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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.

74 publications regarding Respiratory
  • Author:
    Guerin J-C; Roche N; Vicaut E; Piperno D; Granet G; Jannin M; Deschamps F; Godard P
    Title:
    Early detection of COPD in primary care: Which tools?
    Source:
    Rev Mal Respir Article in Press (2012)
    Abstract:
    Introduction: The early diagnosis of COPD in general practice is not satisfactory. Objectives: To evaluate the impact of different diagnostic tools (Piko-6, Software) in general practice (GP). Methods: A multicentre, randomised, controlled study in GP assessing the effect of the tested strategies on the rate of referrals for spirometry and the rate of detection of airflow obstruction. Results: One thousand one hundred and three patients (55 years old, 60% males, 31 years of smoking habits) were included by 248 GP. The rates of referal to a pneumologist were significantly higher in the Software (50% of patients), and Piko/Software (47%) groups than in the Control (22%) and Piko groups (28%). A high proportion (44%) of lung function tests recommended by the GP were not performed, often because of patient refusal. The confirmation rates were lower in the Software and Piko/Software groups (47% and 43%, respectively) compared with the Piko and Control groups (68% and 79%, respectively). Concordance between PFT and Piko-6 for the diagnosis of airflow obstruction was poor (about 50%). Conclusions: The use of software in association or not with the Piko-6 was useful for GPs to identify patients to refer for further lung function testing, but did not improve the confirmation of the obstructive syndrome, mainly due to reluctance of patients to go on to have further lung function tests. The use of a diagnostic tool (software and/or mini-spirometry) does however seem to improve early COPD detection.
  • 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 < 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.
  • Author:
    Miravitles M; Lior C; Calvo E; Diaz S; Diaz-Cuervo H; Gonzales-Rojas N
    Title:
    Validation of the Spanish version of the Chronic Obstructive Pulmonary Disease-Population Screener (COPD-PS). Its usefulness and that of FEV 1/FEV 6 for the diagnosis of COPD [Validación de la versión traducida del Chronic Obstructive Pulmonary Disease-Population Screener (COPD-PS). Su utilidad y la del FEV 1/FEV 6 para el diagnóstico de enfermedad pulmonar obstructiva crónica]
    Source:
    Med Clin (Barc) 139 (12), 522-530 (2012)
    Abstract:
    Background and objectives: The chronic obstructive pulmonary disease (COPD) is a highly undiagnosed disease. The use of short screening questionnaires designed to detect chronic airflow obstruction may help to the early diagnosis of COPD. Patients and method: This was an observational, cross-sectional epidemiological study aimed to validate the translated into Spanish version of the COPD-PS questionnaire. Socio-demographic and clinical data of participants were collected, as well as their answers to the COPD-PS and EQ-5D questionnaires. The ratio FEV 1/FEV 6 was measured with the COPD-6 device. The psychometric properties of the questionnaire and the diagnostic yield of the FEV 1/FEV 6 ratio were analysed, both referred to the gold standard of post-bronchodilator FEV 1/FVC < 0.7. Results: Ten primary care centers participated in the study and included 94 controls and 79 cases with chronic airflow obstruction. Questionnaire characteristics were: feasibility, 2.3% of participants did not answer at least one item; mean time to fill the questionnaire was 47.7 seconds; 4.7% of individuals had a 0 score. Validity, moderate correlation with EQ-5D scores and moderate-high with FEV 1; the scores of COPD-PS were related to all parameters associated with COPD. A cut off of 4 units had the best sensitivity/specificity ratio and correctly classified 78% of participants. For the FEV 1/FEV 6 ratio, a cut off of 0.75 correctly classified 85% of individuals. Conclusions: The COPD-PS questionnaire demonstrated good psychometric properties. A cut off score of 4 has excellent predictive value. A ratio of 0.75 in the FEV 1/FEV 6 provides an excellent correlation with the ratio FEV 1/FVC and is useful for the identification of individuals with chronic airflow obstruction. © 2011 Elsevier Espana, S.L. Todos los derechos reservados.
  • Author:
    Hettle, R; Wouters, H; Ayres J; Gani R; Kelly S; Lion M; Decramer M
    Title:
    Cost-utility analysis of tiotropium versus usual care in patients with COPD in the UK and Belgium
    Source:
    Respir Med 106 (12), 1722-1733 (2012)
    Abstract:
    Objective: To evaluate the cost-utility of adding tiotropium to usual care versus usual care alone for patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in the UK and Belgium. Methods: A four-state Markov model was developed with three disease severity states (moderate, severe, very severe) and death. Severity was based on post-bronchodilator FEV 1 and transitions were based on outcomes of the Understanding Potential Long Term Impacts on Function with Tiotropium (UPLIFT ®) trial. Utilities were derived from EQ-5D scores for a subset of UPLIFT ® patients. UK costs were evaluated separately for England (E), and for Scotland, Wales and Northern Ireland (SWNI). Belgian (B) costs were obtained from local sources. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA). Results: Adding tiotropium to usual care resulted in an incremental cost per patient of 969 (B), £796 (E), and £812 (SWNI), and incremental QALYs of 0.052 (B), and 0.051 (E, SWNI). The four-year incremental cost-effectiveness ratios (ICER) were 18,617 (B), £15,567 (E) and £15,890 (SWNI) per QALY. Probability of tiotropium being cost-effective at £30,000 (50,000) per QALY gained was greater than 60%. Conclusions: At willingness to pay thresholds of £() 30,000 per QALY gained, adding tiotropium to usual care is cost-effective. © 2012 Elsevier Ltd. All rights reserved.
  • Author:
    Evans C; Cipolla D; Chesworth T; Aqurell E; Ahrens R; Conner D; Dissanayake S; Dolovich M; Doub W; Fuglsang A; Arieta AG; Golden M; Hermann R; Hochhaus G; Holmes S; Lafferty P; Lyapustina S; Nair P; O'Connor D; Parkins D; Peterson I; Reisner C; Sandell D; Singh GJP; Weda M; Watson P
    Title:
    Equivalence considerations for orally inhaled products for local action-ISAM/IPAC-RS European workshop report
    Source:
    J Aerosol Med Pulm Drug Deliv 25 (3), 117-139 (2012)
    Abstract:
    The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified.
  • Author:
    Taskin DP; Celli B R; Decramer M; Lystig T; Liu D; Kesten S
    Title:
    Efficacy of tiotropium in COPD patients and FEV-60 participating in tne UPLIFT trial.
    Source:
    COPD: J Chronic Obstruct Pulm Dis 9 (3), 289-296 (2012)
    Abstract:
    GOLD stage II COPD encompasses patients with FEV 1 50-80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV 1 <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT® trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV 1 =60% predicted from UPLIFT®. Outcomes included pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. Of the 5,992 UPLIFT® cohort, 1,210 (632 tiotropium, 578 control) had baseline post-bronchodilator FEV 1 =60% predicted (range 60-78%), mean age was 64 years, 70% were men, and mean SGRQ total score was 39.9 units. Mean annual rate of post-bronchodilator FEV 1 decline was 41 (tiotropium) and 49 (control) mL/year (P = 0.07); corresponding pre-bronchodilator values were 32 and 37 mL/year (P = 0.24). Morning pre-drug FEV 1 and FVC improvements for tiotropium versus control were 87-127 mL and 139-186 ml, respectively (P < 0.001, all time-points). SGRQ total score improvements (tiotropiumcontrol) were 2.0-3.4 units (P < 0.05 for all); a higher percentage of patients had an improvement of =4 units with tiotropium (P <0.05). Tiotropium reduced risk for an exacerbation (HR [95% CI] = 0.83 0.71, 0.96) and mortality for the 4-year protocol-defined treatment period (HR [95% CI] = 0.66 0.45, 0.96). Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV 1 =60% predicted, supporting current GOLD guidelines for COPD treatment. (ClinicalTrials.gov number NCT00144339). © 2012 Informa Healthcare USA, Inc. Reaxys Database Information
  • Author:
    Cockayne DA; Cheng DT; Waschki B; Sridhar S; Ravindran P; Hilton H; Kourteva G; Bitter H; Pillai SG; Visvanathan S; Mueller K-C; Holz O; Magnussen H; Watz H; Fine JS
    Title:
    Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.
    Source:
    PLoS ONE 7 (6) art.no.e38629 (2012)
    Abstract:
    The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-a and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV 1, FEV 1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV 1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-a) formed another cluster associated with both DLCO and FEV 1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV 1/FVC were stronger in patients without metabolic syndrome (r = -0.52, p = 0.005 and r = -0.61, p = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r = -0.25, p = 0.47 and r = -0.15, p = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV 1, FEV 1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD. © 2012 Cockayne et al
  • Author:
    Magnussen H; Paggiaro P; Schmidt H; Kesten S; Metzdorf N; Maltais F
    Title:
    Effect of combination treatment on lung volumes and exercise endurance time in COPD.
    Source:
    Respir Med Article in Press (2012)
    Abstract:
    Background: Data comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid (ICS) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) are scarce, though these therapeutic strategies are widely used in clinical practice. Methods: We performed a randomized, crossover clinical trial of two × 8 weeks comparing tiotropium (18 µg once daily) + salmeterol (50 µg twice daily) (T + S) to salmeterol + fluticasone (50/500 µg twice daily) (S + F) in COPD (forced expiratory volume in 1 s (FEV 1) =65% predicted, and thoracic gas volume (TGV) =120% predicted). Coprimary endpoints were postbronchodilator TGV and exercise endurance time (EET). Results: In 309 patients, at baseline, prebronchodilator FEV 1 was 1.36 L (46% predicted), TGV was 5.42 L (165% predicted), and EET = 458 s. Relative to S + F, T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks (p < 0.0001) and 87 ± 44 ml after 8 weeks (p < 0.05). EET was nonsignificantly increased following T + S treatment (20 ± 15 s at 4 weeks, 15 ± 13 s at 8 weeks) vs. S + F. BORG dyspnea score at exercise isotime was reduced in favor of T + S. Conclusion: The two bronchodilators decreased hyperinflation significantly more than one bronchodilator and ICS. This difference was not reflected in EET. (ClinicalTrials.gov number, NCT00530842) © 2012 Elsevier Ltd. All rights reserved. Reaxys Database Information
  • Author:
    Lokke A; Ulrik C S; Dahl R; Plauborg L; Dollerup J; Kristiansen L C; Cording P H; Dehlendorff C
    Title:
    Detection of previously undiagnosed cases of COPD in a high-risk population identified in general practice
    Source:
    COPD: J Chronic Obstruct Pulm Dis 9 (5), 458-465 (2012)
    Abstract:
    Background and Aim: Under-diagnosis of COPD is a widespread problem. This study aimed to identify previously undiagnosed cases of COPD in a high-risk population identified through general practice. Methods: Participating GPs (n 241) recruited subjects with no previous diagnosis of lung disease, >35 yrs, and at least one respiratory symptom. Age, smoking status, pack-years, BMI, dyspnoea score (MRC), and pre-bronchodilator spirometry data was obtained. Subjects with airway obstruction (FEV1/FVC ? 0.7) at initial spirometry were tested for reversibility, according to Danish COPD guidelines, with bronchodilator and, if necessary, corticosteroids in order to confirm a diagnosis of COPD. Results: A total of 4.049 (49 females) subjects were included; mean age 58 yrs, BMI 27, and 32 pack-years. The COPD prevalence was 21.7; 8.3 in subjects younger than 48 years. Most patients were classified in GOLD stages I and II (36 and 50, respectively). The number needed to screen (NNS) for a new diagnosis of COPD was 4.6. COPD diagnosis was related to gender, age, BMI (p < 0.001), pack-years, and cough (p < 0.001), wheezing (p < 0.001) and sputum production (p 0.002). A threshold of 10 pre-test risk of COPD would have reduced the number of spirometry tests by 35 although 90 of the patients with COPD would still have been identified (NNS 3.9). Conclusions: Of the at-risk subjects studied, 22 were diagnosed with COPD. A case-finding strategy providing questionnaire assessment and diagnostic spirometry to high-risk subjects in primary care, and therefore, identifies a large proportion of undiagnosed COPD patients, especially in the early stages of the disease. © 2012 Informa Healthcare USA, Inc.
