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Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex.To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p0.012) and prevented by antioxidants. Oxidants reduced (p0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress.Ineffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.

BACKGROUND: Increased numbers of activated neutrophils have been reported in the bronchial mucosa of patients with stable chronic obstructive pulmonary disease (COPD), particularly in severe disease. OBJECTIVES: To investigate the expression of neutrophilic chemokines and adhesion molecules in bronchial biopsies from patients with stable COPD of different severity (GOLD stages I-IV) compared with age-matched control subjects, smokers with normal lung function and never smokers. METHODS: The expression of CCL5, CXCL1, 5, 6, 7 and 8, CXCR1, CXCR2, CD11b and CD44 was measured in the bronchial mucosa using immunohistochemistry, confocal immunofluorescence, real-time quantitative polymerase chain reaction (RT-QPCR) and Western blotting (WB). RESULTS: The numbers of CCL5+ epithelial cells and CCL5+ and CXCL7+ immunostained cells were increased in the bronchial submucosa of patients with stable severe COPD compared with control never smokers and smokers with normal lung function. This was also confirmed at the level of mRNA expression. The numbers of CCL5+ cells in the submucosa of patients with COPD were 2-15 times higher than any other chemokines. There was no correlation between the number of these cells and the number of neutrophils in the bronchial submucosa. Compared with control smokers, the percentage of neutrophils co-expressing CD11b and CD44 receptors was significantly increased in the submucosa of patients with COPD. CONCLUSION: The increased expression of CCL5 and CXCL7 in the bronchial mucosa of patients with stable COPD, together with an increased expression of extracellular matrix-binding receptors on neutrophils, may be involved in the pathogenesis of COPD.

Background: The predominant emphysema phenotype is associated with more severe airflow limitation in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate whether COPD patients, with or without emphysema quantitatively confirmed by high resolution computed tomography (HRCT), have different COPD severity as assessed by the BODE index (body mass index, airflow obstruction, dyspnoea, exercise performance) and inspiratory capacity to total lung capacity ratio (IC/TLC), and by different biological markers of lung parenchymal destruction. Methods: Twenty six outpatients with COPD and eight healthy non-smokers were examined. Each subject underwent HRCT scanning, pulmonary function tests, cell counts, and measurements of neutrophil elastase, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in induced sputum, as well as measurement of desmosine, a marker of elastin degradation in urine, plasma and sputum. Results: Patients with HRCT confirmed emphysema had a higher BODE index and lower IC/TLC ratio than subjects without HRCT confirmed emphysema and controls. Forced expiratory volume in 1 second (FEV 1 ), FEV 1 /forced vital capacity ratio, and carbon monoxide transfer coefficient were lower, whereas the number of eosinophils, MMP-9, and the MMP-9/TIMP-1 ratio in sputum were higher in patients with emphysema. In COPD patients the number of sputum eosinophils was the biological variable that correlated positively with the HRCT score of emphysema (p = 0.04). Conclusions: These results suggest that COPD associated with HRCT confirmed emphysema is characterised by more severe lung function impairment, more intense airway inflammation and, possibly, more serious systemic dysfunction than COPD not associated with HRCT confirmed emphysema.

