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colon; Cytokines; Disease Models, Animal; Fluticasone; Inflammation; Mice; Peroxidase; Rats; Rats, Wistar; Sapogenins

Currently, functional assessment to monitor therapeutic response in feline lower airway disease (FLAD) has limited application.. To evaluate if expiratory indices derived from pseudo-tidal breathing flow-volume loop (pTBFVL) representing lower airway obstruction would decrease after clinical improvement and to investigate the correlation between functional phenotype and inflammatory cell type in bronchoalveolar lavage (BAL) fluid.. Nineteen client-owned cats with FLAD.. Prospective observational study. Functional assessment with pTBFVL indices (eg, peak to mid-expiratory flow; PEF/EF50) and conventional barometric whole body plethysmography (BWBP) parameters (eg, enhanced pause) was carried out before receiving treatment. BAL was performed to analyze inflammatory cell types. Signs were assessed by scoring. The cats were treated with glucocorticoids daily and functional testing was repeated.. Loop indices PEF/EF50 and PEF/EF25 were significantly decreased after treatment (P < .001). Conventional BWBP parameters were not significantly different before and after treatment. Cats with PEF/EF50 > 1.51 before treatment had a significantly higher granulocyte (eosinophil plus neutrophil) percentage in BAL fluid (P = .014). Granulocyte percentage in BAL fluid was strongly correlated with PEF/EF25 (P = .001, rs = 0.74) and moderately correlated with PEF/EF50 (P = .022, rs = 0.57), whereas eosinophil or neutrophil percentage alone had no significant correlation with functional parameters.. Functional parameters including PEF/EF50 and PEF/EF25 can be used for monitoring therapeutic response. The presence of airflow limitation during mid- to late expiration is affected by the overall extent of granulocyte infiltration.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cat Diseases; Cats; Fluticasone; Inflammation; Lung Diseases; Prednisolone; Respiratory Therapy

Asthma exacerbations contribute to corticosteroid insensitivity. LPS is ubiquitous in the environment. It causes bronchoconstriction and airway inflammation and may therefore exacerbate allergen responses. This study examined whether LPS and ovalbumin co-administration could exacerbate the airway inflammatory and functional responses to ovalbumin in conscious guinea pigs and whether these exacerbated responses were insensitive to inhaled corticosteroid treatment with fluticasone propionate (FP).. Guinea pigs were sensitized and challenged with ovalbumin and airway function recorded as specific airway conductance by whole body plethysmography. Airway inflammation was measured from lung histology and bronchoalveolar lavage. Airway hyper-reactivity (AHR) to inhaled histamine was examined 24 h after ovalbumin. LPS was inhaled alone or 24 or 48 h before ovalbumin and combined with ovalbumin. FP (0.05-1 mg·mL(-1) ) or vehicle was nebulized for 15 min twice daily for 6 days before ovalbumin or LPS exposure.. Ovalbumin inhalation caused early (EAR) and late asthmatic response (LAR), airway hyper-reactivity to histamine and influx of inflammatory cells into the lungs. LPS 48 h before and co-administered with ovalbumin exacerbated the response with increased length of the EAR, prolonged response to histamine and elevated inflammatory cells. FP 0.5 and 1 mg·mL(-1) reduced the LAR, AHR and cell influx with ovalbumin alone, but was ineffective when guinea pigs were exposed to LPS before and with ovalbumin.. LPS exposure exacerbates airway inflammatory and functional responses to allergen inhalation and decreases corticosteroid sensitivity. Its widespread presence in the environment could contribute to asthma exacerbations and corticosteroid insensitivity in humans.