  • Author:
    Buhl R; Welte T; Vogelmeier C; Gillissen A; Voshaar T; Kögler H; Liu D; Glaab T
    Title:
    Early Treatment of COPD with Tiotropium [Evidenz für eine frühzeitige Therapie der COPD mit Tiotropium
    Source:
    Pneumologie Article in Press (2012)
    Abstract:
    Background: In a prespecified subgroup analysis of the 4-year trial "Understanding Potential Long-term Impacts on Function with Tiotropium", the efficacy of tiotropium versus control in patients with moderate COPD (GOLD II) was examined and compared with the pooled results of patients with more severe disease (GOLD III/IV). Methods: Randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 5993 patients over a period of 4 years. Patients received either tiotropium 18 ?g or placebo once-daily. The study endpoints were the annual FEV 1decline as well as lung function parameters, health status, exacerbations and all-cause mortality. Results: 46 % of the patients had moderate disease (GOLD II; tiotropium: n = 1384, control group: n = 1355) with a mean postbronchodilator FEV 1 of 1.63 (0.37) L (59 % predicted). In these patients with moderate COPD, tiotropium significantly improved the absolute FEV 1 values (pre-bronchodilator FEV 1: 101 - 119 ml, post-bronchodilator FEV 1: 52 - 82 ml, p &lt; 0.001) and the postbronchodilator FEV 1decline compared with the control patients (43 (2) vs. 49 (2) ml/year; p = 0.024). In addition, there was a statistically significant improvement in the annual exacerbation rate (tiotropium: 0.56, control: 0.7; p &lt; 0.0001), the time to first exacerbation (tiotropium: 23.09, control: 17.47 months; p &lt; 0.0001) and health status (tiotropium vs. control: minus 2.7 - 4 units; p &lt; 0.0001) in the tiotropium group. Conclusions: The results of this subgroup analysis support current guideline recommendations and indicate that already patients with moderate COPD (GOLD stage II) benefit clinically from treatment with tiotropium. © Georg Thieme Verlag KG.
  • Author:
    Kerstjens H A M; Engel M; dahl R; Paggiaro P; Beck E; Vandewalker M; Sigmund R; Seibold W; Moroni-Zentgraf P; Bateman E D
    Title:
    Tiotropium in asthma poorly controlled with standard combination therapy
    Source:
    N Engl J Med 367 (13), 1198-1207 (2012)
    Abstract:
    BACKGROUND: Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs). METHODS: In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 ?g) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV 1) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. RESULTS: The patients had a mean baseline FEV 1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV 1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P = 0.01) and 154±32 ml in trial 2 (P&lt;0.001). The predose (trough) FEV 1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P = 0.01) and 111±30 ml (P&lt;0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups. CONCLUSIONS: In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.) Copyright © 2012 Massachusetts Medical Society.
  • Author:
    McSharry DG; Ryan S; Calverley P; Edwards J C; McNicholas W T
    Title:
    Sleep quality in chronic obstructive pulmonary disease
    Source:
    Respirology 17 (7), 1119-1124 (2012)
    Abstract:
    Background and objective: Previous reports have shown that patients with chronic obstructive pulmonary disease (COPD) sleep poorly, but the underlying basis remains speculative. The aim of this retrospective study was to determine potential predictors of poor sleep quality in COPD patients. Methods: This is a secondary analysis of two previously published trials investigating the impact of long-acting bronchodilators on nocturnal oxygen saturation in moderate to severe COPD patients. One hundred and six patients with established COPD were studied. Each patient underwent overnight polysomnography studies in a dedicated university-affiliated sleep laboratory. Epworth Sleepiness Scores, spirometry and daytime arterial oxygen tension (PaO 2) were also recorded. Univariate and multivariate analysis sought independent predictors of sleep quality from baseline demographic, spirometry and oximetry values. Results: Patients' age was 66.4 ± 7.3 years (mean ± standard deviation), forced expiratory volume in 1 s (FEV 1) 33.4 ± 12.9% predicted and daytime PaO 2 64 ± 7.5 mm Hg. In comparison with historical normative populations, the cohort demonstrated impaired sleep quality. Sleep efficiency was 66 ± 17% and sleep stage analysis revealed altered architecture with diminished periods of rapid eye movement sleep (12.7 ± 8.3%). In multivariate analysis, daytime PaO 2 correlated independently with sleep efficiency (P = 0.041), whereas FEV 1 positively correlated with arousal index, and age correlated negatively with rapid eye movement sleep duration. Conclusions: Sleep quality is poor in patients with severe COPD compared with normative populations of similar age, and daytime hypoxaemia is independently associated with impaired sleep efficiency. This retrospective analysis investigates sleep quality and seeks its predictors in patients with severe COPD. We demonstrate poor sleep quality in these patients manifesting as reduced sleep efficiency and reduced percentage of rapid eye movement sleep. Furthermore, the data suggest a significant association between daytime hypoxaemia and sleep quality. © 2012 Asian Pacific Society of Respirology.
  • Author:
    Pieper M P
    Title:
    The non-neuronal cholinergic system as novel drug target in the airways
    Source:
    Life Sci Article in Press (2012)
    Abstract:
    The parasympathetic nervous system is a key regulator of the human organism involved in the pathophysiology of various disorders through cholinergic mechanisms. In the lungs, acetylcholine (ACh) released by vagal nerve endings stimulates muscarinic receptors thereby increasing airway smooth muscle tone. Contraction of airway smooth muscle cells leads to increased respiratory resistance and dyspnea. An additional branch of the cholinergic system is the non-neuronal cholinergic system expressed in nearly all cell types present in the airways. Activation of this system may contribute to an increased cholinergic tone in the lungs, inducing pathophysiological processes like inflammation, remodeling, mucus hypersecretion and chronic cough. Selective muscarinic receptor antagonists specifically inhibit acetylcholine at the receptor inducing bronchodilation in patients with obstructive airway diseases. This paper reviews preclinical pharmacological research activities on anticholinergics including experimental models of asthma and chronic obstructive pulmonary disease, COPD. It discloses various options to follow up the non-neuronal cholinergic system as a novel drug target for the treatment of key aspects of obstructive airway diseases, in particular those of a chronic nature. © 2012 Elsevier Inc. All rights reserved.
  • Author:
    Dibonaventura MD; Paulose-Ram R; Su J; McDonald M; Zou KH; Wagner J-S; Shah H
    Title:
    The burden of chronic obstuctive pulmonary disease among employed adults.
  • Author:
    Diederichs CP; Wellmann J; Bartels DB; Ellert U; Hoffmann W; Berger K
    Title:
    How to weight chronic diseases in multimorbidity indices? Development of a new method on the basis of individual data from five population based studies.
    Source:
    J Clin Epidemiol 65 (6), 679-685 (2012)
  • Author:
    Profita M; Bonanno A; Montalbano AM; Albano GD; Riccobono L; Siena L; Casarosa P; Ferraro M; Pieper MP; Gjomarkaj M
    Title:
    Beta 2 long-acting and anticholinergic drugs control TGF-beta1-mediated neutrophilic inflammation in COPD.
    Source:
    Biochim Biophys Acta Mol Basis Dis 1822 (7), 1079-1089 (2012)
  • Author:
    Morenz K; Biller H; Wolfram F; Leonhardt S; Rueter D; Glaab T; Uhlig S; Hohlfeld J M
    Title:
    Detection of air trapping in chronic obstructive pulmonary disease by low frequency ultrasound.
    Source:
    BMC Pulm Med 12 art.no.8 (2012)
    Abstract:
    Background: Spirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication.Methods: Seventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed ?F. Measurements were repeated after inhalation of salbutamol.Results: We found significant differences in ?F between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably.Conclusions: We conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD.Trial Registration: ClinicalTrials.gov: NCT01080924. © 2012 Morenz et al; licensee BioMed Central Ltd.
  • Author:
    Ahmedat A S; Wamken M; Juergens U R; Pieper P; Racke K
    Title:
    Beta 2-adrenoceptors and muscarinic receptors mediate opposing effects on endothelin-1 expression in human lung fibroblasts
    Source:
    Eur J Pharmacol 691 (1-3), 218-224 (2012)
    Abstract:
    Abstract Human lung fibroblasts are a potential source of endothelin-1 (ET-1), a pro-fibrotic mediator. The present study explored possible muscarinic and ß-adrenergic modulations of ET-1 expression in human lung fibroblasts. MRC-5 human lung fibroblasts were cultured. Expression of prepro-endothelin-1 (ppET-1) mRNA was determined by quantitative real time PCR. [ 3H]-Proline incorporation was determined as measure of collagen synthesis. The muscarinic agonist oxotremorine induced, in a tiotropium-sensitive manner, a three-fold increase in ppET-1 mRNA. The ß 2-adrenoceptor agonist olodaterol caused a reduction of ppET-1 mRNA by 45%. Olodaterol also opposed the stimulatory effect of oxotremorine. The effect of olodaterol was mimicked by the protein kinase A agonist 6-Bnz-cAMP, whereas the Epac (exchange protein activated by cAMP) agonist 8-CPT-2'-O-Me-cAMP was less effective. Transforming growth factor-ß 1 (TGF-ß, 0.3 and 1 ng/ml) induced a three- and eight-fold increase in pp-ET-1 mRNA, respectively. Olodaterol opposed the effect of 0.3, but not that of 1 ng/ml TGF-ß. Likewise, 6-Bnz-cAMP opposed the effect of 0.3, but not that of 1 ng/ml TGF-ß. TGF-ß inhibited ß 2-adrenoceptor mRNA expression, maximally by 90%. Muscarinic agonist-induced stimulation of [ 3H]-proline incorporation was attenuated by the endothelin ET1 receptor antagonist bosentan. In conclusion, ET-1 expression in human lung fibroblasts is regulated by stimulatory muscarinic receptors and inhibitory ß 2-adrenoceptors. Since muscarinic up-regulation of ET-1 contributes to pro-fibrotic effects of muscarinic stimuli, inhibition of ET-1 expression could contribute to long-term beneficial effects of long-acting ß 2-adrenoceptor agonists and long-acting muscarinic antagonists. However, excessive exposure to TGF-ß results in loss of ß-adrenoceptor expression and function of its down-stream signaling. © 2012 Elsevier B.V. All rights reserved. -------------------------------------------------------------------------- ------ Reaxys Database Information |
  • Author:
    Glaab T; Vogelmeier C; Hellmann A; Buhl R
    Title:
    Guideline-based survey of outpatient COPD management by pulmonary specialists in Germany.