Objectives The stepwise management of asthma outlined in the BTS/SIGN guideline recommends stepping down asthma patients where control is achieved. The aim of this analysis was to estimate the costs and health outcomes associated with step down of controlled patients on high dose fluticasone/salmeterol (FP/S 1000/100 μg daily) to either extrafine beclometasone/formoterol (BDP/F 400/24 μg) pMDI or medium dose FP/S (500/100 μg) dry powder in the UK setting. Methods A patient-level simulation Markov model was constructed to enable the simulation of a cohort of patients through three comparative arms (FP/S 1000/100, FP/S 500/100, BDP/F 400/24). Transition probabilities and healthcare resources costs were derived from a recent multinational clinical trial comparing BDP/F 400/24 μg vs FP/S 500/100 μg as step down therapy in asthma. Direct costs and health state utilities were sourced from UK costs and published literature. The cost of FP/S 1000/100 was calculated considering the dry powder formulation. An additional analysis was conducted considering the suspension formulation. The analysis was conducted from a UK health system perspective, based on 6 months horizon. Probabilistic sensitivity analyses were conducted. Results The analysis showed that there was an ICER (Incremental Cost-Effectiveness Ratio) of 32 000 GBP/QALY (Quality Adjusted Life Years) associated with high dose dry powder FP/S 1000/100 μg vs extrafine BDP/F 400/24 μg and an ICER of approximately 36 800 GBP/QALY associated with medium dose dry powder FP/S 500/100 μg vs BDP/F 400/24 μg. Additional analysis showed that there was an ICER of 85 200 GBP/QALY associated with high dose suspension formulation FP/S 1000/100 μg vs extrafine BDP/F 400/24 μg. Conclusions BTS/SIGN guideline recommend that when asthma control is achieved, treatment can be stepped down to the lowest dose that maintains control. It was found that maintaining controlled patients on high dose FP/S is not cost-effective. Extrafine BDP/F 400/24 μg daily can be considered to be a cost-effective option in the UK to maintain control of asthmatic patients stepped down from high dose FP/S 1000/100 μg daily dry powder or suspension formulations and the magnitude of cost effectiveness is estimated to be highest when stepping down from the suspension formulation.

Introduction Many patients with low risk of COPD exacerbations receive twice-daily ( bid ) LABA/ICS, salmeterol/fluticasone (SFC), for maintenance treatment. This study evaluated the effect of switching these patients to a once-daily ( od ) LABA, indacaterol, monotherapy. Methods INSTEAD was a 26-week double-blind, double-dummy study in patients aged ≥40 years, with moderate COPD (post-bronchodilator FEV 1 50–80% predicted) and no exacerbations in the past 12 months, who were receiving SFC 50/500 μg bid for ≥3 months prior to study entry. Patients were randomised (1:1) to continue with SFC 50/500 μg or to be switched (with no washout) to indacaterol 150 μg. The primary objective was to demonstrate non-inferiority of indacaterol to SFC, measured by trough FEV 1 after 12 weeks (non-inferiority margin: 60 mL). Trough FEV1 was also evaluated at 4, 8 and 26 weeks. TDI and SGRQ-C total scores were evaluated at Weeks 12 and 26; the annualised rate of exacerbations and safety were evaluated over 26 weeks. Results A total of581 patients were randomised (indacaterol: 293; SFC: 288); 85.4% completed the study. The primary endpoint was met, with a LSM difference in trough FEV 1 between indacaterol and SFC of –9 mL (95% CI: –45 to 26 mL; p = 0·002 for NI). There were no significant differences between treatments in trough FEV 1 at any of the other visits (Baseline and Weeks 4, 8 and 26). The TDI and SGRQ-C total scores and their responder rates were similar between two treatments, at both Weeks 12 and 26 (Table 1). During the 26 week treatment period, 79.5% and 74.7% of patients in the indacaterol and SFC groups, respectively, experienced no exacerbations. There was no statistically significant difference between treatments in the rate of all COPD exacerbations per year, with rates of 0.57 vs 0.67, respectively (RR 0.86 [95% CI 0.62, 1.20]; p = 0.367). Adverse events (AEs) and serious AEs were comparable between the treatment arms. Conclusion Indacaterol was non-inferior to SFC in terms of bronchodilation and showed similar efficacy in terms of breathlessness, health status, and exacerbation rate indicating that this group of patients can be switched from SFC to indacaterol 150 µg with no loss in efficacy.

