(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Inflammation

To summarize the evidence of small airways involvement in chronic obstructive pulmonary disease (COPD) pathophysiology, and to evaluate the efficacy of extrafine formulations of inhaled corticosteroids (ICS) in combination with long-acting beta. A search of the PubMed database was conducted using the keywords "COPD", "small airways", "inflammation" and "extrafine formulation." The search was limited to entries published in English before August 2016. Only studies conducted in humans were considered.. Publications were included on the basis of relevance.. COPD is a common preventable and treatable disease, characterized by persistent and progressive airflow limitation. With improved understanding of COPD pathophysiology, small airways (internal diameter <2 mm), a well-known major site of COPD-associated inflammation and remodeling, have emerged as a potential target for COPD pharmacologic therapies. The ability of extrafine formulations of ICS in combination with LABAs to achieve central and peripheral lung deposition, and the implications of the enhanced efficacy that this may bring, are discussed by examining findings from the development trials plan of the extrafine formulation of beclometasone dipropionate/formoterol fumarate (Foster. There is an urgent need for improved and reliable techniques for small airways assessment in order to detect early damage, disease progression and response to treatment. Evidence from randomized clinical trials supports the benefits of extrafine ICS/LABA formulations in COPD, real world studies are necessary to confirm this.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aerosol Propellants; Airway Remodeling; Beclomethasone; Dosage Forms; Drug Compounding; Formoterol Fumarate; Humans; Inflammation; Pulmonary Disease, Chronic Obstructive

Topics: Adrenergic beta-Agonists; Airway Resistance; Albuterol; Anti-Inflammatory Agents; Beclomethasone; Bronchodilator Agents; Drug Monitoring; Ethanolamines; Exercise Tolerance; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inflammation; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Treatment Outcome

Recently, bronchial asthma has been widely recognized as a chronic inflammatory disorder of the airways. In the course of inflammation, many kinds of inflammatory cells such as lymphocytes, especially Th2 lymphocytes, mast cells, eosinophills, bronchial epithelial cells interact each other by so-called cytokine network. Bronchial hyperreactivity, which is a characteristic phenomenon in bronchial asthma, is induced as a result of bronchial inflammation. According to the inflammation theory of pathogenesis of bronchial asthma, anti-inflammatory treatment using inhaled corticosteroid is recommended as the first choice of asthma therapy. Bronchial biopsy proved decrease of the number of infiltrating inflammatory cells such as T lymphocytes, eosinophils and mast cells in the bronchial submucosal tissue after inhaled steroid treatment. Improvement of bronchial reactivity after inhaled steroid therapy was also reported. Recently, a certain group of so-called steroid resistant asthma has been known and the mechanism of it is now under investigation.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchi; Bronchial Diseases; Bronchial Hyperreactivity; Cytokines; Eosinophils; Humans; Inflammation; Inflammation Mediators; Mast Cells; T-Lymphocytes

Allergen avoidance is important in allergic asthma management. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett. Asthma Quality of Life Questionnaire (AQLQ) scores were collected in a previous study. TTO of improvements in Quality of Life was analysed for difference (TLA-placebo) in Area-under-Curve using backwards deletion from 12, 9, 6, 3 down to 1 month for the AQLQ total score, the four individual domains and specifically the sleep question.. Patients with uncontrolled asthma on GINA step 4 (n = 87)) reported a statistically significant and clinically relevant (≥0.5 point) improvement in total AQLQ score (0.57; p = 0.009) after 3 months treatment for TLA over placebo. The shortest TTO was within 1 month for the environmental domain (0.68; p = 0.016) and the sleep question (0.771; p = 0.037). TTO for the emotional and symptom domains was 3 months (0.66; p = 0.020 and 0.64; p = 0.014 respectively) and for the activity domain 6 months (0.47; p = 0.036).. Nocturnal avoidance of allergens using TLA provided a statistically significant and clinically relevant improvement in total AQLQ score within 3 months in patients in the GINA 4 + ACT<18 group. Questions related to sleep quality may provide the first signal of response already within a month after commencing treatment.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Air Movements; Allergens; Asthma; Beclomethasone; Environment, Controlled; Exhalation; Female; Humans; Hypersensitivity; Inflammation; Male; Nitric Oxide; Quality of Life; Severity of Illness Index; Sleep; Temperature; Time Factors

Asthma is a chronic inflammatory airway disease of the whole bronchial tree. In this exploratory study we investigated the effects of beclomethasone/formoterol (becl/form) and budesonide/formoterol (bud/form) fixed combinations on lung function and airway inflammation in patients with mild to moderate asthma.. 22 adult patients with asthma (mean FEV1 91.6% pred.) were recruited to this prospective phase IV, double-blind, double-dummy, two-way cross-over, single-centre, randomised study. After a 7 days run-in period with bud 200 μg bid patients were randomised to receive 4 weeks of becl/form (100/6 μg) bid in a pressurised metered dose inhaler or bud/form (160/4.5 μg) bid administered via dry powder inhaler. We measured spirometry, bodyplethysmography, impulse oscillometry, nitric oxide (NO) and its alveolar fraction (CAlv), and assessed sputum cellularity.. CAlv significantly decreased after 4 weeks of treatment in each treatment period. The adjusted geometric mean (log transformed data, end of treatment vs. baseline) was 0.942 ppb (95% CI: 0.778-1.141 ppb) for becl/form and 0.903 ppb (95% CI: 0.741-1.099 ppb) for bud/form. Impulse oscillometry revealed a significant decrease in mean Delta R5-R20 of -0.033 kPa * L(-1) * sec(-1) for becl/form (95% CI: -0.064 to -0.002) and of -0.048 033 kPa * L(-1) * sec(-1) for bud/form (95% CI: -0.079 to -0.017). Other parameters of lung function and NO showed numerically small and in most cases statistically non-significant changes.. In patients with mild to moderate asthma pre-treated with inhaled corticosteroids, the use of ICS/LABA formulations led to improvements of CAlv and Delta R5-R20 indicating that these parameters might be helpful to further assess the effects of inhaled ICS/LABA combinations on lung function and airway inflammation.

