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Background Inhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma. Methods This phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2–3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of

Tanja Plate,1 Felix W Friedrich,1 Jutta Beier2 1AstraZeneca GmbH, Wedel, Germany; 2Insaf - Respiratory Research Institute GmbH, Wiesbaden, GermanyCorrespondence: Felix W FriedrichAstraZeneca GmbH, Tinsdaler Weg 183, Wedel D-22880, GermanyTel +49 162 1398835Fax +49 4103 70873707Email felix.friedrich@astrazeneca.comBackground: LABA (long-acting β 2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD. Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient. To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings.Objective and Methods: The main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice. Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended. Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures. Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™). Furthermore, a number of exacerbations and early morning COPD symptoms were documented.Results: In total, 3653 patients were enrolled. FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p< 0.0001), GLY/IND (0.06± 0.38/0.05± 0.51 L; p< 0.0001 and p=0.0025) and UME/VL (0.12± 0.39/0.10± 0.52 L; p< 0.0001). CAT scores decreased indicating improved COPD (AB/FF, 4.17± 8.30; GLY/IND, 3.66± 7.88; UME/VL, 4.06± 7.96; p< 0.0001). Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups. A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%.Conclusion: In summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions. All three treatments were well tolerated.Keywords: chronic obstructive pulmonary disease, combination therapy, bronchodilators, chronic bronchitis, long-acting muscarinic antagonists, long-acting β2-agonists

Abstract Indacaterol (IND; 150 μg), glycopyrronium (GLY; 50 μg) and mometasone furoate (MF; 160 μg [high-dose ICS] and 80 μg [medium-dose ICS]) have been formulated as a once-daily (o.d.) fixed-dose combination treatment delivered via the Breezhaler® device for the treatment of patients with asthma. In this randomized (n = 116), double-blind, double-dummy, active comparator-controlled, three-period cross-over study we evaluated the benefit of o.d. IND/GLY/MF versus twice daily (b.i.d.) salmeterol/fluticasone propionate combination (SFC; 50/500 μg; high-dose ICS) treatment (NCT03063086). Overall, 107 patients completed the study. The study met its primary objective by demonstrating superiority of o.d. IND/GLY/MF at medium and high-dose ICS over b.i.d. SFC (high-dose ICS) in peak FEV1 after 21 days of treatment (+ 172 mL with high-dose and + 159 mL with medium-dose IND/GLY/MF versus SFC, p Trial registration ClinicalTrials.gov, (Identifier: NCT03063086), EudraCT start date: May 11, 2017; First patient first visit / study initiation date: May 31, 2017.

BackgroundNavafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and β-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD.MethodsThis phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol (UMEC/VI); 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 15. Secondary end-points included change from baseline in peak FEV1; change from baseline in Breathlessness, Cough and Sputum Scale (BCSS); change from baseline in COPD Assessment Tool (CAT); adverse events; and pharmacokinetics.Results73 participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares (LS) mean difference 0.202 L; p1 between navafenterol and UMEC/VI (LS mean difference −0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all pConclusionOnce-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.

Jutta Beier,1 Robert Mroz,2,3 Anne-Marie Kirsten,4 Ferran Chuecos,5 Esther Garcia Gil5 1insaf Respiratory Research Institute, Wiesbaden, Germany; 2Centrum Medycyny Oddechowej, 3Medical University of Białystok, Białystok, Poland; 4Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 5AstraZeneca PLC, Barcelona, Spain Background: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study. Methods: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 µg twice daily (BID), tiotropium 18 µg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed. Results: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P

Kai-Michael Beeh,1 Jutta Beier,1 Henning Candler,2 Thomas Wittig2 1Insaf Respiratory Research Institute,Wiesbaden, Germany; 2G. Pohl-Boskamp GmbH & Co KG, Hohenlockstedt, Germany Background: Treating symptoms and preventing exacerbations are key components of chronic obstructive pulmonary disease (COPD) long-term management. Recently, a more tailored treatment approach has been proposed, in particular for two well-established clinical phenotypes, frequent exacerbators and chronic bronchitis-dominant COPD. ELOM-080 has demonstrated clinical efficacy in treating symptoms and preventing exacerbations in subjects with chronic bronchitis. However, little is known about the potential effects of ELOM-080 in COPD patients. Aim: To evaluate the effect on exacerbation, cough sputum, and general state of health of long-term treatment with ELOM-080 in COPD patients with an exacerbation history and chronic bronchitis. Methods: We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled parallel-group clinical trial of a 6-month treatment with ELOM-080 (3×300mg) in patients with chronic bronchitis and concomitant COPD. The primary outcome was the proportion of subjects with at least one exacerbation over the 6-month study period. Secondary outcomes included the total number of exacerbations (ie, cumulative occurrence of exacerbations during the study period) and the proportion of acute exacerbations necessitating an antibiotic treatment, monthly evaluations of sputum and cough symptoms, and the general state of health and a safety analysis. Results: Of 260 randomized subjects, 64patients fulfilled the inclusion criteria for COPD (ELOM-080: 35, placebo: 29). Compared to placebo, ELOM-080 reduced the percentage of subjects with at least one exacerbation (29% versus 55%, P=0.031) and a reduction in the overall occurrence of exacerbations (ELOM-080: 10, placebo: 21, P=0.012) during the winter season. The percentage of asymptomatic or mildly symptomatic patients (sputum/expectoration and cough) was consistently higher in the ELOM-080 group compared to placebo, with statistical significant differences after 2 and 3 months of treatment (2 months: ELOM-080 25%, placebo 11%, P

Introduction: Indacaterol (IND, LABA), glycopyrronium (GLY, LAMA) and mometasone furoate (MF, ICS) have been formulated as a once-daily (o.d.) fixed-dose combination therapy (IND/GLY/MF) delivered via the Breezhaler® device for the treatment of asthma. We report data from two Phase II studies (B2208 and B2209). Methods: Both studies had a randomized, double-blind, 3-period crossover design. B2208 included 116 adult patients with moderate-to-severe asthma (on LABA/ICS, FEV1 %predicted B2209 included 37 adult patients with mild-to-moderate asthma (on low- or medium-dose ICS, FEV1 %predicted ≥60− Results: In B2208, 44.6% and 47.3% of patients on high- or medium-dose IND/GLY/MF, respectively, achieved near-normal lung function (FEV1 [AUC0–24h] ≥80% of predicted normal) compared with 34.4% with S/F (p In B2209, 48.4% of patients on medium-dose IND/GLY/MF achieved normal lung function (FEV1 [AUC0–24h] ≥90% of predicted normal) vs 6.7% on placebo. The odds ratio (OR) (95% CI) of being rescue medication free was 1.87 (1.03, 3.41) and 1.44 (0.80, 2.59) when treated with high- or medium-dose IND/GLY/MF, respectively, compared with S/F (B2208). The OR (95% CI) was 11.51 (3.77, 35.14) for medium-dose IND/GLY/MF vs placebo (B2209). Conclusion: Patients with asthma are more likely to achieve normal or near-normal lung function and to remain rescue medication free with IND/GLY/MF compared with high-dose S/F or placebo.