Topics: Administration, Inhalation; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Resistance; Fluticasone; Guinea Pigs; Histamine; Inflammation; Lipopolysaccharides; Lung; Male; Ovalbumin; Plethysmography, Whole Body

Localized inflammation of lumbar dorsal root ganglia (DRG) may contribute to low back pain. Local injections of corticosteroids used for low back pain are sometimes ineffective. Many corticosteroids activate not only the target glucocorticoid receptor (GR) but also the mineralocorticoid receptor (MR), which may have proinflammatory effects countering the effects of GR activation.. A low back pain model was implemented in rats (n = 6 to 10 per group) by locally inflaming the L5 DRG. Sensory neuron excitability and mechanical hypersensitivity of the hind paws were measured. Tested steroids were applied locally to the inflamed DRG or orally.. The selective MR blocker eplerenone reduced pain behaviors when given orally starting at the time of surgery, or starting 7 days later. The highly GR-selective agonist fluticasone, applied locally to the inflamed DRG, was much more effective in reducing mechanical hypersensitivity. The MR/GR agonist 6-α methylprednisolone, commonly injected for low back pain, reduced mechanical hypersensitivity when applied locally to the DRG but was less effective than fluticasone. Its effectiveness was improved by combining it with local eplerenone. All tested steroids reduced hyperexcitability of myelinated sensory neurons (n = 71 to 220 cells per group) after inflammation, particularly abnormal spontaneous activity.. This preclinical study indicates the MR may play an important role in low back pain involving inflammation. Some MR effects may occur at the level of the sensory neuron. It may be useful to consider the action of clinically used steroids at the MR as well as at the GR.

Topics: Androstadienes; Animals; Disease Models, Animal; Eplerenone; Fluticasone; Ganglia, Spinal; Inflammation; Low Back Pain; Methylprednisolone; Mineralocorticoid Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Spironolactone

COPD (chronic obstructive pulmonary disease) is a common lung disease characterized by airflow limitation and systemic inflammation. Recently, adipose tissue mediated inflammation has gathered increasing interest in the pathogenesis of the disease. In this study, we investigated the role of novel adipocytokines nesfatin-1 and visfatin in COPD by measuring if they are associated with the inflammatory activity, lung function, or symptoms. Plasma levels of NUCB2/nesfatin-1 and visfatin were measured together with IL-6, IL-8, TNF- α , and MMP-9, lung function, exhaled nitric oxide, and symptoms in 43 male patients with emphysematous COPD. The measurements were repeated in a subgroup of the patients after four weeks' treatment with inhaled fluticasone. Both visfatin and NUCB2/nesfatin-1 correlated positively with plasma levels of IL-6 (r = 0.341, P = 0.027 and rho = 0.401, P = 0.008, resp.) and TNF- α (r = 0.305, P = 0.052 and rho = 0.329, P = 0.033, resp.) and NUCB2/nesfatin-1 also with IL-8 (rho = 0.321, P = 0.036) in patients with COPD. Further, the plasma levels of visfatin correlated negatively with pulmonary diffusing capacity (r = -0.369, P = 0.016). Neither of the adipokines was affected by fluticasone treatment and they were not related to steroid-responsiveness. The present results introduce adipocytokines NUCB2/nesfatin-1 and visfatin as novel factors associated with systemic inflammation in COPD and suggest that visfatin may mediate impaired pulmonary diffusing capacity.

Topics: Adult; Aged; Androstadienes; Biomarkers; Calcium-Binding Proteins; Case-Control Studies; Cytokines; DNA-Binding Proteins; Fluticasone; Forced Expiratory Volume; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Lung; Male; Middle Aged; Nerve Tissue Proteins; Nicotinamide Phosphoribosyltransferase; Nitric Oxide; Nucleobindins; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha

It has been suggested that smoking asthmatics benefit less from corticosteroid treatment than never-smoking asthmatics. We investigated differences in blood and sputum inflammatory profiles between ex-, current-, and never-smokers and assessed their ICS treatment response after 2-week and 1-year treatment.. We analyzed FEV1, PC20 methacholine and PC20 AMP, (differential) cell counts in sputum and blood in ex-, current- and never-smokers at baseline (n=114), after 2-week treatment with fluticasone 500 or 2000 μg/day (n=76) and after 1-year treatment with fluticasone 500 μg/day or a variable dose of fluticasone based on a self-management plan (n=64).. A total of 114 patients were included (29 ex-, 30 current- and 55 never-smokers. At baseline, ex- and current-smokers had less eosinophils in sputum and blood than never-smokers. Blood neutrophil counts were higher in current- than in never-smokers. A higher number of cigarettes smoked daily was associated with lower blood and sputum eosinophils. After 2-week ICS treatment, FEV1 %predicted improved less in current-smokers than never-smokers (2.4% versus 8.1%, p=0.010) and ex-smokers tended to improve less than never-smokers (4.1%, p=0.067). In contrast, no differences in ICS treatment response in lung function or inflammatory cells were found between the three groups after 1 year.. Ex- and current-smokers have less eosinophils and more neutrophils in their sputum and blood than never-smokers. Although ex- and current-smokers have a reduced short-term corticosteroid treatment response, we did not find a difference in their long-term treatment response.