Topics: Administration, Inhalation; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide, Formoterol Fumarate Drug Combination; Cross-Over Studies; Double-Blind Method; Drug Combinations; Female; Formoterol Fumarate; Humans; Inflammation; Male; Patient Compliance; Prospective Studies; Respiratory Function Tests; Severity of Illness Index; Sputum

In an attempt to establish how treatment with inhaled extra-fine beclomethasone/formoterol (I-EF-BDP/F) formulation differs from other combinations of inhaled corticosteroid (ICS) and long acting beta-agonist (LABA), we studied lung function and markers of airway inflammation upon switching to the extra-fine formulation and after 8 weeks of treatment with it.. We carried out a real-life clinical observation of undercontrolled asthmatic patients switched over from dry powder inhalers of fluticasone/salmeterol and budesonide/formoterol to I-EF-BDP/F (Foster(®), Chiesi Farmaceutici S.p.A., Italy). The effects of 8-weeks of treatment were documented by means of visual analog scale (VAS), quality of life by Asthma Quality of Life Questionnaire (AQLQ), spirometry and markers of airway or systemic inflammation: exhaled breath temperature (EBT), blood eosinophils (Eos), and high sensitivity C-reactive protein (CRP). Before/after treatment differences between forced vital capacity percent of predicted (%FVC), a simple indicator of small airways involvement, were calculated and subjects were ranked accordingly to reflect the magnitude of the therapeutic response. Subjects above the 75th percentile (n = 15), "top responders", were then compared with those below the 25th percentile (n = 15) "poor responders".. On average, the 59 patients completing the study (mean age ± SD 51 ± 12 years, 38 women) had significant improvement in VAS and QLQ scores at the end of the treatment period (49.1 ± 2.4 vs. 73.1 ± 2.05 and 146.1 ± 2.7 vs. 176.7.1 ± 3.4 respectively, P < 0.001), but not in the inflammatory indicators (EBT, CRP and Eos). However, when comparing the "top responders" with the "poor responders", significant improvement in these inflammatory indicators was observed: EBT significantly decreased from 34.04/mean/± 0.30/s.e.m./[°C] to 33.57 ± 0.33, P = 0.003, Eos in blood fell from 381.7 ± 91.2 [cells/μL] to 244.2 ± 43.2, P = 0.02. Before/after treatment differences in hsCRP decreased significantly in the top responders compared with the poor responders (Mann-Whitney test, P = 0.04).. Asthmatic subjects who had the most improvement in FVC after transition to I-EF-BDP/F from other combined ICS/LABA preparations also demonstrated a significant decrease in some indicators of airway/systemic inflammation. These results support the notion that I-EF-BDP/F exerts an effect also at the level of the small airways through a reduction of the level of air trapping. Patients in whom inflammation of the small airways plays an important clinical role are the ones to derive most benefit from this small airways tailored treatment. However, improved compliance due to the "promise of a new drug" effect should also be considered as contributing to the treatment results.

Topics: Administration, Inhalation; Adult; Albuterol; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; C-Reactive Protein; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Particle Size; Quality of Life; Spirometry; Statistics, Nonparametric; 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

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

Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bronchodilator Agents; Eosinophilia; Female; Glucocorticoids; Humans; Inflammation; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Sputum; Treatment Outcome

Extra-fine particle formulations of hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) exhibit clinical effects comparable with conventional particle formulations of chlorofluorocarbon beclometasone dipropionate (CFC-BDP) at half the dose. There is little data comparing their effects on inflammation. We have evaluated the effects of HFA-BDP and CFC-BDP on pulmonary and systemic markers of asthmatic inflammation.. A double-blind randomized crossover trial was undertaken comparing the anti-inflammatory effects of HFA-BDP (100 and 400 microg/day) and CFC-BDP (200 and 800 microg/day). Treatment with montelukast was evaluated as add-on to the higher dose of BDP.. Compared with baseline after withdrawal of usual asthma therapy, 100 microg of HFA-BDP significantly attenuated serum eosinophilic cationic protein levels (0.61-fold change, 95% CI 0.49-0.77; a 39% reduction, P < 0.001), but 200 microg of CFC-BDP did not (0.87-fold change, 95% CI 0.63-1.23; P = 1). A dose of 800 microg of CFC-BDP and 400 microg of HFA-BDP led to reductions in exhaled nitric oxide (0.57-fold change, 95% CI 0.44-0.73; a 43% reduction, P < 0.001 and 0.65-fold change, 95% CI 0.47-0.91; a 35% reduction, P = 0.008, respectively); and peripheral eosinophils (-74 cells/microl, 95% CI -146 to -2; P = 0.020 and -77 cells/microl, 95% CI -140 to -14; P = 0.012, respectively). Montelukast further reduced exhaled nitric oxide (0.81-fold change, 95% CI 0.66-0.98; P = 0.028) with 400 microg HFA-BDP and eosinophils (-44 cells/microl, 95% CI -80 to -8; P = 0.012) with 800 microg CFC-BDP, but not vice versa.. Chlorofluorocarbon beclometasone dipropionate and HFA-BDP have differential effects on pulmonary and systemic inflammation, which dictate the additive effects of montelukast.

