Value through Innovation02 July 2015

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

105 publications regarding Respiratory
  • Author:
    Hafner S; Wagner K; Wepler M; Matallo J; Gröger M; McCook O; Scheuerle A; Huber-Lang M; Frick M; Weber S; Stahl B; Jung B; Calzia E; Georgieff M; Möller P; Dietl P; Radermacher P; Wagner F
    Title:
    Physiological and immune-biological characterization of a long-term murine model of blunt chest trauma
    Source:
    Shock 43 (2), 140-147 (2015)
    Abstract:
    Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually, despite normalized lung mechanics and gas exchange. Anesthetized spontaneously breathing male C57BL/6J mice underwent a blast wave-induced blunt chest trauma or sham procedure. Twelve and 24 h later, blood gases and lung mechanics were measured, together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit); heme oxygenase 1 (HO-1), activated caspase-3, Bcl-xL, and Bax expression (Western blotting); nuclear factor-.B activation (electrophoretic mobility shift assay); nitrotyrosine formation; and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by hematoxylin and eosin and periodic acid-Schiff staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase in HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups. Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis.
  • Author:
    Hendeles L; Daley-Yates PT; Hermann R; de Backer J; Dissanayake S; Horhota ST
    Title:
    Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products
    Source:
    AAPS J, 11 Article in Press (2015)
    Abstract:
    In the session on .Pharmacodynamic studies to demonstrate efficacy and safety., presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration.time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of .-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.
  • Author:
    Kerstjens HAM; Casale TB; Bleecker ER; Meltzer EO; Pizzichini E; Schmidt O; Engel M; Bour L; Verkleij CB; Moroni-Zentgraf P; Bateman ED
    Title:
    Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: Two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials
    Source:
    Lancet Respir Med Article in Press (2015)
    Abstract:
    Background: In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting .2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids. Methods: We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18-75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60-90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 .g or 2.5 .g, twice-daily salmeterol 50 .g, or placebo, while maintaining inhaled corticosteroids. Patients and study investigators were masked to treatment allocation. Prespecified co-primary endpoints, assessed at week 24 in the full analysis set, were peak FEV1 response, measured within the first 3 h after evening dosing; trough FEV1 response; and responder rate assessed according to the seven-question Asthma Control Questionnaire (ACQ-7). These studies are registered with ClinicalTrials.gov, numbers NCT01172808 and NCT01172821. Findings: Between Aug 24, 2010, and Nov 13, 2012, we randomly assigned 2103 patients to the tiotropium 5 .g group (n=519), the tiotropium 2.5 .g group (n=520), the salmeterol group (n=541), or the placebo group (n=523); 1972 (94%) patients completed the study. Peak and trough FEV1 responses were significantly greater with tiotropium and salmeterol than with placebo and were similar in both studies. With pooled data, difference versus placebo in peak FEV1 was 185 mL (95% CI 146-223) in the tiotropium 5 .g group, 223 mL (185-262) in the tiotropium 2.5 .g group, and 196 mL (158-234) in the salmeterol group (all p<0.0001); difference in trough FEV1 was 146 mL (95% CI 105-188), 180 mL (138-221), and 114 mL (73-155; all p<0.0001), respectively. There were more ACQ-7 responders in the tiotropium 5 .g (OR 1.32, 95% CI 1.02-1.71; p=0.035) and 2.5 .g (1.33, 1.03-1.72; p=0.031) groups, and the salmeterol group (1.46, 1.13-1.89; p=0.0039), than in the placebo group. 48 (2%) of 2100 patients had serious adverse events (tiotropium 5 .g n=11, tiotropium 2.5 .g n=12, salmeterol n=11, placebo n=14). Interpretation: Once-daily tiotropium add-on to medium-dose inhaled corticosteroids reduces airflow obstruction and improves asthma control in patients with moderate symptomatic asthma. Patterns of response with both tiotropium doses were similar to those of salmeterol, and all active compounds had good safety and tolerability. Tiotropium is a safe and effective bronchodilator, and an alternative to salmeterol in this patient population. Funding: Boehringer Ingelheim.
  • Author:
    Halpin DMG; Dahl R; Hallmann C; Mueller A; Tashkin D
    Title:
    Tiotropium handihaler® and respimat®in copd: A pooled safety analysis
    Source:
    Int J COPD 10, 239-259 (2015)
    Abstract:
    Introduction: Tiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler® (18 µg once daily) or Respimat® Soft Mist. inhaler (5 µg once daily). The recent TIOtropium Safety and Performance In Respimat®(TIOSPIR.) study demonstrated that both exhibit similar safety profles. This analysis provides an updated comprehensive safety evaluation of tiotropium® using data from placebo-controlled HandiHaler® and Respimat® trials. Methods: Pooled analysis of adverse event (AE) data from tiotropium HandiHaler® 18 µg and Respimat® 5 µg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration $4 weeks). Incidence rates, rate ratios (RRs), and 95% confdence intervals (CIs) were determined for HandiHaler® and Respimat® trials, both together and separately. Results: In the 28 HandiHaler® and 7 Respimat® trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler®; 2,440 with Respimat®) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was signifcantly lower in the tiotropium than in the placebo group (HandiHaler® and Respimat® pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs. Conclusion: This analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler® or Respimat®(overall and separately) in patients with COPD.
  • Author:
    Sakamoto A; Matsumaru T; Yamamura N; Suzuki S; Uchida Y; Tachikawa M; Terasaki T
    Title:
    Drug Transporter Protein Quantification of Immortalized Human Lung Cell Lines Derived from Tracheobronchial Epithelial Cells (Calu-3 and BEAS2-B), Bronchiolar-Alveolar Cells (NCI-H292 and NCI-H441), and Alveolar Type II-like Cells (A549) by Liquid Chromatography-Tandem Mass Spectrometry
    Source:
    J Pharm Sci Article in Press (2015)
    Abstract:
    Understanding the mechanisms of drug transport in the human lung is an important issue in pulmonary drug discovery and development. For this purpose, there is an increasing interest in immortalized lung cell lines as alternatives to primary cultured lung cells. We recently reported the protein expression in human lung tissues and pulmonary epithelial cells in primary culture, (Sakamoto A, Matsumaru T, Yamamura N, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T. 2013. J Pharm Sci 102(9):3395-3406) whereas comprehensive quantification of protein expressions in immortalized lung cell lines is sparse. Therefore, the aim of the present study was to clarify the drug transporter protein expression of five commercially available immortalized lung cell lines derived from tracheobronchial cells (Calu-3 and BEAS2-B), bronchiolar-alveolar cells (NCI-H292 and NCI-H441), and alveolar type II cells (A549), by liquid chromatography-tandem mass spectrometry-based approaches. Among transporters detected, breast cancer-resistance protein in Calu-3, NCI-H292, NCI-H441, and A549 and OCTN2 in BEAS2-B showed the highest protein expression. Compared with data from our previous study,(Sakamoto A, Matsumaru T, Yamamura N, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T. 2013. J Pharm Sci 102(9):3395-3406) NCI-H441 was the most similar with primary lung cells from all regions in terms of protein expression of organic cation/carnitine transporter 1 (OCTN1). In conclusion, the protein expression profiles of transporters in five immortalized lung cell lines were determined, and these findings may contribute to a better understanding of drug transport in immortalized lung cell lines.
  • Author:
    Hafner S; Wagner K; Wepler M; Matallo J; Gröger M; McCook O; Scheuerle A; Huber-Lang M; Frick M W; eber S; Stahl B; Jung B; Calzia E; Georgieff M; Möller P; Dietl P; Radermacher P; Wagner F
    Title:
    Physiological and Immune-Biological Characterization of a Long-Term Murine Model of Blunt Chest Trauma
    Source:
    Shock Article in Press (2014)
    Abstract:
    ABSTRACT: Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually despite normalized lung mechanics and gas exchange. Anesthetized, spontaneously breathing male C57BL/6J mice underwent a blast wave induced blunt chest trauma or sham procedure. 12 and 24 hours later, blood gases and lung mechanics were measured together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit), heme oxygenase-1 (HO-1), activated Caspase-3, Bcl-xL, and Bax expression (western blotting), nuclear factor-.B activation (electrophoretic mobility shift assay), nitrotyrosine formation, and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by HE and PAS staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase of HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups.Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis.
  • Author:
    Wex E; Thaler E; Blum S; Lamb D
    Title:
    A novel model of IgE-mediated passive pulmonary anaphylaxis in rats
    Source:
    PLoS ONE 9 (12) art.no.e116166 (2014)
    Abstract:
    Mast cells are central effector cells in allergic asthma and are augmented in the airways of asthma patients. Attenuating mast cell degranulation and with it the early asthmatic response is an important intervention point to inhibit bronchoconstriction, plasma exudation and tissue oedema formation. To validate the efficacy of novel pharmacological interventions, appropriate and practicable in vivo models reflecting mast cell-dependent mechanisms in the lung, are missing. Thus, we developed a novel model of passive pulmonary anaphylaxis in rats. Rats were passively sensitized by concurrent intratracheal and intradermal (ear) application of an anti-DNP IgE antibody. Intravenous application of the antigen, DNP-BSA in combination with Evans blue dye, led to mast cell degranulation in both tissues. Quantification of mast cell degranulation in the lung was determined by (1) mediator release into bronchoalveolar lavage, (2) extravasation of Evans blue dye into tracheal and bronchial lung tissue and (3) invasive measurement of antigen-induced bronchoconstriction. Quantification of mast cell degranulation in the ear was determined by extravasation of Evans blue dye into ear tissue. We pharmacologically validated our model using the SYK inhibitor Fostamatinib, the H1-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG) and the .2-adrenergic receptor agonist Formoterol. Fostamatinib was equally efficacious in lung and ear. Desloratadine effectively inhibited bronchoconstriction and ear vascular leakage, but was less effective against pulmonary vascular leakage, perhaps reflecting the differing roles for histamine receptor sub-types. DSCG attenuated both vascular leakage in the lung and bronchoconstriction, but with a very short duration of action. As an inhaled approach, Formoterol was more effective in the lung than in the ear. This model of passive pulmonary anaphylaxis provides a tissue relevant readout of early mast cell activity and pharmacological benchmarking broadly reflects responses observed in patients with asthma.
  • Author:
    Vogelberg C; Engel M; Moroni-Zentgraf P; Leonaviciute-Klimantavic; Sigmund R; Downie J; Nething K; Vevere V; Vandewalker M
    Title:
    Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study
    Source:
    Respir Med 108 (9), 1268-1276 (2014)
    Abstract:
    Introduction Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat® SoftMist. inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment. Methods This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 .g, 2.5 .g and 1.25 .g versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0-3h)). Results From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0-3h) response for tiotropium 5 .g was significantly greater versus placebo (p = 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 .g (p < 0.00001) and 1.25 .g (p = 0.0134) versus placebo, but not for 2.5 .g (p = 0.0975), while FEV1 area under the curve(0-3h) responses were significant for all doses (p = 0.00001-0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity. Conclusion This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS.
  • Author:
    Horhota S T
    Title:
    Evaluation of comparative performance of orally inhaled drug products in view of the classical bioequivalence paradigms: An analysis of the current scientific and regulatory dilemmas of inhaler evaluation
    Source:
    J Aerosol Med Pulm Drug Deliv 27 (6), 408-413 (2014)
    Abstract:
    Since the early 1960s, there has been a continuous evolution in scientific understanding regarding bioequivalence (BE) of oral dosage forms, intermittently punctuated by some breakthrough research findings and conceptual advances. The accumulated knowledge from this body of research has been translated into a sophisticated risk management framework of regulations and guidelines supported by an extensive set of tools and decision rules. This has permitted us to arrive at a state that now allows, in the majority of cases, not only the unrestricted substitution of a generic product for the innovator version, but also unquestioned substitution between different generic manufacturers. This framework has been successfully extended or adapted to go beyond oral dosage forms to include, for example, topical semisolid applications and nasal sprays. In the case of orally inhaled locally acting drug products (OIP), a similar level of success has yet to be realized. For OIP's, the risk management toolbox is incompletely outfitted due to missing science, knowledge, and experience in some key areas. This article presents a gap analysis of the situation highlighting unresolved residual risks. Assessment of the residual risks by US and EU medicines authorities has interestingly led to different regulatory positions with respect to BE for this class of drug products in these two regions. A parallel comparison with the history for BE of oral dosage forms shows that resolution for inhaled products will come eventually with the final outcome and timeframe, depending as much on science as it does on economics and the degree to which legislators intervene.
  • Author:
    Casaburi R; Maltais F; Porszasz J; Albers F; Deng Q; Iqbal A; Paden HA; O'Donnell DE
    Title:
    Effects of tiotropium on hyperinflation and treadmill exercise tolerance in mild to moderate chronic obstructive pulmonary disease
    Source:
    Ann Am Thorac Soc 11 (9), 1351-1361 (2014)
    Abstract:
    Rationale: Bronchodilator therapy represents a potentially valuable therapeutic option to increase exercise tolerance and enhance lung function in mild to moderate chronic obstructive pulmonary disease (COPD). Objectives: To determine effects of tiotropium on pulmonary hyperinflation and exercise tolerance in patients with symptomatic Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and 2 COPD who experienced inspiratory capacity decrease greater than or equal to 100 ml during incremental and constant work rate treadmill exercise. Methods: This 22-week, randomized, double-blind, two-period crossover study evaluated the efficacy of once-daily tiotropium bromide (18 mg) versus placebo in patients with GOLD 1 and 2 COPD. Primary endpoint was between-group (tiotropium vs. placebo) difference in inspiratory capacity at isotime (i.e., at the time the shortest test ended) during constant work rate treadmill exercise from baseline to the end of a 6-week treatment period. Key secondary endpoints included differences in exercise duration and exertional dyspnea. Safety was assessed by recording adverse events. MeasurementsandMain. Results: Study population comprised 48 patients with GOLD 1 COPD and 78 patients with GOLD 2 COPD. Resting inspiratory capacity significantly improved with tiotropium versus placebo in the overall (P , 0.0001), GOLD 1 (P = 0.0183), and GOLD 2 (P , 0.0001) groups. Isotime inspiratory capacity was significantly enhanced during exercise in the overall (P = 0.0087) and GOLD 2 (P = 0.0494) groups after tiotropium versus placebo. Tiotropium versus placebo significantly enhanced exercise duration in the GOLD 2 group (P = 0.0070) but not in the GOLD 1 or overall patient groups. In the overall group, increase in exercise duration seen with tiotropium was well correlated with the increase in isotime inspiratory capacity (r = 0.463, P , 0.0001). Conclusions: Resting and exercise hyperinflation were ameliorated by bronchodilator therapy with tiotropium in the overall GOLD 1 plus 2 COPD group. Exercise tolerance was enhanced in GOLD 2, but not GOLD 1, COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01072396).
  • Author:
    White ES; Brown KK; Collard HR; Conoscenti CS; Cosgrove GP; Flaherty KR; Leff JA; Martinez FJ; Roman J; Rose D; Violette S; Kaminski N
    Title:
    Open-access biorepository for idiopathic pulmonary fibrosis: The way forward
    Source:
    Ann Am Thorac Soc 11 (8), 1171-1175 (2014)
    Abstract:
    Although widespread use of animal modeling has transformed pulmonary research, the overarching goal of biomedical research is to enhance our understanding of human physiology and pathology. Thus, we believe that future gains in understanding human lung disease will be enhanced when studying patient-derived samples becomes an integral part of the investigational process. For idiopathic pulmonary fibrosis (IPF), investigators need quality human specimens, collected in a standardized fashion, along with carefully annotated, long-term clinical and outcomes data to address current knowledge gaps. Access to human lung tissues through commercial entities or the Lung Tissue Resource Consortium, an NHLBI-funded consortium, has demonstrated the feasibility of this approach. However, these samples are not always well annotated or collected uniformly and are limited in their breadth to address future IPF research needs. Therefore, we propose leveraging ongoing and future studies in IPF to establish a biorepository that will meet current and future needs of IPF investigations. Specifically, we propose that blood, cell, and lung samples, linked to robust longitudinal clinical phenotyping generated from future industry, federally sponsored, and investigator-initiated clinical studies be prospectively and uniformly collected and stored in a biorepository and linked registry. Here we outline standardized methodologies that would allow specimens and clinical data collected from different studies to be integrated and accessible to the IPF research community for investigations that will inform future basic and translational research in IPF. Such a biorepository needs the combined efforts of all stakeholders, to be driven by projected future scientific needs and to be available to all qualified researchers. We believe this infrastructure is crucial, is feasible, and would accelerate research in IPF.