Introduction: Indacaterol (IND, LABA), glycopyrronium (GLY, LAMA) and mometasone furoate (MF, ICS) have been formulated as a once-daily (o.d.) fixed-dose combination therapy (IND/GLY/MF) delivered via the Breezhaler® device for treatment of asthma. We report data from an active-comparator-controlled (B2208) and a placebo-controlled (B2209) study. Methods: Both studies had a randomized, double-blind, 3-period crossover design. B2208 included 116 adult patients with moderate-to-severe asthma (on LABA and medium- or high-dose ICS, FEV1 %predicted B2209 included 37 adult patients with mild-to-moderate asthma (on low- or medium-dose ICS, FEV1 %predicted ≥60− Results: In B2208, both high- and medium-dose IND/GLY/MF showed superior treatment effect (mean difference) vs S/F on trough FEV1 (124 mL [95%CI: 86, 161] and 105 mL [95% CI: 67, 143], respectively) and FVC (AUC0-24h) (104 mL [95%CI: 66, 142] and 86 mL [95% CI: 48, 125], respectively [all p In B2209, mean improvement in trough FEV1 by IND/GLY/MF was 544 mL vs. placebo (95% CI: 460, 628 mL; p Conclusion: IND/GLY/MF o.d. consistently demonstrates clinically and statistically significant improvements in lung function compared with high-dose S/F b.i.d. and placebo in patients with mild, moderate and severe asthma in two separate Phase II studies.

Kai Michael Beeh,1 Anne-Marie Kirsten,2 Ana-Maria Tanase,3 Alexia Richard,3 Weihua Cao,4 Bettina Hederer,3 Jutta Beier,1 Oliver Kornmann,5 Richard N van Zyl-Smit6 1Insaf Respiratory Research Institute Wiesbaden, Wiesbaden, Germany; 2Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5IKF Pneumologie, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany; 6Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa Background and purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use.Materials and methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313).Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL (P

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD).AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout.In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone.In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol.

Inhaled long-acting β2-agonists or long-acting muscarinic antagonists monotherapies are recommended as the first choice of treatment for patients with symptomatic chronic obstructive pulmonary disease. The different but complementary modes of action of these treatments make them suited for use in a fixed-dose combination. Aclidinium bromide 400 µg (a long-acting muscarinic antagonist) twice daily improves patient lung function and health status and reduces breathlessness compared with placebo, and is well tolerated. Combining these effects with the rapid onset of action of formoterol fumarate 12 µg in a twice-daily treatment may provide 24-h relief from chronic obstructive pulmonary disease symptoms. This review discusses the aclidinium/formoterol 400/12 µg combination clinical trial data to date.

Summary Introduction QVA149 is a novel, inhaled, once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β 2 -agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the effects of QVA149 on exercise tolerance, hyperinflation, lung function and lung volumes versus placebo and tiotropium. Methods Patients with moderate-to-severe COPD were randomized to QVA149 110/50 μg, placebo or tiotropium 18 μg once daily in a blinded, 3-period crossover study for 3 weeks. The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo. Results Eighty-five patients were randomized; 86% completed the study. QVA149 significantly improved exercise endurance time at Day 21 compared with placebo (least squares mean treatment difference 60 s [ p = 0.006]). No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found. Dynamic inspiratory capacity (IC) at exercise isotime, trough forced expiratory volume in 1 s, residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study. The safety profiles were similar across groups. Conclusions In patients with moderate-to-severe COPD, once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise. Trial registration : ClinicalTrials.gov NCT01294787. Take home message: Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD.

Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0–24) at week 6. Secondary and additional endpoints included FEV1 AUC12–24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety. Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0–24 and FEV1 AUC12–24 were significantly increased from baseline with aclidinium (Δ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (Δ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (

Selectins, a family of cell adhesion molecules, are involved in leukocyte extravasation to sites of inflammation. We investigated the safety and efficacy of the inhaled pan-selectin antagonist Bimosiamose in patients with chronic obstructive pulmonary disease (COPD). 77 COPD patients (mean forced expiratory volume in 1 s, 57% pred.) were enrolled in a cross-over, double-blind, randomized, Placebo-controlled, multi-center trial. Bimosiamose (10 mg) or Placebo was inhaled twice daily via the breath actuated nebulizer Akita2 Apixneb™ for 28 days on top of standard bronchodilator therapy. Efficacy was assessed by measurement of inflammatory parameters in induced sputum (differential cell count, interleukin-8, matrix-metalloproteinase-9, myeloperoxidase) and lung function at day 28 of both treatment periods. The total adverse event ratio of Bimosiamose compared to Placebo treatment was balanced. Compared to Placebo, treatment with Bimosiamose led to a decrease of the interleukin-8 concentration (-9.49 ng/mL, 95%CI -18.8 to -2.7 ng/mL, p = 0.008), for the neutrophil count a difference of -0.368 × 10(6) cells/mL (95%CI -1.256 to 0.407 × 10(6)/mL, p = 0.313) was found. The macrophage count decreased by -0.200 × 10(6) cells/mL (95%CI -0.365 to -0.044 × 10(6) cells/mL, p = 0.012). Most lung function parameters showed a small numeric increase. Inhalation of Bimosiamose for 28 days was safe and well tolerated in patients with COPD. It led to an attenuation of airway inflammation (EudraCT 2009-017257-35; NCT ID: NCT01108913).

