Pulmonary Research Institute at Hospital Grosshansdorf

Großhansdorf, Germany

Pulmonary Research Institute at Hospital Grosshansdorf

Großhansdorf, Germany
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von Leupoldt A.,University of Hamburg | Taube K.,Atem Reha GmbH | Henkhus M.,University of Hamburg | Dahme B.,University of Hamburg | Magnussen H.,Pulmonary Research Institute at Hospital Grosshansdorf
Biological Psychology | Year: 2010

Dyspnea is the cardinal symptom of chronic obstructive pulmonary disease (COPD). Affective states can profoundly impact upon the perception of dyspnea, but little is known about this relationship in patients with COPD. We, therefore, examined the impact of viewing positive versus negative affective picture series on perceived dyspnea during two cycle ergometer exercise tests (CEET) in 30 patients with COPD. Whereas cardiopulmonary measures indicated comparable exercise intensity during both CEETs, parallel viewing of negative affective pictures resulted in increased dyspnea ratings compared to positive affective pictures. Regression analyses showed that only during positive picture viewing increases in the affective unpleasantness of dyspnea, but not in the sensory intensity of dyspnea, during CEETs were predictive of greater dyspnea during everyday activities and reduced health-related quality of life. The results suggest that negative affective states increase perceived dyspnea in patients with COPD and underline the importance of targeting the affect-dyspnea-relationship in this patient group. © 2009 Elsevier B.V.

Waschki B.,Pulmonary Research Institute at Hospital Grosshansdorf | Watz H.,Pulmonary Research Institute at Hospital Grosshansdorf | Albert P.S.,University of Liverpool | Shrikrishna D.,Imperial College London | And 8 more authors.
Respiratory Medicine | Year: 2012

Background: Little is known about COPD patients' compliance with physical activity monitoring and how activity relates to disease characteristics in a multi-center setting. Methods: In a prospective study at three Northern European sites physical activity and clinical disease characteristics were measured in 134 COPD patients (GOLD-stage II-IV; BODE index 0-9) and 46 controls. Wearing time, steps per day, and the physical activity level (PAL) were measured by a multisensory armband over a period of 6 consecutive days (in total, 144h). A valid measurement period was defined as ≥22 h wearing time a day on at least 5 days. Results: The median wearing time was 142 h:17 min (99%), 141 h:1min (98%), and 142 h:24 min (99%), respectively in the three centres. A valid measurement period was reached in 94%, 97%, and 94% of the patients and did not differ across sites (P = 0.53). The amount of physical activity did not differ across sites (mean steps per day, 4725 ± 3212, P = 0.58; mean PAL, 1.45 ± 0.20, P = 0.48). Multivariate linear regression analyses revealed significant associations of FEV 1, 6-min walk distance, quadriceps strength, fibrinogen, health status, and dyspnoea with both steps per day and PAL. Previously unrecognized correlates of activity were grade of fatigue, degree of emphysema, and exacerbation rate. Conclusions: The excellent compliance with wearing a physical activity monitor irrespective of study site and consistent associations with relevant disease characteristics support the use of activity monitoring as a valid outcome in multi-center studies. © 2012 Elsevier Ltd. All rights reserved.

Jones P.W.,St George's, University of London | Rennard S.I.,University of Nebraska Medical Center | Agusti A.,CIBER ISCIII | Chanez P.,Aix - Marseille University | And 6 more authors.
Respiratory Research | Year: 2011

Background: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).Methods: In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.Results: At 12 and 28 weeks, aclidinium improved trough FEV1versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies.Conclusion: Aclidinium is effective and well tolerated in patients with moderate to severe COPD.Trial registration: ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II). © 2011 Jones et al; licensee BioMed Central Ltd.

Cockayne D.A.,Hoffmann-La Roche | Cheng D.T.,Hoffmann-La Roche | Waschki B.,Pulmonary Research Institute at Hospital Grosshansdorf | Waschki B.,Hospital Grosshandorf | And 13 more authors.
PLoS ONE | Year: 2012

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV 1, FEV 1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV 1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV 1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV 1/FVC were stronger in patients without metabolic syndrome (r = -0.52, p = 0.005 and r = -0.61, p = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r = -0.25, p = 0.47 and r = -0.15, p = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV 1, FEV 1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD. © 2012 Cockayne et al.

Singh D.,University of Manchester | Magnussen H.,Pulmonary Research Institute at Hospital Grosshansdorf | Kirsten A.,Pulmonary Research Institute at Hospital Grosshansdorf | Mindt S.,Klinische Forschung Hamburg GmbH | And 4 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2012

This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 μg, 200 μg, 400 μg (via Genuair ®*), formoterol 12 μg (via Aerolizer ®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV 1) normalised area under the curve (AUC) 0-12 on Day 7. Secondary endpoints were: change from baseline in FEV 1 normalised AUC 12-24, FEV 1 normalised AUC 0-24 and morning pre-dose FEV 1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV 1 normalised AUC 0-12 vs placebo (p < 0.0001). FEV 1 normalised AUC 12-24, FEV 1 normalised AUC 0-24, and morning pre-dose FEV 1 were also statistically significantly greater with all aclidinium doses vs placebo (p < 0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 μg vs 100 μg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV 1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 μg and 400 μg as suitable doses for further investigation in Phase III trials. © 2012 Elsevier Ltd.