  • Author:
    Griebsch I; Palmer M; Fayers PM; Ellis S
    Title:
    Is progression-free survival associated with a better health-related quality of life in patients with lung cancer? Evidence from two randomised trials with afatinib
    Source:
    BMJ Open 4 (10) art.no.e005762 (2014)
    Abstract:
    Objective: Progression-free survival (PFS) is frequently used as an efficacy end point in oncology clinical trials. However, there is limited evidence to support a positive association between improvement in PFS and improvement in health-related quality of life (HRQoL). The association between PFS and HRQoL was evaluated in two randomised trials. Materials and methods: Data from two randomised controlled trials in patients with non-small cell lung cancer (NSCLC; LUX-Lung 1 and LUX-Lung 3) were used to investigate HRQoL in patients to determine whether tumour progression is accompanied by worsening HRQoL. HRQoL was assessed using the cancer-specific European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30, the EuroQol EQ-5D overall utility and EuroQol EQ visual analogue scale. In both studies, progression was evaluated by independent review using RECIST criteria (primary end point) and also by investigator assessment. The relationship between tumour progression and HRQoL was evaluated using analysis of covariance and a longitudinal model. Results: Compliance with HRQoL questionnaire completion was high. In both studies, patients with progression consistently experienced numerically poorer HRQoL at the time of progression than patients without progression. Differences in mean scores were statistically significant (p<0.05) between patients with and without progression at week 4 in all analyses in LUX-Lung 1 and at multiple time points in LUX-Lung 3. Results from the longitudinal analysis showed that progression (by independent review and investigator assessment) appears to have consistent negative impact on all three HRQoL measures (all p<0.0001). Conclusions: Tumour progression in patients with NSCLC was associated with statistically significant worsening in HRQoL. These findings confirm the value of PFS as a patient-relevant end point
  • Author:
    Yawn BP; Duvall K; Peabody J; Albers F; Iqbal A; Paden H; Zubek VB; Wadland WC
    Title:
    The impact of screening tools on diagnosis of chronic obstructive pulmonary disease in primary care
    Source:
    Am J Prev Med 47 (5), 563-575 (2014)
    Abstract:
    Background Chronic obstructive pulmonary disease (COPD) is frequently misdiagnosed or undiagnosed, which can delay disease management interventions. Purpose The Screening, Evaluating and Assessing Rate CHanges of diagnosing respiratory conditions in primary care 1 (SEARCH1) study assessed whether screening using the COPD Population Screener (COPD-PS) questionnaire to detect COPD risk factors and symptoms, with or without a handheld spirometer (copd-6) to detect airflow limitation, can increase yields of COPD diagnosis and respiratory-related clinician actions in primary care. Design A prospective, multi-center, pragmatic, comparative-effectiveness, cluster-randomized study conducted from September 2010 to October 2011 (data analyzed from December 2011 to January 2013). Participants Men and women aged .40 years visiting their participating primary care practice for any reason. Intervention Practices were randomized to three study arms: COPD-PS + copd-6, COPD-PS alone, and usual care (no interventions). No practices received any specific education about COPD or its diagnosis. Main outcome measures The primary endpoint was yield of new clinical COPD diagnosis; the secondary endpoint was yield of respiratory-related clinician actions. Results Of 9,704 patients enrolled, 8,770 had no prior COPD diagnosis and were included in endpoint analyses. Both interventions significantly increased COPD diagnostic yield over 8 weeks. Compared with a mean yield of 0.49% (0.13%) (controls), yields were 1.07% (0.20%) (OR=2.20, 95% CI=1.26, 3.84, p=0.006) and 1.16% (0.22%) (OR=2.38, 95% CI=1.38, 4.13, p=0.002) for COPD-PS and COPD-PS+copd-6 study arms, respectively. Respiratory-related clinician actions were not significantly different across study arms. Conclusions Office-based assessment can significantly increase COPD diagnosis by primary care physicians. Future trials must evaluate whether screening can improve outcomes for patients with COPD.
  • Author:
    Aguilaniu B; Roth H; Gonzalez-Bermejo J; Jondot M; Maitre J; Denis F; Similowski T
    Title:
    A simple semipaced 3-minute chair rise test for routine exercise tolerance testing in COPD
    Source:
    Int J COPD 9, 1009-1019 (2014)
    Abstract:
    The functional work capacity of chronic obstructive pulmonary disease (COPD) patients is usually assessed with walk tests such as the 6-minute walk test (6MWT) or the shuttle test. Because these exercise modalities require a controlled environment which limits their use by pulmonologists and severely restricts their use among general practitioners, different modalities of a short (1 minute or less) sit-to-stand test were recently proposed. In this study, we evaluated a new modality of a semipaced 3-minute chair rise test (3CRT) in 40 patients with COPD, and compared the reproducibility of physiological responses and symptoms during the 3CRT and their interchangeability with the 6MWT. The results demonstrate that physiological variables, heart rate, pulse oxygen saturation, work done, and symptoms (Borg dyspnea and fatigue scores), during the 3CRT were highly reproducible, and that the physiological responses and symptoms obtained during the 3CRT and the 6MWT were interchangeable for most patients. Moreover, these preliminary data suggest that patients able to perform more than 50 rises during 3 minutes had no significant disability. The simplicity and ease of execution of the 3CRT will facilitate the assessment of exercise symptoms and disability in COPD patients during routine consultations with pulmonologists and general practitioners, and will thus contribute to the improved management of COPD patients.
  • Author:
    ZuWallack R; Allen L; Hernandez G; Ting N; Abrahams R
    Title:
    Efficacy and safety of combining olodaterol Respimat® and tiotropium HandiHaler® in patients with COPD: Results of two randomized, double-blind, active-controlled studies
    Source:
    Int J COPD 9, 1133-1144 (2014)
    Abstract:
    Background: Combining bronchodilators with different mechanisms of action may improve efficacy and reduce risk of side effects compared to increasing the dose of a single agent in chronic obstructive pulmonary disease (COPD). We investigated this by combining two long-acting bronchodilators: once-daily muscarinic antagonist tiotropium and once-daily beta2-agonist olodaterol.
  • Author:
    Siebenand S
    Title:
    Neuer SGLT-2-inhibitor: Der dritte im bunde
    Source:
    Pharm Ztg 28 (2014)
    Abstract:
    No Abstract available
  • Author:
    Fastenau A; Muris JW; De Bie RA; Hendriks EJ; Asijee GM; Beekman E; Gosselink R; Van Schayck OC
    Title:
    Efficacy of a physical exercise training programme COPD in primary care: Study protocol of a randomized controlled trial
    Source:
    BMC Public Health 14 art. no.788 (2014)
    Abstract:
    Methods/design. In this randomized controlled trial situated in the primary care setting, 102 patients with mild to moderate airflow obstruction (FEV1. 50% of predicted), dyspnoea and a physically inactive lifestyle will be randomized to an intervention or control group. The intervention group receives a 4-month physical exercise training programme at a local physiotherapy practice, which includes exercise training, resistance training, breathing exercises and advises on how to increase the level of physical activity. The control group receives usual care, i.e. advises on how to increase the level of physical activity and a sham treatment at a local physiotherapy practice of which no physiological training stimulus can be expected. Primary outcome is functional exercise capacity at 4-months measured on the six-minute walk distance. Secondary outcomes include peripheral muscle strength, physical activity in daily life, health related quality of life, Medical Research Council (MRC) dyspnoea score and patients' perceived effectiveness. Follow-up measurement will take place at 6 months after baseline. Discussion. This will be one of the first studies to evaluate the efficacy of a physical exercise training programme in patients with mild to moderate COPD completely recruited and assessed in primary care. The results of this trial may give a unique insight into the potential of the implementation of an easy, close-to-home rehabilitation programme. Trial registration. The Netherlands National Trial Register NTR1471. Background: Chronic obstructive pulmonary disease (COPD) is recognized as a systemic illness with significant extra-pulmonary features, such as exercise intolerance and muscle weakness. Pulmonary rehabilitation has been shown to be very effective in counteracting these consequences in patients with more advanced COPD. However, limited data is available on the efficacy of a physical exercise training programme in patients with mild to moderate COPD in primary care. Furthermore, it is unknown if improved exercise capacity translates into enhanced daily physical activities. The aim of this paper is to describe the design of a randomized controlled trial to assess the efficacy of a physical exercise training programme in patients with mild to moderate COPD.
  • Author:
    Bradley JM; Koker P; Deng Q; Moroni-Zentgraf P; Ratjen F; Geller DE; Stuart Elborn J
    Title:
    Testing two different doses of tiotropium Respimat® in cystic fibrosis: Phase 2 randomized trial results
    Source:
    PLoS ONE 9 (9) art.no.e106195 (2014)
    Abstract:
    Background: Tiotropium is a once-daily, long-acting anticholinergic bronchodilator with the potential to alleviate airway obstruction in cystic fibrosis. Our objective was to evaluate the efficacy and safety of 2.5 and 5 .g once-daily tiotropium delivered via the Respimat Soft Mist Inhaler vs. placebo in people with cystic fibrosis. Methods: This phase 2, 12-week, randomized, double-blind, placebo-controlled parallel-group study of tiotropium Respimat as add-on to usual cystic fibrosis maintenance therapy included people with cystic fibrosis with pre-bronchodilator forced expiratory volume in 1 second (FEV1) .25% predicted. Co-primary efficacy end points were change from baseline in percent-predicted FEV1area under the curve from 0 to 4 hours (FEV1AUC0-4h), and trough FEV1at the end of week 12. Findings: A total of 510 subjects with cystic fibrosis aged 5-69 years were randomized. Both doses of tiotropium resulted in significant improvement compared with placebo in the co-primary efficacy end points at the end of week 12 (change from baseline in percent-predicted FEV1AUC0-4h: 2.5 .g: 2.94%, 95% confidence interval 1.19-4.70, p = 0.001; 5 .g: 3.39%, 95% confidence interval 1.67-5.12, p = 0.0001; in percent-predicted trough FEV1:2.5 .g: 2.24%, p = 0.2; 5 .g: 2.22%, p = 0.02). There was a greater benefit with tiotropium 5 vs. 2.5 .g. No treatment-related adverse events or unexpected safety findings were observed in patients taking tiotropium. Conclusions: Tiotropium significantly improved lung function in people with cystic fibrosis. The improvement was greater with the higher dose than the lower dose, with no difference in adverse events.
  • Author:
    Swigris JJ; Esser D; Conoscenti CS; Brown KK
    Title:
    The psychometric properties of the St George's Respiratory Questionnaire (SGRQ) in patients with idiopathic pulmonary fibrosis: A literature review
    Source:
    Health Qual Life Outcomes 12 (1) art.no. 124 (2014)
    Abstract:
    Assessment of health-related quality of life (HRQL) is particularly important in patients with progressive and incurable diseases such as idiopathic pulmonary fibrosis (IPF). The St George's Respiratory Questionnaire (SGRQ) has frequently been used to measure HRQL in patients with IPF, but it was developed for patients with obstructive lung diseases. The aim of this review was to examine published data on the psychometric performance of the SGRQ in patients with IPF. A comprehensive search was conducted to identify studies reporting data on the internal consistency, construct validity, test-retest reliability, and interpretability of the SGRQ in patients with IPF, published up to August 2013. In total, data from 30 papers were reviewed. Internal consistency was moderate for the SGRQ symptoms score and excellent for the SGRQ activity, impact and total scores. Validity of the SGRQ symptoms, activity, impact and total scores was supported by moderate to strong correlations with other patient-reported outcome measures and with a measure of exercise capacity. Most correlations were moderately strong between SGRQ activity or total scores and forced or static vital capacity, the most commonly used marker of IPF severity. There was evidence that changes in SGRQ domain and total scores could detect within-subject improvement in health status, and differentiate groups of patients whose health status had improved, declined or remained unchanged. Although the SGRQ was not developed specifically for use with patients with IPF, on balance, its psychometric properties are adequate and suggest that it may be a useful measure of HRQL in this patient population. However, several questions remain unaddressed, and further research is needed to confirm the SGRQ's utility in IPF.
  • Author:
    Strobel B; Leparc G; Lämmle B; Hildebrandt T; Stierstorfer B; Lamla T; Kreuz S
    Title:
    AAV-Tgfb1 vs. Bleomycin: Analysis of gene expression profiles in two models of pulmonary fibrosis
    Source:
    ERS 2014 Congress, Munich, Sep 7-10, 2014
  • Author:
    Strobel B; Leparc G; Lämmle B; Hildebrandt T; Stierstorfer B; Lamla T; Kreuz S
    Title:
    AAV-Tgfb1 vs. Bleomycin: Analysis of gene expression profiles in two models of pulmonary fibrosis
    Source:
    ERS 2014 Congress, Munich, Sep 7-9, 2014
  • Author:
    Kistler KD; Nalysnyk L; Rotella P; Esser D
    Title:
    Lung transplantation in idiopathic pulmonary fibrosis: A systematic review of the literature
    Source:
    BMC Pulm Med 14 (1) art.no. 139 (2014)
    Abstract:
    Background: Idiopathic pulmonary fibrosis (IPF) is a distinct form of interstitial pneumonia with unknown origin and poor prognosis. Current pharmacologic treatments are limited and lung transplantation is a viable option for appropriate patients. The aim of this review was to summarize lung transplantation survival in IPF patients overall, between single (SLT) vs. bilateral lung transplantation (BLT), pre- and post Lung Allocation Score (LAS), and summarize wait-list survival. Methods: A systematic review of English-language studies published in Medline or Embase between 1990 and 2013 was performed. Eligible studies were those of observational design reporting survival post-lung transplantation or while on the wait list among IPF patients. Results: Median survival post-transplantation among IPF patients is estimated at 4.5 years. From ISHLT and OPTN data, one year survival ranged from 75% - 81%; 3-year: 59% - 64%; and 5-year: 47% - 53%. Post-transplant survival is lower for IPF vs. other underlying pre-transplant diagnoses. The proportion of IPF patients receiving BLT has steadily increased over the last decade and a half. Unadjusted analyses suggest improved long-term survival for BLT vs. SLT; after adjustment for patient characteristics, the differences tend to disappear. IPF patients account for the largest proportion of patients on the wait list and while wait list time has decreased, the number of transplants for IPF patients has increased over time. OPTN data show that wait list mortality is higher for IPF patients vs. other diagnoses. The proportion of IPF patients who died while awaiting transplantation ranged from 14% to 67%. While later transplant year was associated with increased survival, no significant differences were noted pre vs. post LAS implementation; however a high LAS vs low LAS was associated with decreased one-year survival. Conclusions: IPF accounts for the largest proportion of patients awaiting lung transplants, and IPF is associated with higher wait-list and post-transplant mortality vs. other diagnoses. Improved BLT vs. SLT survival may be the result of selection bias. Survival pre- vs. post LAS appears to be similar except for IPF patients with high LAS, who have lower survival compared to pre-LAS. Data on post-transplant morbidity outcomes are sparse.
  • Author:
    Roskell NS; Anzueto A; Hamilton A; Disse B; Becker K
    Title:
    Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: An indirect comparison of olodaterol and indacaterol
    Source:
    Int J COPD 9, 813-824 (2014)
    Abstract:
    Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network. Conclusion: When compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD. © 2014 Roskell et al.