  • Author:
    May S; Jensen B; Wolkenhauer M; Schneider M; Lehr C M
    Title:
    Dissolution techniques for in vitro testing of dry powders for inhalation
    Source:
    Pharm Res 29 (8), 2157-2166 (2012)
    Abstract:
    Purpose To evaluate different dissolution testing methods and subsequently develop a simple to perform but reproducible and discriminating dissolution technique for inhalative powders. Methods From a dry powder a fraction of aerosolized particles with an aerodynamic particle size below 5 ?m was collected on regenerated cellulose membranes using an abbreviated Andersen cascade impactor. The membrane was then transferred to the respective dissolution set up either paddle apparatus with membrane holder, flow through cell or Franz diffusion cell. Results All tested dissolution techniques could discriminate between good and poorly soluble substances, but only the paddle apparatus differentiated between small variations of solubility. We showed that membrane coverage and particle diameter play an important role for the dissolution rate. The profiles were fitted with mathematical models (e.g., Weibull, first order) choosing the best fit for determination of the mean dissolution time. Furthermore, a correlation between the dissolution profiles obtained with Franz cell compared to paddle apparatus could be shown. Conclusion The paddle apparatus with membrane holder has the best discrimination power with optimal reproducibility. © Springer Science+Business Media, LLC 2012.
  • Author:
    Boer LM; Asijee GM; van Schayck OCP; Schermer TRJ
    Title:
    How do dysponea scales compare with measurement of functional capacity in patients with COPD and at risk of COPD?
    Source:
    Prim Care Respir J Article in Press (2012)
  • Author:
    May S; Jensen B; Wolkenhauser M; Schneider M; Lehr CM
    Title:
    Dissolution techniques for in vitro testing of dry powders for inhalation.
    Source:
    Pharm Res, 1-10 Article in Press (2012)
  • Author:
    Dacosta Dibonaventura M; Paulose-Ram R; Su J; McDonald M; Zou KH; Wagner J-S; Shah H
    Title:
    The impact of COPD on quality of life, productivity loss, and resource use among the elderly united states workforce.
    Source:
    COPD: J Chronic Obstruct Pulm Dis 9 (1), 46-57 (2012)
  • Author:
    Gnadt M; Trammer B; Freiwald M; Kardziev B; Bayliss MK; Edwards CD; Schmidt M; Friedel G; Hoegger P
    Title:
    Methacholine delays pulmonary absorption of inhaled beta 2-agonists due to competition for organic cation/carnitine transporters.
    Source:
    Pulm Pharmacol Ther 25 (1), 124-134 (2012)
    Abstract:
    Background: The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting ? 2-agonist GW597901 with salbutamol and to determine the influence of an induced bronchoconstriction on the pharmacokinetics of the compounds using a human lung reperfusion model. Methods: In an initial study with six lung perfusions the pharmacokinetic properties of the ? 2-agonists were determined. We then investigated the influence of an induced bronchoconstriction on the pulmonary absorption in six lung lobes for each drug. Therefore, methacholine (MCh) challenge agent was nebulised prior to administration of the ? 2-agonists. Results: As expected, the extent of pulmonary absorption of salbutamol into the perfusate was more pronounced than for the more lipophilic GW597901. Although the observed differences were not statistically significant they were further supported by analysis of tissue concentrations. In contrast, we observed a statistically significant influence of the bronchoprovocation with MCh on the pulmonary absorption of both ? 2-agonists, but this effect was not limited to a successfully induced bronchoconstriction. A prominent decline of salbutamol distribution into perfusion fluid was also observed when the organic cation transporter substrate carnitine was nebulised prior to the bronchodilator. Conclusions: Nebulised methacholine had a significant influence on the pharmacokinetics of bronchodilators. Since we observed this effect independently of a successfully induced bronchoconstriction and also after nebulisation of carnitine we suggest a significant delay of pulmonary absorption of inhaled salbutamol and GW597901 due to competition for a cation/carnitine drug transporter, most likely OCTN2.
  • Author:
    Carrero-Gonzles L; Kaulisch T; Ruiz-Cabello J; Perez-Sanchez JM; Peces-Barba G; Stiller D; Rodriguez I
    Title:
    Apparent diffusion coefficient of hyperpolarized 3He with minimal influence of the residual gas in small animals.
    Source:
    NMR Biomed Article in Press (2012)
  • Author:
    Sattah MV; Aye SS; Azen C; Kort JJ; Jones BE; Escalante P
    Title:
    Interferon-gamma release assay T-SPOT.RTM..TB and HIV-related tuberculosis.
    Source:
    Int J Tuberc Lung Dis 16 (2), 281-282 (2012)
  • Author:
    Schmidt M; Michel MC
    Title:
    How can 1 + 1 = 3? .beta.2.-adrenergic and glucocorticoid receptor agonist synergism in obstructive airway diseases.
    Source:
    Mol Pharmacol 80 (6), 955-958 (2011)
    Abstract:
    For a long time it was believed that ? 2-adrenergic receptor agonists used in the treatment of obstructive airway diseases worked primarily on airway smooth muscle cells, causing relaxation, whereas glucocorticoids primarily improved airway function via their anti-inflammatory action, indicating that their clinical synergism occurred at the organism rather than the cellular level. However, it is now becoming clear that both drug classes can affect airway function at multiple levels, including an integrated effect on several cell types. This article summarizes data on the molecular interaction between the two receptor systems, particularly with relevance to phenomena of ? 2-adrenergic receptor desensitization and glucocorticoid insensitivity in the airways. These molecular interactions may contribute to the observed clinical synergism between both drug classes in the treatment of obstructive airway diseases.
  • Author:
    Tsuyusaki J; Kuroda F; Kasuya Y; Ishizaki S; Yamauchi K; Sugimoto H; Kono T; Iwamura C; Nakayama T; Tatsumi K
    Title:
    Cigarette smoke-induced pulmonary inflammation is attenuated in CD69-deficient mice.
    Source:
    J Recept Signal Transduct 31 (6), 434-439 (2011)
    Abstract:
    Cluster of differentiation 69 (CD69) has been identified as a lymphocyte early activation marker, and recent studies have indicated that CD69 mediates intracellular signals and plays an important role in various inflammatory diseases. Cigarette smoke (CS) is a strong proinflammatory stimulus that induces the release of proinflammatory mediators by recruiting macrophages and neutrophils into the lung tissue, and is one of the main risk factors for a number of chronic diseases. However, the potential role of CD69 in CS-induced pulmonary inflammation has not been determined. To address to this question, CD69-deficient (KO) and wild-type (WT) mice were subjected to CS-induced acute pulmonary inflammation. After the exposure with CS, the expression of CD69 in the lung of WT mice was significantly induced, it was predominantly observed in macrophages. In conjunction with this phenomenon, neutrophil and macrophage cell counts, and expression of several cytokines were significantly higher in the bronchoalveolar lavage fluid (BALF) of CS-exposed WT mice compared with air-exposed WT mice. Likewise, the CS-induced accumulation of inflammatory cells and cytokines expression were significantly lower in CD69-KO mice than in WT mice. These results suggest that CD69 on macrophages is involved in CS-induced acute pulmonary inflammation.
  • Author:
    Arrieta O; Cardona AF; Federico Bramuglia G; Gallo A; Campos-Parra AD; Serrano S; Castro M; Aviles A; Amorin E; Kirchuk R; Cuello M; Borbolla J; Riemersma O; Becerra H; Rosell R
    Title:
    Genotyping non-small cell lung cancer (NSCLC) in latin America.
    Source:
    J Thorac Oncol 6 (11), 1955-1959 (2011)
    Abstract:
    Introduction: Frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is different between ethnic groups; however, there is no information in Latin-American population. Methods: A total of 1150 biopsies of NSCLC patients from Latin America (Argentina, Colombia, Peru, and Mexico) were used extracting genomic DNA to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 650 samples. In Mexico, Scorpions ARMS was also used to obtain a genetic profile. Results: We report the frequency of mutations in EGFR and KRAS genes in four Latin-American countries (n = 1150). Frequency of EGFR mutations in NSCLC was 33.2% (95% confidence interval [CI] 30.5-35.9) (Argentina 19.3%, Colombia 24.8%, Mexico 31.2%, and Peru 67%). The frequency of KRAS mutations was 16.6% (95% CI 13.8-19.4). EGFR mutations were independently associated with adenocarcinoma histology, older age, nonsmokers, and absence of KRAS mutations. Overall response rate to tyrosine kinase inhibitors in EGFR-mutated patients (n = 56) was 62.5% (95% CI 50-75) with a median overall survival of 16.5 months (95% CI 12.4-20.6). Conclusions: Our findings suggest that the frequency of EGFR mutations in Latin America lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world.
  • Author:
    Bleecker ER; Busse WW; Donohue JF; Garfinkel S; Lystig T; Manuel RC; Schlenker-Herceg R; Wise RA
    Title:
    Comparison of ipratropium bromide and albuterol sulfate chlorofluorocarbon metered-dose inhaler and albuterol hydrofluoroalkane metered-dose inhaler in crossover trial in patients with moderate-to-serve asthma.
    Source:
    J Allergy Clin Immunol 127 (2) (Supp.[S]), AB83 (2011)
  • Author:
    Ahmedat S; Warnken-Uhlich M; Fuhrmann M; Juergens UR; Pieper M; Racke K
    Title:
    Beta2-adrenoceptors and muscarinic receptors mediate opposing effects on endothelin-1 (ET-1) expression in human lung fibroblasts.