Topics: Acetates; Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Chemistry, Pharmaceutical; Chlorofluorocarbons; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Humans; Hydrocarbons, Fluorinated; Inflammation; Nitric Oxide; Particle Size; Quinolines; Sulfides

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

Exhaled nitric oxide (eNO) is an easily measured marker of airway inflammation. This study was undertaken to evaluate the usefulness of serial eNO in investigating the dose-response relationship for inhaled beclomethasone (BDP), and to compare eNO with other markers of airway inflammation. Following withdrawal of inhaled corticosteroid (ICS) therapy, 65 patients entered a double-blind, parallel-group, placebo-controlled trial of 50, 100, 200 or 500 microg x BDP x day(-1) for eight weeks. eNO and spirometry were performed weekly and a hypertonic saline challenge with sputum induction was performed at the beginning and end of treatment. The relationship between the dose of ICS and changes in eNO and forced expiratory volume in one second (FEV1) was linear at 1 week and at the end of treatment. A linear dose-response relationship was also seen for sputum eosinophils. Changes in eNO correlated significantly with changes in sputum eosinophils. Changes in the provocative dose of saline causing a 15% fall in FEV1 saline did not differ across the treatment groups nor did they correlate with changes in other measurements. Exhaled nitric oxide may be used to assess the dose-response relationship for the anti-inflammatory effects of inhaled beclomethasone. The relationship found in this study was linear over the dose range 0-500 microg x day(-1) soon after commencing therapy and continued over time.

Topics: Administration, Inhalation; Adult; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Breath Tests; Bronchial Hyperreactivity; Dose-Response Relationship, Drug; Double-Blind Method; Eosinophils; Female; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Peak Expiratory Flow Rate; Saline Solution, Hypertonic; Sputum

The hypothesis that eosinophilic airway inflammation is present in many patients presenting with respiratory symptoms suggestive of asthma but with normal lung function was tested. Thirty-six consecutive patients presenting with these features were studied. Twenty-five asthmatics and 43 healthy volunteers served as control groups. Signs of eosinophilic inflammation in blood and induced sputum were studied. Patients with respiratory symptoms were single-blindly treated with inhaled beclomethasone dipropionate (BDP), 800 microg daily, or placebo for 3 months, and re-examined at 3 months and 1 yr. Patients with respiratory symptoms had higher numbers of blood and sputum eosinophils than healthy persons (p<0.0001), but the degree of eosinophilic inflammation was less pronounced than in asthmatics (p<0.01). Three-month's treatment with BDP significantly reduced total symptom score (p<0.001), cough score (p<0.0001), and the number of blood eosinophils (p<0.01). For cough alone, the improvement was significant compared with placebo (p<0.05). The patients were followed-up for 1 yr, and 17 (55%) still had symptoms but retained normal lung function. Four (13%) patients had developed asthma and another 10 (32%) had become free of symptoms. Using lung function measurements and induced sputum analyses, a group of patients with symptoms suggestive of asthma and signs of eosinophilic airway inflammation but without enough airflow variability to be diagnosed as asthmatics were detected. They seemed to respond favourably to inhaled beclomethasone dipropionate treatment.

Topics: Administration, Inhalation; Adult; Anti-Inflammatory Agents; Asthma; Beclomethasone; Blood Cells; Eosinophilia; Female; Follow-Up Studies; Humans; Inflammation; Lung; Male; Middle Aged; Reference Values; Respiratory Tract Diseases; Single-Blind Method; Sputum

To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers.. This was a randomized, placebo-controlled, double-blinded clinical trial.. The subjects were recruited from the community by advertising.. Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily.. Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days.. Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment.. With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.

Topics: Administration, Inhalation; Adult; Anti-Inflammatory Agents; Beclomethasone; Bronchi; Bronchial Provocation Tests; Double-Blind Method; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Inflammation; Lung; Male; Maximal Midexpiratory Flow Rate; Mucous Membrane; Nebulizers and Vaporizers; Neutrophils; Permeability; Radiopharmaceuticals; Smoking; Sputum; Technetium Tc 99m Pentetate; Vital Capacity

Bronchial asthma is characterized by airway wall remodeling. Matrix metalloproteinases (MMPs) are members of a family of proteolytic enzymes that degrade the extracellular matrix and that restrain the effects of their tissue inhibitors (TIMPs). Treatment with inhaled corticosteroids may prevent airway remodeling in asthma. However, the effects of corticosteroid treatment on MMPs and TIMPs in asthma are unknown.. We examined the effects of inhaled beclomethasone dipropionate (BDP) on the expression of MMP-9 and TIMP-1 and subepithelial collagen deposition in bronchial biopsy specimens from 30 subjects with asthma.. Inhaled BDP, 800 microg daily, or placebo was administered for 6 months in a double-blind, parallel-group study, and bronchial biopsies were performed before and after treatment. Biopsy specimens were examined for extent of collagen type III in the subepithelial basement membrane by means of immunohistochemistry, and expression of both epithelial and submucosal MMP-9 and TIMP-1 was quantitated. Numbers of inflammatory cells were also determined.. We observed significant decreases in collagen type III deposition (P <.01) and the expression of submucosal MMP-9 (P <.01) and a significant increase in the expression of submucosal TIMP-1 (P <.05) in the BDP group. Significant correlations were found between the subepithelial collagen type III deposition and epithelial (r (s ) = 0.37, P <.05) and submucosal expression of MMP-9 (r (s ) = 0.47, P <.01). Additionally, the number of many inflammatory cells and myofibroblasts in airway mucosa were significantly decreased in the BDP group.. Our findings suggest that corticosteroid treatment of asthma can reduce subepithelial collagen deposition by downregulation of MMP-9 expression and upregulation of TIMP-1 expression.