  • Author:
    Koch A; Pizzichini E; Hamilton A; Hart L; Korducki L; De Salvo MC; Paggiaro P
    Title:
    Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: Results from two replicate 48-week studies
    Source:
    Int J COPD 9, 697-714 (2014)
    Abstract:
    Two replicate, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies investigated the long-term efficacy and safety of once-daily olodaterol via Respimat® versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy. Patients received once-daily olodaterol 5 or 10 .g, twice-daily formoterol 12 .g, or placebo. Co-primary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0-3 hours response, FEV1 trough response, and Mahler transition dyspnea index total score after 24 weeks; secondary end points included St George's Respiratory Questionnaire. Overall, 904 (Study 1222.13) and 934 (Study 1222.14) patients received treatment. Olodaterol significantly improved FEV1 area under the curve from 0-3 hours versus placebo in both studies (with olodaterol 5 .g, 0.151 L and 0.129 L; with olodaterol 10 .g, 0.165 L and 0.154 L; for all comparisons P,0.0001) and FEV1 trough responses versus placebo (0.053-0.085 L; P,0.01), as did formoterol. Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo. Post hoc analysis using pattern mixture modeling (accounting for discontinuations) demonstrated statistical significance for olodaterol versus placebo. St George's Respiratory Questionnaire total score was significantly improved with olodaterol, but not formoterol, versus placebo. No safety signals were identified from adverse-event or other safety data. Once-daily olodaterol 5 .g and 10 .g is efficacious in patients with moderate to very severe chronic obstructive pulmonary disease on usual-care maintenance therapy, with a satisfactory safety profile. © 2014 Koch et al.
  • Author:
    Vogelberg C; Engel M; Moroni-Zentgraf P; Leonaviciute-Klimantavic; Sigmund R; Downie J; Nething K; Vevere V; Vandewalker M
    Title:
    Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study
    Source:
    Respir Med Article in Press (2014)
    Abstract:
    Introduction: Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat® SoftMist. inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment. Methods: This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 .g, 2.5 .g and 1.25 .g versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0-3h)). Results: From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0-3h) response for tiotropium 5 .g was significantly greater versus placebo (p = 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 .g (p &lt; 0.00001) and 1.25 .g (p = 0.0134) versus placebo, but not for 2.5 .g (p = 0.0975), while FEV1 area under the curve(0-3h) responses were significant for all doses (p = 0.00001-0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity. Conclusion: This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. ClinicalTrials.gov identifier; NCT01122680. © 2014.
  • Author:
    Willson J; Bateman ED; Pavord I; Lloyd A; Krivasi T; Esser D
    Title:
    Cost effectiveness of tiotropium in patients with asthma poorly controlled on inhaled glucocorticosteroids and long-acting beta- agonists
    Source:
    Appl Health Econ Health Policy 12 (4), 447-459 (2014)
    Abstract:
    Background: A considerable proportion of patients with asthma remain uncontrolled or symptomatic despite treatment with a high dose of inhaled glucocorticosteroids (ICSs) and long-acting .2-agonists (LABAs). Tiotropium Respimat® added to usual care improves lung function, asthma control, and the frequency of non-severe and severe exacerbations, in a population of adult asthma patients who are uncontrolled despite treatment with ICS/LABA. Objective: This study estimated the cost effectiveness of tiotropium therapy as add-on to usual care in asthma patients that are uncontrolled despite treatment with ICS/LABA combination from the perspective of the UK National Health Service (NHS). Methods: A Markov model was developed which considers levels of asthma control and exacerbations. The model analysed cost and quality-adjusted life-years (QALYs); sensitivity and scenario analyses were also conducted to test the robustness of the base case outcomes. All costs are given at 2012 prices. Results: The model found that in this category of asthma with unmet need, add-on tiotropium therapy generated an incremental 0.24 QALYs and £5,238 costs over a lifetime horizon, resulting in an incremental cost-effectiveness ratio of £21,906 per QALY gained. Sensitivity analysis suggested that findings were most dependent on the costs of managing uncontrolled asthma and the cost of treatment with tiotropium. Conclusion: In this modelled analysis of two clinical trials, tiotropium was found to be cost effective when added to usual care in patients who remain uncontrolled despite treatment with high-dose ICS/LABA. Further research should investigate the long-term treatment effectiveness of tiotropium. © 2014 Springer International Publishing.
  • Author:
    Beeh K-M; Moroni-Zentgraf P; Ablinger O; Hollaenderova Z; Unseld A; Engel M; Korn S
    Title:
    Tiotropium Respimat® in asthma: A double-blind, randomised, dose-ranging study in adult patients with moderate asthma
    Source:
    Respir Res 15 (1) art. no. 61 (2014)
    Abstract:
    Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, when administered via Respimat® SoftMist. inhaler (tiotropium Respimat®) significantly reduces the risk of severe exacerbations and improves lung function in patients with severe persistent asthma that is not fully controlled despite using inhaled corticosteroids (ICS) and long-acting .2-agonists. To further explore the dose-response curve in asthma, we investigated the efficacy and safety of three different doses of tiotropium Respimat® as add-on to ICS in symptomatic patients with moderate persistent asthma.Methods: In this randomised, double-blind, placebo-controlled, four-way crossover study, patients were randomised to tiotropium Respimat® 5 .g, 2.5 .g or 1.25 .g or placebo Respimat®, once daily in the evening. Each treatment was administered for 4 weeks, without washout between treatment periods. Eligibility criteria included .60% and .90% of predicted normal forced expiratory volume in 1 second (FEV1) and seven-question Asthma Control Questionnaire mean score of .1.5. Patients were required to continue maintenance treatment with stable medium-dose ICS for at least 4 weeks prior to and during the treatment period. Long-acting .2-agonists were not permitted during the treatment phase. The primary efficacy end point was peak FEV1 measured within 3 hours after dosing (peak FEV1(0-3h)) at the end of each 4-week period, analysed as a response (change from study baseline).Results: In total, 149 patients were randomised and 141 completed the study. Statistically significant improvements in peak FEV1(0-3h) response were observed with each tiotropium Respimat® dose versus placebo (all P &lt; 0.0001). The largest difference from placebo was with tiotropium Respimat® 5 .g (188 mL). Trough FEV1 and FEV1 area under the curve (AUC)(0-3h) responses were greater with each tiotropium Respimat® dose than with placebo (all P &lt; 0.0001), and both were greatest with 5 .g. Peak forced vital capacity (FVC)(0-3h), trough FVC and FVC AUC(0-3h) responses, versus placebo, were greatest with tiotropium Respimat® 5 .g (P &lt; 0.0001, P = 0.0012 and P &lt; 0.0001, respectively). Incidence of adverse events was comparable between placebo and all tiotropium Respimat® groups.Conclusions: Once-daily tiotropium Respimat® add-on to medium-dose ICS improves lung function in symptomatic patients with moderate asthma. Overall, improvements were largest with tiotropium Respimat® 5 .g.Trial registration: ClinicalTrials.gov identifier NCT01233284. © 2014 Beeh et al.; licensee BioMed Central Ltd.
  • Author:
    Willson J; Bateman ED; Pavord I; Lloyd A; Krivasi T; Esser D
    Title:
    Cost Effectiveness of Tiotropium in Patients with Asthma Poorly Controlled on Inhaled Glucocorticosteroids and Long-Acting beta- Agonists
    Source:
    Appl Health Econ Health Policy Article in Press (2014)
    Abstract:
    Background A considerable proportion of patients with asthma remain uncontrolled or symptomatic despite treatment with a high dose of inhaled glucocorticosteroids (ICSs) and long-acting beta2-agonists (LABAs). Tiotropium Respimat® added to usual care improves lung function, asthma control, and the frequency of non-severe and severe exacerbations, in a population of adult asthma patients who are uncontrolled despite treatment with ICS/LABA. Objective This study estimated the cost effectiveness of tiotropium therapy as add-on to usual care in asthma patients that are uncontrolled despite treatment with ICS/LABA combination from the perspective of the UK National Health Service (NHS). Methods A Markov model was developed which considers levels of asthma control and exacerbations. The model analysed cost and quality-adjusted life-years (QALYs); sensitivity and scenario analyses were also conducted to test the robustness of the base case outcomes. All costs are given at 2012 prices. Results The model found that in this category of asthma with unmet need, add-on tiotropium therapy generated an incremental 0.24 QALYs and £5,238 costs over a lifetime horizon, resulting in an incremental cost-effectiveness ratio of £21,906 per QALY gained. Sensitivity analysis suggested that findings were most dependent on the costs of managing uncontrolled asthma and the cost of treatment with tiotropium. Conclusion In this modelled analysis of two clinical trials, tiotropium was found to be cost effective when added to usual care in patients who remain uncontrolled despite treatment with high-dose ICS/LABA. Further research should investigate the long-term treatment effectiveness of tiotropium. © 2014 Springer International Publishing Switzerland.
  • Author:
    Tashkin DP; Metzdorf N; Hallmann C; Leimer I; Lee T; Decramer M
    Title:
    Authors' response to Walker et al.
    Source:
    Thorax 69 (4), 385 (2014)
    Abstract:
    no abstract available
  • Author:
    Magnussen H; Watz H; Kirsten A; Decramer M; Dahl R; Calverley PMA; Towse L; Finnigan H; Tetzlaff K; Disse B
    Title:
    Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale
    Source:
    Respir Med 108 (4), 593-599 (2014)
    Abstract:
    Long-acting bronchodilators in combination with inhaled corticosteroids (ICS) are recommended to decrease the risk of recurrent exacerbations in patients with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3-4 chronic obstructive pulmonary disease (COPD). There is increasing concern about the clinical benefit and long-term safety of ICS use in COPD patients. The WISDOM (Withdrawal of Inhaled Steroids During Optimised bronchodilator Management) study (NCT00975195) aims to evaluate the need for ICS use via stepwise withdrawal of ICS in COPD patients (GOLD 3-4 with a history of at least one exacerbation during the 12-month period prior to screening) receiving dual bronchodilation. During the 6-week run-in period, 2456 patients receive tiotropium 18 .g once daily, salmeterol 50 .g twice daily and fluticasone 500 .g twice daily. In a randomized, double-blind, parallel-group, active-controlled fashion, one group of patients continues to receive tiotropium, salmeterol and fluticasone, while the second group initiates stepwise withdrawal of fluticasone. The primary end point is time to first moderate or severe exacerbation following randomized treatment over 52 weeks. Lung function, symptoms and safety are also assessed. A sub-study aims to identify sub-populations and markers of steroid need. This study will determine the benefit of continued ICS therapy in combination with dual long-acting bronchodilators in COPD. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Richeldi L; Cottin V; Flaherty KR; Kolb M; Inoue Y; Raghu G; Taniguchi H; Hansell DM; Nicholson AG; Le Maulf F; Stowasser S; Collard HR
    Title:
    Design of the INPULSIS. trials: Two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis
    Source:
    Respir Med 108 (7), 1023-1030 (2014)
    Abstract:
    Background: Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that nintedanib 150 mg twice daily had clinical benefits with an acceptable safety profile. Methods: The INPULSIS. trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150 mg twice daily with placebo in patients with IPF. Eligible patients were aged .40 years with a diagnosis of IPF within 5 years before randomization who had undergone a chest high-resolution computed tomography (HRCT) scan within 1-year before screening, and who had a forced vital capacity (FVC) of .50% predicted and a diffusing capacity for carbon monoxide of 30-79% predicted. Participants were randomized 3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the annual rate of decline in FVC. The key secondary endpoints are change from baseline in the total score on the St. George's Respiratory Questionnaire (a measure of health-related quality of life) over 52 weeks and time to first acute exacerbation. Results: Enrolment of 1066 patients in 24 countries was completed in September 2012. Results: will be reported in the first half of 2014. Conclusion: The INPULSIS. trials will determine the efficacy of nintedanib in patients with IPF, including its impact on disease progression as defined by decline in FVC, acute exacerbations and health-related quality of life. In addition, they will characterise the adverse event profile of nintedanib in this patient population. © 2014 The Authors.
  • Author:
    Burgel P-R; Paillasseur J-L; Dusser D; Roche N; Liu D; Liu Y; Furtwaengler A; Metzdorf N; Decramer M
    Title:
    Tiotropium might improve survival in subjects with COPD at high risk of mortality
    Source:
    Respir Res 15 (1) art. no. 64 (2014)
    Abstract:
    Background: Inhaled therapies reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations, but their effect on mortality is less well established. We hypothesized that heterogeneity in baseline mortality risk influenced the results of drug trials assessing mortality in COPD.Methods: The 5706 patients with COPD from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study that had complete clinical information for variables associated with mortality (age, forced expiratory volume in 1 s, St George's Respiratory Questionnaire, pack-years and body mass index) were classified by cluster analysis. Baseline risk of mortality between clusters, and impact of tiotropium were evaluated during the 4-yr follow up.Results: Four clusters were identified, including low-risk (low mortality rate) patients (n = 2339; 41%; cluster 2), and high-risk patients (n = 1022; 18%; cluster 3), who had a 2.6- and a six-fold increase in all-cause and respiratory mortality compared with cluster 2, respectively. Tiotropium reduced exacerbations in all clusters, and reduced hospitalizations in high-risk patients (p < 0.05). The beneficial effect of tiotropium on all-cause mortality in the overall population (hazard ratio, 0.87; 95% confidence interval, 0.75-1.00, p = 0.054) was explained by a 21% reduction in cluster 3 (p = 0.07), with no effect in other clusters.Conclusions: Large variations in baseline risks of mortality existed among patients in the UPLIFT® study. Inclusion of numerous low-risk patients may have reduced the ability to show beneficial effect on mortality. Future clinical trials should consider selective inclusion of high-risk patients. © 2014 Burgel et al.; licensee BioMed Central Ltd.
  • Author:
    Bereznicki BJ; Peterson GM; Jackson SL; Walters H; Hardley FL; Gavagna GA; Marshall DC
    Title:
    Describing drivers of and barriers to persistence with tiotropium in patients with chronic obstructive pulmonary disease: A mixed-methods approach
    Source:
    Int J Pharm Pract Article in Press (2014)
    Abstract:
    Objective: To understand the factors influencing persistence with tiotropium in patients with chronic obstructive pulmonary disease (COPD). Methods: Patients classified as 'persistent' or 'non-persistent' with tiotropium were identified from pharmacy dispensing records. Patients were compared for health status, beliefs and behaviours using data from questionnaires and interviews. Key findings: Perceptions of the risks and benefits of medication, fear of worsening illness, and the GP's emphasis on the importance of the medication were key determinants of tiotropium persistence. Conclusions: Perceptions, attitudes and beliefs of patients and doctors influence persistence with tiotropium. These complex interactions need to be targeted to improve persistence with medicines in COPD. © 2014 Royal Pharmaceutical Society.
  • Author:
    Leiner S
    Title:
    A respiratory product for children - Development and submission experiences
    Source:
    Int J Pharm 469 (2), 263-264 (2014)
    Abstract:
    The article highlights experiences for the development and submission of an inhalation product for children. © 2014 Elsevier B.V.
  • Author:
    Excoffon C
    Title:
    In vitro testing for inhalative drugs
    Source:
    Internal Report for CPE Lyon, France
  • Author:
    Beekman E; Mesters I; Hendriks EJM; Muris JWM; Wesseling G; Evers SMAA; Asijee GM; Fastenau A; Hoffenkamp HN; Gosselink R; van Schayck OCP; de Bie RA
    Title:
    Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: A cohort-nested randomised controlled trial
    Source:
    BMC Pulm Med 14 (1) art. no. 71 (2014)
    Abstract:
    Background: Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation.Methods/Design: A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC &lt; 0.7 and FEV1 &lt; 80% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index &lt; 0.6) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients' perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion.Discussion: Ways to minimise potential problems regarding the execution of this study will be discussed.Trial registration: The Netherlands National Trial Register NTR1972. © 2014 Beekman et al.; licensee BioMed Central Ltd.