    Source:
    BPS Winter Meeting, London (Great Britain), Dec 13-15, 2011.Eur J Pharmacol Article in press (2012)
    Abstract:
    Human lung fibroblasts are a potential source of endothelin-1 (ET-1), a pro-fibrotic mediator. The present study explored possible muscarinic and ?-adrenergic modulations of ET-1 expression in human lung fibroblasts. MRC-5 human lung fibroblasts were cultured. Expression of prepro-endothelin-1 (ppET-1) mRNA was determined by quantitative real time PCR. [ 3H]-Proline incorporation was determined as measure of collagen synthesis. The muscarinic agonist oxotremorine induced, in a tiotropium-sensitive manner, a three-fold increase in ppET-1 mRNA. The ? 2-adrenoceptor agonist olodaterol caused a reduction of ppET-1 mRNA by 45%. Olodaterol also opposed the stimulatory effect of oxotremorine. The effect of olodaterol was mimicked by the protein kinase A agonist 6-Bnz-cAMP, whereas the Epac (exchange protein activated by cAMP) agonist 8-CPT-2?-O-Me-cAMP was less effective. Transforming growth factor-? 1 (TGF-?, 0.3 and 1 ng/ml) induced a three- and eight-fold increase in pp-ET-1 mRNA, respectively. Olodaterol opposed the effect of 0.3, but not that of 1 ng/ml TGF-?. Likewise, 6-Bnz-cAMP opposed the effect of 0.3, but not that of 1 ng/ml TGF-?. TGF-? inhibited ? 2-adrenoceptor mRNA expression, maximally by 90%. Muscarinic agonist-induced stimulation of [ 3H]-proline incorporation was attenuated by the endothelin ET1 receptor antagonist bosentan. In conclusion, ET-1 expression in human lung fibroblasts is regulated by stimulatory muscarinic receptors and inhibitory ? 2-adrenoceptors. Since muscarinic up-regulation of ET-1 contributes to pro-fibrotic effects of muscarinic stimuli, inhibition of ET-1 expression could contribute to long-term beneficial effects of long-acting ? 2-adrenoceptor agonists and long-acting muscarinic antagonists. However, excessive exposure to TGF-? results in loss of ?-adrenoceptor expression and function of its down-stream signaling.
  • Author:
    Kesten St; Celli B; Decramer M; Liu D; Tashkin D
    Title:
    Adverse helth consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial.
    Source:
    Respir Res 12, 129 (2011)
  • Author:
    Kariyawasam S; Strait E; Jordan D; Kroll J
    Title:
    Development of a real-time polymerase chain reaction assay for detection of actinobacillus suis in porcine lung.
    Source:
    J Vet Diagn Invest 23 (5), 885-889 (2011)
  • Author:
    Miravitlles M; Llor C; Calvo E; Diaz S; Diaz-Cuervo H
    Title:
    Validation of the Spanish version of the chronic obstructive pulmonary disease-population screener (COPD-PS). Its usefulness and that of FEV1/FEV6 for the diagnosis of COPD.
    Source:
    Med Clin (Barc) Article in Press (2011)
    Abstract:
    Background and objectives: The chronic obstructive pulmonary disease (COPD) is a highly undiagnosed disease. The use of short screening questionnaires designed to detect chronic airflow obstruction may help to the early diagnosis of COPD. Patients and method: This was an observational, cross-sectional epidemiological study aimed to validate the translated into Spanish version of the COPD-PS questionnaire. Socio-demographic and clinical data of participants were collected, as well as their answers to the COPD-PS and EQ-5D questionnaires. The ratio FEV 1/FEV 6 was measured with the COPD-6 device. The psychometric properties of the questionnaire and the diagnostic yield of the FEV 1/FEV 6 ratio were analysed, both referred to the gold standard of post-bronchodilator FEV 1/FVC < 0.7. Results: Ten primary care centers participated in the study and included 94 controls and 79 cases with chronic airflow obstruction. Questionnaire characteristics were: feasibility, 2.3% of participants did not answer at least one item; mean time to fill the questionnaire was 47.7 seconds; 4.7% of individuals had a 0 score. Validity, moderate correlation with EQ-5D scores and moderate-high with FEV 1; the scores of COPD-PS were related to all parameters associated with COPD. A cut off of 4 units had the best sensitivity/specificity ratio and correctly classified 78% of participants. For the FEV 1/FEV 6 ratio, a cut off of 0.75 correctly classified 85% of individuals. Conclusions: The COPD-PS questionnaire demonstrated good psychometric properties. A cut off score of 4 has excellent predictive value. A ratio of 0.75 in the FEV 1/FEV 6 provides an excellent correlation with the ratio FEV 1/FVC and is useful for the identification of individuals with chronic airflow obstruction.
  • Author:
    Berard E; Bongard V; Roche N; Perez T; Broquires D; Taraszkiewicz D; Fieves S; Denis F; Escamilla R; Ferries J
    Title:
    Undiagnosed airflow limitation in patients at cardiovascular risk.
    Source:
    Arch Cardiovasc Dis 104 (12), 619-626 (2011)
    Abstract:
    Background: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) share risk factors and impair each other's prognosis. Aims: To assess the prevalence of airflow limitation (AL) compatible with COPD in a population at cardiovascular risk and to identify determinants of AL. Methods: All consecutive patients referred to the cardiovascular prevention unit of a university hospital in 2009 were studied in a cross-sectional analysis. Patients answered questionnaires on socioeconomic status, medical history and lifestyle, and underwent extensive physical examinations, biological measures and spirometry testing. AL was defined as FEV1/FVC < 0.70, without any history of asthma. Determinants of AL were assessed using logistic regression. Results: The sample comprised 493 participants (mean age 57.4 ± 11.1 years); 60% were men, 18% were current smokers, 42% were ex-smokers and 10% of patients had a history of CVD. Ten-year risk of coronary heart disease (CHD) according to the Framingham equation was intermediate (10-20%) for 25% of patients and high (> 20%) for 10%. Prevalence of AL was 5.9% (95% confidence interval [CI] 4.0-8.3%) in the whole population and 4.3% (2.6-6.6%) among subjects in primary cardiovascular prevention. AL was independently associated with CVD (adjusted odds ratio 4.18, 95% CI 1.72-10.15; P = 0.002) but not with Framingham CHD risk. More than 80% of patients screened with AL had not been diagnosed previously and more than one in two patients was asymptomatic. Conclusion: Patients with CVD are at increased risk of AL and thus should benefit from AL screening as they are frequently asymptomatic.
  • Author:
    Dalby RN; Eicher J; Zierenberg B
    Title:
    Development of Respimat soft mist inhaler and its clinical utility in respiratory disorders.
    Source:
    Med Devices Evid Res 4 (1) (2011)
    Abstract:
    The Respimat® Soft Mist™ Inhaler (SMI) (Boehringer Ingelheim International GmbH, Ingelheim, Germany) was developed in response to the need for a pocket-sized device that can generate a single-breath, inhalable aerosol from a drug solution using a patient-independent, reproducible, and environmentally friendly energy supply. This paper describes the design and evolution of this innovative device from a laboratory concept model and the challenges that were overcome during its development and scaleup to mass production. A key technical breakthrough was the uniblock, a component combining flters and nozzles and made of silicon and glass, through which drug solution is forced using mechanical power. This allows two converging jets of solution to collide at a controlled angle, generating a fne aerosol of inhalable droplets. The mechanical energy comes from a spring which is tensioned by twisting the base of the device before use. Additional features of the Respimat® SMI include a dose indicator and a lockout mechanism to avoid the problems of tailing-off of dose size seen with pressurized metered dose inhalers. The Respimat® SMI aerosol cloud has a unique range of technical properties. The high fine particle fraction allied with the low velocity and long generation time of the aerosol translate into a higher fraction of the emitted dose being deposited in the lungs compared with aerosols from pressurized metered dose inhalers and dry powder inhalers. These advantages are realized in clinical trials in adults and children with obstructive lung diseases, which have shown that the efficacy and safety of a pressurized metered dose inhaler formulation of a combination bronchodilator can be matched by a Respimat® SMI formulation containing only one half or one quarter of the dose delivered by a pressurized metered dose inhaler. Patient satisfaction with the Respimat® SMI is high, and the long duration of the spray is of potential benefit to patients who have difficulty in coordinating inhalation with drug release.
  • Author:
    Onoue S; Sato H; Ogawa K; Kojo Y; Aoki Y; Kawabata Y; Wada K; Mizumoto T; Yamada S
    Title:
    Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats.
    Source:
    Eur J Pharm Biopharm 80 (1), 54-60 (2012)
    Abstract:
    The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317 nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100 ?g-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10 mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.
  • Author:
    Dellweg D; Hohn E; Barchfeld Th; Kohler D; Wachtel H; Pieper MP; Glaab Th
    Title:
    In vitro validation of a respimat.RTM. adapter for delivery of inhaled bronchodilators during mechanical ventilation.
    Source:
    J Aerosol Med Pulm Drug Deliv 24 (6), 285-292 (2011)
    Abstract:
    Background: Inhaled bronchodilators are frequently used in patients with chronic obstructive pulmonary disease (COPD). However, there has been no efficient way to administer the long-acting anticholinergic tiotropium to mechanically ventilated patients. The aim of this in vitro study was to compare the fine particle dose (FPD) output of a specifically designed adapter with other accessory devices for the delivery of bronchodilators using the Respimat (RMT) inhaler by simulating the specific inhalation flow profiles of patients with COPD. Methods: Using characteristic flow profiles from COPD patients being weaned off mechanical ventilation, an in vitro study was performed analyzing the FPD achieved with different accessory devices (connectors, spacers, AeroTrachPlus valved holding chamber), which can be used to deliver drugs from pressurized metered dose inhalers (pMDI) and RMT inhalers to artificial airways. Fenoterol pMDI, tiotropium RMT, and a fixed-dose combination of salbutamol and ipratropium delivered by pMDI or RMT, were used as bronchodilators. Aerosols were collected by a next-generation impactor. Results: The RMT inhaler, combined with a new in-line adapter, was superior to other inhaler device connector or spacer combinations in FPD delivery during simulated mechanical ventilation (p<0.01). The outcome with the RMT inhaler/RMT adapter combination during simulation of mechanical ventilation was comparable to the measurements with the RMT/AeroTrachPlus valved holding chamber during simulation of spontaneous breathing. The delivery rates of the RMT adapter were not significantly affected by the administered bronchodilators or by the type of artificial airway (endotracheal or tracheostomy tube) employed. Conclusions: The RMT inhaler combined with the prototype in-line adapter was better than the other accessory device combinations in fine particle deposition of inhaled bronchodilators during mechanical ventilation. Further research is required to determine the clinical relevance of these in vitro findings.
  • Author:
    Bosnjak B; Stelzmueller B; Epstein MM; Erb K
    Title:
    Treatment of allergic asthma: Modulation of Th2 cells and their responses.
    Source:
    Respir Res 12 arn. 114 (2011)
    Abstract:
    Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.