Jutta Beier1, Jan van Noord2, Amanda Deans3, Jean Brooks3, Claire Maden3, Suus Baggen4, Rashmi Mehta5, Anthony Cahn31INSAF Respiratory Research Institute, Germany; 2Atrium Medisch Centrum, The Netherlands; 3GlaxoSmithKline, Stockley Park, UK; 4GlaxoSmithKline, Zeist, The Netherlands; 5GlaxoSmithKline, RTP, NC, USABackground: GSK233705 is an inhaled, long-acting muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This study was performed to see if the addition of GSK233705 to salmeterol would provide greater bronchodilation than salmeterol or tiotropium alone in COPD.Methods: In an incomplete-block, three-period, crossover design, dually responsive patients received three of the following five treatments: GSK233705 20 µg plus salmeterol 50 µg twice-daily; GSK233705 50 µg plus salmeterol 50 µg twice-daily; salmeterol 50 µg or placebo, each twice-daily; and tiotropium 18 µg or placebo once-daily for 7 days. Each treatment period was separated by a 14-day washout. The primary efficacy endpoint was morning (trough) forced expiratory volume in 1 second (FEV1) on Day 8, following 7 days of treatment. Secondary endpoints included pulmonary function, plethysmography, pharmacokinetics of GSK233705 and salmeterol, adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory parameters.Results: A total of 47 patients were randomized. The mean % predicted normal postbronchodilator FEV1 was 55% at screening. Compared with placebo (n = 24), the adjusted mean change from baseline in trough FEV1 on Day 8 was 215 mL higher with GSK233705 20 µg + salmeterol (n = 23) and 203 mL higher with GSK233705 50 µg + salmeterol (n = 27), whereas with salmeterol (n = 27) and tiotropium (n = 28) the changes were 101 mL and 118 mL higher, respectively. The primary efficacy results were supported by the results from the other secondary lung function assessments. AEs were reported by similar proportions of patients across the treatment groups, with headache the most frequently reported treatment-related AE reported by one subject receiving each of GSK233705 20 µg + salmeterol, tiotropium, and placebo. No significant differences were seen in vital signs, ECGs, or laboratory parameters between the groups.Conclusion: The addition of GSK233705 to salmeterol in partially reversible COPD patients resulted in greater bronchodilation than salmeterol or tiotropium alone and was well tolerated.Keywords: COPD, bronchodilation, dual therapy, LAMA, LABA

Bronchodilators are the cornerstone of severe chronic obstructive pulmonary disease (COPD) treatment to improve airflow, symptoms, exercise tolerance, and exacerbations. There is convincing evidence that regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. Long-acting β-2-agonists include the twice-daily drugs formoterol and salmeterol and, more recently, once-daily indacaterol. Studies with head-to-head comparisons of long-acting bronchodilators are scant, but novel data from controlled trials with the once-daily β(2)-agonist indacaterol indicate superior bronchodilation and clinical efficacy of indacaterol at recommended doses over twice-daily long-acting β(2)-agonists, and at least equipotent bronchodilation compared with once-daily tiotropium. The recent therapeutic developments in COPD underscore a shift from short-acting bronchodilators with multiple dosings per day to reduced dosing frequency and prolonged duration of action, including once-daily treatment, with more consistent effects on various clinical outcomes. This review summarizes relevant clinical data for twice-daily β-2-agonists in COPD, and further focuses on novel data for once-daily indacaterol, including head-to-head comparison trials.

Introduction: Indacaterol is a novel once daily long-acting beta agonist (LABA) developed for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Aims: This review summarizes preclinical and clinical data of indacaterol, including all data generated during the phase II trial program, and further discusses the outlook and potential of the drug in the future treatment of COPD and asthma. Evidence review: Clinical studies suggest that indacaterol produces rapid and sustained bronchodilation in COPD patients and asthmatics of different severities. Until now, clinical studies of up to 28 days’ duration have been published that have confirmed the suitability of indacaterol for once daily dosing, along with a favorable overall safety and tolerability profile. Outcomes summary: Indacaterol monotherapy has potential in COPD, where antiinflammatory treatment is not fully established and issues about a potential risk of LABA use causing excess mortality have not been raised. In addition, indacaterol represents an option for future combination therapies in both asthma and COPD. However, more data are required, particularly in COPD, to fully assess the therapeutic potential of indacaterol in improving symptoms, quality of life, exacerbation rates, disease progression, exercise capacity, and hyperinflation. The currently ongoing phase III clinical trial program will add knowledge in respect to many long-term efficacy outcomes and gather further safety and tolerability data in both asthma and COPD.

This study aimed to evaluate the effect of a LTB 4 receptor antagonist on inflammatory markers in induced sputum, in particular sputum neutrophilia, in ex-smokers with moderate stable chronic obstructive pulmonary disease (COPD). The trial followed a double-blind, randomized, cross-over design including two treatment periods (4 weeks) separated by a 4-week washout period. Sputum inductions and lung function measurements were carried out at the beginning of each period, and after 2 and 4 weeks. Twenty-four patients were included (18/6 m/f; mean (±S.D.) age 64±5 years; FEV 1 57±10% predicted); the per-protocol population comprised 17 patients. No significant differences occurred between LTB019 and placebo regarding the percentage of sputum neutrophils (treatment means, 68.0% vs. 69.3%), total cell count (in units of 10 6 /mL, log e of treatment means: 1.56 vs. 1.27), or the levels of MPO, IL-8, and TNF-α. There were also no differences in FEV 1 , FVC, or the use of rescue medication. We therefore conclude that a 4-week treatment with LTB019 had no effect on sputum neutrophil numbers and related cytokine levels in these patients, despite the plasma concentrations achieved being similar to those shown to prevent the ex vivo LTB 4 -induced upregulation of CD11b/18 on neutrophils. The present data suggest that LTB 4 antagonism by LTB019 is not a promising therapeutic approach for attenuating chronic airway neutrophilia, at least in patients with moderate COPD.

In patients with chronic obstructive pulmonary disease (COPD) classified as moderate onwards, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines recommend regular treatment with one or more long-acting bronchodilators, such as beta(2)-agonists or anticholinergics. In contrast to currently available long-acting beta(2)-agonists, which have a duration of action of 12 h, indacaterol has demonstrated effective 24-h bronchodilation on once-daily dosing. A double-blind, randomised, placebo-controlled study was conducted to compare the safety, tolerability and efficacy of indacaterol with that of placebo, over a 28-day period, in patients with moderate COPD (as defined by GOLD 2001 criteria; equivalent to moderate-to-severe COPD in the GOLD 2005 criteria). Patients were randomised 2:2:1 to receive indacaterol 400 microg or 800 microg or placebo once-daily (between 07:00 and 11:00 h) via a single-dose dry-powder inhaler for 28 days. Assessments included monitoring of adverse events (AEs), blood chemistry (including serum potassium and blood glucose), vital signs (blood pressure and heart rate), electrocardiograms and spirometry. One hundred and sixty-three patients were randomised, with 155 (95%) completing the study. There were no statistically significant differences between treatment groups in the overall incidence of AEs, with AEs reported by 35%, 51% and 25% of patients in the indacaterol 400 microg, 800 microg and placebo groups, respectively. The majority of AEs were mild or moderate in severity, and there were no study-drug related serious AEs. There were no statistically significant differences between indacaterol groups and placebo in mean pulse rate and QTc interval, and isolated statistically significant (p