  • Author:
    Schmelzer Dr C; Dick Dr C
    Title:
    Lost in Terminology of Quality Attributes of Inhalation Products! Terms currently used by EPAG Member Companies to Encourage Harmonization in International Pharmacopeias, Regulatory Guidelines and Literature
    Source:
    RDD (Respiratory Drug Delivery Conference) 2014
  • Author:
    Baker CL; Zou KH; Su J
    Title:
    Long-acting bronchodilator use after hospitalization for COPD: An observational study of health insurance claims data
    Source:
    Int J COPD 9, 431-439 (2014)
    Abstract:
    Background: Treatment of stable chronic obstructive pulmonary disease (COPD) with long-acting bronchodilator (LABD) medications is recommended by the 2014 Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines. The primary objective of this study was to examine LABD prescription fills after a COPD-related hospitalization. Methods: This retrospective observational study used claims from Truven Health MarketScan® Commercial and Medicare Supplemental databases. Patients (age .40, commercial; age .65, Medicare supplemental) had a first hospitalization with a primary COPD diagnosis between April 1, 2009 and June 30, 2011 (index hospitalization) and were continuously enrolled for 1 year before and 9 months after hospitalization. Patients were categorized according to pre-index and/or post-index pharmacy claims. Results: A total of 27,738 patients had an index hospitalization and met inclusion/exclusion criteria. Of those, 19,783 patients had COPD as a primary or secondary diagnosis during the year before index hospitalization and were included in the analysis. Approximately one quarter of the patients (26.32%) did not fill a prescription for an LABD or short-acting bronchodilator both 90 days before and 90 days after hospitalization. During the 90-day pre-index period, 40.57% of patients filled an LABD (with or without a short-acting bronchodilator) prescription. Over half of the patients (56.88%) filled an LABD prescription at some point during the 180-day post-index period, but, of those, a significantly greater proportion of patients filled an LABD prescription in the 1- to 90-day post-index period than in the 91- to 180-day post-index period (51.27% versus 43.66%; P<0.0001). Conclusion: A significant proportion of COPD patients in this study did not fill an LABD prescription before hospitalization for COPD. Moreover, hospitalization did not appear to greatly impact LABD initiation. Lastly, patients who did not fill an LABD prescription within the first 90 days posthospitalization were not likely to fill an LABD prescription later. Taken together, the results of this study suggest that many patients with COPD are undertreated. © 2014 Baker et al.
  • Author:
    Beekman E; Mesters I; Hendriks EJM; Muris JWM; Wesseling G; Evers SMAA; Asijee GM; Fastenau A; Hoffenkamp HN; Gosselink R; van Schayck OCP; de Bie RA
    Title:
    Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: A cohort-nested randomised controlled trial
    Source:
    BMC Pulm Med 14 (1) art.no.71 (2014)
    Abstract:
    Background: Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation.Methods/Design: A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC &lt; 0.7 and FEV1 &lt; 80% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index &lt; 0.6) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients' perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion.Discussion: Ways to minimise potential problems regarding the execution of this study will be discussed.Trial registration: The Netherlands National Trial Register NTR1972. © 2014 Beekman et al.; licensee BioMed Central Ltd.
  • Author:
    Leidy NK; Sexton CC; Jones PW; Notte SM; Monz BU; Nelsen L; Goldman M; Murray LT; Sethi S
    Title:
    Measuring respiratory symptoms in clinical trials of COPD: Reliability and validity of a daily diary
    Source:
    Thorax 69 (5), 443-449 (2014)
    Abstract:
    Background: Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease. Objective: To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT). Methods: Qualitative: patient focus group and interviews to address content validity. Quantitative: secondary data analyses to test reliability and validity. Results: Qualitative: n=84; mean (SD) age 65(10) years, FEV1 1.2(0.4) L; 44% male. Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure. Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male. Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough &amp; Sputum, and RS-Chest Symptoms; secondorder FA supported a general factor and total score. Reliability (total and subscales):0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively. Validity: Total scores correlated significantly (p &lt; 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p &lt; 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p &lt; 0.0001 (RS-Cough &amp; Sputum with Symptoms). RS-Breathlessness correlated with rescue medication use (r=0.32, p &lt; 0.0001), clinician-reported mMRC (r=0.33, p &lt; 0.0001), and FEV1% predicted (r=-0.17, p &lt; 0.05). E-RS scores differentiated groups based on chronic bronchitis diagnosis (p &lt; 0.01-0.001), smoking status (p &lt; 0.05-0.001), and rescue medication use (p &lt; 0.05-0.0001). Conclusions: Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD. Further study of sensitivity to change is warranted.
  • Author:
    Meyer G; Vicaut E; Danays T; Agnelli G; Becattini C; Beyer-Westendorf J; Bluhmki E; Bouvaist H; Brenner B; Couturaud F; Dellas C; Empen K; Franca A; Galiè N; Geibel A; Goldhaber SZ; Jimenez D; Kozak M; Kupatt C; Kucher N; Lang IM; Lankeit M; Meneveau N; Pacouret G; Palazzini M; Petris A; Pruszczyk P; Rugolotto M; Salvi A; Schellong S; Sebbane M; Sobkowicz B; Stefanovic BS; Thiele H; Torbicki A; Verschuren F; Konstantinides SV
    Title:
    Fibrinolysis for patients with intermediate-risk pulmonary embolism
    Source:
    N Engl J Med 370 (15), 1402-1411 (2014)
    Abstract:
    BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P = 0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P = 0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P = 0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P = 0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
  • Author:
    Tibletti M; Paul J; Stiller D; Rasche V
    Title:
    Relevance of respiratory gating for proton Lung MRI
    Source:
    Annual Meeting of the ISMRM, Milano, Italy, May 10-16, 2014
  • Author:
    Leidy NK; Sexton CC; Jones PW; Notte SM; Monz BU; Nelsen L; Goldman M; Murray LT; Sethi S
    Title:
    Measuring respiratory symptoms in clinical trials of COPD: Reliability and validity of a daily diary
    Source:
    Thorax 69 (5), 443-449 (2014)
    Abstract:
    Background: Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease. Objective: To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT). Methods: Qualitative: patient focus group and interviews to address content validity. Quantitative: secondary data analyses to test reliability and validity. Results: Qualitative: n=84; mean (SD) age 65(10) years, FEV1 1.2(0.4) L; 44% male. Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure. Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male. Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough &amp; Sputum, and RS-Chest Symptoms; secondorder FA supported a general factor and total score. Reliability (total and subscales):0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively. Validity: Total scores correlated significantly (p &lt; 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p &lt; 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p &lt; 0.0001 (RS-Cough &amp; Sputum with Symptoms). RS-Breathlessness correlated with rescue medication use (r=0.32, p &lt; 0.0001), clinician-reported mMRC (r=0.33, p &lt; 0.0001), and FEV1% predicted (r=-0.17, p &lt; 0.05). E-RS scores differentiated groups based on chronic bronchitis diagnosis (p &lt; 0.01-0.001), smoking status (p &lt; 0.05-0.001), and rescue medication use (p &lt; 0.05-0.0001). Conclusions: Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD. Further study of sensitivity to change is warranted.
  • Author:
    Meyer G; Vicaut E; Danays T; Agnelli G; Becattini C; Beyer-Westendorf J; Bluhmki E; Bouvaist H; Brenner B; Couturaud F; Dellas C; Empen K; Franca A; Galiè N; Geibel A; Goldhaber SZ; Jimenez D; Kozak M; Kupatt C; Kucher N; Lang IM; Lankeit M; Meneveau N; Pacouret G; Palazzini M; Petris A; Pruszczyk P; Rugolotto M; Salvi A; Schellong S; Sebbane M; Sobkowicz B; Stefanovic BS; Thiele H; Torbicki A; Verschuren F; Konstantinides SV
    Title:
    Fibrinolysis for patients with intermediate-risk pulmonary embolism
    Source:
    N Engl J Med 370 (15), 1402-1411 (2014)
    Abstract:
    BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P = 0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P = 0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P = 0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P = 0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
  • Author:
    Vietri J; Burslem K; Su J
    Title:
    Poor asthma control among US workers: Health-related quality of life, work impairment, and health care use
    Source:
    J Occup Environ Med 56 (4), 425-430 (2014)
    Abstract:
    Objective: This study examined the impact of asthma control on health-related outcomes among employed US asthma sufferers treated with prescription medicines. Methods: Data from the 2011 National Health and Wellness Survey (N = 75,000) were used. The Asthma Control Test, validated measures of health-related quality of life, work productivity and activity impairment, and questions assessing health care use were included. Results: Of the 2026 employed asthma sufferers treated with prescription medicines included, 39.7% had Asthma Control Test scores indicating poorly controlled asthma. After adjusting for covariates, workers with poorly controlled asthma had worse health-related quality of life, work and activity impairment, and more health care use than those with well-controlled asthma. Conclusions: Poorly controlled asthma in employed patients treated with prescription medicines is common, and associated with negative health outcomes. Workers, employers, and payers could all benefit from improvements in asthma control. © 2014 by American College of Occupational and Environmental Medicine
  • Author:
    Hohlfeld JM; Sharma A; Van Noord JA; Cornelissen PJG; Derom E; Towse L; Peterkin V; Disse B
    Title:
    Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease
    Source:
    J Clin Pharmacol 54 (4), 405-414 (2014)
    Abstract:
    The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 .g compared to powder 18 .g and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 .g, and placebo), and open-label powder 18 .g, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (C max,ss), and area under the plasma concentration-time profile (AUC0-6h,ss), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/ Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 .g over powder 18 .g was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss, indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 .g and solution 5 .g were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 .g at lower systemic exposure supports tiotropium solution 5 .g for maintenance treatment of COPD. © 2013 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology
  • Author:
    Duechs MJ; Tilp C; Tomsic C; Gantner F; Erb KJ
    Title:
    Development of a novel severe triple allergen asthma model in mice which is resistant to dexamethasone and partially resistant to TLR7 and TLR9 agonist treatment
    Source:
    PLoS ONE 9 (3) art no e91223 (2014)
    Abstract:
    Severe asthma is characterised by persistent inflammation, hyperreactivity and remodeling of the airways. No efficient treatment is available, this is particularly the case for steroid resistant phenotypes. Our aim therefore was to develop a preclinical model showing characteristics of severe human asthma including steroid insensitivity. Mice were first sensitized with ovalbumin, extracts of cockroach or house dust mite followed by a challenge period of seven weeks. Further to this, an additional group of mice was sensitized with all three allergens and then challenged with allergen alternating weekly between allergens. All three allergens applied separately to the mice induced comparably strong Th2-type airway inflammation, airway hyperreactivity and airway remodeling, which was characterised by fibrosis and increased smooth muscle thickness. In contrast, application of all three allergens together resulted in a greater Th2 response and increased airway hyperreactivity and a stronger albeit not significant remodeling phenotype compared to using HDM or CRA. In this triple allergen model dexamethasone application, during the last 4 weeks of challenge, showed no suppressive effects on any of these parameters in this model. In contrast, both TLR7 agonist resiquimod and TLR9 agonist CpG-ODN reduced allergen-specific IgE, eosinophils, and collagen I in the lungs. The TLR9 agonist also reduced IL-4 and IL-5 whilst increasing IFN-. and strongly IL-10 levels in the lungs, effects not seen with the TLR7 agonist. However, neither TLR agonist had any effect on airway hyperreactivity and airway smooth muscle mass. In conclusion we have developed a severe asthma model, which is steroid resistant and only partially sensitive to TLR7 and TLR9 agonist treatment. This model may be particular useful to test new potential therapeutics aiming at treating steroid resistant asthma in humans and investigating the underlying mechanisms responsible for steroid insensitivity. © 2014 Duechs et al.
  • Author:
    Leidy NK; Kimel M; Ajagbe L; Kim K; Hamilton A; Becker K
    Title:
    Designing trials of behavioral interventions to increase physical activity in patients with COPD: Insights from the chronic disease literature
    Source:
    Respir Med 108 (3), 472-481 (2014)
    Abstract:
    Objectives: There is increasing evidence that physical activity (PA) can affect health outcomes, particularly in chronic disease. While pharmacologic therapy and exercise training can improve exercise capacity, increasing PA requires behavior change. This review examined clinical trials testing the effectiveness of behavioral interventions to increase PA in adults with chronic disease to inform future research in COPD. Methods: Embase and PubMed searches of studies published in English, 1995-2011. Inclusion criteria: Adults .45 years; COPD, diabetes, heart failure, obesity; exercise or PA endpoint; behavioral intervention described in sufficient detail to permit interpretation. Results: 932 abstracts screened; 169 articles retrieved; 36 reviewed. Most were randomized trials (n = 32, 89%); 2 arms (n = 26, 72%), sample sizes 40-100 (n = 15, 42%); recruitment through clinical settings (n = 28, 78%); disease severity as primary eligibility criterion (n = 23, 64%); mean duration: 10 months (range: 1-84). Exercise intervention: aerobic activity, 30-60 min (n = 20, 56%), 3-5 times/week (n = 20, 56%). Behavioral intervention: Counseling (n = 19, 53%) with personal follow-up (n = 12, 33%). Control group: Exercise without behavioral intervention (n = 14, 39%) or usual care (n = 15, 42%). Significant effects were reported in 15 of 25 (60%) studies testing exercise capacity (6-minute walk, cycle, treadmill), 19 of 26 (73%) testing PA (pedometer, activity log, questionnaire), 11 of 22 (50%) measuring quality of life, and 8 of 13 (62%) capturing behavioral endpoints. Conclusions This review provides insight into the range of designs, interventions, and outcome measures used in studies testing methods to improve PA in chronic disease with implications for designing trials in COPD. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Claus S; Weiler C; Schiewe J; Friess W
    Title:
    How can we bring high drug doses to the lung?
    Source:
    Eur J Pharm Biopharm 86 (1), 1-6 (2014)
    Abstract:
    In the last decades, dry powder inhalation has become a very attractive option for pulmonary drug delivery to treat lung diseases like cystic fibroses and lung infections. In contrast to the traditional pulmonary application of drugs for asthma and chronic obstructive pulmonary disease, these therapies require higher lung doses to be administered. The developments and improvements toward high dose powder pulmonary drug delivery are summarized and discussed in this chapter. These include the invention and improvement of novel inhaler devices as well as the further development of formulation principles and new powder engineering methods. The implementation of these strategies is subsequently described for some prototypes and formulations in research and development stage as well as for already marketed dry powder products. Finally, possible adverse effects that can occur after inhalation of high powder doses are shortly addressed.© 2013 Elsevier B.V. All rights reserved.
  • Author:
    Strobel B
    Title:
    Exploration of respiratory drug targets by Adeno-associated virus mediated gene transfer
    Source:
    Pre-Meeting Workshop, DG-GT Jahrestagung, Uni Ulm, Germany, Mar 19, 2014
  • Author:
    Strobel B
    Title:
    Pulmonary disease modeling using AAV vectors
    Source:
    Pre-Meeting der DGGT Jahrestagung in Ulm, Mar 19, 2014
  • Author:
    Dollinger H; Jung B
    Title:
    Anti-inflammatory approaches for the treatment of respiratory diseases
    Source:
    Presentation for Frontiers in Medicinal Chemistry, Tübingen Mar 16-19, 2014
  • Author:
    Konstan MW; Döring G; Heltshe SL; Lands LC; Hilliard KA; Koker P; Bhattacharya S; Staab A; Hamilton A
    Title:
    A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis
    Source:
    J Cystic Fibros 13 (2), 148-155 (2014)
    Abstract:
    Background: Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB4-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 BS in CF patients. Methods: CF patients aged .6years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24weeks. Co-primary endpoints were change in FEV1 and incidence of pulmonary exacerbation. Results: After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38). Conclusions: While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events. © 2014 European Cystic Fibrosis Society.