  • Author:
    Richeldi L; Costabel U; Selman M; Hansell DM; Kim DS; Nicholson AG; Brown KK; Flaherty KR; Noble PW; Raghu G; Brun M; Gupta A; Juhel N; Klueglich M; Du Bois RM
    Title:
    Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.
    Source:
    N Engl J Med 365 (12), 1079-1087 (2011)
    Abstract:
    BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. METHODS: In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. RESULTS: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683.)
  • Author:
    van Noord JA; Smeets JJ; Drenth BM; Rascher J; Pivovarova A; Hamilton AL; Cornelissen PJG
    Title:
    24-hour bronchodilation following a single dose of the novel beta2-agonist olodaterol in COPD.
    Source:
    Pulm Pharmacol Ther 24 (6), 666-672 (2011)
    Abstract:
    Background: Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting ?2-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration. Objective: To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat® Soft Mist™ Inhaler in COPD patients. Methods: A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV1, FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 ?g, 5 ?g, 10 ?g and 20 ?g; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV1. Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 ?g. Results: 36 patients were assigned to treatment; mean baseline prebronchodilator FEV1 was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV1 post-dose (p &lt; 0.001); a clear dose-response relationship was observed, with values ranging from 0.070 L for olodaterol 2 ?g to 0.119 L for olodaterol 20 ?g. Similarly, olodaterol was superior to placebo (p &lt; 0.001) in peak FEV1 (0.121 L to 0.213 L) and average FEV1 both during the daytime (0-12 h; ranging from 0.099 L to 0.184 L) and night-time (12-24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV1. Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 ?g-40 ?g; in most patients, no plasma levels could be detected following the 2 ?g dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events. Conclusions: Olodaterol appears to be a promising long-acting ?2-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.
  • Author:
    Deschl U; Vogel J; Aufderheide M
    Title:
    Development of an in vitro exposure model for investigating the biological effects of therapeutic aerosols on human cells from the respiratory tract.
    Source:
    Exp Toxicol Pathol 63 (6), 593-598 (2011)
    Abstract:
    Respiratory diseases like asthma or COPD are gaining more and more importance worldwide due to an increased exposure of humans to inhalable compounds such as cigarette smoke, diesel exhaust or other forms of environmental pollution. Therefore, a high impact on national health systems is expected, meaning long-term treatment, with periodic examinations accompanied by high costs. Although a number of efficient drugs for these disease patterns, like Tiotropium (antimuscarinic), Salmetron (beta-antagonist) or corticosteroids, are already available, a great deal of effort has to be put into the development of new drugs and therapy concepts. In this context, in vitro methods may be useful to establish more efficient prescreening procedures to analyze, for example, the toxicity of new compounds during the research and development process. These studies should aim to achieve a better selection of substances relevant for further development and a final reduction in the number of animal experiments. Therefore, we established an in vitro exposure device that allows the analysis of inhalable compounds for their pharmacological and toxicological effects. This CULTEX (R) device is composed of an exposure entity representing the in vivo respiratory air compartment and a basal feeding compartment representing the subepithelium. Both compartments are connected by porous transwells on which cells form an epithelium-like cell layer. We have used this system for exposing human lung cells directly to liquid aerosols and present the first data with regard to aerosolized model substances.
  • Author:
    Disse B; Metzdorf N; Bender H
    Title:
    Tiotropium mist inhaler: Manufacturer's reply to letter by Seed and colleagues - art. No. d5365
    Source:
    Br Med J 343 (7821), PD5365-D5365 (2011)
  • Author:
    Nieves D; Isla D; Gonzalez-Rojas N; Brosa M; Finnern HW
    Title:
    Treatment patterns, use of resources, and costs of advanced non-small-cell lung cancer patients in Spain: results from a Delphi panel.
    Source:
    Clin Transl Oncol 13 (7), 460-471 (2011)
    Abstract:
    Approximately 80-85% of lung cancer patients are diagnosed with non-small-cell lung cancer (NSCLC), of which 50% of patients present with advanced or metastatic disease. The objective of this study was to describe treatment patterns, use of resources and costs associated with treating advanced or metastatic NSCLC patients in Spain. A two-round Delphi consensus panel of clinical experts was carried out to describe local clinical patterns based on treatment algorithms from SEOM and ASCO treatment guidelines. The panel consisted of 19 oncologists and 1 hospital pharmacist, who were asked during the first round to define therapeutic pathways for NSCLC by the patients' performance status, age and histology; to quantify the use of resources associated with the preparation and administration of anticancer pharmacotherapy; management of adverse events associated with anticancer pharmacotherapy; and best supportive care (BSC). The second round was used to try to reduce the variability of responses in some questions and to further describe differences between intravenous and oral therapy. 2009 unit costs were applied to the use of resources described by the clinical experts. The perspective of the study was from the Spanish National Healthcare System. Performance status guided therapy decision and led to differences in costs. Patients with a performance status of 0-2 were expected to receive anticancer pharmacotherapy while patients with a performance status of 3-4 received BSC including analgesics and corticosteroids. Anticancer pharmacotherapies containing cisplatin or carboplatin were used preferably in first-line treatment, while the usual second- and third-line treatments were docetaxel, erlotinib or pemetrexed monotherapy. The importance of the cost of anticancer pharmacotherapy as a proportion of total healthcare costs was higher for combination therapies containing bevacizumab or pemetrexed. The anticancer pharmacotherapies associated with adverse events like febrile neutropenia or infection increased the total treatment cost. Administration costs were more relevant in regimens containing cisplatin and were low for orally administered therapies. The total cost per patient with advanced or metastatic NSCLC from starting anticancer therapy until death was estimated to be between zs11,301 and zs32,754 depending on the number of treatment lines received. In the treatment of advanced or metastatic NSCLC, healthcare costs are impacted by line of treatment, patient performance status, type of administration of therapy and adverse event management.
  • Author:
    Fabbri LM; Bateman ED; Kornmann O; Schmidt P; Pivovarova A; Engel M
    Title:
    Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma.
    Source:
    J Allergy Clin Immunol 128 (2), 315-322 (2011)
    Abstract:
    Background: The efficacy and safety of inhaled long-acting beta(2)-adrenergic agonists in asthmatic patients with the B16-Arg/Arg genotype has been questioned, and the use of antimuscarinics has been proposed as an alternative in patients whose symptoms are not controlled by inhaled corticosteroids (ICSs). Objective: We compared the efficacy and safety of the long-acting anticholinergic tiotropium with salmeterol and placebo added to an ICS in B16-Arg/Arg patients with asthma that was not controlled by ICSs alone. Methods: In a double-blind, double-dummy, placebo-controlled trial, after a 4-week run-in period with 50 mu g of twice-daily salmeterol administered through a metered-dose inhaler, 388 asthmatic patients were randomized 1:1:1 to 16 weeks of treatment with 5 mu g of Respimat tiotropium administered daily in the evening, 50 mu g of salmeterol administered twice daily through a metered-dose inhaler, or placebo. Patients aged 18 to 67 years demonstrated reversibility to bronchodilators, and their symptoms were uncontrolled by regular ICSs (400-1000 mg of budesonide/equivalent). ICS regimens were maintained throughout the trial. The mean weekly morning peak expiratory flow (PEF) before randomization was 358 +/- 115.7 L/min (range, 80.3-733.0 L/min). Results: Changes in weekly PEF from the last week of the run-in period to the last week of treatment (primary end point: change in PEF) were -3.9 +/- 4.87 L/min (n = 128) for tiotropium and -3.2 +/- 4.64 L/min (n = 134) for salmeterol, and these were superior to placebo (-24.6 +/- 4.84 L/min, n = 125, P < .05). Tiotropium was noninferior to salmeterol (estimated difference, -0.78 L/min [95% CI, -13.096 to 11.53]; P = .002; alpha = .025, 1-sided; noninferiority, 20 L/min). Tiotropium and salmeterol were numerically superior to placebo in some patient-reported secondary outcomes. Adverse events were comparable across treatments. Conclusion: Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. Safety profiles were comparable. - DERWENT Abstract - This double-blind, double-dummy, placebo-controlled study compared the efficacy and safety of inhaled titropium with inhaled salmeterol and placebo added to inhaled corticosteroids (ICS) in 388 B16-Arg/Arg patients with asthma. Changes in weekly PEF from the last wk of the run-in period to the last wk of treatment were -3.9 l/min for tiotropium (5 ug) and -3.2 l/min for salmeterol (50 ug), and these were superior to placebo. Tiotropium was noninferior to salmeterol. Tiotropium and salmeterol were numerically superior to placebo in some patient-reported secondary outcomes. Adverse events were comparable across treatments. Thus, tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma.
  • Author:
    Beaumont JL; Victorson D; Wortman K; Cella D; Su J; Shah H; Baker ChL
    Title:
    Examining web equivalence and risk faktor sensitivity of the COPD population screener.
    Source:
    Value Health 14 (4), 506-512 (2011)
    Abstract:
    Objectives: The primary aim was to assess the equivalence of an Internet-based chronic obstructive pulmonary disease-population screener (COPD-PS) relative to a validated paper-and-pencil version. A secondary aim was to compare groups based on known COPD risk factors, such as smoking status and gender. Methods: Using an online panel survey organization, participants were randomized to internet or paper-and-pencil assessment where they completed the COPD-PS and other study forms. A subset of respondents also completed a test-retest reliability assessment. Finally, several thousand additional online respondents completed the COPD-PS for risk factor analyses. Results: A total of 1006 adults completed the randomized study (N = 504 online, N = 502 by mail). There were no differences between the arms in mean COPD-PS scores (mean difference: 0.12; 95% confidence interval: -0.14-+0.37; P = 0.365). In the web arm, 106/504 (21.0%) exceeded the screening cut-off compared to 101/502 (20.1%) in the paper-administration arm (difference in proportions: 0.9%; 95% confidence interval: -4.1%-+5.9%; P = 0.720). Subgroup analyses on a separate cohort of 3001 adults demonstrated hypothesized differences between groups defined by smoking status, presence of COPD, and shortness of breath. Conclusion: The methods of administration that were evaluated in this study (internet vs. paper and pencil) resulted in no significant differences in COPD-PS mean scores. Furthermore, the predictive utility of the COPD-PS was not different between methods of administration, even after accounting for age and smoking status.
  • Author:
    Choi SW; Victorsen DE; Yount S; Cella D; Anton S
    Title:
    Development of a conceptual framework and calibrated item banks to measure patient-reported dyspnea severity and related functional limitations.