Topics: Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Biomarkers; Bronchial Provocation Tests; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Leukocyte Count; Male; Neutrophils; Smoking; Smoking Cessation; Sputum

Pre-clinical evaluation of asthma therapies requires animal models of chronic airways inflammation, airway hyperresponsiveness (AHR) and lung remodelling that accurately predict drug effectiveness in human asthma. However, most animal models focus on acute allergen challenges where chronic inflammation and airway remodelling are absent. Chronic allergen challenge models have been developed in mice but few studies use guinea-pigs which may be more relevant to humans. We tested the hypothesis that a chronic rather than acute pulmonary inflammation model would best predict clinical outcome for asthma treatments. Guinea-pigs sensitized with ovalbumin (OVA) received single (acute) or nine OVA inhalation challenges at 48 h intervals (chronic). Airways function was recorded as specific airways conductance (sG(aw)) in conscious animals for 12 h after OVA challenge. AHR to inhaled histamine, inflammatory cell influx and lung histology were determined 24 h after the single or 9th OVA exposure. The inhaled corticosteroid, fluticasone propionate (FP), the phosphodiesterase 4 inhibitor, roflumilast, and the inducible nitric oxide synthase (iNOS) inhibitor, GW274150, orally, were administered 24 and 0.5 h before and 6 h after the single or final chronic OVA exposure. Both models displayed early (EAR) and late (LAR) asthmatic responses to OVA challenge, as falls in sG(aw), AHR, as increased histamine-induced bronchoconstriction, and inflammatory cell influx. Tissue remodelling, seen as increased collagen and goblet cell hyperplasia, occurred after multiple OVA challenge. Treatment with FP and roflumilast inhibited the LAR, cell influx and AHR in both models, and the remodelling in the chronic model. GW274150 also inhibited the LAR, AHR and eosinophil influx in the acute model, but not, together with the remodelling, in the chronic model. In the clinical setting, inhaled corticosteroids and phosphodiesterase 4 inhibitors are relatively effective against most features of asthma whereas the iNOS inhibitor GW274150 was ineffective. Thus, while there remain certain differences between our data and clinical effectiveness of these antiasthma drugs, a chronic pulmonary inflammation guinea-pig model does appear to be a better pre-clinical predictor of potential asthma therapeutics than an acute model.

Topics: Acute Disease; Administration, Inhalation; Administration, Oral; Aminopyridines; Androstadienes; Animals; Anti-Asthmatic Agents; Asthma; Benzamides; Bronchial Hyperreactivity; Chronic Disease; Cyclopropanes; Disease Models, Animal; Fluticasone; Guinea Pigs; Histamine; Inflammation; Male; Ovalbumin; Sulfides; Time Factors

Inhaled corticosteroids (ICSs) are often prescribed as the first line therapy for pulmonary diseases such as asthma. The biggest concern of using steroid therapy is the systemic side effects at high dose. To reduce the side effects, the pharmaceutical industry has been putting effort to generate new drugs with maximized topical efficacy. One of the key challenges is to differentiate efficacy from local versus systemic contribution in preclinical animal models. Fluticasone with various formulations was used as a model compound to explore the possibilities to demonstrate lung targeted efficacy by intratracheally instillation in the lipopolysaccharide induced inflammation rat model. Fluticasone formulations contained various surfactant concentrations and particle sizes to achieve lung retention and lower systemic exposure. Neutrophil infiltration in broncoalveolar lavage fluid and cytokine production in whole blood were measured to assess pulmonary efficacy versus systemic efficacy. PK/PD characterization of fluticasone with various formulations in the rat inflammation model provided an integrated approach in preclinical to evaluate lung targeted efficacy for ICS. Our study concluded that the combination of the rat LPS model and fluticasone is not suitable to use for establishing potency and dose requirement for new drug candidate designed for topical only efficacy.