  • Author:
    Dollinger H; Jung B
    Title:
    Anti-inflammatory approaches for the treatment of respiratory diseases (variant B not including Nintedanib in case Dev. does not grant releas of corrected former variant in time)
    Source:
    Presentation for Frontiers in Medicinal Chemistry, Tübingen, Germany,16-19 Mar, 2014
  • Author:
    Dollinger H; Jung B
    Title:
    Anti-inflammatory Approaches for the Treatment of Respiratory Diseases
    Source:
    Abstract for a presentation at Frontiers in Medicinal Chemistry, Tübingen, Germany, 16-19 Mar, 2014
  • Author:
    Jeong J; Aly SS; Cano JP; Polson D; Kass PH; Perez AM
    Title:
    Stochastic model of porcine reproductive and respiratory syndrome virus control strategies on a swine farm in the United States
    Source:
    Am J Vet Res 75 (3), 260-267 (2014)
    Abstract:
    no Abstract available
  • Author:
    Leidy NK; Kimel M; Ajagbe L; Kim K; Hamilton A; Becker K
    Title:
    Designing trials of behavioral interventions to increase physical activity in patients with COPD: Insights from the chronic disease literature
    Source:
    Respir Med 108 (3), 472-481 (2014)
    Abstract:
    no Abstract available
  • Author:
    Leidy NK; Sexton CC; Jones PW; Notte SM; Monz BU; Nelsen L; Goldman M; Murray LT; Sethi S
    Title:
    Measuring respiratory symptoms in clinical trials of COPD: Reliability and validity of a daily diary
    Source:
    Thorax Article in Press (2014)
    Abstract:
    no Abstract available
  • Author:
    Magnussen H; Watz H; Kirsten A; Decramer M; Dahl R; Calverley PMA; Towse L; Finnigan H; Tetzlaff K; Disse B
    Title:
    Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale
    Source:
    Respir Med article in press (2014)
    Abstract:
    Long-acting bronchodilators in combination with inhaled corticosteroids (ICS) are recommended to decrease the risk of recurrent exacerbations in patients with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3-4 chronic obstructive pulmonary disease (COPD). There is increasing concern about the clinical benefit and long-term safety of ICS use in COPD patients. The WISDOM (Withdrawal of Inhaled Steroids During Optimised bronchodilator Management) study (NCT00975195) aims to evaluate the need for ICS use via stepwise withdrawal of ICS in COPD patients (GOLD 3-4 with a history of at least one exacerbation during the 12-month period prior to screening) receiving dual bronchodilation. During the 6-week run-in period, 2456 patients receive tiotropium 18 .g once daily, salmeterol 50 .g twice daily and fluticasone 500 .g twice daily. In a randomized, double-blind, parallel-group, active-controlled fashion, one group of patients continues to receive tiotropium, salmeterol and fluticasone, while the second group initiates stepwise withdrawal of fluticasone. The primary end point is time to first moderate or severe exacerbation following randomized treatment over 52 weeks. Lung function, symptoms and safety are also assessed. A sub-study aims to identify sub-populations and markers of steroid need. This study will determine the benefit of continued ICS therapy in combination with dual long-acting bronchodilators in COPD. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Konstan MW; Döring G; Heltshe SL; Lands LC; Hilliard KA; Koker P; Bhattacharya S; Staab A; Hamilton A
    Title:
    A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis
    Source:
    J Cystic Fibros Article in press (2014)
    Abstract:
    Background: Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB4-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 BS in CF patients. Methods: CF patients aged . 6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV1 and incidence of pulmonary exacerbation. Results: After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38). Conclusions: While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events. © 2014 European Cystic Fibrosis Society.
  • Author:
    Bosnjak B; Tilp C; Tomsic C; Dekan G; Pieper MP; Erb KJ; Epstein MM
    Title:
    Tiotropium bromide inhibits relapsing allergic asthma in BALB/c mice
    Source:
    Pulm Pharmacol Ther 27 (1), 44-51 (2014)
    Abstract:
    Recurrent relapses of allergic lung inflammation in asthmatics may lead to airway remodeling and lung damage. We tested the efficacy of tiotropium bromide, a selective long-acting, muscarinic receptor antagonist as an adjunct therapy in relapses of allergic asthma in mice. We compared the effectiveness of local intranasal administration of tiotropium and dexamethasone in acute and relapsing allergic asthma in BALB/c mice. Although tiotropium at low doses is a potent bronchodilator, we tested higher doses to determine effectiveness on inflammation and mucus hypersecretion. A 5-day course of twice daily intranasal tiotropium or dexamethasone (1 mg/kg (b.w.)) suppressed airway eosinophils by over 87% during disease initiation and 88% at relapse compared to vehicle alone. Both drugs were comparable in their capacity to suppress airway and parenchymal inflammation and mucus hypersecretion, though tiotropium was better than dexamethasone at reducing mucus secretion during disease relapse. Despite treatment with either drug, serum antigen-specific IgE or IgG1 antibody titres remained unchanged. Our study indicates that tiotropium at higher doses than required for bronchodilation, effectively suppresses inflammation and mucus hypersecretion in the lungs and airways of mice during the initiation and relapse of asthma. Tiotropium is currently not approved for use in asthma. Clinical studies have to demonstrate the efficacy of tiotropium in this respiratory disease. © 2013 Elsevier Ltd.
  • Author:
    Wanka S; Kappl M; Wolkenhauer M; Butt H-J
    Title:
    Measuring adhesion forces in powder collectives by inertial detachment
    Source:
    Langmuir 29 (52), 16075-16083 (2013)
    Abstract:
    One way of measuring adhesion forces in fine powders is to place the particles on a surface, retract the surface with a high acceleration, and observe their detachment due to their inertia. To induce detachment of micrometer-sized particles, an acceleration in the order of 500 000g is required. We developed a device in which such high acceleration is provided by a Hopkinson bar and measured via laser vibrometry. Using a Hopkinson bar, the fundamental limit of mechanically possible accelerations is reached, since higher values cause material failure. Particle detachment is detected by optical video microscopy. With subsequent automated data evaluation a statistical distribution of adhesion forces is obtained. To validate the method, adhesion forces for ensembles of single polystyrene and silica particles on a polystyrene coated steel surface were measured under ambient conditions. We were able to investigate more than 150 individual particles in one experiment and obtained adhesion values of particles in a diameter range of 3-13 .m. Measured adhesion forces of small particles agreed with values from colloidal probe measurements and theoretical predictions. However, we observe a stronger increase of adhesion for particles with a diameter larger than roughly 7-10 .m. We suggest that this discrepancy is caused by surface roughness and heterogeneity. Large particles adjust and find a stable position on the surface due to their inertia while small particles tend to remain at the position of first contact. The new device will be applicable to study a broad variety of different particle-surface combinations on a routine basis, including strongly cohesive powders like pharmaceutical drugs for treatment of lung diseases. © 2013 American Chemical Society.
  • Author:
    Schmidt T; Bierhals T; Kortüm F; Bartels I; Liehr T; Burfeind P; Shoukier M; Frank V; Bergmann C; Kutsche K
    Title:
    Branchio-otic syndrome caused by a genomic rearrangement: Clinical findings and molecular cytogenetic studies in a patient with a pericentric inversion of chromosome 8
    Source:
    Cytogenet Genome Res 142 (1), 1-6 (2013)
    Abstract:
    Branchio-oto-renal (BOR) syndrome is an autosomal dominantly inherited developmental disorder, which is characterized by anomalies of the ears, the branchial arches and the kidneys. It is caused by mutations in the genes EYA1,SIX1 and SIX5. Genomic rearrangements of chromosome 8 affecting the EYA1 gene have also been described. Owing to this fact, methods for the identification of abnormal copy numbers such as multiplex ligation-dependent probe amplification (MLPA) have been introduced as routine laboratory techniques for molecular diagnostics of BOR syndrome. The advantages of these techniques are clear compared to standard cytogenetic and array approaches as well as Southern blot. MLPA detects deletions or duplications of a part or the entire gene of interest, but not balanced structural aberrations such as inversions and translocations. Consequently, disruption of a gene by a genomic rearrangement may escape detection by a molecular genetic analysis, although this gene interruption results in haploinsufficiency and, therefore, causes the disease. In a patient with clinical features of BOR syndrome, such as hearing loss, preauricular fistulas and facial dysmorphisms, but no renal anomalies, neither sequencing of the 3 genes linked to BOR syndrome nor array comparative genomic hybridization and MLPA were able to uncover a causative mutation. By routine cytogenetic analysis, we finally identified a pericentric inversion of chromosome 8 in the affected female. High-resolution multicolor banding confirmed the chromosome 8 inversion and narrowed down the karyotype to 46,XX,inv(8)(p22q13). By applying fluorescence in situ hybridization, we narrowed down both breakpoints on chromosome 8 and found the EYA1 gene in q13.3 to be directly disrupted. We conclude that standard karyotyping should not be neglected in the genetic diagnostics of BOR syndrome or other Mendelian disorders, particularly when molecular testing failed to detect any causative alteration in patients with a convincing phenotype. © 2013 S. Karger AG, Basel.
  • Author:
    Rabe KF; Fabbri LM; Israel E; Kögler H; Riemann K; Schmidt H; Glaab T; Vogelmeier CF
    Title:
    Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: A prespecified substudy of the POET-COPD trial
    Source:
    Lancet Respir Med 2 (1), 44-53 (2014)
    Abstract:
    Background: The effect of .2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. Methods: We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. Findings: 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0.0130) and Gly16Gly (p=0.0018) genotypes (proportion of patients with at least one exacerbation was 32.3% in Arg16Arg, 39.8% in Arg16Gly, and 42.1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0.0164; Arg16Arg p=0.0316; proportion of patients with at least one exacerbation was 28.3% in Arg16Arg, 31.6% in Arg16Gly, and 39.2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0.0198; not Arg16Gly p=0.64; proportion of patients with at least one exacerbation was 35.9% in Arg16Arg, 46.7% in Arg16Gly, and 44.8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. Interpretation: Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting .-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of .-adrenergic polymorphisms and their association with clinical features of COPD. Funding: Boehringer Ingelheim and Pfizer. © 2014 Elsevier Ltd.
  • Author:
    Leidy NK; Kimel M; Ajagbe L; Kim K; Hamilton A; Becker K
    Title:
    Designing trials of behavioral interventions to increase physical activity in patients with COPD: Insights from the chronic disease literature
    Source:
    Respir Med Article in press (2013)
    Abstract:
    Objectives: There is increasing evidence that physical activity (PA) can affect health outcomes, particularly in chronic disease. While pharmacologic therapy and exercise training can improve exercise capacity, increasing PA requires behavior change. This review examined clinical trials testing the effectiveness of behavioral interventions to increase PA in adults with chronic disease to inform future research in COPD. Methods: Embase and PubMed searches of studies published in English, 1995-2011. Inclusion criteria: Adults .45 years; COPD, diabetes, heart failure, obesity; exercise or PA endpoint; behavioral intervention described in sufficient detail to permit interpretation. Results: 932 abstracts screened; 169 articles retrieved; 36 reviewed. Most were randomized trials (n = 32, 89%); 2 arms (n = 26, 72%), sample sizes 40-100 (n = 15, 42%); recruitment through clinical settings (n = 28, 78%); disease severity as primary eligibility criterion (n = 23, 64%); mean duration: 10 months (range: 1-84). Exercise intervention: aerobic activity, 30-60 min (n = 20, 56%), 3-5 times/week (n = 20, 56%). Behavioral intervention: Counseling (n = 19, 53%) with personal follow-up (n = 12, 33%). Control group: Exercise without behavioral intervention (n = 14, 39%) or usual care (n = 15, 42%). Significant effects were reported in 15 of 25 (60%) studies testing exercise capacity (6-minute walk, cycle, treadmill), 19 of 26 (73%) testing PA (pedometer, activity log, questionnaire), 11 of 22 (50%) measuring quality of life, and 8 of 13 (62%) capturing behavioral endpoints. Conclusions: This review provides insight into the range of designs, interventions, and outcome measures used in studies testing methods to improve PA in chronic disease with implications for designing trials in COPD. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Rabe KF; Fabbri LM; Israel E; Kögler H; Riemann K; Schmidt H; Glaab T; Vogelmeier CF
    Title:
    Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial
    Source:
    Lancet Respir Med Article in press (2013)
    Abstract:
    Background: The effect of .2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. Methods: We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. Findings: 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0.0130) and Gly16Gly (p=0.0018) genotypes (proportion of patients with at least one exacerbation was 32.3% in Arg16Arg, 39.8% in Arg16Gly, and 42.1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0.0164; Arg16Arg p=0.0316; proportion of patients with at least one exacerbation was 28.3% in Arg16Arg, 31.6% in Arg16Gly, and 39.2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0.0198; not Arg16Gly p=0.64; proportion of patients with at least one exacerbation was 35.9% in Arg16Arg, 46.7% in Arg16Gly, and 44.8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. Interpretation: Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting .-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of .-adrenergic polymorphisms and their association with clinical features of COPD. Funding: Boehringer Ingelheim and Pfizer. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Tautermann CS; Kiechle T; Seeliger D; Diehl S; Wex E; Banholzer R; Gantner F; Pieper MP; Casarosa P
    Title:
    Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor
    Source:
    J Med Chem 56 (21), 8746-8756 (2013)
    Abstract:
    Antagonizing the human M3 muscarinic receptor (hM3R) over a long time is a key feature of modern bronchodilating COPD drugs aiming at symptom relief. The long duration of action of the antimuscarinic drug tiotropium and its kinetic subtype selectivity over hM2R are investigated by kinetic mapping of the binding site and the exit channel of hM3R. Hence, dissociation experiments have been performed with a set of molecular matched pairs of tiotropium on a large variety of mutated variants of hM3R. The exceedingly long half-life of tiotropium (of more than 24 h) is attributed to interactions in the binding site; particularly a highly directed interaction of the ligands' hydroxy group with an asparagine (N5086.52) prevents rapid dissociation via a snap-lock mechanism. The kinetic selectivity over hM2R, however, is caused by differences in the electrostatics and in the flexibility of the extracellular vestibule. Extensive molecular dynamics simulations (several microseconds) support experimental results. © 2013 American Chemical Society.
  • Author:
    Baker CL; Zou KH; Su J
    Title:
    Risk assessment of readmissions following an initial COPD-related hospitalization
    Source:
    Int J COPD 8, 551-559 (2013)
    Abstract:
    Background: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a leading cause of hospitalizations and readmissions in the US. Reducing the frequency of hospital readmission is a high priority of US health care organizations and government agencies. This study evaluated the risk factors associated with readmissions among commercially insured adults aged 40-65 years in the US who were hospitalized for COPD. Methods: This retrospective cohort study used anonymized claims data from the Truven Health MarketScan® Commercial Claims and Encounters database. The patients included were aged 40-65 years, had an index hospitalization with a primary diagnosis of COPD between July 1, 2008 and June 30, 2010 (continuously enrolled 12 months before and after), and were alive at hospital discharge. Patients with cystic fibrosis or tuberculosis or who were transferred to another inpatient facility after hospital discharge were excluded. All readmissions regardless of diagnosis, and separately a subset of all readmissions that had COPD as a primary or secondary diagnosis (COPD-related), were examined. Univariate descriptive statistics and multivariable regression methods were used. Results: Of the 18,568 patients with index COPD hospitalizations, 6,095 (32.83%) met the eligibility criteria. Of those, 503 (8.25%) were readmitted within the first 30 days post-index hospitalization and 2,527 (41.46%) within the first year (COPD-related 340 [5.58%] and 1,681 [27.58%], respectively). The median time to the first readmission post initial discharge was 4.0 months, with a mean of 5.0 ± 3.4 months. Multivariable regression analyses showed that comorbid conditions and health care utilization in the pre-index period were significant predictors for readmission both 30 and 90 days following index hospitalization. Conclusion: A relatively high readmission rate was observed for patients aged 40-65 years. The results suggest that attention to patient comorbidities and pre-index/index health care service utilization may help identify hospitalized COPD patients at higher risk for readmission. © 2013 Baker et al.
  • Author:
    heng DT; Kim DK; Cockayne DA; Belousov A; Bitter H; Cho MH; Duvoix A; Edwards LD; Lomas DA; Miller BE; Reynaert N; Tal-Singer R; Wouters EFM; Agustí A; Fabbri LM; Rames A; Visvanathan S; Rennard SI; Jones P; Parmar H; MacNee W; Wolff G; Silverman EK; Mayer RJ; Pillai SG
    Title:
    Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease
    Source:
    Am J Respir Crit Care Med 188 (8), 948-957 (2013)
    Abstract:
    Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemicbiomarker identifiedinthis study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Measurements and Main Results: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P &lt; 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbonmonoxide (P=0.01) in the TESRA study. Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Copyright © 2013 by the American Thoracic Society.