Until now, the conducting of clinical trials by nurses has scarcely come under scientific examination. Particularly in Germany, the field of activity has only been treated marginally in the health-care and nursing sciences. In Germany, the term 'Study Nurse' is used not only for members of the nursing profession but across disciplines; it is one of the most widely used terms. An explorative, descriptive study has been conducted employing a modified version of the Work Sampling Method. 79 Study Nurses were anonymously surveyed using a self-administered workload catalogue. 85 participated in the survey that focused on demographics, qualifications, and salary. In every workload catalogue, contact with other colleagues as well as job activities and the time spent on each activity were documented over twenty days. Study Nurses are mostly members of the nursing profession. They work mostly at university clinics and are responsible for conducting clinical trials. This applies to all trials that license medicinal products but also for trials initiated by investigators. While trial-specific documentation is their most time-intensive task, the overall role of Study Nurses encompasses a very broad range of activities. For the most part, they work alone and independently but have various contacts mainly to patients and the investigator. Future research should take into consideration the motivation for opting for the job of Study Nurse and the question of whether through their training and experience nurses are better qualified than other healthcare professionals.

Aims The aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation. Methods Two randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2–140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8–70 mg bimosiamose disodium twice daily. In both studies 4 ml of the drug solution was administered via nebulizer over 15 min. Adverse events, vital signs, ECG, clinical laboratory parameters and forced expiratory volume in 1 s (FEV1) data were recorded and nasopharyngeal examinations were performed to address the safety and tolerability. Blood was collected for the determination of plasma concentrations of bimosiamose. Results All subjects completed the study. No deaths or severe adverse events occurred. Eleven mild adverse events occurred in the dose-escalation study and 34 in the multiple-dose study after inhalation of bimosiamose disodium. Adverse events were more frequent at the highest dose (140 mg) of the dose-escalation study. For placebo treatment one moderate adverse event was observed in the dose-escalation study after placebo treatment, eight mild and three moderate adverse events occurred in the multiple-dose study. Bimosiamose was detected in plasma (maximum concentration 64 ng ml−1) only at doses ≥50 mg given twice daily and 105 mg once daily. For the highest dose a median value of 5746 h ng ml−1 was determined for the AUC over the entire period of treatment of the multiple-dose study. Conclusion The results suggest that single and multiple inhalation of bimosiamose disodium up to 70 mg is well tolerated in healthy males. Systemic bioavailability after inhalation is low.

Aim: To collect clinical and pharmacokinetic (PK) data for QAW039 (fevipiprant), a novel oral CRTh2 receptor antagonist, for asthma treatment. Methods: We assessed efficacy (change in trough FEV 1 from baseline to day 29), ACQ scores, PK of QAW039 and safety vs placebo (PBO). Atopic patients (pts) with mild-to-moderate persistent asthma (ACQ scores ≥1.5) and predicted FEV 1 between 60-85% at baseline were randomised to QAW039 500mg or PBO once-daily for 28 days after a run-in period of up to 28 days where ICS or combinations ICS and LABAs were withdrawn. Results: A total of 170 pts were randomised to QAW039 (n=82) and PBO (n=88). There were no significant differences between QAW039 and PBO groups for trough FEV 1 or ACQ in the whole population. Amongst the various subgroup analyses conducted, positive results were seen in the subgroup of pts (QAW039, n=28; PBO, n=37) with airflow limitation of 1 with significant improvement for both FEV 1 (Δ[QAW-PBO]=+207mL; 90%CI: 96, 319; p=0.002) and ACQ7 (Δ[QAW-PBO]=-0.41; 90%CI: -0.69, -0.13; p=0. 009). QAW039 (n=82) reached a mean maximum concentration (C max ) of 3440ng/mL on day 28 at a median T max of 1h (range 0.5–4h). The AUC tau ratio (day 28 AUC 0-24h –day 1 AUC 0-24h ) of 1.2 indicated modest accumulation of QAW039 upon repeat dosing. Most AEs were mild/moderate and balanced between both groups with no SAEs. Conclusion: QAW039 may improve lung function and asthma control in pts with greater severity of airflow limitation and had a favourable safety profile in all treated pts. Positive results were seen in a post-hoc subgroup analysis and are thus interpreted with caution.

Background: Aclidinium bromide/formoterol fumarate fixed-dose combination (FDC) twice daily (BID) is approved in Europe for the treatment of COPD. Aim: To evaluate overall and cardiovascular (CV) safety of aclidinium/formoterol FDC vs salmeterol/fluticasone propionate FDC in patients with COPD. Methods: Safety data were analysed from a 24-week, randomised, double-blind, Phase IIIb study of aclidinium/formoterol 400/12 µg BID or salmeterol/fluticasone 50/500 µg BID in patients with COPD ([NCT01908140][1]). Adverse events (AEs) were monitored, including cardiac, cerebrovascular and serious AEs (SAEs). Laboratory tests and electrocardiograms (ECG) were recorded. Results: The safety population included 933 patients: mean age 63.4 years; 65.1% male. At baseline 52.8% had hypertensive disorders, 11.8% had diabetes and 21.8% had cardiac disorders. Incidence of AEs and SAEs was similar across groups (Table). Incidence of cardiac and cerebrovascular AEs was low in both groups (Table). AEs related to inhaled corticosteroids (ICS) were more common in patients receiving salmeterol/fluticasone than in the aclidinium/formoterol group (Table). Laboratory and ECG results were similar across groups. Conclusions: Aclidinium/formoterol and salmeterol/fluticasone FDCs were well tolerated in patients with COPD. Incidence of CV AEs was low. ![Figure][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01908140&atom=%2Ferj%2F46%2Fsuppl_59%2FPA989.atom [2]: pending:yes