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Asthma; Beclomethasone; Biopsy; Bronchi; Collagen; Collagenases; Female; Humans; Inflammation; Male; Matrix Metalloproteinase 9; Middle Aged; Mucous Membrane; Placebos; Tissue Inhibitor of Metalloproteinase-1

Pathological studies of bronchial biopsy specimens have confirmed the apparent thickening of lamina reticularis of the epithelial basement membrane. Corticosteroids have proven to be most effective in modifying airway inflammation. However, there is not much data on the effects of corticosteroid-treatment on the basement membrane.. To investigate the effects of inhaled beclomethasone dipropionate (BDP) on the thickness of basement membrane and cellular infiltration into the bronchial mucosa, and the expression of growth factors in patients with asthma.. We studied bronchial biopsies from 24 asthmatic patients before and after treatment with inhaled BDP, 400 microg twice a day or placebo, for 6 months in a double-blind manner. Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. The thickness of the basement membrane was determined by electron microscopy. Inflammatory cells and the expression of growth factors were examined by immunohistochemistry in endobronchial biopsy specimens.. After 6 months of treatment, we observed a significant improvement of asthma symptoms (P<0.01), PEF (P<0.01), diurnal variation of PEF (P<0.05), and airway responsiveness (P< 0.05) in the BDP group compared with the placebo group. This was accompanied by a significant decrease in the thickness of the lamina reticularis (P < 0.001), and in the number of activated eosinophils (P<0.01), T-lymphocytes (P<0.01), and fibroblasts (P < 0.05) in BDP-treated patients. There was also a reduction in the expression of insulin-like growth factor (IGF)-I (P < 0.01). Significant correlation was found between the IGF-I expression and collagen thickening (rs = 0.34, P<0.01), and the number of fibroblasts (rs = 0.45, P < 0.01).. These results suggest that corticosteroid treatment in asthma can reduce the lamina reticular thickness by modulation of IGF-I expression with consequent inhibition of the airway infiltration by inflammatory cells, and therefore may help to prevent remodelling of the airways.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Basement Membrane; Beclomethasone; Bronchi; Bronchoscopy; Double-Blind Method; Forced Expiratory Volume; Humans; Inflammation; Insulin-Like Growth Factor I; Microscopy, Electron; Middle Aged; Mucous Membrane; Peak Expiratory Flow Rate

The measurement of exhaled nitric oxide (ENO) is recognized as a marker of airway inflammation. ENO was measured in 10 nonsteroid-treated asthmatics at recruitment, during 3 weeks of inhaled beclomethasone (1000 microg/day) and for 3 weeks after withdrawal. Baseline ENO was increased in asthma compared with nonasthmatics (85.0+/-54.5 vs. 24.5+/-14.8 ppb, p < 0.0001). After inhaled steroid, there was no significant change in forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC), but methacholine PC20 rose significantly (p = 0.0345). ENO (mean+/-SD; % baseline) fell after 1 week on steroid to 60.6+/-31.1 and rose to 95.3+/-46.1 at 1 week after withdrawal. ENO did not correlate with PC20 or FEV1. The changes in ENO and PC20 were inversely correlated (r2 = 0.325). ENO may be an index of airway inflammation and therapeutic response in bronchial asthma.

Topics: Administration, Inhalation; Adult; Asthma; Beclomethasone; Breath Tests; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cross-Over Studies; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Methacholine Chloride; Nitric Oxide; Vital Capacity

The object of this study was to examine the hypothesis that meter-dosed, inhaled beclomethasone administered to premature infants beginning at birth in a tapering dosage schedule over the first 12 days of life attenuates bronchoalveolar lining fluid oxyradical inflammation concomitant with modulation of bronchopulmonary dysplasia. The design of this study was an unblinded, uncontrolled phase I, pilot investigation of inhaled beclomethasone primarily examining safety and administration. The setting was a tertiary care neonatal intensive care unit. Intubated, premature infants were studied longitudinally to 36 weeks corrected gestational age. Meter-dosed, inhaled beclomethasone was administered in a tapering dosage schedule over the first 12 days of life. Endotracheal tube aspirates were collected on Days 2, 4, and 6 of life and assayed for various markers of bronchoalveolar lining fluid oxyradical stress. Infants were also assessed with regards to a number of relevant clinical variables and presence or absence of bronchopulmonary dysplasia at 36 weeks corrected gestational age. Although no differences in clinical outcome were apparent in comparing nine control infants with nine beclomethasone-treated infants, bronchoalveolar lining fluid from control infants exhibited evidence of apparent phospholipid peroxidation (enhanced polyunsaturated fatty acid consumption) on Day 2 of life compared to beclomethasone-treated infants. Significant differences were noted for percent arachidonic acid, total polyunsaturated fatty acids and ratio of polyunsaturated fatty acids, to saturated fatty acids. The ratio of monohydroxyl linolenic acid to native linoleic acid (a more specific marker of lipid peroxidation) as well as myeloperoxidase activity (a marker of neutrophil oxyradical stress) tended to be higher in the control group but did not achieve statistical significance for this small subject number study. No adverse reactions related to meter-dosed, inhaled beclomethasone were noted in the treatment group; most specifically no evidence of hypothalamic-pituitary-adrenal axis suppression was noted in either control or beclomethasone-treated infants. Meter-dosed, inhaled beclomethasone in the dosage schedule utilized was safe and appeared to moderate bronchoalveolar lining fluid phospholipid peroxidation. Small numbers of infants entered into the present investigation preclude comments on clinical efficacy because of the likelihood of a statistical type 2 error. However