  • Author:
    Bosnjak B; Tilp C; Tomsic C; Dekan G; Pieper MP; Erb KJ; Epstein MM
    Title:
    Tiotropium bromide inhibits relapsing allergic asthma in BALB/c mice
    Source:
    Pulm Pharmacol Ther Article in press (2013)
    Abstract:
    Recurrent relapses of allergic lung inflammation in asthmatics may lead to airway remodeling and lung damage. We tested the efficacy of tiotropium bromide, a selective long-acting, muscarinic receptor antagonist as an adjunct therapy in relapses of allergic asthma in mice. We compared the effectiveness of local intranasal administration of tiotropium and dexamethasone in acute and relapsing allergic asthma in BALB/c mice. Although tiotropium at low doses is a potent bronchodilator, we tested higher doses to determine effectiveness on inflammation and mucus hypersecretion. A 5-day course of twice daily intranasal tiotropium or dexamethasone (1 mg/kg (b.w.)) suppressed airway eosinophils by over 87% during disease initiation and 88% at relapse compared to vehicle alone. Both drugs were comparable in their capacity to suppress airway and parenchymal inflammation and mucus hypersecretion, though tiotropium was better than dexamethasone at reducing mucus secretion during disease relapse. Despite treatment with either drug, serum antigen-specific IgE or IgG1 antibody titres remained unchanged. Our study indicates that tiotropium at higher doses than required for bronchodilation, effectively suppresses inflammation and mucus hypersecretion in the lungs and airways of mice during the initiation and relapse of asthma. Tiotropium is currently not approved for use in asthma. Clinical studies have to demonstrate the efficacy of tiotropium in this respiratory disease. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Wise RA; Anzueto A; Cotton D; Dahl R; Devins T; Disse B; Dusser D; Joseph E; Kattenbeck S; Koenen-Bergmann M; Pledger G; Calverley P
    Title:
    Tiotropium respimat inhaler and the risk of death in COPD
    Source:
    N Engl J Med 369, 16-1491 1501 (2013)
    Abstract:
    BACKGROUND: Tiotropium delivered at a dose of 5 .g with the Respimat inhaler showed efficacy similar to that of 18 .g of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. METHODS: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a oncedaily dose of 2.5 .g or 5 .g, as compared with tiotropium HandiHaler at a oncedaily dose of 18 .g. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 .g or 2.5 .g vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 .g vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. RESULTS: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 .g vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 .g vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 .g vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. CONCLUSIONS: Tiotropium Respimat at a dose of 5 .g or 2.5 .g had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 .g in patients with COPD. Copyright © 2013 Massachusetts Medical Society.
  • Author:
    Fle.ar M; Jahnz-Rózyk K; Enache G; Martynenko T; Kristufek P; krinjari-Cincar S; Kadlecová P; Martinovic G
    Title:
    SOSPES: SPIRIVA® observational study measuring SGRQ score in routine medical practice in central and eastern Europe
    Source:
    Int J Chronic Obstruct Pulm Dis 8, 483-492 (2013)
    Abstract:
    Purpose: The long-acting inhaled anticholinergic agent, tiotropium, is recommended as first-line maintenance therapy for moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) to improve symptoms, exercise tolerance, health status, and to reduce exacerbations. Few studies have evaluated the therapeutic efficacy of tiotropium in patients in routine clinical conditions. The current study was designed to investigate the therapeutic efficacy of tiotropium delivered via the HandiHaler® device on the health status of patients with COPD with Global initiative for chronic Obstructive Lung Disease (GOLD) disease classification 2-4 in six central and eastern European countries in a real-life clinical setting. Methods: The study was an open-label, prospective, uncontrolled, and single-arm surveillance study with three clinic visits during a 6-month observation period (baseline, and months 3 and 6). Health status was measured using the disease-specific St George's Respiratory Questionnaire (SGRQ). The primary efficacy endpoint was the mean change from baseline in SGRQ total score at the end of the 6-month observational period. Results: Patients treated with tiotropium 18 .g once daily showed statistically significant and clinically meaningful reduction (improvement) of 21.7 units in the SGRQ total score, regardless of smoking status or cardiac comorbidities at enrollment (P < 0.0001). The analysis also showed that age, treatment compliance, and GOLD disease classification were significant factors that impact the health status of patients with COPD differently. Conclusion: These results provide further support for the use of the tiotropium HandiHaler® as first-line maintenance treatment of patients with COPD with a clinician-assessed disease. © 2013 Fle.ar et al, publisher and licensee Dove Medical Press Ltd.
  • Author:
    Tang Y; Massey D; Zhong N-S
    Title:
    Evaluation of the efficacy and safety of tiotropium bromide (5.g) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease
    Source:
    Chin Med J 126 (19), 3603-3607 (2013)
    Abstract:
    Background A pharmacokinetic study in an Asian population showed that tiotropium 5 .g via Respimat leads to the same plasma levels compared to 18 .g via HandiHaler. The objective of the trial was to compare the efficacy and safety of longterm treatment (1 year) with tiotropium bromide (5.g) via Respimat® with placebo in patients with chronic obstructive pulmonary disease (COPD). Methods A total of 3991 patients were randomized in this double-blind, placebo controlled, parallel group study, while in China 338 patients (309 males, 29 females) received either tiotropium bromide (n=167) or placebo (n=171). Tiotropium bromide solution or matching placebo was delivered via Respimat® at a dosage of 5.g (2 × 2.5 .g/puff) once daily for 48 weeks. Co-primary endpoints were trough forced expiratory volume in one second (FEV1) and the time to first exacerbation. Results Statistically significant improvements in trough FEV1 and trough forced vital capacity (FVC) in the tiotropium group were achieved at weeks 4, 24, and 48 compared with those in the placebo group. A statistically significant difference (P=0.0027) in favour of tiotropium was also observed for the time to first exacerbation. The total numbers of exacerbations during treatment were 90 and 128 in the tiotropium and placebo groups, respectively, with a rate ratio of 0.69 (P=0.0164). The difference between the treatment groups in the adjusted mean changes from baseline of St. George Respiratory Questionnaire (SGRQ) total score was -3.9 (95% CI: -7.5, -0.2) and was of statistical significance (P=0.0367). The incidences of serious adverse events (SAEs) in the tiotropium and placebo groups were 16.2% and 17.0%, respectively. Seven deaths occurred whilst patients were on treatment, four in the tiotropium group and three in the placebo group, all of which were assessed as non-related study drugs by the investigators. Conclusions Tiotropium significantly improved lung function and quality of life, delayed the time to first exacerbation, reduced the number of exacerbations. Overall, tiotropium was well tolerated.
  • Author:
    W-Y Lee; T Southworth; S Booth; K Wetzel; A Fowler; D Singh
    Title:
    The late asthmatic response is associated with an increase in IL-5 in induced sputum in asthmatics using inhaled corticosteroids
    Source:
    British Thoracic Society (BTS) Meeting, London/UK, Dec 4-6, 2013
  • Author:
    Janssens W; Liu Y; Liu D; Kesten S; Tashkin DP; Celli BR; Decramer M
    Title:
    Quality and reproducibility of spirometry in COPD patients in a randomized trial (UPLIFT®)
    Source:
    Respir Med 107 (9), 1409-1416 (2013)
    Abstract:
    Background This study explores spirometry quality and reproducibility in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial. Methods Four-year, randomized, double-blind, placebo-controlled, multicenter trial in 5993 patients with chronic obstructive pulmonary disease. Within-test variability of pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1) was compared across study visits. Between-test variability of best pre- or post-FEV1 values between two visits 6 months apart was compared at the start, middle and end of the trial. Results Three or more acceptable maneuvers were obtained in 93% of visits. Within-test variability of pre- and post-FEV1 (mean standard deviation: 0.092 and 0.098 L) decreased during the trial. Between-test variability also decreased: pre-FEV1 (visit 3-5 = 0.141 ± 0.138 L; visit 9-11 = 0.129 ± 0.121 L; visit 17-19 = 0.121 ± 0.122 L); post-FEV1 (0.139 ± 0.140, 0.126 ± 0.123, 0.121 ± 0.122 L, respectively), and was dependent on age, sex, smoking status and disease stage, but not on bronchodilator response or study treatment. Conclusion Spirometry quality in UPLIFT® was good and improved during the trial. Between-test variability across patient subgroups suggests that relevant cut-offs for individual disease monitoring are difficult to establish. Trial registration number NCT00144339. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Bárbara C; Rodrigues F; Dias H; Cardoso J; Almeida J; Matos MJ; Simão P; Santos M; Ferreira JR; Gaspar M; Gnatiuc L; Burney P
    Title:
    Chronic obstructive pulmonary disease prevalence in lisbon, portugal: The burden of obstructive lung disease study
    Source:
    Rev Port Pneumol 19 (3), 96-105 (2013)
    Abstract:
    Background: There is a great heterogeneity in the prevalence of Chronic Obstructive Pulmonary Disease (COPD) demonstrates a great heterogeneity across the world. The Burden of Obstructive Lung Disease (BOLD) initiative was started to measure the prevalence of COPD in a standardized way. We aimed to estimate the prevalence of COPD in Portuguese adults aged 40 years or older of a target population of 2,700 000 in the Lisbon region, in accordance with BOLD protocol. Methods: A stratified, multi-stage random sampling procedure was used which included 12 districts. The survey included a questionnaire with information on risk factors for COPD and reported respiratory disease and a post-bronchodilator spirometry performed at survey centres. Results: For the 710 participants with questionnaires and acceptable spirometry, the overall weighted prevalence of GOLD stage I+ COPD was 14.2% (95% C.I. 11.1, 18.1), and stage II+ was 7.3% (95% C.I. 4.7, 11.3). Unweighted prevalence was 20.2% (95% C.I.17.4, 23.3) for stage I+ and 9.5% (95% C.I. 7.6, 11.9) for stage II+. Prevalence of COPD in GOLD stage II+ increased with age and was higher in men. The prevalence of GOLD stage I+ COPD was 9.2% (95% C.I. 5.9, 14.0) in never smokers versus 27.4% (95% C.I. 18.5, 38.5) in those who had smoked >20 pack-years. The agreement between previous doctor diagnosis and spirometric diagnosis was low, with 86.8% of underdiagnosed individuals. Conclusions: The 14.2% of COPD estimated prevalence indicates that COPD is a common disease in the Lisbon region. In addition, a large proportion of underdiagnosed disease was detected. The high prevalence of COPD with a high level of underdiagnosis, points to the need of raising awareness of COPD among health professionals, and requires more use of spirometry in the primary care setting. © 2011 Sociedade Portuguesa de Pneumologia.
  • Author:
    Cardoso J; Ferreira JR; Almeida J; Santos JM; Rodrigues F; Matos MJ; Gaspar M
    Title:
    Chronic obstructive pulmonary disease in portugal: Pneumobil (1995) and 2002 prevalence studies revisited
    Source:
    Rev Port Pneumol 19 (3), 88-95 (2013)
    Abstract:
    Background: Chronic Obstructive Pulmonary Disease (COPD) has been a leading cause of morbidity and mortality worldwide, over the years. In 1995, the implementation of a respiratory function survey seemed to be an adequate way to draw attention to neglected respiratory symptoms and increase the awareness of spirometry surveys. By 2002 there were new consensual guidelines in place and the awareness that prevalence of COPD depended on the criteria used for airway obstruction definition. The purpose of this study is to revisit the two studies and to turn public some of the data and respective methodologies. Methods: From Pneumobil study database of 12,684 subjects, only the individuals with 40+ years old (n = 9.061) were selected. The 2002 study included a randomized representative sample of 1,384 individuals with 35-69 years old. Results: The prevalence of COPD was 8.96% in Pneumobil and 5.34% in the 2002 study. In both studies, presence of COPD was greater in males and there was a positive association between presence of COPD and older age groups. Smokers and ex-smokers showed a higher proportion of cases of COPD. Conclusions: Prevalence in Portugal is lower than in other European countries. This may be related to lower smokers' prevalence. Globally, the most important risk factors associated with COPD were age over 60 years, male gender and smoking exposure. All aspects and limitations regarding different recruitment methodologies and different criteria for defining COPD cases highlight the need of a standardized method to evaluate COPD prevalence and associated risks factors, whose results can be compared across countries, as it is the case of BOLD project. © 2012 Sociedade Portuguesa de Pneumologia.
  • Author:
    Cooper CB; Celli BR; Jardim JR; Wise RA; Legg D; Guo J; Kesten S
    Title:
    Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: A randomized trial
    Source:
    Chest 144 (2), 490-497 (2013)
    Abstract:
    Background: Disease progression in COPD is associated with a decline in exercise performance over time. We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time (ET) over 2 years. Methods: This was a randomized, double-blind, placebo-controlled trial of tiotropium, 18 m g daily, in patients with COPD (FEV 1 /FVC < 70%; postbronchodilator FEV 1 < 65%). The primary end point was ET at 90% of baseline maximum work rate at 96 weeks. Secondary end points were ET at other visits, ET by smoking status, spirometry, and St. George's Respiratory Questionnaire (SGRQ). Results: A total of 519 patients were randomized (tiotropium 260, placebo 259). Mean age was 65 years, 77% were men, 34% were continuing smokers, and mean FEV 1 was 1.25 L (44% predicted). Signifi cantly more patients discontinued placebo (hazard ratio [95% CI], 0.61 [0.44-0.83]). Baseline ET was 301 s (improvement tiotropium/placebo was 13% overall; P = .009; 18% at 48 weeks, P = .004; 13% at 96 weeks, P = .106). In patients with baseline ET between 2 and 10 min (n = 404), improvement at 96 weeks was 19% (P = .04). Current smokers had higher ET with tiotropium vs placebo (P = .018). FEV 1 /FVC improved with tiotropium (P < .01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units (P = .007). Conclusions: Treadmill ET was numerically greater over 2 years with tiotropium vs placebo. However, the 96-week difference was not statistically signifi cant. Spirometry and health status also improved with tiotropium over 2 years, attesting to the benefi ts of long-acting bronchodilator therapy. © 2013 American College of Chest Physicians.
  • Author:
    Hamdam J; Sethu S; Smith T; Alfirevic A; Alhaidari M; Atkinson J; Ayala M; Box H; Cross M; Delaunois A; Dermody A; Govindappa K; Guillon J-M; Jenkins R; Kenna G; Lemmer B; Meecham K; Olayanju A; Pestel S; Rothfuss A; Sidaway J; Sison-Young R; Smith E; Stebbings R; Tingle Y; Valentin J-P; Williams A; Williams D; Park K; Goldring C
    Title:
    Safety pharmacology - Current and emerging concepts
    Source:
    Toxicol Appl Pharmacol Article in press (2013)
    Abstract:
    Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. © 2013 Elsevier Inc. All rights reserved.
  • Author:
    Anzueto A; Niewoehner DE; Leimer I; Rühmkorf F; Celli BR; Decramer M; Tashkin DP
    Title:
    A post hoc pooled analysis of exacerbations among US participants in randomized controlled trials of tiotropium
    Source:
    Respir Med Article in press (2013)
    Abstract:
    Background: Exacerbations are a defining outcome of chronic obstructive pulmonary disease (COPD). We evaluated the effect of tiotropium on COPD exacerbations and related hospitalizations among patients from the USA enrolled in clinical trials. Methods: Data were pooled from six randomized, double-blind, placebo-controlled trials (6 to .12 months' duration) of tiotropium in patients with COPD. Exacerbations were defined retrospectively as an increase in or new onset of &gt;1 respiratory symptom lasting for .3 days and requiring treatment with systemic corticosteroids and/or antibiotics. Time to first exacerbation or hospitalization and exacerbation rates were analyzed at 6 months, and at 1 year for studies .1 year. Results: In total, 4355 patients (tiotropium, 2268, placebo, 2087; mean age 66.5 years; forced expiratory volume in 1 s [FEV1] 1.03 L [35.5% predicted]) were analyzed at 6 months and 2455 at 1 year (tiotropium 1317, placebo 1138; mean age 65.5 years; FEV1 1.03 L [37.0% predicted]). Tiotropium delayed time to first exacerbation or first hospitalized exacerbation at 6 months (hazard ratios [HRs], 0.80, 0.65, respectively; p &lt; 0.001 vs placebo) and 1 year (HRs, 0.73 and 0.55; p &lt; 0.001 vs placebo) and reduced exacerbation rates and hospitalization rates (6 months: HRs, 0.79, 0.64; 1 year: HRs, 0.78, 0.56, respectively; all p &lt; 0.01 vs placebo). Tiotropium significantly reduced exacerbations, irrespective of inhaled corticosteroid use at baseline. Tiotropium was not associated with an increased risk of cardiac-related events. Conclusions: Tiotropium significantly reduced the risk and rates of exacerbations and hospitalizations among US patients with COPD. © 2013 The Authors.