Topics: Acute Disease; Administration, Inhalation; Androstadienes; Animals; Anti-Inflammatory Agents; Area Under Curve; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fluticasone; Inflammation; Lipopolysaccharides; Lung; Male; Metabolic Clearance Rate; Rats; Rats, Sprague-Dawley

Clinical manifestations suggest that air pollution may induce deterioration of respiratory health. Some air pollutants, including sulfite, may play a role in the exacerbation of asthma. Sulfites are formed at bronchial mucosa from inhaled sulfur dioxide. It has been previously reported that sodium sulfite (Na(2)SO(3)) has pro-inflammatory properties and enhances neutrophil adhesion to A549 cells. Interleukin-8 (IL-8) plays a critical role in attracting inflammatory cells and is an excellent marker of pulmonary cell activation. To date, there have not been any reports on the effect of asthma drugs on the suppression of IL-8 production induced by sulfite in A549 cells or the involvement of specific signal transduction pathways. Thus, our study assessed the effects of salmeterol, fluticasone, and montelukast on human epithelial lung cell inflammation as well as the inhibitors in different signal transduction pathways.. A549 human lung epithelial cells were cultured under the following conditions: (1) treated with sodium sulfite (0, 100, 500, 1000, 2500 uM) for 16 hours; (2) cultured for 1 hour in the presence of SB203580, PD98059, SP600125, or wedeloactone, then co-incubated with sodium sulfite for another 16 hours; (3) cultured for 4 hours in the presence of salmeterol, fluticasone, or montelukast, then stimulated with sodium sulfite at a concentration of 1000 uM for 16 hours. We collected the supernatants from the above conditions and performed enzyme-linked immunosorbent assay (ELISA) to measure the IL-8 concentration.. IL-8 production increased after treatment with sodium sulfite at 1000 to 2500 uM (p

Topics: Acetates; Air Pollutants; Albuterol; Androstadienes; Anti-Asthmatic Agents; Cell Line; Cell Survival; Cyclopropanes; Dose-Response Relationship, Drug; Epithelial Cells; Fluticasone; Humans; Inflammation; Interleukin-8; Lung; Quinolines; Salmeterol Xinafoate; Signal Transduction; Sulfides; Sulfites

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Inflammation; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Treatment Outcome

Topics: Adult; Androstadienes; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Capillary Permeability; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Serum Albumin; Vascular Endothelial Growth Factor A

Airway microcirculation is abnormal in asthma but the role of vascular changes in asthma deteriorations remains poorly defined. We prospectively assessed the vascular changes accompanying worsening of asthma control by using an inhaled corticosteroid (ICS) dose-reduction model.. To evaluate airway vascularity, vascular permeability and expression of vascular endothelial growth factor (VEGF) in early asthma deterioration induced by ICS back-titration.. Twenty mild-to-moderate persistent symptomatic asthmatics on low-to-moderate ICS were recruited and treated with 4 weeks of high-dose fluticasone propionate (1000 microg/day) to achieve symptom control. This was followed by dose reduction to half of the pre-study doses for 4-8 weeks until the symptoms began to return. Endobronchial biopsy and bronchoalveolar lavage (BAL) samples were obtained after both treatment periods.. Vascularity as measured by the number and size of blood vessels, as well as VEGF expression did not change following ICS reduction. Even on high-dose ICS, perivascular albumin staining and BAL microalbumin levels in asthmatic subjects, as markers of permeability, were elevated when compared with normal subjects and both further increased significantly after ICS reduction. There was a significant association between changes in vascular leakiness and clinical deterioration. Increases in airway albumin correlated with previously reported increases in airway wall infiltration with T lymphocytes.. Our results suggest that airway vascular leakage is a major pathophysiologic feature of early asthma deterioration, occurring before recrudescence of cellular inflammation.