Magnussen H.,Pulmonary Research Institute at Hospital Grosshansdorf | Paggiaro P.,University of Pisa | Schmidt H.,Boehringer Ingelheim | Kesten S.,Boehringer Ingelheim | And 2 more authors.
Respiratory Medicine | Year: 2012

Background: Data comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid (ICS) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) are scarce, though these therapeutic strategies are widely used in clinical practice. Methods: We performed a randomized, crossover clinical trial of two × 8 weeks comparing tiotropium (18 μg once daily) + salmeterol (50 μg twice daily) (T + S) to salmeterol + fluticasone (50/500 μg twice daily) (S + F) in COPD (forced expiratory volume in 1 s (FEV1) ≤65% predicted, and thoracic gas volume (TGV) ≥120% predicted). Coprimary endpoints were postbronchodilator TGV and exercise endurance time (EET). Results: In 309 patients, at baseline, prebronchodilator FEV1 was 1.36 L (46% predicted), TGV was 5.42 L (165% predicted), and EET = 458 s. Relative to S + F, T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks (p < 0.0001) and 87 ± 44 ml after 8 weeks (p < 0.05). EET was nonsignificantly increased following T + S treatment (20 ± 15 s at 4 weeks, 15 ± 13 s at 8 weeks) vs. S + F. BORG dyspnea score at exercise isotime was reduced in favor of T + S. Conclusion: The two bronchodilators decreased hyperinflation significantly more than one bronchodilator and ICS. This difference was not reflected in EET. (ClinicalTrials.gov number, NCT00530842) © 2012 Elsevier Ltd. All rights reserved.

Ritz T.,University of Hamburg | Kullowatz A.,University of Hamburg | Goldman M.D.,University of Texas at El Paso | Smith H.-J.,CareFusion | And 3 more authors.
Journal of Applied Physiology | Year: 2010

In asthma, airways constrict in response to emotion and stress, but underlying mechanisms, potential extrathoracic contributions, and associations with airway pathophysiology have not been elucidated. We therefore investigated the role of the cholinergic pathway in emotion-induced airway responses in patients with asthma and the association of these responses with airway pathophysiology. Patients with asthma (n = 54) and healthy participants (n = 25) received either 40 μg ipratropium bromide or a placebo in a double-blind double-dummy cross-over design in two laboratory sessions with experimental emotion induction. Stimuli were preevaluated films and pictures of pleasant, unpleasant, and neutral quality. Respiratory resistance and reactance at 5 and 20 Hz were measured continuously before and during presentations, together with respiration by impedance plethysmography and end-tidal Pco2 by capnometry. In addition, measures of airway inflammation, (fraction of exhaled nitric oxide), airway hyperreactivity (methacholine challenge), and reversibility of obstruction were obtained. Respiratory resistance at 5 and 20 Hz increased during unpleasant stimuli in asthma patients. This response was blocked by ipratropium bromide and was not substantially associated with asthma severity, airway inflammation, hyperreactivity and reversibility, or pattern of ventilation and Pco2. Under the placebo condition, changes in resistance during unpleasant films were positively correlated with patients' reports of psychological asthma triggers. In conclusion, airway constriction to unpleasant stimuli in asthma depends on an intact cholinergic pathway, is largely due to the central airways, and is not substantially associated with other indicators of airway pathology. Its link to the perceived psychological triggers in patients' daily lives suggests a physiological basis for emotion-induced asthma. Copyright © 2010 the American Physiological Society.

Beier J.,Insaf Respiratory Research Institute | Kirsten A.-M.,Pulmonary Research Institute at Hospital Grosshansdorf | Mruz R.,Medical University of Bialystok | Segarra R.,Almirall | And 3 more authors.
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2013

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 (<1.5%) or serious AEs (<3%) occurred in any group. Conclusions: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated. © 2013 Informa Healthcare USA, Inc.

Watz H.,Pulmonary Research Institute at Hospital Grosshansdorf | Bock D.,Revotar Biopharmaceuticals AG | Meyer M.,Revotar Biopharmaceuticals AG | Schierhorn K.,Revotar Biopharmaceuticals AG | And 8 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2013

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 × 106 cells/mL (95%CI -1.256 to 0.407 × 106/mL, p = 0.313) was found. The macrophage count decreased by -0.200 × 106 cells/mL (95%CI -0.365 to -0.044 × 106 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). © 2012 Elsevier Ltd.

Kirsten A.,Pulmonary Research Institute at Hospital Grosshansdorf | Watz H.,Pulmonary Research Institute at Hospital Grosshansdorf | Kretschmar G.,Pulmonary Research Institute at Hospital Grosshansdorf | Pedersen F.,Pulmonary Research Institute at Hospital Grosshansdorf | And 3 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2011

Selectins, a family of cell adhesion molecules, are involved in the activation and extravasation of leukocytes in inflammatory diseases. Inhalation of ozone induces an inflammation of the airways, which is dominated by neutrophils. We investigated the effect of repeated inhalations of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy volunteers. In a double-blind, placebo-controlled, randomized, cross-over study Bimosiamose (10 mg bid) was inhaled via a breath actuated nebulizer (AKITA2 APIXNEB ®) for 4 days. Treatment was followed by inhalation of ozone (250 ppb) for 3 h with intermittent exercise. Induced sputum was collected 3 h post ozone challenge for analysis of cellular and non-cellular composition.18 subjects were randomized and completed the study. All treatments were safe and well tolerated. Compared to placebo Bimosiamose reduced the numbers of sputum neutrophils by 40% (p = 0.068) and concentrations of interleukin-8 and matrix-metalloproteinase-9 in sputum supernatant by 35% (p = 0.004) and 46% (p = 0.022), respectively. Inhalation of Bimosiamose showed favourable anti-inflammatory effects on ozone-induced airway inflammation in healthy volunteers. Further studies have to proof and translate this anti-inflammatory effect of Bimosiamose into a clinical benefit in patients with chronic obstructive pulmonary disease.(ClinTrialgov Ident: NCT01108913). © 2011 Elsevier Ltd.

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