  • Author:
    Sakamoto A; Matsumaru T; Yamamura N; Uchida Y; Tachikawa M; Ohtsuki S; Terasaki T
    Title:
    Quantitative expression of human drug transporter proteins in lung tissues: Analysis of regional, gender, and interindividual differences by liquid chromatography-tandem mass spectrometry
    Source:
    J Pharm Sci 102 (9), 3395-3406 (2013)
    Abstract:
    The purpose of the present study was to clarify the expression levels of transporter proteins in human lung tissue and to analyze regional and interindividual differences in primary cultured epithelial cells. Organic cation/carnitine tranporter 1 (OCTN1) protein expression was highest (2.08 ± 1.19 fmol/.g protein) in human lung tissue, followed by multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein expression (1.41 ± 0.41, 1.30 ± 1.29 fmol/.g protein, respectively). Interestingly, the same expression levels of OATP2B1 protein were demonstrated among the epithelial cells derived from all pulmonary regions for the first time. These results suggest that OCTN1 may be the best target transporter protein for pulmonary disease drug design, and OATP2B1 may be an alternative target. MRP1 protein expression was also high and mainly localized in bronchial and alveolar regions. Regarding interindividual differences, the MRP1 protein showed a significant 18-fold maximal difference in the bronchial region among five donors. Sixteen of the 18 transporters showed higher expression in female lungs than in male lungs, especially MRP8 showed a 7.32-fold maximal difference. In conclusion, the protein expression profiles of pulmonary drug transporters and regional, gender, and interindividual differences were clarified. These findings may provide significant insights for pulmonary disease drug design and indicate that administration by inhalation may be viable. © 2013 Wiley Periodicals, Inc.
  • Author:
    R. Lewis; L. Chachi; Y. Amrani; P. Bradding
    Title:
    A comparison of b2-adrenoceptor desensitisation induced by olodaterol and formoterol in human lung mast cells and airway smooth muscle cells
    Source:
    ERS, Barcelona, Spain, Sep 7-9, 2013
  • Author:
    Luigi Costa,; Michael Roth,; Michael Tamm,; Pieter Borger
    Title:
    Tiotropium and olodaterol exert anti-proliferative effects on pulmonary fibroblasts of asthmatic patients in vitro
    Source:
    ERS, Barcelona, Spain, Sep 7-9, 2013
  • Author:
    Carrero-Gonzalez L; Tibiletti M; Kirchherr A; Gehrke N; Kaulisch T; Briel A; Rasche V; Stiller D
    Title:
    (Dynamic) Contrast-enhanced MRI of pulmonary perfusion
    Source:
    World Molecular lmaging Congress 2013,Savannah, USA, Sep 2013
  • Author:
    Leiner Dr S
    Title:
    A respiratory product for young children
    Source:
    EuPFI (European Paediatric Formulation Initiative)
    Abstract:
    -
  • Author:
    Williams G; Bickmann D; Schiewe J; Hauviller C; Blatchford C; Doub W; Mitchell J; Nichols S; Suman J; Weda M
    Title:
    Towards Standardizing Methodology for Quantifying the Fine Particle Mass (Dose) of Active Pharmaceuticallngredient (API) from Nasal Products (NPs)
    Source:
    Poster abstract for the annual "Drug Delivery to the Lung (DDL)" conference, Edinburgh 2013
    Abstract:
    Pharmacopeial methods for the assessment of inhaled nasal products (NPs), including nasal pressurized metered­ dose inhalers and aqueous spray pumps, Iack methodology for determining the mass of fine partielas that may penetrate beyond the nasopharynx and deposit in the airways of the lungs with undesirable consequences. A multidisciplinary team of the European Pharmaceutical Aerosol Group (EPAG) has undertaken an experimental assessment of methods to determine this parameter. This evaluation involved development and testing of a new induction port intended to simulate the discharge of a NP into the nasal cavity, using a cascade impactor (Cl) to provide finepartiefe dose < 10 [Jm aerodynamic diameter (FPD). This approach could form the basis for new Ph. Eur. methodology that would support the requirements of an EMA guidance on pharmaceutical quality of NPs.
  • Author:
    Müller T; Schiewe J; Smal R; Weiler C; Steckel H
    Title:
    Preparation and characterization of crystalline, semi-crystaline and fully amorphous powders of hydrophilic and lipophilic active pharmaceutical ingredients
    Source:
    Drug Delivery to the Lungs, Conference, Edinburgh,Scottland Dec 11-13, 2013
  • Author:
    Engel Michael; Schmidt Hendrick; Moroni-Zentgraf Petra
    Title:
    Efficacy of tiotropium in patients with asthma in relation to allergic status.
    Source:
    J Allergy Clin Immunol 131 (2) (1), AB1 (2013)
    Abstract:
    RATIONALE: The response of patients with asthma to some medications may be influenced by their allergic status. Tiotropium, a long-acting anticholinergic, has demonstrated efficacy and safety in patients with asthma (Kerstjens et al. NEJM 2012), but the relationship between response and patient allergic status has not been published in detail. METHODS: Analysis of prespecified subgroups was performed using data from two replicate, 48-week, placebo-controlled trials (N5912) conducted in patients with asthma on at least ICS+LABA randomized to adding tiotropium 5.mu.g Respimat or placebo once daily. The subgroup of patients with potentially allergic asthma was identified using three criteria: total serum IgE, blood eosinophils, or clinician judgment (CJ). Allergic status was positive if serum IgE was >430 .mu.g/L, blood eosinophils were >0.6.times.10 /L, or CJ was .mchlt.yes..mchgt. RESULTS: Peak FEV1 improved with tiotropium irrespective of allergic status in Trial 1 (IgE [subgroup3treatment interaction, P=0.86] and eosinophils [P=0.46]) and in Trial 2 (IgE [P=0.98]; eosinophils P=0.18]; and CJ [P=0.29]). Predose (trough) FEV1improved with tiotropium compared with placebo, irrespective of allergic status, across all three criteria (Trial 1 [IgE, P=0.85; eosinophils, P=0.83; and CJ, P=0.15]; Trial 2 [IgE, P=0.58; eosinophils, P=0.38; and CJ, P=0.85]). Pooled data analyses revealed that time to first severe asthma exacerbation and time to first asthma worsening were both increased with tiotropium compared with placebo, regardless of allergic status, based on the three criteria. Overall, adverse events were balanced. CONCLUSIONS: Tiotropium improved lung function and asthma control in patients with poorly controlled asthma despite treatment with ICS+LABA, irrespective of their allergic status.
  • Author:
    Schleputz M; Bernau M; Kanzler SS; Uhlig S; Martin C
    Title:
    Neurally-induced bronchoconstriction in precision-cut lung slices of guinea pigs is modulated by lipopolysaccharide and neurotrophins.
    Source:
    Naunyn Schmiedebergs Arch Pharmakol 386 (1), 71 (2013)
    Abstract:
    Rationale: Inflammation, a hallmark of asthma and COPD, contributes to neural modulation and consequential airway hyperresponsiveness (AHR). To further study this concept the present investigation aimed to characterize the effect of lipopolysaccharide (LPS) as well as neurotrophins and their receptors on neurally-induced bronchoconstriction (BC) in precision-cut lung slices (PCLS) of guinea pigs. Methods: PCLS were prepared from Dunkin Hartley guinea pigs. PCLS were incubated with LPS (500 ng/mL) for 18 h to mimic inflammation and thereafter TNF release was measured by ELISA. Neurotrophic receptors (TrkA, -B, -C, p75NTR, GFR.alpha.) were analyzed by Western-blotting. Electric field stimulation (EFS) of PCLS was performed to induce neural BC. BC was monitored by videomicroscopy and the initial airway area was defined as 100% initial airway area (IAA). Frequency-response curves (1-100 Hz) were conducted on untreated PCLS (control) or on pretreated PCLS, incubated with LPS (500 ng/mL for 18 h), nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), or glial derived neurotrophic factor (GDNF) (each at 50 ng/mL for 20 min or 24 h). Results: LPS application in guinea pig PCLS led to a 128-fold induction of TNF release and augmented BC in frequency-response curves (44%-IAA vs. 63%-IAA in control for frequencies .gtoreq. 50 Hz). The expression of TrkA, -B, -C, p75NTR and GFR.alpha. was detected in PCLS. Among the neurotrophins studied NGF and GDNF (44%-IAA and 41%-IAA, respectively, vs. 63%-IAA in control for frequencies .gtoreq. 50 Hz) increased the neurallyinduced BC after short incubation periods. In contrast, after incubation for 24 h only NT3 (46%-IAA for frequencies .gtoreq. 50 Hz) enhanced BC in comparison to the control (61%-IAA for frequencies .gtoreq. 50 Hz). Conclusion: Since TNF levels were elevated after LPS, a pro-inflammatory state could be confirmed in PCLS, leading to AHR after EFS. Distinct neurotrophic factors are capable to induce AHR. The fast effects of NGF and GDNF may be based on direct modulation of neurotransmission, i.e. action potential profiles, whereas NT3 may involve altered transcription based changes of nerve function.
  • Author:
    Metzdorf N; Hallmann C; Disse B
    Title:
    Thorax editorial by Jenkins and Beasley related to tiotropium respimat Thorax editorial by Jenkins and Beasley related to tiotropium respimat
    Source:
    Thorax 68 (8), 782 (2013)
    Abstract:
    no abstract available
  • Author:
    Janssens W; Liu Y; Liu D; Kesten S; Tashkin DP; Celli BR; Decramer M
    Title:
    Quality and reproducibility of spirometry in COPD patients in a randomized trial (UPLIFT®)
    Source:
    Respir Med Article in Press (2013)
    Abstract:
    Background: This study explores spirometry quality and reproducibility in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial. Methods: Four-year, randomized, double-blind, placebo-controlled, multicenter trial in 5993 patients with chronic obstructive pulmonary disease. Within-test variability of pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1) was compared across study visits. Between-test variability of best pre- or post-FEV1 values between two visits 6 months apart was compared at the start, middle and end of the trial. Results: Three or more acceptable maneuvers were obtained in 93% of visits. Within-test variability of pre- and post-FEV1 (mean standard deviation: 0.092 and 0.098 L) decreased during the trial. Between-test variability also decreased: pre-FEV1 (visit 3-5 = 0.141 ± 0.138 L; visit 9-11 = 0.129 ± 0.121 L; visit 17-19 = 0.121 ± 0.122 L); post-FEV1 (0.139 ± 0.140, 0.126 ± 0.123, 0.121 ± 0.122 L, respectively), and was dependent on age, sex, smoking status and disease stage, but not on bronchodilator response or study treatment. Conclusion: Spirometry quality in UPLIFT® was good and improved during the trial. Between-test variability across patient subgroups suggests that relevant cut-offs for individual disease monitoring are difficult to establish. Trial registration number: NCT00144339. © 2013 Elsevier Ltd.
  • Author:
    Peng R; Sridhar S; Tyagi G; Phillips JE; Garrido R; Harris P; Burns L; Renteria L; Woods J; Chen L; Allard J; Ravindran P; Bitter H; Liang Z; Hogaboam CM; Kitson C; Budd DC; Fine JS; Bauer CMT; Stevenson CS
    Title:
    Bleomycin Induces Molecular Changes Directly Relevant to Idiopathic Pulmonary Fibrosis: A Model for "Active" Disease
    Source:
    PloS ONE 8 (4) e59348 (2013)
    Abstract:
    The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGF? was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease. © 2013 Peng et al.
  • Author:
    Kaplan A G
    Title:
    Ciclesonide delivery in the small airways: Serving a newfound need
    Source:
    Hot Top Respir Med 23, 7-12 (2013)
    Abstract:
    Once considered the "quiet zone" of the lungs, the small airways are now known to be an important site of airway resistance and inflammatory response. Evidence of a pronounced immune response and reduced steroid responsiveness during the night in the small airways of patients with nocturnal asthma suggests that they may be especially important in this hard-to-treat condition. Until recently, devices delivering inhaled corticosteroids could not effectively reach the small airways; typically, just 30% of the medication reached this target. The advent of hydrofluoroalkane (HFA) propellants delivering extra-fine particles has solved this problem. Ciclesonide is a nonhalogenated inhaled glucocorticoid that is delivered in a fine particle spray via an HFA-pressurized metereddose inhaler. Because it is only converted into its active metabolite in the lungs, ciclesonide attenuates the risk of oropharyngeal side effects. It has not been shown to effect hypothalamic-pituitary-adrenal axis function, thanks to extensive first-pass metabolism and it being highly protein-bound in serum. © FBCommunication - Modena (Italy).
  • Author:
    Abrahams R; Moroni-Zentgraf P; Ramsdell J; Schmidt H; Joseph E; Karpel J
    Title:
    Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD
    Source:
    Respir Med 107 (6), 854-862 (2013)
    Abstract:
    Background: To determine the safety and efficacy of BEA2180, an anticholinergic agent in patients with chronic obstructive pulmonary disease (COPD). Methods: Smokers or ex-smokers ?40 years with COPD and a postbronchodilator forced expiratory volume in 1 s (FEV1) &lt;80% predicted and FEV1/forced vital capacity ?70% participated in this multinational, randomised, double-blind, parallel study. Patients received BEA2180 (50, 100 or 200 ?g), tiotropium (5 ?g) or placebo once daily via Respimat® Soft Mist™. The primary endpoint was trough FEV1 after 24 weeks. Secondary endpoints included Transition Dyspnoea Index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score, exacerbations and adverse events. Results: Patients (n = 2080, 64.5% male) had a mean age of 64.2 years and a baseline FEV1 of 1.2 L. Trough FEV1 at 24 weeks with all BEA2180 doses (0.044-0.087 L) and tiotropium 5 ?g (0.092 L) was significantly higher (p &lt; 0.0001) than placebo (-0.034 L) and BEA2180 (200 ?g) was noninferior to tiotropium. Mean TDI focal scores were higher with BEA2180 (1.43-1.48) or tiotropium (1.46) versus placebo (0.94; p ? 0.01 for all). Mean SGRQ total scores also improved with BEA2180 (40.1-40.7) or tiotropium (39.5) compared with placebo (43.0, p &lt; 0.01 for all). COPD exacerbation rates were reduced for all active treatments, reaching statistical significance for BEA2180 (50 and 200 ?g) (p &lt; 0.05, for both). Conclusion: All study doses of BEA2180 improved lung function, reduced symptoms and exacerbations, and improved health status in COPD; all treatments were well tolerated. Clinical trial identifier: NCT00528996. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Barbara C; Rodrigues F; Dias H; Cardoso J; Almeida J; Matos M J; Simao P; Santos M; Ferreira J R; Gaspar M; Gnatiuc L; Burney P
    Title:
    Chronic Obstructive Pulmonary Disease Prevalence in Lisbon, Portugal: The Burden of Obstructive Lung Disease Study [Prevalência da doença pulmonar obstrutiva crónica em Lisboa, Portugal: estudo Burden of Obstructive Lung Disease]
    Source:
    Rev Port Pneumol Article in press (2013)
    Abstract:
    Background: There is a great heterogeneity in the prevalence of Chronic Obstructive Pulmonary Disease (COPD) demonstrates a great heterogeneity across the world. The Burden of Obstructive Lung Disease (BOLD) initiative was started to measure the prevalence of COPD in a standardized way. We aimed to estimate the prevalence of COPD in Portuguese adults aged 40 years or older of a target population of 2,700 000 in the Lisbon region, in accordance with BOLD protocol. Methods: A stratified, multi-stage random sampling procedure was used which included 12 districts. The survey included a questionnaire with information on risk factors for COPD and reported respiratory disease and a post-bronchodilator spirometry performed at survey centres. Results: For the 710 participants with questionnaires and acceptable spirometry, the overall weighted prevalence of GOLD stage I+ COPD was 14.2% (95% C.I. 11.1, 18.1), and stage II+ was 7.3% (95% C.I. 4.7, 11.3). Unweighted prevalence was 20.2% (95% C.I.17.4, 23.3) for stage I+ and 9.5% (95% C.I. 7.6, 11.9) for stage II+. Prevalence of COPD in GOLD stage II+ increased with age and was higher in men. The prevalence of GOLD stage I+ COPD was 9.2% (95% C.I. 5.9, 14.0) in never smokers versus 27.4% (95% C.I. 18.5, 38.5) in those who had smoked >20 pack-years. The agreement between previous doctor diagnosis and spirometric diagnosis was low, with 86.8% of underdiagnosed individuals. Conclusions: The 14.2% of COPD estimated prevalence indicates that COPD is a common disease in the Lisbon region. In addition, a large proportion of underdiagnosed disease was detected. The high prevalence of COPD with a high level of underdiagnosis, points to the need of raising awareness of COPD among health professionals, and requires more use of spirometry in the primary care setting. © 2011 Sociedade Portuguesa de Pneumologia.