Topics: Adult; Androstadienes; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Capillary Permeability; Female; Fluticasone; Humans; Inflammation; Male; Middle Aged; Serum Albumin; Vascular Endothelial Growth Factor A

Asthma affects 300 million people worldwide and continues to be a major cause of morbidity and mortality. Disease relevant animal models of asthma are required for benchmarking of novel therapeutic mechanisms in comparison to established clinical approaches. We demonstrate that chronic exposure of mice to house dust mite (HDM) extract results in allergic airway inflammation, that can be significantly attenuated by therapeutic intervention with phosphodiesterase 4 inhibition and corticosteroid treatment. Female BALB/c mice were administered intranasally with HDM (Dermatophagoides pteronyssinus) extract daily for five weeks, and therapeutic intervention with anti-inflammatory treatment (dexamethasone 1 mg/kg subcutaneous once daily, prednisolone 10mg/kg orally twice daily, fluticasone 3, 10 and 30 microg intranasally twice daily, roflumilast 10 mg/kg orally twice daily and intranasally 10 and 30 microg twice daily) was initiated after three weeks of exposure. Chronic HDM extract exposure resulted in significant airway inflammation, demonstrated by bronchoalveolar lavage cell infiltration and lung tissue inflammatory gene expression by TaqMan low density array. Chronic steroid treatment significantly inhibited these parameters. In addition, roflumilast caused a significant reduction in airway inflammatory cell infiltration. We have demonstrated that chronic HDM-induced allergic inflammation can be significantly ameliorated by steroid treatment, and that phosphodiesterase 4 inhibition modulates inflammatory cell infiltration. Therefore, the murine HDM model may be a useful tool for evaluating new targets for the treatment of asthma.

Topics: Aminopyridines; Androstadienes; Animals; Anti-Inflammatory Agents; Asthma; Benzamides; Bronchoalveolar Lavage; Cyclopropanes; Dermatophagoides pteronyssinus; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluticasone; Glucocorticoids; Inflammation; Mice; Mice, Inbred BALB C; Phosphodiesterase Inhibitors; Prednisolone

Fluticasone furoate (FF) is a novel enhanced-affinity glucocorticoid that has been developed as topical therapy for allergic rhinitis. The pharmacological properties of FF have been investigated using a number of in vitro experimental systems. FF demonstrated very potent glucocorticoid activity in several key pathways downstream of the glucocorticoid receptor (GR) as follows: the transrepression nuclear factor-kappaB (NF-kappaB) pathway, the transactivation glucocorticoid response element pathway, and inhibition of the proinflammatory cytokine tumor necrosis factor-alpha. Furthermore, FF showed the greatest potency compared with other glucocorticoids for preserving epithelial integrity and reducing epithelial permeability in response to protease- and mechanical-induced cell damage. FF showed a 30- to >330,000-fold selectivity for GR-mediated inhibition of NF-kappaB vs. the other steroid hormone receptors, substantially better than a number of other clinically used glucocorticoids. In studies examining the respiratory tissue binding properties of glucocorticoids, FF had the largest cellular accumulation and slowest rate of efflux compared with other clinically used glucocorticoids, consistent with greater tissue retention. The in vivo anti-inflammatory activity of FF was assessed in the Brown Norway rat ovalbumin-induced lung eosinophilial model of allergic lung inflammation. At a dose of only 30 microg, FF achieved almost total inhibition of eosinophil influx in the lung, an inhibition that was greater than that seen with the same dose of fluticasone propionate. In conclusion, the potent and selective pharmacological profile of FF described here could deliver an effective, safe, and sustained topical treatment of respiratory inflammatory diseases such as allergic rhinitis and asthma.

Topics: Androstadienes; Animals; Cell Line, Tumor; Cell Membrane Permeability; Chlorocebus aethiops; Disease Models, Animal; Epithelial Cells; Fluticasone; Glucocorticoids; Humans; Hypersensitivity; Inflammation; Lipopolysaccharides; NF-kappa B; Pancreatic Elastase; Rats; Rats, Inbred BN; Receptors, Steroid; Respiration Disorders; Tumor Necrosis Factor-alpha