Topics: Administration, Inhalation; Beclomethasone; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Fatty Acids; Female; Gestational Age; Humans; Hypothalamo-Hypophyseal System; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Lipid Peroxidation; Lung Diseases; Male; Nebulizers and Vaporizers; Peroxidase; Phospholipids; Pilot Projects; Pituitary-Adrenal System; Reactive Oxygen Species; Severity of Illness Index

Chronic bronchitis is associated with airways obstruction and inflammation. In order to determine whether aerosolized beclomethasone can modulate airway inflammation and diminish airway obstruction, subjects with chronic bronchitis performed spirometry and underwent bronchoalveolar lavage (BAL) before and after receiving 6 wk of therapy (five puffs four times a day) with either aerosolized beclomethasone (n = 20) or placebo (n = 10) in a double-blinded, randomized fashion. All subjects received aerosolized albuterol before each use of the study medications. Before BAL, the airways were visually assessed for the appearance of inflammation and assigned a score, the bronchitis index. BAL was performed by instilling five 20-ml aliquots of saline into each of three sites and pooling and separately analyzing the returns from the first aliquots to yield a "bronchial sample." The bronchial lavages were repeated in an additional three sites to increase the volume of fluid available for analysis. The fluid was prepared for cytologic examination by cytocentrifugation. Albumin (as a measure of epithelium permeability) and lactoferrin and lysozyme (as measures of serous cell activity) were measured in unconcentrated BAL fluid by enzyme-linked immunosorbent assay, and concentrations in epithelial lining fluid were estimated using urea as an internal marker for dilution. After treatment, the beclomethasone group, but not the placebo group, showed improvement in FVC (p = 0.02), FEV1 (p = 0.002), and 25 to 75% forced expiratory flow (p = 0.006). Associated with the improvement in spirometry, the bronchitis index fell (13.5 +/- 1.0 versus 10.75 +/- 1.1, p = 0.02) in the beclomethasone-treated group, but not the placebo-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adult; Aerosols; Airway Obstruction; Albumins; Beclomethasone; Blood Gas Analysis; Bronchitis; Bronchoalveolar Lavage Fluid; Bronchoscopy; Chronic Disease; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Inflammation; Lactoferrin; Male; Middle Aged; Muramidase; Smoking; Transferrin; Vital Capacity

Asthma is a chronic lung disease that injures and constricts the airways. This study evaluates the effects of agmatine on ovalbumin (OVA)-induced allergic inflammation of the airways.. OVA sensitization by intraperitoneal injection was used to induce airway inflammation in mice on days 0 and 7; then the mice were challenged using beclomethasone (150 µg/kg, inhalation), a standard anti-asthmatic drug, from day 14 to day 16. Furthermore, agmatine (200 mg/kg) was intraperitoneally injected on day 0 and then daily for 16 days, followed by OVA challenge. The lung weight ratio, total and differential cell counts, TNF-α, interleukin-5 (IL-5) and IL-13 in bronchoalveolar lavage fluid (BALF), lung nitrite/nitrate (NO), and oxidative parameters were determined. Moreover, histopathological and immunohistochemical staining was employed.. Injection of agmatine (200 mg/kg) for 16 days significantly attenuated inflammation of the airways. The levels of BALF inflammatory cells, TNF-α, IL-5, IL-13, lung NO, and malondialdehyde (MDA), significantly decreased with concomitant elevation of superoxide dismutase (SOD) levels. Histological and immunohistochemical analyses of mast cells paralleled to biochemical improvements.. Finally, this study illustrated that agmatine attenuates the allergic inflammation of airways caused by OVA by mitigating cytokines release, NO expression, and oxidative stress.

Topics: Agmatine; Animals; Anti-Asthmatic Agents; Beclomethasone; Cytokines; Disease Models, Animal; Inflammation; Interleukin-13; Interleukin-5; Lung; Malondialdehyde; Mice; Mice, Inbred BALB C; Nitrates; Nitrites; Ovalbumin; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis.. We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment.. Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD.. Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Topics: Adrenal Cortex Hormones; Beclomethasone; Colitis; Diarrhea; Humans; Immune Checkpoint Inhibitors; Inflammation; Male; Retrospective Studies