Background Asthma is characterized by increased recruitment of inflammatory cells from the circulation into the airways. As selectins mediate tethering and rolling of leukocytes on the vascular endothelium, they constitute a promising target for the therapeutic modulation of inflammation. We evaluated the effect of inhaled bimosiamose (TBC1269), a synthetic pan-selectin antagonist, on allergen-induced late asthmatic reactions (LAR) in mild asthmatics. Methods Twelve male subjects with mild allergic asthma (only beta-agonists prn) with demonstrable LAR (fall of FEV 1 3–8 h after allergen inhalation >15% of baseline) at screening completed a randomized, double-blind, placebo-controlled clinical cross-over-trial. Subjects were treated with inhaled bimosiamose 70 mg bid or matching placebo on days 1–3 and 70 mg once on the morning of day 4. On day 4 following the last inhalation of study drug, an allergen challenge was performed. The primary endpoint was the maximum fall in FEV 1 between 3 and 8 h after allergen inhalation on active treatment vs. placebo. Secondary endpoints included early asthmatic response, exhaled nitric oxide, and airway hyperresponsiveness to methacholine 24 h post allergen. Results Bimosiamose significantly attenuated the maximum LAR compared to placebo by 50.2% (placebo mean±SEM fall −13.10±2.30%, bimosiamose −6.52±3.86%, treatment effect p =0.045; linear mixed-effects model). There was no effect of active treatment on early asthmatic response, post allergen airway hyperresponsiveness or exhaled nitric oxide, and peripheral blood cells. Conclusions Administration of the pan-selectin antagonist bimosiamose is effective in a human allergen challenge model of asthma. The result of this proof-of-concept exploratory trial is the first study that demonstrates clinical efficacy of selectin-antagonists as novel therapeutic strategy in asthma.

This article describes current and future tendencies in the development of curriculum planning for health care professions in Germany, using the example of midwifery education. In particular, it discusses 'output-based control' of curriculum planning giving consideration to issues related to German education, health policies and professional educational theories with a view to the general international development. The results of this analysis constitute the starting point for the conceptual planning of a dissertation at the medical faculty of the Berlin Charite with the goal of developing a competency model for the curriculum planning of midwifery education, thus creating a modern curriculum as a basis for a fundamental reform of German midwifery education.

Es ist wenig darüber bekannt, wie Kinder mit Asthma bronchiale ihre eigenen Möglichkeiten, mit den Asthmasymptomen umzugehen, einschätzen. Diese deskriptive Studie erfasst die Häufigkeit und Effektivität der Bewältigungsstrategien von Kindern mit Asthma bronchiale (n = 29). Ein amerikanisches Selbstbeurteilungsinstrument, der Schoolager’s Coping Strategies Inventory (SCSI) wurde in seiner deutschen Übersetzung eingesetzt, um seine Anwendbarkeit bei deutschen Kindern zu überprüfen. Die Ergebnisse zeigen: Der Fragebogen ist im Deutschen anwendbar (Alpha-Koeffizient der Häufigkeit 0.72 und der Effektivität 0.71). Lediglich zwei Strategien sollten in der deutschen Übersetzung verändert werden, um die Verständlichkeit bei deutschen Kindern zu verbessern. Es zeigt sich, dass die fünf am häufigsten eingesetzten Strategien, «Ich sehe fern oder höre Musik», «Ich male, schreibe oder lese etwas», «Ich tue etwas dagegen», «Ich spiele ein Spiel oder etwas anderes» und «Ich spreche mit jemand anderem» auch als effektivste eingeschätzt wurden. Weiterhin fällt auf, dass es Strategien gibt, die Kinder selten einsetzen und trotzdem als effektiv ansehen. Der Vergleich der Studien aus den USA und Deutschland zeigt, dass Kinder beider Länder sich mit Fernsehen und Musikhören gut ablenken können. Aggressive Verhaltensweisen spielen keine Rolle.

Background Asthma is an inflammatory disease of the airways, but in clinical practice inflammation is rarely monitored. The aim of this study was to assess the level of airway inflammation in steroid naïve adult and pediatric patients with intermittent asthma over one year. Methods 54 children and 50 adults with intermittent asthma (GINA step 1) were included. On up to 6 visits lung function, airway hyperresponsiveness to methacholine (PC20FEV1), sputum eosinophils and exhaled nitric oxide (FeNO) were assessed. Results 36 pediatric and 34 adult patients were able to produce at least three adequate sputum samples over the study period and were included into the analysis. In 8 children (22%) the percentage of sputum eosinophils was always below 2.5%. A higher level of eosinophils (>2.5%) was found on at least one visit in 16 (44%) and always >2.5% in 12 children (33%). In the adult group the respective numbers were 14 patients (41%) with always low (

Background Airway hyperresponsiveness and inflammation can be noninvasively studied by bronchial provocation using direct (histamine) or indirect (adenosine 5′-monophosphate [AMP]) stimuli and induced sputum. Objective To report on the immediate effects of histamine and AMP challenge on induced sputum neutrophil counts and related mediator levels. Methods We performed a single-masked, randomized, placebo-controlled, 3-way, crossover, methodological study in 14 atopic patients (median age, 25 years; 8 males; mean ± SD forced expiratory volume in 1 second, 99% ± 5%) without anti-inflammatory medication use. At baseline, sputum induction was performed. Bronchial challenges with AMP, histamine, or placebo were performed 48 hours later. Thirty minutes after challenge, sputum induction was performed again. Challenge periods in each patient were separated by more than 2 weeks. Sputum cells and the mediators leukotriene B 4 , interleukin 8, myeloperoxidase, and albumin were quantified. Results Comparing median challenge-induced relative changes in cells and mediators, neither histamine nor AMP challenge altered the induced sputum neutrophil counts (histamine, 2.7%; AMP, 2.95%; placebo, −2%; P > .07 for all), interleukin 8 levels (histamine, 2.4 ng/mL; AMP, −3.8 ng/mL; placebo, −0.2 ng/mL; P > .06), leukotriene B 4 levels (histamine, −4.8 pg/mL; AMP, 3 pg/mL; placebo, 6 pg/mL; P > .08), or myeloperoxidase levels (histamine, 0.16 μg/mL; AMP, 0 μg/mL; placebo, −0.03 μg/mL; P > .07). Sputum albumin levels were increased after histamine challenge compared with AMP and placebo challenge ( P Conclusions Histamine and AMP provocation have no major effects on induced neutrophil counts and related mediator levels in atopic patients, whereas histamine challenge induces plasma leakage. Potential interactions of noninvasive methods to evaluate airway reactivity and inflammation should be carefully considered.