To investigate the effect of the Ginkgo Biloba Extract (GBE) on the asthma and examine its possible mechanisms, 75 asthma patients were divided into 4 groups and the patients were respectively treated with fluticasone propionate for 2 weeks or 4 weeks, or treated with fluticasone propionate plus GBE for 2 weeks or 4 weeks. Fifteen healthy volunteers served as healthy controls. Sputum inhalation with inhaling hypertonic saline (4%-5%) was performed. Lung ventilatory function and forced expiratory volume in one second (FEV1) were measured. The numbers of different cells in induced sputum were calculated. The expression of PKCalpha in the cells was immunocytochemically detected and the percentages of positive cells in different cells were counted. Interleukin-5 (IL-5) in sputum supernatants was detected with enzyme-linked immunosorbent assay. The percentage of eosinophils, lymphocytes, PKCalpha positive inflammatory cells and the concentration of IL-5 in asthmatic patients were higher than those in the controls (P<0.05), and the eosinophils, lymphocytes, positive expression of PKCalpha and the level of IL-5 were significantly decreased in asthmatic patients after they were treated with fluticasone propionate or fluticasone propionate plus GBE. However, they were still significantly higher than those of the controls. Compared to the group treated with glucocorticosteroid for 2 weeks, no significant decrease was found in the percentage of eosinophils, lymphocytes, PKCalpha positive inflammatory cells and the IL-5 in the supernatant of induced sputum. Compared with the group treated with glucocorticosteroid for 2 or 4 weeks, significant decrease in the same parameters was observed in the group treated with fluticasone propionate and GBE for 4 weeks. The IL-5 level in the supernatant of induced sputum was positively correlated with the percentage of PKCalpha-positive inflammatory cells and the percentage of eosinophils in the induced sputum in asthma patient groups respectively (n=150, r= 0.83, P<0.01; n=150, r=0.76, P<0.01). The FEV1 was negatively correlated with the percentage of PKCalpha-positive inflammatory cells and the IL-5 levels in supernatant of induced sputum in asthma patients respectively (n=150, r=-0.77, P<0.01; n=150, r= -0.64, P<0.01). It is concluded that GBE could significantly decrease the infiltration of inflammatory cells such as eosinophils and lymphocytes in the asthmatic airway and relieve the airway inflammation. GBE may decrease the ac

Topics: Adult; Androstadienes; Asthma; Case-Control Studies; Drugs, Chinese Herbal; Female; Fluticasone; Ginkgo biloba; Humans; Inflammation; Interleukin-5; Male; Phytotherapy; Plant Extracts; Protein Kinase C-alpha; Sputum; Young Adult

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aerosol Propellants; Androstadienes; Anti-Allergic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchial Provocation Tests; Bronchial Spasm; Ethanol; Fluticasone; Humans; Inflammation; Male; Solvents; TRPV Cation Channels

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Drug Therapy, Combination; Fluticasone; Humans; Inflammation; Research Design; Salmeterol Xinafoate; Treatment Outcome

Ciclesonide is a novel, inhaled corticosteroid under development for the treatment of asthma. Ciclesonide is activated to desisobutyryl-ciclesonide (des-CIC) in the lungs to provide potent anti-inflammatory activity. The investigations herein compared the activity of ciclesonide with fluticasone in animal models to assess efficacy/potency as an airway anti-inflammatory and the comparative side effect potential to consider the therapeutic ratio of each compound. In radioligand binding assays, des-CIC and fluticasone exhibited comparable high-affinity binding to the glucocorticoid receptor, whereas ciclesonide exhibited 100-fold less binding affinity. In the Brown Norway rat model of antigen-induced airway eosinophilia and in a model of Sephadex-induced lung edema, ciclesonide and fluticasone exhibited comparable efficacy. Interestingly, following 7-day intratracheal administration, ciclesonide elicited adrenal involution with a potency that was 44-fold less than fluticasone. Furthermore, ciclesonide was 22-fold less active than fluticasone in eliciting hypoplasia of the femoral growth plate. These data support the concept that ciclesonide acts as a parent compound that, when delivered to the airways, can be transformed into the active metabolite des-CIC, resulting in local high anti-inflammatory activity. Furthermore, ciclesonide possesses equivalent anti-inflammatory efficacy through pulmonary activation with a significantly improved safety profile in preclinical animal models compared with fluticasone.