Glucocorticoid drugs are widely used to treat immune-related diseases, but their use is limited by side effects and by resistance, which especially occurs in macrophage-dominated diseases. In order to improve glucocorticoid therapies, more research is required into the mechanisms of glucocorticoid action. In the present study, we have used a zebrafish model for inflammation to study glucocorticoid effects on the innate immune response. In zebrafish larvae, the migration of neutrophils towards a site of injury is inhibited upon glucocorticoid treatment, whereas migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in the expression of genes that encode neutrophil-specific chemoattractants (Il8 and Cxcl18b) are attenuated by the synthetic glucocorticoid beclomethasone, but that beclomethasone does not attenuate the induction of the genes encoding Ccl2 and Cxcl11aa, which are required for macrophage recruitment. RNA sequencing on FACS-sorted macrophages shows that the vast majority of the wounding-induced transcriptional changes in these cells are inhibited by beclomethasone, whereas only a small subset is glucocorticoid-insensitive. As a result, beclomethasone decreases the number of macrophages that differentiate towards a pro-inflammatory (M1) phenotype, which we demonstrated using a

Topics: Amputation, Surgical; Animals; Beclomethasone; Cell Differentiation; Cell Movement; Cell Tracking; Chemotactic Factors; Gene Expression Regulation; Glucocorticoids; Inflammation; Larva; Macrophages; Morpholinos; Neutrophils; Phenotype; Transcriptome; Wound Healing; Zebrafish

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

The impact of inhaled corticosteroids (ICS) on eosinophilic inflammation in asthma is well established, but their effect in a real-life setting has not been extensively studied. Our purpose was to investigate the effect of ICS on airway and systemic inflammation as well as on clinical outcomes in patients with asthma from clinical practice.. We conducted a retrospective analysis on asthmatics from a secondary care centre in whom ICS were initiated/increased (n=101), stopped/decreased (n=60) or remained stable (n=63, used as a control group) between two visits with available sputum and blood cell counts.. Our results confirm the effectiveness of ICS on eosinophilic inflammation in real life and demonstrate that their clinical benefit seems to be restricted to eosinophilic asthmatics. Our data also support a try for stepping-down ICS in non-eosinophilic asthmatics.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Asthma; Beclomethasone; Case-Control Studies; Dose-Response Relationship, Drug; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Quality of Life; Respiratory Function Tests; Retrospective Studies; Sputum

Glucocorticoids are steroid hormones that are secreted upon stress. Their effects are mediated by the glucocorticoid receptor, which acts as a transcription factor. Because the antiinflammatory activity of glucocorticoids has been well established, they are widely used clinically to treat many inflammatory and immune-related diseases. However, the exact specificity, mechanisms, and level of regulation of different inflammatory pathways have not been fully elucidated. In the present study, a tail fin amputation assay was used in 3-day-old zebrafish larvae to study the immunomodulatory effects of the synthetic glucocorticoid beclomethasone. First, a transcriptome analysis was performed, which showed that upon amputation mainly immune-related genes are regulated. This regulation was inhibited by beclomethasone for 86% of regulated genes. For two immune-related genes, tlr4bb and alox5ap, the amputation-induced increase was not attenuated by beclomethasone. Alox5ap is involved in eicosanoid biosynthesis, but the increase in leukotriene B4 concentration upon amputation was abolished, and lipoxin A4 levels were unaffected by beclomethasone. Furthermore, we studied the migration of neutrophils and macrophages toward the wound site. Our results show that amputation induced migration of both types of leukocytes and that this migration was dependent on de novo protein synthesis. Beclomethasone treatment attenuated the migratory behavior of neutrophils in a glucocorticoid receptor-dependent manner but left the migration of macrophages unaffected. In conclusion, beclomethasone has a dramatic inhibitory effect on the amputation-induced proinflammatory gene regulation, and this is reflected in an inhibition of the neutrophil migration but not the migration of macrophages, which are likely to be involved in inflammation resolution.

Topics: Animals; Beclomethasone; Cell Movement; Gene Expression Profiling; Gene Expression Regulation; Glucocorticoids; Inflammation; Macrophages; Neutrophils; Receptors, Glucocorticoid; Wound Healing; Zebrafish

The study included 38 men with moderately severe chronic obstructive pulmonary disease (COPD) (mean age 60.6 ± 10.2 yr) and 42 ones with severe COPD (mean age 61.2 ± 7.2 yr). They were treated with tiotropium bromide, formoterol and beclomethasone dipropionate for 24 weeks (stage 1), TB alone for 12 weeks (stage 2) and TB+formoterol (long-acting bronchodilators, LABD) for another 12 weeks. Each stage was followed by evaluation of COPD symptoms using the St-George's Hospital questionnaire, daily requirements for short-acting beta-2 agonists (SABA), heart rate (HR), forced expiratory volume in the 1st second (FEV-1) before and after SABA test, hemoglobin saturation with oxygen in arterial blood during pulse oxymetry before and after 6 min walking test, blood surfactant protein D level (SP-D). The control group was comprised of 34 healthy men (mean age 62.3 ± 5.8 yr). Patients with moderately severe COPD experienced worsening of clinical symptoms (p < 0.001), required more SABA (p < 0.001), had increased HR (p = 0.01) and SP-D levels (p = 0.01) whereas FEV-1 (p = 0.05) decreased during stage 2 as compared with stage 1. Positive dynamics of all these variables except COPD symptoms and HR was observed at stage 3. Alteration in the extent of basal therapy in patients with stage III COPD did not result in dynamics of clinical and laboratory characteristics. The data obtained suggest the necessity of combined therapy with LABD or triple basal therapy of moderately severe COPD and the possibility of therapy with one or two LABD having different sites of action in the patients with clinically stable stage II COPD.