  • Author:
    Cardoso J; Ferreira J R; Almeida J; Santos J M; Rodrigues F; Matos M J; Gaspar M
    Title:
    Chronic Obstructive Pulmonary Disease in Portugal: Pneumobil (1995) and 2002 prevalence studies revisited [Doença Pulmonar Obstrutiva Crónica em Portugal: estudo Pneumobil (1995) e estudo de prevalência de 2002 revisitados]
    Source:
    Rev Port Pneumol Article in press (2013)
    Abstract:
    Background: Chronic Obstructive Pulmonary Disease (COPD) has been a leading cause of morbidity and mortality worldwide, over the years. In 1995, the implementation of a respiratory function survey seemed to be an adequate way to draw attention to neglected respiratory symptoms and increase the awareness of spirometry surveys. By 2002 there were new consensual guidelines in place and the awareness that prevalence of COPD depended on the criteria used for airway obstruction definition. The purpose of this study is to revisit the two studies and to turn public some of the data and respective methodologies. Methods: From Pneumobil study database of 12,684 subjects, only the individuals with 40+ years old (n = 9.061) were selected. The 2002 study included a randomized representative sample of 1,384 individuals with 35-69 years old. Results: The prevalence of COPD was 8.96% in Pneumobil and 5.34% in the 2002 study. In both studies, presence of COPD was greater in males and there was a positive association between presence of COPD and older age groups. Smokers and ex-smokers showed a higher proportion of cases of COPD. Conclusions: Prevalence in Portugal is lower than in other European countries. This may be related to lower smokers' prevalence. Globally, the most important risk factors associated with COPD were age over 60 years, male gender and smoking exposure. All aspects and limitations regarding different recruitment methodologies and different criteria for defining COPD cases highlight the need of a standardized method to evaluate COPD prevalence and associated risks factors, whose results can be compared across countries, as it is the case of BOLD project. © 2012 Sociedade Portuguesa de Pneumologia.
  • Author:
    Schymeinsky J; Mayer H; Tomsic C; Tilp C; Schuetz J D; Cui Y; Wollin L; Gantner F; Erb K J
    Title:
    The Absence of Mrp4 Has No Effect on the Recruitment of Neutrophils and Eosinophils into the Lung after LPS, Cigarette Smoke or Allergen Challenge
    Source:
    PloS ONE 8 (4) art no e61193 (2013)
    Abstract:
    The multidrug resistance protein 4 (Mrp4) is an ATP-binding cassette transporter that is capable of exporting the second messenger cAMP from cells, a process that might regulate cAMP-mediated anti-inflammatory processes. However, using LPS- or cigarette smoke (CS)-inflammation models, we found that neutrophil numbers in the bronchoalveolar lavage fluid (BALF) were similar in Mrp4-/- and Mrp4+/+ mice treated with LPS or CS. Similarly, neutrophil numbers were not reduced in the BALF of LPS-challenged wt mice after treatment with 10 or 30 mg/kg of the Mrp1/4 inhibitor MK571. The absence of Mrp4 also had no impact on the influx of eosinophils or IL-4 and IL-5 levels in the BALF after OVA airway challenge in mice sensitized with OVA/alum. LPS-induced cytokine release in whole blood ex vivo was also not affected by the absence of Mrp4. These data clearly suggest that Mrp4 deficiency alone is not sufficient to reduce inflammatory processes in vivo. We hypothesized that in combination with PDE4 inhibitors, used at suboptimal concentrations, the anti-inflammatory effect would be more pronounced. However, LPS-induced neutrophil recruitment into the lung was no different between Mrp4-/- and Mrp4+/+ mice treated with 3 mg/kg Roflumilast. Finally, the single and combined administration of 10 and 30 mg/kg MK571 and the specific breast cancer resistance protein (BCRP) inhibitor KO143 showed no reduction of LPS-induced TNF? release into the BALF compared to vehicle treated control animals. Similarly, LPS-induced TNF? release in murine whole blood of Mrp4+/+ or Mrp4-/- mice was not reduced by KO143 (1, 10 ?M). Thus, BCRP seems not to be able to compensate for the absence or inhibition of Mrp4 in the used models. Taken together, our data suggest that Mrp4 is not essential for the recruitment of neutrophils into the lung after LPS or CS exposure or of eosinophils after allergen exposure. © 2013 Schymeinsky et al.
  • Author:
    Izquierdo-Alonso J L; rodriguez-Gonzálezmoro J; De Lucas-Ramos P; Unzueta I; Ribera X; Antón E; Martin A
    Title:
    Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD)
    Source:
    Respir Med 107 (5), 724-731 (2013)
    Abstract:
    Aim: To determine the prevalence and analyze the most relevant clinical characteristics of three clinical phenotypes of COPD: emphysema (type 1), chronic bronchitis (type 2) or COPD-asthma (type 3). Method: Observational, multicenter study performed with 331 COPD patients recruited in pulmonology outpatient services. The stratification in three phenotypes was performed with imaging tests, pulmonary function, and a standardized clinical questionnaire. Results: The 43.2% presented an emphysematous phenotype, 44.7% were chronic bronchitic and the other 12.1% presented a phenotype showing mixed characteristics with asthma. There were no significant differences in the smoking level, in the gasometric values or time of disease evolution. Type 1 patients showed lower FEV1 values in comparison with types 2 and 3, 46.6% (21.1), 55.2% (21.2) and 54.4% (21.8), respectively (p &lt; 0.05), and greater levels of dyspnea (p &lt; 0.05). No significant differences were observed in the percentage of patients who had at least one exacerbation in the last year (68.8%, 63.9%, 64.9%; p = 0.25), in the number of exacerbations (p = 0.56), in the number of visits to the ER (total and due to COPD), or in the number of hospital admittances. Type 2 patients showed a greater prevalence of cardiovascular comorbidities and of sleep apnea syndrome (4.9%, 23.6% and 12.5%, respectively, p &lt; 0.001). Conclusions: In COPD, emphysematous patients present worse pulmonary function and greater dyspnea, although there were no differences in the use of hospital health care resources. The greater comorbidity in Group 2 patients may require specific strategies in this subgroup of patients. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Hoogendoorn M; Al M J; Beh K M; Bowles D; Van der Schulenburg J M; Lungershausen J; Monz B U; Schmidt H; Vogelmeier C; Mölken M P M H R-V
    Title:
    Cost-effectiveness of tiotropium versus salmeterol: The POET-COPD trial
    Source:
    Eur Respir J 41 (3), 556-564 (2013)
    Abstract:
    The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were J126 (95% uncertainty interval (UI) J55-195) and J170 (95% UI J77- 260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010-0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of J87 (95% UI J19-157). The incremental cost-effectiveness ratio was J1,961 per exacerbation avoided from the SHI perspective and J2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were J3,488 from the SHI perspective and J8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds.
  • Author:
    Ferguson G T; Ghafouri M; Dai L; Dunn L J
    Title:
    COPD patient satisfaction with ipratropium bromide/albuterol delivered via respimat: A randomized, controlled study
    Source:
    Int J Chronic Obstruct Pulm Dis 8, 139-150 (2013)
    Abstract:
    Background: Ipratropium bromide/albuterol Respimat inhaler (CVT-R) was developed as an environmentally friendly alternative to ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI), which uses a chlorofluorocarbon propellant. Objective: The objective of this study was to evaluate patient satisfaction, device usage, and long-term safety of CVT-R compared to CVT-MDI, and to the simultaneous administration of ipratropium bromide hydrofluoroalkane (HFA; I) and albuterol HFA (A) metered-dose inhalers as dual monotherapies (I + A). Design: This is a 48-week, open-label, randomized, active-controlled, parallel-group study (n = 470) comparing CVT-R to CVT-MDI and to I + A. Participants: Patients were at least 40 years of age, diagnosed with chronic obstructive pulmonary disease (COPD), and current or exsmokers. Interventions: Patients were randomized to receive: (1) CVT-R, one inhalation four times daily (QID); or (2) CVT-MDI, two inhalations QID; or (3) I + A two inhalations of each inhaler QID. Main measures: Patient Satisfaction and Preference Questionnaire (PASAPQ) performance score (primary endpoint) and adverse events. Key results: PASAPQ performance score was significantly higher (CVT-R versus CVT-MDI, 9.6; and CVT-R versus I + A, 6.2; both P, 0.001) when using CVT-R compared to CVT-MDI or I + A at all visits starting from week 3, while CVT-MDI and I + A treatment groups were similar. Time to first COPD exacerbation was slightly longer in the CVT-R group compared to the other treatment groups, although it did not reach statistical significance (CVT-R versus CVT-MDI, P = 0.57; CVT-R versus I + A, P = 0.22). Rates of withdrawal and patient refusal to continue treatment were lower in CVT-R compared with CVT-MDI and I + A groups (CVT-R versus CVT-MDI, P = 0.09; CVT-R versus I + A, P = 0.005). The percentage of patients reporting adverse events and serious adverse events was similar across all three treatment groups. Conclusion: CVT-R is an effective, environmentally friendly inhaler that provides patients with a high level of user satisfaction and may positively impact clinical outcomes while having no adverse impacts on patients using the device. © 2013 Ferguson et al, publisher and licensee Dove Medical Press Ltd.
  • Author:
    Rabe K F; Fabbri L M; Vogelmeier C; Kögler H; Schmidt H; Beeh K M; Glaab T
    Title:
    Seasonal distribution of COPD exacerbations in the prevention of exacerbations with tiotropium in COPD trial
    Source:
    Chest 143 (3), 711-719 (2013)
    Abstract:
    Background: There is still a lack of data on the seasonality of exacerbations of COPD based on large randomized studies using COPD exacerbations as primary end points. The objective of this study was to assess the seasonal pattern of moderate and severe exacerbations and analyze the influence of associated baseline factors. We also determined the timing of second exacerbations and the potential impact of the 2009 influenza A(H1N1) pandemic on exacerbations. Methods: Analyses of exacerbation rates across treatment groups were adjusted for differing times on treatment by means of descriptive statistics based on the 1-year Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) trial, in which exacerbations were the primary end point. Results: Of the 7,376 patients who were randomized, a total of 4,411 exacerbations were reported in 2,691 patients. Mean monthly exacerbation rates during winter were 2.16-fold higher than during summer, regardless of baseline characteristics (age, sex, COPD severity, smoking status, BMI, inhaled corticosteroid use, cardiovascular comorbidity, concomitant cardiovascular medication). Second exacerbations after a previous event in October to March occurred 1 month earlier than during the warmer half of the season. The portion of exacerbation-related hospitalizations remained constant throughout the year. Most exacerbations were treated with antibiotics and reached a peak in the colder season. All-cause mortality showed a seasonal pattern similar to exacerbations. The 2009 A(H1N1) pandemic was not associated with an increase in exacerbation rates or deaths. Conclusions: This analysis presented a marked impact of season on exacerbation outcomes, antibiotic treatment, timing of second exacerbations, and all-cause mortality. © 2013 American College of Chest Physicians.
  • Author:
    Abrahams R; Moroni-Zentgraf P; Ramsdell J; Schmidt H; Joseph E; Karpel J
    Title:
    Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD
    Source:
    Respir Med Article in Press (2013)
    Abstract:
    Background: To determine the safety and efficacy of BEA2180, an anticholinergic agent in patients with chronic obstructive pulmonary disease (COPD). Methods: Smokers or ex-smokers =40 years with COPD and a postbronchodilator forced expiratory volume in 1 s (FEV1) &lt;80% predicted and FEV1/forced vital capacity =70% participated in this multinational, randomised, double-blind, parallel study. Patients received BEA2180 (50, 100 or 200 µg), tiotropium (5 µg) or placebo once daily via Respimat® Soft Mist™. The primary endpoint was trough FEV1 after 24 weeks. Secondary endpoints included Transition Dyspnoea Index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score, exacerbations and adverse events. Results: Patients (n = 2080, 64.5% male) had a mean age of 64.2 years and a baseline FEV1 of 1.2 L. Trough FEV1 at 24 weeks with all BEA2180 doses (0.044-0.087 L) and tiotropium 5 µg (0.092 L) was significantly higher (p &lt; 0.0001) than placebo (-0.034 L) and BEA2180 (200 µg) was noninferior to tiotropium. Mean TDI focal scores were higher with BEA2180 (1.43-1.48) or tiotropium (1.46) versus placebo (0.94; p = 0.01 for all). Mean SGRQ total scores also improved with BEA2180 (40.1-40.7) or tiotropium (39.5) compared with placebo (43.0, p &lt; 0.01 for all). COPD exacerbation rates were reduced for all active treatments, reaching statistical significance for BEA2180 (50 and 200 µg) (p &lt; 0.05, for both). Conclusion: All study doses of BEA2180 improved lung function, reduced symptoms and exacerbations, and improved health status in COPD; all treatments were well tolerated. Clinical trial identifier: NCT00528996. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Izquierdo-Alonso J L; Rodriguez-GonzalezMoro J; de Lucas-Ramos P; Unzeta I; Ribera X; Antón E; Martin A
    Title:
    Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD)
    Source:
    Respir Med Article in Press (2013)
    Abstract:
    Aim: To determine the prevalence and analyze the most relevant clinical characteristics of three clinical phenotypes of COPD: emphysema (type 1), chronic bronchitis (type 2) or COPD-asthma (type 3). Method: Observational, multicenter study performed with 331 COPD patients recruited in pulmonology outpatient services. The stratification in three phenotypes was performed with imaging tests, pulmonary function, and a standardized clinical questionnaire. Results: The 43.2% presented an emphysematous phenotype, 44.7% were chronic bronchitic and the other 12.1% presented a phenotype showing mixed characteristics with asthma. There were no significant differences in the smoking level, in the gasometric values or time of disease evolution. Type 1 patients showed lower FEV1 values in comparison with types 2 and 3, 46.6% (21.1), 55.2% (21.2) and 54.4% (21.8), respectively (p &lt; 0.05), and greater levels of dyspnea (p &lt; 0.05). No significant differences were observed in the percentage of patients who had at least one exacerbation in the last year (68.8%, 63.9%, 64.9%; p = 0.25), in the number of exacerbations (p = 0.56), in the number of visits to the ER (total and due to COPD), or in the number of hospital admittances. Type 2 patients showed a greater prevalence of cardiovascular comorbidities and of sleep apnea syndrome (4.9%, 23.6% and 12.5%, respectively, p &lt; 0.001). Conclusions: In COPD, emphysematous patients present worse pulmonary function and greater dyspnea, although there were no differences in the use of hospital health care resources. The greater comorbidity in Group 2 patients may require specific strategies in this subgroup of patients. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Metzdorf N; Hallmann C; Disse B
    Title:
    Thorax
    Abstract:
    no abstract available
  • Author:
    Vogelmeier C; Fabbri L M; Rabe K F; Beeh K-M; Schmidt H; Metzdorf N; Glaab T
    Title:
    Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients
    Source:
    Respir Med 107 (1), 75-83 (2013)
    Abstract:
    The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naïve to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD ®) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naïve (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naïve patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p &lt; 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD. © 2012 Elsevier Ltd. All rights reserved.