Topics: Adrenal Glands; Androstadienes; Animals; Anti-Asthmatic Agents; Binding, Competitive; Blood Proteins; Bone Diseases, Metabolic; Dextrans; Eosinophils; Femur; Femur Head; Fluticasone; Growth Plate; Inflammation; Pregnenediones; Protein Binding; Pulmonary Edema; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Receptors, Steroid; Thymus Gland

CD163 is a membrane glycoprotein of the cysteine-rich scavenger receptor superfamily. Upon an inflammatory stimulus CD163 undergoes ectodomain shedding and the soluble protein has been shown to play a role in downregulation of inflammation. The purpose of the present study was to identify a physiological activator of CD163 shedding that is consistently present under inflammatory conditions. Therefore, we elucidated whether oxidative stress or 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is involved in shedding of CD163. Oxidative stress induced by H(2)O(2) or a NO donor as well as 8-iso-PGF(2alpha) induced significant shedding of CD163. In contrast, release of CD163 was not stimulated by PGF(2alpha). We identified both calcium and reactive oxygen species as common cellular mediators of CD163 release. Since shedding of both CD163 and tumor necrosis factor-alpha (TNFalpha) is known to be mediated by a TIMP-3-sensitive metalloproteinase we examined whether release of TNFalpha was induced by the same mediators that trigger shedding of CD163. Only oxidative stress generated by H(2)O(2) as well as 8-iso-PGF(2alpha) and PGF(2alpha) enhanced TNFalpha secretion. Thus, we identified novel common and divergent activators of shedding of CD163 and TNFalpha. These inducers of shedding are present in inflammation and might play an important role in membrane protein cleavage.

Topics: Androstadienes; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Calcium; Chelating Agents; Cyclosporine; Dinoprost; Egtazic Acid; Fluticasone; Humans; Hydrogen Peroxide; Inflammation; Monocytes; Oxidative Stress; Reactive Oxygen Species; Receptors, Cell Surface; S-Nitroso-N-Acetylpenicillamine; Tumor Necrosis Factor-alpha

In asthma a dysregulation of eosinophil apoptosis and an imbalance of metalloproteinase-9 (MMP-9) and tissue inhibitor metalloproteinase-1 (TIMP-1) play an important role in airway inflammation and remodelling. We evaluated the effects of a low dose of inhaled fluticasone proprionate (FP) (100 microg bid by Diskus) for 4 weeks in 24 steroid naive patients with mild persistent asthma, symptomatic and with a sputum eosinophilia >or=3% on clinical outcomes and inflammatory markers such as the induced sputum eosinophils, the induced sputum apoptotic eosinophils, the levels of MMP-9 and TIMP-1 and their molar ratio in the induced sputum supernatants. After FP treatment forced expiratory volume (FEV1) and FEV1/forced vital capacity values, PEF (L/min), sputum apoptotic eosinophils, and MMP-9/TIMP-1 molar ratio in sputum supernatants of asthmatic subjects were significantly increased in comparison with baseline, while sputum eosinophils significantly decreased. Change (Delta) in FEV1 after treatment with FP negatively correlated with the Delta in sputum eosinophils, while the Delta in MMP-9 values positively correlated with Delta in TIMP-1 values. This study shows that the clinical improvement achieved by the use of low doses of FP in asthmatics is related, at least in part, to the resolution of eosinophilic inflammation and the downregulation of remodelling markers.

Topics: Administration, Inhalation; Adult; Androstadienes; Anti-Inflammatory Agents; Apoptosis; Asthma; Down-Regulation; Eosinophilia; Eosinophils; Female; Fluticasone; Humans; Inflammation; Male; Matrix Metalloproteinase 9; Middle Aged; Tissue Inhibitor of Metalloproteinase-1; Treatment Outcome