Topics: Aged; Anti-Asthmatic Agents; Beclomethasone; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

This study examined the effect of montelukast and beclomethasone on airway remodeling in murine model of asthma. Mice were sensitized by i.p. injection of ovalbumin (OVA) on days 0 and 14, and then challenged by nebulization of 1% OVA 3 days/week for 6 or 10 weeks. Results of 6-week OVA-challenged group showed moderate inflammation, but the 10-week OVA-challenged group exhibited mild inflammation. The OVA challenge (6 and 10 weeks) exhibited marked airway fibrosis, illustrated by significant increase in goblet cell hyperplasia and epithelial thickness, increased lung content of collagen and transforming growth factor-β(1), together with a decrease in nitric oxide production; also, there was an increase in bronchoalveolar lavage fluid level of interleukin-13. Administration of montelukast or beclomethasone before each OVA challenge was capable of restoring most of the measured parameters to near normal levels. Inhalation of beclomethasone has a similar role in airway remodeling as montelukast, but its effects in regulating inflammatory changes is less pronounced than montelukast.

Topics: Acetates; Administration, Inhalation; Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Beclomethasone; Cyclopropanes; Disease Models, Animal; Inflammation; Male; Mice; Ovalbumin; Quinolines; Severity of Illness Index; Sulfides; Time Factors

We describe two cases of peristomal inflammation which resulted in pain, poor adhesion of the stoma bag and faecal leaking. The inflammation did not respond to regular cleaning and barrier film sprays, but dramatically improved with the application of a beclometasone dry powder aerosol inhaler sprayed onto the inflamed skin around the stoma site. A steroid inhaler was used to decrease the peristomal inflammation without affecting the adhesion of the stoma bag which could be caused by creams.

Topics: Aged; Beclomethasone; Dermatitis; Enterostomy; Glucocorticoids; Humans; Inflammation; Male; Middle Aged; Nebulizers and Vaporizers; Surgical Stomas; Treatment Outcome

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

Topics: Anti-Asthmatic Agents; Asthma; Beclomethasone; Humans; Inflammation; Radiography, Thoracic

These studies were designed to assess the pharmacodynamic interaction between formoterol and beclomethasone dipropionate (BDP) in controlling the bronchoconstriction and inflammatory response induced by various challenges in guinea-pigs and rats. In anaesthetised guinea-pigs, superfusion of the formoterol/BDP combination into the tracheal lumen had significantly more effect than the single components in antagonising the bronchoconstricting and inflammatory responses to acetylcholine or ovalbumin in a standard model of airway hyper-responsiveness. After ovalbumin challenge, the combination completely protected animals from death at doses lower than those effective when given separately. The combination, at doses ineffective individually, even counteracted the development of lung oedema induced by sephadex in the rat. Finally, in tracheal strips from ovalbumin-sensitised guinea-pigs pre-treatment with BDP (30 mg kg(-1) i.m.) completely reversed the rightward shift of the formoterol dose-response curve due to beta(2)-receptor desensitisation. In conclusion, these results indicate that formoterol and BDP together induce a favourable pharmacodynamic interaction which can be considered more than additive, at least in these experimental settings.

Topics: Acetylcholine; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Albuterol; Animals; Anti-Inflammatory Agents; Beclomethasone; Bronchial Hyperreactivity; Bronchoconstriction; Bronchodilator Agents; Dextrans; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Ethanolamines; Formoterol Fumarate; Guinea Pigs; Inflammation; Male; Ovalbumin; Pulmonary Edema; Rats; Receptors, Adrenergic, beta-2; Trachea

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

Airway wall thickening has been assumed to cause airway hyperresponsiveness, but a protective effect against airway narrowing has also been suggested. We investigated the relationship between airway wall thickness as assessed by helical computed tomography and two components of airway responsiveness, airway sensitivity and reactivity, in patients with stable asthma with (n = 23) and without (n = 22) inhaled steroid treatment. A cross-section of the apical bronchus of the right upper lobe was obtained. Airway wall area corrected by body surface area was measured as an index of wall thickness. Airway sensitivity and reactivity were measured by continuous inhalation of methacholine, on the basis of the methacholine respiratory resistance dose-response curve. The eosinophil count in sputum was determined in 16 patients [steroid (+) group] and 14 patients [steroid (-) group]. In both groups of patients, airway sensitivity was not related to airway reactivity. Airway sensitivity was related to eosinophil count [r = 0.57 in the steroid (+) group and r = 0.49 in the steroid (-) group], but not to airway wall thickness. In contrast, airway reactivity negatively correlated with airway wall thickness [r = -0.56 in the steroid (+) group and r = -0.55 in the steroid (-) group] but not with eosinophil count. Our results suggest that airway wall thickening attenuates airway reactivity in patients with asthma. These findings may have important implications in pathophysiology and in the treatment of airway remodeling.