Oxidative stress associated with increased presence of neutrophils is an important feature of inflammatory airways diseases like asthma or chronic obstructive pulmonary disease. We studied the in vitro effect of piclamilast (RP73401), a selective phosphodiesterase (PDE)-4 inhibitor, compared to theophylline and prednisolone, on respiratory burst of sputum cells from mild asthmatics and COPD patients. Sputum cells were harvested from mild asthmatics and stable COPD patients and treated with piclamilast, theophylline or prednisolone. Respiratory burst was assessed by luminol-dependent chemoluminescence after stimulation with 10 microM n-formyl-met-leu-phe (FMLP). Piclamilast inhibited FMLP-induced respiratory burst of sputum cells in a concentration-dependent manner (asthma: EC50 approximately 100 nM, max. inhibition: 97.5+/-5% at 100 microM; COPD: EC50 approximately 1 microM, max. inhibition: 70.6+/-4.5% at 100 microM), whereas maximal inhibition observed with theophylline (asthma: max. inhib. 27+/-15%; COPD: 6+/-2%, both p0.05 vs. piclamilast) and prednisolone (asthma: 16+/-6%; COPD: 7.8+/-6.2%, both p0.05 vs. piclamilast) was weaker. Inhibition by piclamilast was largely reversed through pretreatment of cells with the adenylcyclase inhibitor SQ22536. We concluded that piclamilast, a selective PDE-4 inhibitor, attenuates the respiratory burst of sputum cells from mild asthmatics and COPD patients in vitro. These data underline the potential of PDE-4 inhibition as a novel therapeutic approach to inflammatory airway diseases like asthma or COPD.

Background: Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic diseases characterized by airflow limitation. Both diseases have a distinct pathogenesis and require unique treatment approaches. Due to some common characteristic traits, asthma and COPD are often lumped together in clinical practice. We sought to develop a simple questionnaire for the distinction of asthma and COPD.Methods: Clinical discriminants of asthma and COPD were retrospectively identified by multiple logistic regression using files from 547 consecutive adult patients presenting to a pulmonary specialist practice with a diagnosis of asthma or COPD. With these features, we generated a simple quantitative questionnaire supporting a diagnosis of COPD with high scores and asthma with low scores (range 0–15 points). Questionnaire results were compared with physician's diagnosis based on GINA and GOLD guidelines including skin tests, spirometry and reversibility data.Results: 210 patients had COPD and 337 had asthma. Age of onset, smoking history, atopy status, and cough quality were significantly associated with a diagnosis of asthma or COPD. Questionnaire scores for COPD patients were higher than those for asthmatics (mean score 10.5±0.18 vs. 4±0.12, P

Der vorliegende Artikel stellt Ergebnisse einer Diplomarbeit im Bereich Pflegepädagogik zum Thema «Mündliche Information von PatientInnen durch Pflegekräfte – Am Beispiel von PatientInnen mit Schlaganfall» vor. Die Literaturrecherche und -analyse zeigt, dass die derzeitige Information von PatientInnen/ SchlaganfallpatientInnen im Gesundheitswesen defizitär ist und erfolgreiche Strategien und Konzepte zur mündlichen Information durch Pflegekräfte im Krankenhaus fehlen. Die Autorinnen entwickeln theoretische Grundlagen für die Gesundheitsinformation als pflegerische Intervention und stellen ein Modell der Gesundheitsinformation als kommunikativer Lehr-Lernprozess zwischen Pflegekraft und PatientIn/ SchlaganfallpatientIn vor, welches prinzipiell auf alle PatientInnengruppen übertragbar ist. Die Gesundheitsinformation erfolgt als nicht tätigkeitsbegleitende pflegerische Intervention innerhalb einer nicht-öffentlichen face-to-face-Kommunikationssituation in den Schritten des Pflegeprozesses. Die Gesundheitsinformation vollzieht sich als wechselseitiger Lernprozess, wobei das Lernen als Informationserzeugung (Konstruktivismus) und Informationsverarbeitung (Kognitivismus) gesehen wird. Beide Prozesse werden durch verschiedene Einflussfaktoren und die aktuelle Krankheitssituation, die Persönlichkeitsmerkmale, den Informationsinhalt und die Umwelt beeinflusst. Die Berücksichtigung dieser Aspekte ist für eine erfolgreiche Gestaltung der Gesundheitsinformation wesentlich und ist durch ein konstruktivistisches Didaktikverständnis realisierbar. Die Wirkung der konzipierten Gesundheitsinformation müsste in einer Evaluationsstudie untersucht werden.

Background Oxidative stress is involved in the pathogenesis of allergic inflammatory diseases, such as rhinitis and asthma. Glutathione is a vital intracellular and extracellular protective pulmonary antioxidant. It plays a key role in regulating oxidant-induced lung epithelial cell function and also in the control of proinflammatory processes. Objective To quantify oxidative stress in sputum of asthmatic patients compared with healthy subjects. Methods We quantified induced sputum supernatant concentrations of total and oxidized glutathione in 20 patients with mild asthma without inhaled corticosteroid treatment, 19 patients with moderate-persistent asthma treated with inhaled corticosteroids (median dose, 900 μg/d of beclomethasone equivalent), and 15 healthy, nonatopic, nonsmoking subjects. Results Total glutathione levels were significantly increased in mild and persistent asthma compared with healthy subjects [geometric mean (95% confidence interval), 9.2 μm (7.1-12 μm) and 8.7 μm (5.9-12.5 μm) vs 4 μm (2.7-6 μm); P = .039 and .042, respectively]. In contrast, there were no differences in total and oxidized glutathione levels between steroid-naive and steroid-treated asthmatic patients ( P > .20 for all comparisons). Persistent, steroid-treated asthmatic patients had higher sputum counts of neutrophils than steroid-naive asthmatic patients [geometric mean (95% confidence interval), 35.6% (28.2%-42.7%) vs 17.7% (11.7%-27.1%), P = .04]. There was a positive correlation of total glutathione with sputum total cells (ρ = 0.32, P = .02). Conclusions Total glutathione is increased in induced sputum of patients with mild and moderate asthma. These data underline the contribution of oxidative stress to the pathogenesis of allergic asthmatic inflammation.