Previous studies have suggested a role for an increased apoptosis of the endothelial cells in the pulmonary capillaries of the alveolar septa in the pathogenesis of human pulmonary emphysema.1 In animal models, circulating endothelial stem cells, characterised by the concomitant expression of CD34+, CD133 and vascular endothelial growth factor receptor 2 (VEGF-R2), may contribute to the repair of lung damage.2 However, it is unknown if a decrease in the blood of these stem cells contributes to the pathogenesis of pulmonary emphysema in humans. The aim of our study was to investigate by flow cytometry the number of total (CD34+) and endothelial stem (triple positive for CD34+/CD133/VEGF-R2) cells in the peripheral venous blood of current and …

Introduction and Objectives Asthma therapy reviews aim to minimise side-effects and achieve cost-effective asthma control. We set out to examine the impact of switching from a fixed dose combination therapy inhaled corticosteroid/long-acting β2 agonist (FDC ICS/LABA) therapy via dry power inhaler (DPI) or metered-dose inhaler (MDI) to beclometasone dipropionate/formoterol (BDP/FOR) via MDI at the same or reduced dose of ICS in stable patients. Methods We utilised the UK’s Optimum Patient Care Research Database to identify suitable primary care patients (aged 18–80 years) with asthma (diagnostic code and/or ≥2 asthma prescriptions in the last year) who were changed from FDC ICS/LABA to a prescription of BDP/FOR MDI at the same or lower BDP-equivalent ICS daily dose following a review of their existing ICS/LABA therapy. The number of exacerbations was measured as an outcome, with exacerbations defined as asthma related hospital, accident and emergency or out-of-hours attendance, GP consultations for lower respiratory tract infection and/or use of acute oral steroids (where asthma related includes all events with a lower respiratory Read code). All patients had 2 years of data: 1 year before and 1 year post therapy switch. Results Out of a total of 365 patients, 334 had complete data for the analysis. 80 of these received a lower dose of BDP/FOR while 254 received an equivalent dose. In the year immediately before their therapy review, 69.5% (n=232) of patients had no exacerbations, compared to 76.9% (n=257) of patients following the review (p=0.075 Wilcoxon signed ranks). Prior to review, 20.4% of patients had 1 exacerbation compared with 12.0% of patients after the change, while 10.2% of patients had >1 exacerbation compared with 11.1% of patients following the review. Conclusion These data suggest an increase in the number of patients not suffering from exacerbations and no deterioration in the number of exacerbations following the alteration in therapy. This indicates that BDP/FOR can be a valid therapy change in real-world patients on existing FDC ICS/LABA therapy.

Introduction and Objectives Combination therapy with an inhaled corticosteroid (ICS) and a long-acting s 2 -agonist (LABA) is the most effective treatment option for patients with asthma uncontrolled with ICS monotherapy.1 In practice, asthma symptoms remain uncontrolled or only partly controlled in many patients. A new therapy option for asthma combining the ICS fluticasone propionate (FLUT) and the LABA formoterol fumarate (FORM) in a single aerosol inhaler (FLUT/FORM; flutiform ® ), has been developed at doses of 100/10, 250/10 and 500/20 μg for twice-daily administration. In this analysis, data were pooled from up to five randomised, double-blind, parallel-group studies in order to assess the efficacy of FLUT/FORM in terms of improvement in lung function (as indicated by change in FEV 1 ). Methods The analysis included adults and adolescents with a range of asthma severities who were treated for 8 or 12 weeks with FLUT/FORM (100/10, 250/10 or 500/20 μg twice daily) or the equivalent nominal dose of FLUT monotherapy (100, 250 or 500 μg twice daily; five studies) or FORM monotherapy (10 μg twice daily; three studies). Results FLUT/FORM was associated with a significantly greater improvement in lung function, as indicated by change in FEV 1 , compared with its individual components (Abstract P110 table 1). FLUT/FORM was superior to FORM with regard to change in pre-dose FEV 1 from baseline to study end; the least-squares (LS) mean difference for FLUT/FORM vs FORM was 0.13 l (95% CI 0.07 to 0.19; p 1 from pre-dose at baseline to 2 h post-dose at study end (LS mean difference FLUT/FORM vs FLUT 0.15 L [95% CI 0.10 to 0.19; p Conclusions The combination of fluticasone/formoterol in a single aerosol inhaler is more effective than fluticasone or formoterol given alone in improving lung function for patients with a range of asthma severities.