    Source:
    Value Health 14 (2), 291-306 (2011)
    Abstract:
    Objectives: Chronic obstructive pulmonary disease is a major global health problem. Although several patient-reported outcome (PRO) measures of chronic obstructive pulmonary disease exist, none were developed using patient-driven concept development. We developed an item bank for dyspnea severity and related functional limitations on the basis of a PRO conceptual framework derived from patient input. Methods: We identified a large pool of existing items based on a conceptual framework and literature review. Using patient and expert review panels and an item refinement/modification process, we developed an item bank aligned with the conceptual framework, which subsequently underwent psychometric testing via an online Internet panel of dyspnea patients (N = 608). Results: Exploratory factor analysis suggested a dominant first factor accounting for about 78% of the total variance. Confirmatory factor analysis supported a unidimensional model. Item response theory analysis demonstrated good model fit, and differential item functioning analyses indicated that the 33-item scale showed potential for measurement equivalence across sex. A 10-item short form produced comparable scores (r = 0.98) and a computerized adaptive-testing simulation indicated efficient measurement with fewer items (mean 4.65 items). Conclusions: An efficient patient-reported measure of dyspnea severity and related functional limitations, based on a patient-driven PRO conceptual framework, is now available for further validation and use.
  • Author:
    Yount SF; Choi SW; Victorson D; Cella D; Ruo B; Anton S; Hamilton A
    Title:
    Brief, valid measures of dyspnea and related functional limitations in chronic obstructive pulmonary disease (COPD).
    Source:
    Value Health 14 (2), 307-315 (2011)
    Abstract:
    Objective: Chronic obstructive pulmonary disease (COPD) is a progressive disease with functional decline leading to disability. Dyspnea, the prominent symptom, can be measured using existing measures, but a lack of consensus about standardization of dyspnea measurement remains. We examined the psychometric performance of two item-response theory- based (IRT) measures of dyspnea and related functional limitations (FLs) in patients with COPD and simulated computerized adaptive testing (CAT) of the banks to determine the number of questions required to achieve high precision. Methods: A total of 102 patients completed banks measuring dyspnea and FLs (33 items), from which the 10-item dyspneaandFL short forms were scored as well as other self-report measures of respiratory and physical function and emotional distress. A subset of patients completed the banks 7 to 10 days later. Pulmonary function test results were obtained from medical charts. Results: The 33-item banks and 10-item short forms had excellent internal consistency (alphas >0.9) and test-retest reliability (intraclass correlation coefficients >0.89). Patients sorted by severity level on the Medical Research Council scale were differentiated by item banks (P < 0.001) and the short forms (P < 0.01). The banks and short forms were also associated with related measures of dyspnea (e.g., Baseline Dyspnea Index, r = 0.47-0.53), physical function (e.g., 36-Item Short Form Health Survey, r = -0.83 to -0.86) and forced expiratory volume in 1 second (r=-0.32 to -0.35). On average, CAT required 4 and 5 items for accurate measurement of dyspnea and FLs, respectively. Conclusion: The Functional Assessment of Chronic Illness Therapy-Dyspnea short forms and banks provide options for brief, psychometrically sound measures of dyspnea and/or FLs in COPD.
  • Author:
    Breitenbuecher F; Hoffarth S; Gauler ThC; Stergar SL; Kasper St; Koehler J; Schuler M; Worm K; Schmid KW; Maerten A
    Title:
    Highly sensitive detection of somatic epidermal growth factor receptor (EGFR) gene mutations in circulating tumor cells (CTC) from patients with non-small cell lung cancer (NSCLC) treated with cisplatin/pemetrexed or afatinib.
    Source:
    J Thorac Oncol 6 (6) (Supp.(S)), S956-S957 (2011)
  • Author:
    Vogelmeier C; Glaab T; Fabbri LM
    Title:
    Tiotropium versus Salmeterol in COPD REPLY. The authors reply.
    Source:
    N Engl J Med 364 (26), 2553-2554 (2011)
  • Author:
    Halpin DMG; Decramer M; Celli B; Kesten S; Leimer I; Tashkin DP
    Title:
    Risk of nonlower respiratory serious adverse events following COPD exacerbations in the 4-year UPLIFT trial.
    Source:
    Lung 189 (4), 261-268 (2011)
    Abstract:
    Introduction: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with systemic consequences. Data from a 4-year trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT®], n = 5,992) were used to determine risk for nonlower respiratory serious adverse events (NRSAEs) following an exacerbation. Methods: Patients with ?1 exacerbation were analyzed. NRSAE incidence rates (incidence rate [IR], per 100 patient-years) were calculated for the 30 and 180 days before and after the first exacerbation. NRSAEs were classified by diagnostic terms and organ classes. Maentel-Haenszel rate ratios (RR) (pre- and postexacerbation onset) along with 95% confidence intervals (CI) were computed. Results: A total of 3,960 patients had an exacerbation. The mean age was 65 years, forced expiratory volume in 1 s (FEV1) was 38% predicted, and 74% were men. For all NRSAEs, the IRs 30 days before and after an exacerbation were 20.2 and 65.2 with RR (95% CI) = 3.22 (2.40-4.33). The IRs for the 180-day periods were 13.2 and 31.0 with RR (95% CI) = 2.36 (1.93-2.87). The most common NRSAEs by organ class for both time periods were cardiac, respiratory system (other), and gastrointestinal. All NRSAEs as well as cardiac events were more common after the first exacerbation, irrespective of whether the patient had cardiac disease at baseline. Conclusions: The findings confirm that, after exacerbations, serious adverse events in other organ systems are more frequent, particularly those that are cardiac in nature. - DERWENT Abstract - This study evaluated the risk of nonlower respiratory serious adverse events (NRSAE) following exacerbations in 3960 COPD patients. For all NRSAE, the incidence rate (IR) 30 days before and after an exacerbation were 20.2 and 65.2 with rate ratios (RR) of 3.22. The IR for the 180-day periods were 13.2 and 31 with RR of 2.36. The most common NRSAE by organ class for both time periods were cardiac, respiratory system, and GI. All NRSAE as well as cardiac events were more common after the 1st exacerbation, irrespective of whether the patient had cardiac disease at baseline. Thus, after exacerbations, serious adverse events in other organ systems are more frequent, particularly those that are cardiac in nature.
  • Author:
    Profita M; Bonanno A; Montalbano AM; Ferraro M; Siena L; Bruno A; Girbino S; Albano GD; Casarosa P; Pieper MP; Gjomarkaj M
    Title:
    Cigarette smoke extract activates human bronchial epithelial cells affecting non-neuronal cholinergic system signaling in vitro.
    Source:
    Life Sci 89 (1-2), 36-43 (2011)
    Abstract:
    Aims: Acetylcholine (ACh) is synthesized by Choline Acetyl-Transferase (ChAT) that exerts its physiological effects in airway epithelial cells via muscarinic receptor (MR) activation. We evaluate the effect of ACh stimulation on human bronchial epithelial cells (16-HBE) and test whether cigarette smoke extract (CSE) can modify the basal cellular response to ACh affecting the non-neuronal cholinergic system signalling. Main methods: ACh stimulated 16-HBE were tested for ACh-binding, Leukotriene B4 (LTB4) release and ERK1/2 and NFkB pathway activation. Additionally, we investigated all the aforementioned parameters as well as ChAT and MR proteins and mRNA expression and endogenous ACh production in CSE-treated 16-HBE. Key findings: We showed that ACh induced in 16-HBE, in a concentration-dependent manner, LTB4 release via the activation of ERK1/2 and NFkB pathways. The addition of Tiotropium (Spiriva®), Gallamine, Telenzepine and 4-DAMP (muscarinic receptor antagonists), as well as of PD 098059 (MAPKK inhibitor) and BAY117082 (inhibitor of IkB? phosphorilation), down-regulated the ACh-induced effects. Additionally, CSE treatment of 16-HBE increased the binding of ACh, and shifted the LTB4 release from the concentration ACh 1 nanoM to 10 nM. Finally, we observed that the treatment of 16-HBE with CSE increased the expression of ChAT, M2 and M3 and of endogenous ACh production in 16-HBE. Tiotropium regulated the LTB4 release and ACh production in CSE treated 16-HBE. Significance: CSE increases the pro-inflammatory activity of human bronchial epithelial cells, and promotes the cellular response to lower concentrations of ACh, by affecting the expression of ChAT and MRs. Tiotropium might prevent pro-inflammatory events generated by ACh together with CSE.
  • Author:
    Kerstjens HAM; Disse B; Schroeder-Babo W; Bantje TA; Gahlemann M; Sigmund R; Engel M; van Noord JA
    Title:
    Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial.
    Source:
    J Allergy Clin Immunol 128 (2), 308-314 (2011)
    Abstract:
    Background: Some patients with severe asthma remain symptomatic and obstructed despite maximal recommended treatment. Tiotropium, a long-acting inhaled anticholinergic agent, might be an effective bronchodilator in such patients. Objective: We sought to compare the efficacy and safety of 2 doses of tiotropium (5 and 10 ?g daily) administered through the Respimat inhaler with placebo as add-on therapy in patients with uncontrolled severe asthma (Asthma Control Questionnaire score, ?1.5; postbronchodilator FEV1, ?80% of predicted value) despite maintenance treatment with at least a high-dose inhaled corticosteroid plus a long-acting ?2-agonist. Methods: This was a randomized, double-blind, crossover study with three 8-week treatment periods. The primary end point was peak FEV1 at the end of each treatment period. Results: Of 107 randomized patients (54% female patients; mean, 55 years of age; postbronchodilator FEV1, 65% of predicted value), 100 completed all periods. Peak FEV1 was significantly higher with 5 ?g (difference, 139 mL; 95% CI, 96-181 mL) and 10 ?g (difference, 170 mL; 95% CI, 128-213 mL) of tiotropium than with placebo (both P &lt; .0001). There was no significant difference between the active doses. Trough FEV1 at the end of the dosing interval was higher with tiotropium (5 ?g: 86 mL [95% CI, 41-132 mL]; 10 ?g: 113 mL [95% CI, 67-159 mL]; both P &lt; .0004). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no significant differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 ?g of tiotropium. Conclusion: The addition of once-daily tiotropium to asthma treatment, including a high-dose inhaled corticosteroid plus a long-acting ?2-agonist, significantly improves lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma. - DERWENT Abstract - This randomized, controlled study evaluated the efficacy and safety of inhaled tiotropium in 107 patients with uncontrolled severe asthma. Peak FEV1 was higher with 5 and 10 ug of tiotropium than with placebo. There was no difference between the active doses. Trough FEV1 at the end of the dosing interval was higher with tiotropium (5 ug). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 ug tiotropium. Thus, the addition of once-daily tiotropium to asthma treatment improves lung function over 24 hr in patients with inadequately controlled, severe, persistent asthma.
  • Author:
    Reck M; Kaiser R; Eschbach C; Stefanic M; Love J; Gatzemeier U; Stopfer P; von Pawel J
    Title:
    A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer.