Background: The pathogenesis of late asthmatic reactions after allergen challenge in contrast to isolated early responses is incompletely understood. Recently, the antioxidant glutathione and endogenous nitrosothiols were shown to protect against bronchoconstriction. We compared reduced (GSH) and oxidized glutathione (GSSG) and nitrosothiols in induced sputum following allergen challenge in mild asthmatics with isolated early (EAR) and dual early and late (LAR) asthmatic responses. Methods: Exhaled nitric oxide, sputum cells and sputum supernatant concentrations of GSH, GSSG and nitrosothiols were quantified 2–5 days prior to and 24 h after allergen challenge in 24 mild asthmatics (12 EAR, 12 LAR, only beta-agonists prn). Results: There were no differences at baseline between EAR and LAR asthmatics for any of the parameters (p > 0.1, all comparisons). Mean ± SD fall in forced expiratory volume in 1 s, expressed as the percentage decrease compared to the baseline value, between 3 and 8 h after allergen challenge was 1 ± 5% in the group of patients without LAR vs. 24.9 ± 8.7% in the group of patients with LAR (p < 0.001). Sputum eosinophils increased in both groups (p < 0.05, both comparisons), whereas neutrophils only increased in LAR subjects (p = 0.06 vs. EAR). In contrast, GSH was significantly increased 24 h after challenge only in EAR asthmatics [geometric mean with 95% confidence intervals: before: 3.3 µM (1.25–7.9 µM), after: 5.9 µM (2.7–12.9 µM), p = 0.05; mean difference vs. LAR subjects: 6 µM (0.1–12 µM), p = 0.048], and the proportion of GSSG was positively correlated with postallergen eosinophils in all patients (rho = 0.4, p = 0.05). There was no change in nitrosothiols after 24 h in either EAR or LAR subjects (p > 0.23, all comparisons). Conclusions: GSH increases 24 h after allergen challenge in isolated early responders. These data suggest that different adoptive responses to allergen may result in different physiologic phenotypes. Further studies on the role of glutathione in allergen-induced bronchoconstriction are clearly warranted.

Measurement of exhaled nitric oxide (eNO) and analysis of induced sputum are both established noninvasive methods for studying airway inflammation in asthma. Both methods are often used sequentially within short time frames. The aim of the present study was to evaluate the influence of sputum induction on eNO in adults and to follow the kinetics of airway eNO production after induction in relation to forced expiratory volume in one second (FEV 1 ). eNO and FEV 1 were measured in 41 adult patients (aged 29 (range 23–50) yrs, 56% male) with asymptomatic atopy or mild asthma (mean FEV 1 97.2±3% predicted) prior to and immediately after sputum induction with hypertonic saline (4%). Sputum induction with isotonic saline was also performed in 13 subjects (control group). Repeatability of eNO decrease after sputum induction was also studied in 27 patients on separate occasions and kinetics of eNO production after sputum induction were followed over 24 h in another 10 patients. Sputum induction with hypertonic, but not isotonic, saline led to a marked decrease in eNO (log) immediately after the procedure (pre: 3.85±0.13 parts per billion (ppb); post: 3.24±0.14 ppb). This decrease was shown to be highly reproducible and not related to a fall in FEV 1 following sputum induction. While FEV 1 returned to baseline within 1 h, decreased eNO levels were observed over 4 h and returned to baseline after 24 h. Hypertonic saline sputum induction leads to a prolonged reduction in exhaled nitric oxide in adult atopics that is reproducible within subjects and not related to a reduction in airflow following sputum induction. This methodological interference should be taken into account when sputum induction and exhaled nitric oxide measurements are performed in the same subject.

BACKGROUND Seasonal allergic rhinitis (SAR) is a risk factor for asthma in affected individuals. Nasal allergic inflammation enhances bone-marrow eosinophil production, mainly via IL-5, and rhinitis patients have increased airway inflammation during the pollen season. OBJECTIVE To assess the impact of nasal allergy on sputum inflammatory markers. METHODS In an open-labelled, randomized, placebo-controlled cross-over study with 16 non-asthmatic SAR patients (median age 25 years, 56% males), the effect of a single nasal allergen challenge performed out of season on induced sputum inflammatory parameters was evaluated. SAR patients were identified by history, skin-prick test and specific IgE. All patients had normal lung function/bronchial hyper-responsiveness out of season and a negative asthma/wheezing history. Sputum cells and supernatant levels of ECP, sICAM, IL-5 and IL-10, and plasma levels of IL-5 and ECP, were measured before and 24 h after nasal allergen challenge. After a washout period of at least 4 weeks, the procedure was repeated with placebo challenge (diluent). RESULTS Nasal allergen challenge led to an increase in sputum ECP (pre = 60 +/- 12, post = 212 +/- 63 micro g/L, P = 0.02 vs. placebo), and sICAM (4.8 +/- 2.7 to 6.5 +/- 2.9 ng/mL, P = 0.02 vs. placebo), whereas IL-10 decreased after provocation (44 +/- 11 to 29 +/- 6 pg/mL, P = 0.06 vs. placebo). Sputum IL-5 was undetectable in all patients. The absolute number of blood and sputum eosinophils did not change significantly after allergen or placebo challenge (P > 0.07, both comparisons). Plasma levels of IL-5 increased after allergen challenge (8.7 +/- 2.9 to 14.5 +/- 3.9 pg/mL, P = 0.001), and the increase in plasma IL-5 was positively correlated with the rise in sputum ECP in a subgroup of 'responders' (n = 12, r = 0.71, P = 0.01). CONCLUSIONS A single nasal allergen challenge in SAR patients increased markers of allergic inflammation in the lower respiratory tract, possibly via pronounced activation of inflammatory cells through circulating immediate-type reaction cytokines like IL-5. These findings may provide additional explanatory data for the high susceptibility of SAR patients to incident asthma.

Study objectives: Neutrophilic inflammation is a major feature of COPD. Induced sputum is increasingly used to monitor inflammatory airway diseases. Although short-term repeatability of selected sputum markers has been extensively studied in several populations, data on the long-term repeatability of induced sputum markers in stable COPD are scant. Design: Sputum supernatant of 12 patients with stable COPD was analyzed on three separate occasions with 4-weekly intervals. Sputum cells and inflammatory markers interleukin (IL)-8 and soluble intercellular adhesion molecule (sICAM)-1 were measured in supernatant using enzymelinked immunosorbent assay. Repeatability of sputum markers was expressed by intraclass correlation coefficients (Ri). Measurements and results: Sputum induction was safe in all patients. None of the sputum parameters analyzed changed significantly throughout the study. The repeatability for cell differential counts in stable COPD was as follows: total cells, Ri 0.07; neutrophils, Ri 0.66; macrophages, Ri 0.47; eosinophils, Ri 0.49; and lymphocytes, Ri 0.58. The repeatability of soluble markers was as follows: IL-8, Ri 0.50; and sICAM, Ri 0.58. Sputum neutrophils were negatively correlated with lung function on each separate occasion, whereas soluble markers were not correlated with sputum cells (p > 0.16, all correlations) or lung function (p > 0.24, all correlations). Conclusions: Clinically stable, moderate COPD is associated with equally stable sputum inflammatory markers. Repeatability of induced-sputum markers of neutrophilic inflammation in stable COPD is satisfactory, even over extended periods of time. These data support the usefulness of serial monitoring of induced-sputum inflammatory markers in COPD. (CHEST 2003; 123:778 –783)