Airway inflammation, one of the major factors leading to lung damage in cystic fibrosis (CF) patients, is associated with an abnormal increase in proinflammatory cytokines. In this work, we demonstrate the increased release of the proinflammatory cytokines after lipopolysaccharide (LPS) stimulation: human interleukin (hIL)-8 in CF and non-CF airway xenografts, and hIL-6 and human growth-related oncogene-alpha (hGRO-alpha), which could be only analyzed in non-CF xenografts. Under basal conditions, we observed that hIL-8 was higher in CF xenografts compared with non-CF. We also report the anti-inflammatory effect of a glucocorticoid, fluticasone propionate (FP), on CF airway epithelium using a humanized model of airway inflammation developed in nude mice. In CF and non-CF tracheal xenografts, airway inflammation was induced by inoculating Pseudomonas aeruginosa LPS (4 h; 1 microg/ml) in the lumen of the xenografts. FP pretreatment (2 h; 10(-8) M) followed by P. aeruginosa LPS stimulation induced a significant reduction of LPS-induced hIL-8 release in airway liquid collected from CF and non-CF tracheal xenografts (85 and 80%, respectively). In non-CF tracheal xenografts, FP treatment before LPS stimulation induced a significant decrease in hIL-6 and hGRO-alpha. From these data, we suggest that FP exerts anti-inflammatory properties that may be appropriate to CF therapy, at an early stage of the disease. In addition, these results demonstrate that the humanized airway model of inflammation provides a relevant tool for analyzing the effects of anti-inflammatory drugs in different diseases in which airway inflammation is implicated.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Body Fluids; Child; Cystic Fibrosis; Cytokines; Female; Fluticasone; Humans; Immunoenzyme Techniques; Inflammation; Interleukin-8; Lipopolysaccharides; Lung; Male; Mice; Mice, Nude; Pseudomonas aeruginosa; Trachea; Transplantation, Heterologous

To analyse informative value of monitoring of NO metabolites concentration in condensate of expired air vapor (EAVC) for definition of bronchial asthma (BA) severity and antiinflammatory effect of basic therapy.. NO metabolites concentration in EAVC was measured with Grace's reagent in 76 adults and 180 children in the course of basic therapy with flixotide, tailed, ketotiphen with intal.. NO metabolites occurred in high concentrations in EAVC of both children and adults. These concentrations were the highest in attacks and in severe BA and were reduced by basic therapy. This effect differed with the drug and its dose, e.g. flixotide and tailed given to children for a month reduced NO metabolites close to concentrations observed in healthy subjects. Ketotiphen and intal for 6 months failed to low NO metabolites significantly.. NO secretion monitoring is sensitive in assessment of respiratory inflammation in BA and is informative in assessment of effectiveness of the basic therapy. In moderate BA children on flixotide and tailed were the first to achieve normal NO secretion in the airways.

Topics: Adolescent; Adult; Age Factors; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biomarkers; Breath Tests; Child; Child, Preschool; Cromolyn Sodium; Female; Fluticasone; Humans; Inflammation; Ketotifen; Male; Nedocromil; Nitric Oxide; Time Factors

Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Androstadienes; Animals; Asthma; Beclomethasone; Benzamides; Budesonide; Cyclic Nucleotide Phosphodiesterases, Type 4; Dexamethasone; Dextrans; Disease Models, Animal; Enzyme Inhibitors; Eosinophil Peroxidase; Eosinophils; Fluticasone; Glucocorticoids; Guinea Pigs; Inflammation; Lung; Male; Ovalbumin; Peroxidases; Pyridines; Rats; Rats, Sprague-Dawley; Rolipram

Recent studies from our laboratory have identified a network of constitutively class II major histocompatibility complex (MHC) (Ia)-bearing dendritic cells (DC) within the epithelium of the conducting airways of laboratory animal species and in humans. These studies have also demonstrated that the density of the DC network increases within the airway epithelium in response to inflammatory challenge. In the present report, we demonstrate that exposure of adult rats to inhaled steroids leads to a rapid but readily reversible decrease both in the number of airway intraepithelial DC, and in their surface Ia expression. Similar changes are also seen in response to high doses of systemic dexamethasone. In addition, we demonstrate that steroid inhalation reduces the rate of postnatal expansion of the airway intraepithelial DC network in rat pups, and prevents the rapid expansion of the DC network in adults which occurs during the acute inflammatory response following inhalation of microbial stimuli.

Topics: Administration, Topical; Androstadienes; Animals; Anti-Inflammatory Agents; Beclomethasone; Budesonide; Dendritic Cells; Epithelium; Female; Fluticasone; Glucocorticoids; Inflammation; Pregnenediones; Rats; Rats, Inbred Strains; Trachea