Topics: Adrenergic beta-Agonists; Aged; Airway Resistance; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Eosinophils; Female; Forced Expiratory Volume; Humans; Hyperplasia; Hypertrophy; Inflammation; Leukocyte Count; Male; Methacholine Chloride; Middle Aged; Severity of Illness Index; Sputum; Tomography, X-Ray Computed

Topics: Administration, Inhalation; Antioxidants; Asthma; Beclomethasone; Glucocorticoids; Humans; Inflammation; Nitrates; Nitrites; Peroxynitrous Acid; Sputum

Damage to the airway epithelium is one prominent feature of chronic asthma. Corticosteroids induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, corticosteroid therapy does not necessarily reverse epithelial damage. We hypothesized that corticosteroids may induce airway epithelial cell apoptosis as one potential explanation for persistent damage. We tested this hypothesis in cultured primary central airway epithelial cells and in the cell line 1HAEo(-). Treatment with dexamethasone, beclomethasone, budesonide, or triamcinolone each elicited a time-dependent and concentration-dependent cell death. This cell death was associated with cleavage of nuclear chromatin, mitochondrial depolarization, cytochrome c extrusion, activation of caspase-9, and expression of phosphatidylserine on the outer cell membrane. Inhibitors of caspase activity blocked apoptotic cell death, as did overexpression of the apoptosis regulators Bcl-2 or Bcl-x(L). We demonstrated that CD95 ligation is not essential for the corticosteroid-induced apoptosis in airway epithelial cells. These data demonstrate that corticosteroids induce apoptotic cell death of airway epithelium. This raises the possibility that at least one of the major components of chronic airway damage in asthma, epithelial shedding and denudation, may in part result from a major therapy for the disease.

Topics: Anti-Asthmatic Agents; Anti-Inflammatory Agents; Apoptosis; Asthma; bcl-X Protein; Beclomethasone; Bronchodilator Agents; Budesonide; Caspase 9; Caspases; Cells, Cultured; Chronic Disease; Cytochrome c Group; Dexamethasone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; fas Receptor; Genes, bcl-2; Humans; Inflammation; Proto-Oncogene Proteins c-bcl-2; Receptors, Interleukin-2; Respiratory Mucosa; Time Factors; Triamcinolone

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

The effect of changes of airway inflammation on airway nonspecific reactivity were studied in 29 patients with chronic asthma. Detailed examinations of bronchial lavage (BAL) fluid and airway responses to histamine, propranolol and exercise were performed before and after treatment. The patients treated with steroids had significant improvements in parameters of BAL fluid cells and mediators with consistent changes of decreasing airway reactivities to propranolol and exercise after treatment. Whereas no significant changes occurred in the patients treated with B2-agonist either in inflammatory parameters or airway responses. On the other hand, airway response to histamine changed little in all asthmatic patients. Our study implied that inhibiting the airway inflammation in asthmatics may lead to marked decrease of airway response to non-mediator stimuli but fail to attenuate bronchial hyperresponse to mediator stimuli like histamine.

Topics: Adult; Albuterol; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Exercise Test; Forced Expiratory Volume; Histamine; Humans; Inflammation; Middle Aged; Propranolol

The very potent topical anti-inflammatory glucocorticosteroids (GCS) most widely used are either 17 alpha-esters of halogenated 16-methyl-17 alpha-hydroxycorticosteroids (e.g. beclomethasone 17 alpha, 21-dipropionate = BDP) or 16 alpha, 17 alpha-acetals of halogenated 16 alpha, 17 alpha-dihydroxy corticosteroids (e.g. triamcinolone acetonide = TA). The purpose of the present investigation was to increase the ratio between the topical anti-inflammatory (TAIP) and the systemic potencies (SP) of GCS 16 alpha, 17 alpha-acetals, as such compounds are not biotransformed in the lung. Structure-activity investigations in rodents showed that fluoro substituents in positions 6 alpha or 9 alpha or both 6 alpha, 9 alpha 9 alpha increased SP more than TAIP. On the other hand, nonsymmetrical 16 alpha, 17 alpha-acetal substitution increased TAIP more than SP. The best TAIP:SP ratio was obtained with budesonide, which contains this new type of acetal substituent, but has no halogen atoms in the steroid nucleus. In the rat and the mouse budesonide has a 5--10 times better TAIP:SP ratio than 16 alpha, 17 alpha-acetonides, like TA, as well as 17 alpha-ester GCS, like BDP. The improved ratio for budesonide is probably due to a high intrinsic GCS activity at the site of application combined with an effective inactivation by biotransformation after systemic absorption. The importance of the inactivation in the liver was verified by experiments in which the biotransformation capacity of the liver was blocked by SKF-525 A.

Topics: Animals; Asthma; Beclomethasone; Budesonide; Glucocorticoids; Humans; Inflammation; Male; Mice; Mice, Inbred Strains; Pregnenediones; Rats; Rats, Inbred Strains

Topical anti-inflammatory ('intracutaneous vasoconstriction') and systemic glucocorticoid potencies (depression of plasma cortisol) were compared in human volunteers after administration of the glucocorticoids budesonide, beclomethasone dipropionate (BDP) and prednisolone. After topical application budesonide was about twice as potent as BDP and more than 1 000 times more potent than prednisolone and hydrocortisone in inducing 'vasoconstriction'. After oral administration, on the other hand, budesonide was one half to one third as potent as BDP in depressing plasma cortisol. After inhalation budesonide was only half as potent as BDP. When inhaled budesonide was compared to oral prednisolone budesonide 1 600 micrograms and prednisolone 5 mg were shown to have the same effect on plasma cortisol. The improved ratio between the topical and the systemic glucocorticoid effect of budesonide, makes the drug a promising alternative for aerosol treatment in asthma.

Topics: Adult; Beclomethasone; Budesonide; Dose-Response Relationship, Drug; Humans; Inflammation; Middle Aged; Prednisolone; Pregnenediones