    Source:
    Ann Oncol 22 (6), 1374-1381 (2011)
    Abstract:
    Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Methods: Patients with locally advanced or metastatic relapsed NSCLC in whom first- or second-line platinumbased chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. Results: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. Conclusion: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration. - DERWENT ABstract - This phase II double-blind, randomized study assessed the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in 73 patients with locally advanced or metastatic relapsed NSCLC whom failed 1st- or 2nd-line platinum-based chemotherapy. Median PFS was 6.9 wk. Median overall survival (OS) was 21.9 wk. Eastern Cooperative Oncology Group (ECOG) 0-1 patients had a median PFS of 11.6 wk, and a median OS of 37.7 wk. Tumor stabilization was achieved in 46% of patients with 1 confirmed PR. Most commonly reported drug-related adverse events were nausea, diarrhea, vomiting, anorexia, abdominal pain, and reversible ALT and AST elevations. Continuous treatment with BIBF 1120 is well tolerated, with no difference in efficacy between treatment arms, PFS and objective response with single-agent treatment in advanced disease warrants further exploration. Methods 73 Patients with locally advanced or metastatic relapsed NSCLC whom failed 1st- or 2nd-line platinum-based chemotherapy were randomized to receive BIBF 1120 at 250 mg b.i.d. (n = 36, 26 male, mean age 62.7 yr) or 150 mg b.i.d. (n = 37, 18 male, mean age 62.4 yr). Results Median PFS for all patients was 6.9 wk. Median OS for all patients was 21.9 wk. PFS was longer in patients with baseline ECOG 0-1 than in those with ECOG 2. Patients with ECOG 0-1 had a median OS of 37.7 wk. Tumor stabilization was achieved in 46% of all patients and 59% in patients with ECOG 0-1. 1 Confirmed PR was observed in patients treated with BIBF 1120 at 250 mg. 4 Patients achieved a maximum decrease of at least 25% in tumor size. Among patients with ECOG 0-1, both doses (150 and 250 mg) of BIBF 1120 had comparable efficacy with 16 and 17 patients in BIBF 1120 at 150 mg and 200 mg experiencing clinical benefit. Adverse events were nausea, diarrhea, vomiting, anorexia, abdominal pain, ALT and AST elevations, dyspnea, hemoptysis, pulmonary bleeding, gamma glutamyl transferase elevation, elevated hepatic enzymes, increased bilirubin, hemorrhage, fatigue, weight decrease, constipation, dysgeusia, and peripheral sensory neuropathy. Within the BIBF 1120 at 150 mg b.i.d. dose group, BIBF 1120 plasma levels increased, with geometric mean BIBF 1120 values of 12.3, 13.2, and 18.2 ng/ml at 1, 2 and 3 hr after drug administration. Within the BIBF 1120 at 150 mg b.i.d. dose group, BIBF 1120 plasma levels increased within the 1st 3 hr after the 1st drug administration, with geometric mean BIBF 1120 values of 18.4, 28.1, 27.8 ng/ml at 1, 2 and 3 hr after drug administration.
  • Author:
    Walter-Kroker A; Kroker A; Mattiucci-Guehlke M; Glaab Th
    Title:
    A practical guide to bioelectrical impedance analysis using the example of chronic obstructive pulmonary disease.
    Source:
    Nutr J 10, 35 (2011)
    Abstract:
    Bioelectrical impedance analysis (BIA) is a simple, inexpensive, quick and non-invasive technique for measuring body composition. The clinical benefit of BIA can be further enhanced by combining it with bioelectrical impedance vector analysis (BIVA). However, there is a substantial lack of information on the practical aspects of BIA/BIVA for those primarily interested in learning how to use and interpret this method in practice. The purpose of this article is to provide some guidance on the use of BIA/BIVA with special attention to practical considerations.This report reflects the authors' practical experience with the use of single-frequency BIA in combination with BIVA, particularly in COPD patients. First, the method and principles of BIA/BIVA are briefly described. Then, a practice-oriented approach to the interpretation and analysis of characteristic examples of altered nutritional and fluid status as seen with BIA/BIVA in COPD patients (e.g. malnutrition in obese and underweight patients with COPD, water retention) is presented.As our examples show BIA/BIVA is an attractive and easy-to-learn tool for quick nutritional assessment and is therefore of great clinical benefit in daily practice.
  • Author:
    Frith P; Crockett A; Beilby J; Marshall D; Attewell R; Ratnanesan A; Gavagna G
    Title:
    Simplified COPD screening: validation of the PiKo-6 in primary care.
    Source:
    Prim Care Respir J 20 (2), 190-198 (2011)
    Abstract:
    AIMS: To determine the accuracy of the forced expiratory volume ratio at one and six seconds (FEV1/FEV6) using a hand-held, expiratory flow meter (PiKo-6®, nSpire Health, Inc.) to screen for chronic obstructive pulmonary disease (COPD) in primary care settings. METHODS: Current and former smokers (> 50 years old) with no previous respiratory diagnosis (case finding [CF] = 204 subjects) or with an asthma diagnosis (differential diagnosis [DD] = 93 subjects) were evaluated using validated questionnaires, pre-bronchodilator (BD) FEV1/FEV6 and post-BD FEV1/forced vital capacity (FVC) spirometry. RESULTS: The PiKo-6® FEV1/FEV6 showed good sensitivity and specificity (areas under the Receiver Operating Characteristic curves [95% confidence intervals]: CF = 0.85 [0.79, 0.90]; DD = 0.88 [0.80, 0.96]) and exceeded the accuracy of the questionnaires. An FEV1/FEV6 cutoff < 0.75 provided optimal sensitivity (CF = 81%; DD = 86%) and specificity (CF = 71%; DD = 67%) for COPD screening. CONCLUSIONS: The PiKo-6® allows simple and reliable screening for COPD which could optimise early referral for spirometry and early, targeted interventions for COPD.
  • Author:
    de Miguel-Diez J; Carrasco-Garrido P; Rejas-Gutierrez J; Martin-Centeno A; Gobartt-Vazquez E; Hernandez-Barrera V; Gil de Miguel A; Jimenez-Garcia R
    Title:
    Inappropriate overuse of inhaled corticosteroids for COPD patients: impact on health costs and health status.
    Source:
    Lung 189 (3), 199-206 (2011)
    Abstract:
    The aim of this study was to evaluate the relationship between inappropriate overuse of inhaled corticosteroids and self-reported health status and the annual cost of patients with stable chronic obstructive pulmonary disease (COPD) recruited in the primary-care setting. An observational, crossover, descriptive study was conducted. Patients with stable COPD and aged ?40 years, evaluated in primary care, were included. Data collected were demographic variables, clinical characteristics, self-reported health status (SF-12), the severity of the illness, treatment, and health-care resource utilization in the past year. The patients were recruited during a period of 3 months (from January 1 to March 31, 2003). Use was considered inappropriate when corticosteroids were prescribed by physicians for patients not meeting criteria for its use as recommended in guidelines. A total of 10,711 patients [75.6% males; mean age = 67.1 (SD = 9.66) years] were evaluated. Disease severity was mild in 35.5% of the cases, moderate in 53.4%, and severe in 11.2%. Among them, 3,697 (34.5%) subjects were prescribed inhaled corticosteroids or drug combinations containing such therapies, with a rate of inappropriate use of 18.2%. Physical health status was significantly lower among patients showing inappropriate corticosteroids use: 37.35 (SD = 9.53) vs. 40.7 (SD = 9.80) (p < 0.05). The annual cost per patient of COPD management was significantly higher in the group with inappropriate inhaled corticosteroids use: €1,590 (SD = 1,834) vs. €1,157 (SD = 1,536) (p < 0.05). Factors statistically associated with inappropriate use of corticosteroids were educational attainment [OR: 2.77 (95% CI: 1.36-5.63) for nonuniversity training], a history of heart disease [OR: 1.42 (95% CI: 1.02-1.97)], depression [OR: 1.47 (95% CI: 1.05-2.05)], any allergy [OR 1.69 (95% CI: 1.13-2.54)], and physical health status [OR 0.97 (95% CI: 0.96-0.98)]. Lack of adherence to the recommended criteria for using inhaled corticosteroids therapy in the management of COPD patients was associated with lower self-reported health status and higher costs. Factors statistically associated with inappropriate use of corticosteroids were educational attainment, a history of heart disease, depression, any allergy, and physical health status.
  • Author:
    Kocks JWH; Asijee GM; Tsiligianni IG; Kerstjens HA; van der Molen T
    Title:
    Functional status measurement in COPD: a review of available methods and their feasibility in primary care.
    Source:
    Prim Care Respir J 20 (3), 269-275 (2011)
    Abstract:
    AIM: Guidelines advocate that improvement in functional status should be a major goal in COPD treatment. Many tools are available to assess aspects of functional status. This review aims to categorise systematically the available tools based on their construct (i.e. what the tool intends to measure) and to rate the tools for use in the primary care setting. METHODS: PubMed was searched with the keywords 'functional status' or 'physical capacity' or 'functional capacity' and 'COPD'. All tools were categorised and rated on their measurement properties, feasibility, and usage in primary care COPD patients. The tools were divided into four constructs - functional capacity, functional performance, functional reserve, and capacity utilisation - and used the following modes of measurement: laboratory tests; semi-laboratory tests; field tests; and patient-reported outcomes. RESULTS: The PubMed search resulted in 364 articles. Thirty-two tools were identified and rated. CONCLUSIONS: In primary care, the 6-minute walking distance test is the most reliable semi-laboratory functional capacity test, but is not very practical. The pedometer is the best functional performance field test. The Medical Research Council (MRC) dyspnoea questionnaire and the functional status domain of the Clinical COPD Questionnaire (CCQ) are the best patient-reported outcome tools to assess functional performance.
  • Author:
    Decramer M; Molenberghs G; Liu D; Celli B; Kesten S; Lystig T; Tashkin DP
    Title:
    Premature discontinuation during the UPLIFT study.
    Source:
    Respir Med 105 (10), 1523-1530 (2011)
    Abstract:
    Rationale: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available. Objective: To obtain better insight into the phenomenon of premature discontinuation. Methods: We analyzed the pattern of discontinuation in the UPLIFT-trial. Measurements and main results: Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p &lt; 0.001). Patients discontinuing were characterized by more severe COPD (p &lt; 0.0001), greater number of pack years (p &lt; 0.002), smaller pre-bronchodilator and post-bronchodilator FEV1 (p &lt; 0.0001 for both), and worse SGRQ scores (p &lt; 0.0001). Rates of decline of FEV1 and SGRQ were greater in non-completers (p &lt; 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV1, male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related. Conclusion: Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials.
  • Author:
    Bogatkevich GS; Ludwicka-Bradley A; Nietert PJ; Akter T; Silver RM; van Ryn J
    Title:
    Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstital lung disease.