Introduction and Objectives Asthma remains uncontrolled in many patients, as indicated by exacerbations, deteriorating symptoms and impaired quality of life. A new option has been developed for the maintenance treatment of asthma, combining the inhaled corticosteroid fluticasone propionate (FLUT) with the long-acting s2-agonist formoterol fumarate (FORM) in a single aerosol inhaler (FLUT/FORM; flutiform®). A pooled analysis of data from up to five randomised, double-blind, parallel-group phase 3 studies assessed the effects of FLUT/FORM on asthma exacerbations. Methods Adults and adolescents with mild, moderate or severe asthma were randomised to FLUT/FORM (100/10, 250/10 or 500/20 μg twice daily), the equivalent nominal dose of FLUT monotherapy (100, 250 or 500 μg twice daily; five studies) or FORM monotherapy (10 μg twice daily; three studies) for 8 or 12 weeks. The endpoints assessed were time to first exacerbation and proportion of patients experiencing an exacerbation. Exacerbations were defined as peak expiratory flow rate >30% below baseline, awakening at night due to asthma, use of rescue medication 3–4 times per day (each on =2 consecutive days; mild-to-moderate exacerbation), need for additional therapy, or emergency visit or hospitalisation due to asthma (severe exacerbation). Results Time to first exacerbation (any severity) was significantly longer with FLUT/FORM (n=641) than with FLUT (n=643; p=0.01). Similarly, time to first exacerbation was significantly longer with FLUT/FORM (n=341) than FORM (n=345; p Conclusions Fluticasone/formoterol significantly reduces the risk of asthma exacerbations compared with its individual components. Combination therapy with fluticasone and formoterol in a single aerosol inhaler may help to improve asthma control and reduce the risk of asthma exacerbations that can impair patients9 quality of life.

Introduction and Objectives Poor asthma control impacts on patients9 health and reduces their quality of life. Despite a rise in the proportion of patients receiving treatment, asthma remains uncontrolled in many patients. A new therapy option combining the inhaled corticosteroid fluticasone propionate (FLUT) with the long-acting s 2 -agonist formoterol fumarate (FORM) in a single aerosol inhaler (FLUT/FORM; flutiform ® ) has been developed for the treatment of asthma. This integrated analysis of data from five randomised, double-blind, parallel-group phase 3 studies assessed the effects of FLUT/FORM compared with FLUT alone on the percentage of asthma control days. Methods Symptomatic adult and adolescent patients with mild, moderate or severe asthma were randomly assigned to receive FLUT/FORM (100/10, 250/10 or 500/20 μg twice daily) or the equivalent nominal dose of FLUT alone (100, 250 or 500 μg twice daily) for 8 or 12 weeks. Most patients randomised to treatment had uncontrolled asthma. The percentage change in asthma control days (defined as those with no use of rescue medication, an asthma symptom score reporting no symptoms and a sleep disturbance score indicating that the patient slept through the night) was assessed from baseline to study end. Results At baseline, the percentage of asthma control days was low in both groups (FLUT/FORM [n=623]: 12.8%; FLUT [n=623]: 12.6%). FLUT/FORM combination therapy was superior to FLUT alone for improvement in percentage of asthma control days. At study end, patients in the FLUT/FORM group experienced a mean of 62.4% asthma control days, an improvement of 49.6% from baseline, whereas FLUT treatment was associated with 54.8% asthma control days (42.2% change from baseline). FLUT/FORM provided a statistically significant improvement in asthma control days compared with FLUT alone (least-squares mean difference [95% CI]: 7.5% [3.21 to 11.84]; p Conclusions Fluticasone/formoterol combination therapy is superior to fluticasone monotherapy for improving the percentage of asthma control days over 8 or 12 weeks9 treatment in adults and adolescents with mild, moderate or severe asthma. These data suggest the combination of fluticasone and formoterol in a single aerosol inhaler will provide an effective option for asthma maintenance therapy.