Background: Neutrophilic inflammation is a major feature of chronic obstructive pulmonary disease (COPD), and several novel therapies aim at the suppression of neutrophils in COPD. Due to the abundance and redundancy of mediators involved in neutrophilic inflammation, there is an ongoing controversy about the feasibility of such anti-neutrophilic approaches. Systemic chemotherapy has broad side effects, including neutrophil toxicity. Objectives: In this observational study, we have measured cellular and neutrophil-related inflammatory markers in induced sputum of COPD patients with unresectable non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Methods: 15 COPD/NSCLC patients were followed during their first course of chemotherapy with cisplatin (60 mg/m2 days 1 and 7) and etoposide (100 mg/m2 days 3, 4, and 5). Sputum induction was performed before, and 3 weeks after chemotherapy. Peripheral blood count, sputum total cells and differentials, and the concentrations of the inflammatory markers interleukin (IL)-8, and matrix metalloproteinase (MMP)-9 in sputum supernatant were analyzed. Results: Similar to COPD controls (n = 12), COPD/NSCLC patients had increased levels of absolute and relative sputum neutrophils, IL-8, and MMP-9 at baseline, when compared with healthy controls (n = 14, p < 0.001, all comparisons). After chemotherapy, there was a significant reduction in peripheral blood leukocytes (pre: 10,736 ± 550, post: 6,536 ± 1,064 cells/µl, p = 0.002) and log neutrophils (pre: 8.9 ± 0.09, post: 8.1 ± 0.2 cells/µl, p = 0.004), whereas log sputum neutrophils (pre: 0.3 ± 0.37, post: 0.18 ± 0.3 cells × 106/ml, p = 0.1) , IL-8 (pre 15.9 ± 3.8, post: 17.7 ± 3.6 ng/ml, p = 0.7), and log MMP-9 (pre: 5.3 ± 0.57, post: 5.6 ± 0.7 ng/ml, p = 0.33) remained unchanged. Conclusion: A single course of platinum-based chemotherapy markedly decreases peripheral blood neutrophils, but has no effect on inflammatory patterns of induced sputum in COPD patients with unresectable NSCLC.

Background: Oxidative stress has repeatedly been linked to the pathogenesis of pulmonary disorders like asthma and chronic obstructive pulmonary disease. Measuring glutathione (GSH) in induced sputum (IS) offers a noninvasive tool to study oxidative stress in airway diseases. Objectives: This study assessed the stability of GSH in sputum supernatant under varying conditions. Methods: GSH in IS of 14 (7 healthy, 4 chronic obstructive pulmonary disease, 3 allergic rhinitis) nonsmoking subjects was quantified spectrophotometrically. The stability of GSH in supernatant was analyzed over 24 h under different ambient conditions (room temperature and cooling at 4°C). Reproducibility of GSH measurements in immediately processed and frozen supernatant (+72 h) was expressed by intraclass correlation coefficient (Ri) and coefficient of repeatability (CR). Results: GSH recovery in supernatant decreased in a time- and temperature-dependent manner. Samples stored at 4°C and room temperature showed a rapid decline of stability after 2 h. Mean GSH concentrations in IS after freezing (–20°C) and thawing after 72 h were not significantly different from GSH values measured immediately after processing of the samples (immediate processing: 17.9 ± 13.9 µM; 72 h freezing: 16.4 ± 12.9 µM, p = 0.2). The reproducibility between immediately processed and frozen samples was excellent (Ri = 0.97; CR = 5.7 µM). Conclusions: Storage of sputum supernatant at room temperature or 4°C leads to a rapid decline of GSH recovery compared with baseline values. Immediate freezing of samples is a suitable and valid alternative to rapid processing and allows collection and shipment of samples for subsequent analysis.

Background: In patients with allergic rhinitis, bronchial hyperresponsiveness (BHR) and airway inflammation may increase during pollen exposure. BHR can be assessed by adenosine-5′-monophosphate (AMP) or methacholine challenge. It has been suggested that BHR to AMP is more closely related to airway inflammation than BHR to methacholine. Seasonal allergic rhinitis offers a dynamic model to study changes in BHR and airway inflammation during natural allergen exposure. Methods: We measured BHR [provocative concentration causing a 20% fall (PC20) in forced expiratory volume in 1 s (FEV1)] to AMP and methacholine, and induced sputum cells in 16 rhinitis patients before and during the 2001 grass pollen season. Results: There was a decrease in PC20 methacholine during pollen exposure (geometric mean PC20 from 3.22 to 1.73 mg/ml, p = 0.0023), whereas no reduction was observed for PC20 AMP (p = 0.11). There was no increase in sputum eosinophils [pre: 0.69% (95% confidence interval 0.22–2.07); during: 1.85 (0.55– 5.6), p = 0.31]. Although the correlation of log PC20 methacholine and log PC20 AMP at baseline was good (r = 0.76, p = 0.001), individual seasonal changes (doubling concentrations) in PC20 methacholine were not correlated with changes in PC20 AMP (ρ = 0.21, p = 0.44). There was no correlation between baseline log PC20 methacholine or seasonal changes in PC20 methacholine and sputum eosinophils (p > 0.12, all correlations). In contrast, there was a significant correlation between seasonal changes in PC20 AMP and changes in sputum eosinophils (ρ = –0.59, p = 0.025). Conclusions: These data show dissimilarity between seasonal changes in PC20 AMP and methacholine in patients with seasonal allergic rhinitis. Moreover, PC20 AMP seems to be more closely related to sputum eosinophils than PC20 methacholine. The clinical significance of this discrepancy is unclear.

Abediterol is a once‐daily, long‐acting β 2‐adrenergic agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. We assessed the efficacy, safety, and tolerability of three dose levels of abediterol, given once daily for 7 days in patients with stable, persistent asthma. This was an ascending‐dose, three‐period incomplete crossover study design investigating three dose levels of abediterol versus placebo (EudraCT No. 2008‐003732‐38). Twenty‐eight male patients (25–59 years) were randomized to one of four treatment sequences (1:1:1:1). Follow‐up was 7 days after final treatment. Spirometry was performed regularly up to 24 h postdose Day 1, up to 36 h postdose Day 7, and at follow‐up. Vital signs, 12‐lead electrocardiogram, and clinical laboratory tests were recorded throughout. Abediterol 2.5, 5, and 10 μg provided clinically and statistically significant improvements from baseline (predose, Day 1) in trough forced expiratory volume in 1 sec (FEV 1) versus placebo on Day 7 (primary endpoint) of 334, 365, and 294 mL, respectively (all P