    Source:
    Arthritis Rheum 63 (5), 1416-1425 (2011)
    Abstract:
    Objective: Activation of the coagulation cascade leading to generation of thrombin has been documented extensively in various forms of lung injury, including that associated with systemic sclerosis. We previously demonstrated that the direct thrombin inhibitor dabigatran inhibits thrombin-induced profibrotic signaling in lung fibroblasts. This study was undertaken to test whether dabigatran etexilate attenuates lung injury in a murine model of interstitial lung disease. Methods: Lung injury was induced in female C57BL/6 mice by a single intratracheal instillation of bleomycin. Dabigatran etexilate was given as supplemented chow beginning on day 1 of bleomycin instillation (early treatment, study of antiinflammatory effect) or on day 8 following bleomycin instillation (late treatment, study of antifibrotic effect). Mice were killed 2 weeks or 3 weeks after bleomycin instillation, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were investigated. Results: Both early treatment and late treatment with dabigatran etexilate attenuated the development of bleomycin-induced pulmonary fibrosis. Dabigatran etexilate significantly reduced thrombin activity and levels of transforming growth factor .beta.1 in BAL fluid, while simultaneously reducing the number of inflammatory cells and protein concentrations. Histologically evident lung inflammation and fibrosis were significantly decreased in dabigatran etexilate-treated mice. Additionally, dabigatran etexilate reduced collagen, connective tissue growth factor, and .alpha.-smooth muscle actin expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins. Conclusion: Inhibition of thrombin using the oral direct thrombin inhibitor dabigatran etexilate has marked antiinflammatory and antifibrotic effects in a bleomycin model of pulmonary fibrosis. Our data provide preclinical information about the feasibility and efficacy of dabigatran etexilate as a new therapeutic approach for the treatment of interstitial lung disease. - DERWENT Abstract - This study tested whether p.o. dabigatran etexilate (DBG, Boehr.Ingelheim) attenuates lung injury in mice with intratracheal bleomycin (BLE)-induced pulmonary fibrosis, a model of interstitial lung disease (ILD). Both early treatment and late treatment with DBG attenuated the development of BLE-induced pulmonary fibrosis. DBG reduced thrombin activity and levels of transforming growth factor (TGF)beta1 in BAL fluid, while simultaneously reducing the number of inflammatory cells and protein concentrations. DBG reduced histologically evident lung inflammation and fibrosis. DBG reduced collagen, connective tissue growth factor (CTGF), and alpha-smooth muscle actin (SMA) expression in BLE-treated mice. Data provide preclinical information about the feasibility and efficacy of DBG as a new therapeutic approach for the treatment of ILD. Methods Lung injury was induced in female C57BL/6 mice (6-8-wk-old, 19-21 g) by a single intratracheal instillation of BLE (0.045 U/mouse). DBG (10 mg/g) was given as supplemented chow beginning on day 1 of BLE instillation (early treatment, study of antiinflammatory effect) or on day 8 following BLE instillation (late treatment, study of antifibrotic effect). Results In contrast to control mice, fewer cellular infiltrates, decreased thickness of alveolar septa, and reduced accumulation of ECM proteins were noted in DBG-treated mice. The beneficial effects of DBG on BLE-induced pulmonary fibrosis were observed not only in mice receiving DBG beginning on the same day as BLE, but also in mice that received DBG beginning on day 8 after BLE treatment. DBG reduced collagen content in BLE-treated mice by 53% when administration began on day 1 and by 37.6% when administration began on day 8. DBG reduced hydroxyproline levels in BLE-treated mice by 63.9% and 38.9% when administered beginning on day 1 and on day 8, respectively. DBG increased the percentage of macrophages and decreased the percentage of neutrophils in BAL fluid in BLE-treated mice. Total protein was reduced by DBG. DBG reduced the level of active thrombin in BAL fluid. DBG increased clotting time and decreased TGF-beta1 levels in BAL fluid and lung tissue. DBG reduced the levels of phosphorylated Smad3 and CTGF and alpha-SMA expression in BLE-treated mice. DBG reduced alpha-SMA expression and organization in lung fibroblasts. Lung fibroblasts isolated from DBG-treated mice exhibited less contractile activity compared with BLE alone-treated mice.
  • Author:
    Casarosa P; Kollak I; Kiechle T; Ostermann A; Schnapp A; Kiesling R; Pieper M; Sieger P; Gantner F
    Title:
    Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol.
    Source:
    J Pharmacol Exp Ther 337 (3), 600-609 (2011)
    Abstract:
    .beta.(2)-Adrenoceptor (.beta.(2)-AR) agonists are powerful bronchodilators and play a pivotal role in the management of pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease. Although these agents first were used many years ago, progress in drug development has resulted in better tolerated, long-acting .beta.(2)-AR agonists (LABAs), such as formoterol and salmeterol. Although LABAs have been on the market for several years, relatively little is known on the rationale(s) behind their long duration of action. In this study, we focused on olodaterol (previously known as BI1744CL), a novel inhaled LABA, which provides a bronchodilating effect lasting 24 h and is currently in Phase III clinical trials. To understand the rationale behind its long duration of action, different aspects of olodaterol were analyzed (i.e., its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the .beta.(2)-AR). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [(3)H]olodaterol/.beta.(2)-AR complex with a dissociation half-life of 17.8 h due to ternary complex formation. The tight binding of olodaterol to the human .beta.(2)-AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity after extensive washout. Taken together, binding, kinetic, and functional data support the existence of a stable complex with the .beta.(2)-AR that, with a dissociation half-life >17 h, might indeed be a rationale for the 24-h duration of action of olodaterol. - DERWENT Abstract - Although long-acting beta2-adrenoceptor (AR)-agonists (LABA) are successfully present on the market since several years, still relatively little is known on the rationale(s) behind their long duration of action. This paper presented the functional and biochemical rationales for the 24-hr long duration of action of olodaterol (BI-1744-CL). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. The tight binding of olodaterol to the hbeta2-AR and stabilization of the ternary complex were confirmed. To understand the rationale behind olodaterol's long duration of action, different aspects of olodaterol were analyzed, i.e. its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the beta2-AR. A pKa of 9.3 was obtained for the protonation of the secondary amine moiety, whereas a pKa of 10.1 reflected the deprotonation of the phenolic function. In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [3H]-olodaterol/beta2AR complex with a dissociation half life of 17.8 hr, due to the ternary complex formation. The tight binding of olodaterol to the hbeta2-AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity following extensive wash-out. After washout at the human beta1-AR, the concentration-response curve of isoprenaline was shifted markedly to the right compared with the control curves.
  • Author:
    Barbara C; Moita J; Cardoso J; Costa R; Redondeiro R; Gaspar M
    Title:
    The importrance of dyspnoea in the diagnosis of chronic obstructive pulmonary disease - a descriptive analysis of a stable cohort in Portugal (SAFE Trial).
    Source:
    Rev Port Pneumol 17 (3), 131-138 (2011)
    Abstract:
    Introduction: The aim of this study was to determine patient-perceived characteristics of Chronic Obstructive Pulmonary Disease (COPD) in patients participating in a large trial evaluating tiotropium bromide. Patients and methods: Baseline symptoms were assessed by means of a standardized questionnaire. Patients reported symptoms that led to diagnosis as well as their current most troublesome symptom. Results: Data were obtained from 298 patients, mostly male (95%), with mean (standard deviation) baseline forced expiratory volume in 1 second of 1.1 (0.4) L (40.6 [13.3] % of predicted), mean disease duration of 14.4 (10.1) years and smoking history of 55.1 (25.3) pack-years. Dyspnoea was the most frequently reported symptom leading to COPD diagnosis (55.0% of patients), followed by cough (33.2%). Dyspnoea was also the current most troublesome symptom (82.6%), followed by cough (8.4%). The presence of dyspnoea or cough was independent of COPD severity. The most commonly reported co-morbidities were cardiovascular disorders (49% of patients), gastrointestinal disorders (20%) and metabolic disorders (16%), mainly diabetes mellitus. Conclusions: This analysis confirms the importance of dyspnoea as the most common symptom leading to initial COPD diagnosis and the symptom most troublesome to patients. Co-morbidities are common among COPD patients, and hence spirometric testing is appropriate in a patient who presents with dyspnoea associated with such a condition.
  • Author:
    Takada Y; Gresh L; Bozec A; Ikeda E; Kamiya K; Watanabe M; Kobayashi K; Asano K; Toyama Y; Wagner EF; Matsuo K
    Title:
    Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1.
    Source:
    Oncogene 30 (36), 3821-3832 (2011)
    Abstract:
    The role of the AP-1 transcription factor Fra-1 (encoded by Fosl1) in inflammatory responses associated with lung disease is largely unknown. Here, we show that Fra-1 overexpression in mice reduced proinflammatory cytokine production in response to injection of lipopolysaccharide (LPS), a Toll-like receptor (TLR)-ligand. Unexpectedly, Fra-1 transgenic mice died rapidly following LPS treatment, showing severe interstitial lung disease and displaying massive accumulation of macrophages and overproduction of several chemokines, including macrophage chemoattractant protein-1 (MCP-1, encoded by Ccl2). To assess the clinical relevance of Fra-1 in lung pathology, mice were treated with the anticancer drug gefitinib (Iressa), which can lead to interstitial lung disease in patients. Gefitinib-treated mice showed increased Fosl1 and Ccl2 expression and developed interstitial lung disease in response to LPS, endogenous TLR ligands and chemotherapy. Moreover, deletion of Fra-1 or blocking MCP-1 receptor signaling in mice attenuated gefitinib-enhanced lethality in response to LPS. Importantly, human alveolar macrophages showed enhanced LPS-induced FOSL1 and CCL2 expression after gefitinib treatment. These results indicate that Fra-1 is an important mediator of interstitial lung disease following gefitinib treatment.
  • Author:
    Cao Z; Zou KH; Baker CL; Su J; Paulose-Ram R; Durden E; Shi N; Shah N
    Title:
    Respiratory-related medical expenditure and inpatient utilisation among COPD patients receiving long-acting bronchodilator therapy.
    Source:
    J Med Econ 14 (2), 147-158 (2011)
    Abstract:
    Objective: To evaluate chronic obstructive pulmonary disease (COPD)-related expenditure and hospitalisation in COPD patients treated with tiotropium versus alternative long-acting bronchodilators (LABDs). Methods: Data were from the Thomson Reuters MarketScan Research Databases. COPD patients â‰135 years with at least one LABD claim between July 1, 2004 and June 30, 2006 were classified into five cohorts based on index LABD: monotherapy with tiotropium, salmeterol/fluticasone propionate, formoterol fumarate, or salmeterol or combination therapy. Demographic and clinical characteristics were evaluated for a 6-month pre-period and COPD-related utilisation and total costs were evaluated for a 12-month follow-up period. LABD relationship to COPD-related costs and hospitalisations were estimated by multivariate generalised linear modelling (GLM) and multivariate logistic regression, respectively. Results: Of 52,274 patients, 53% (n=27,457) were male, 71% (n=37,271) were ?65years, and three LABD cohorts accounted for over 90% of the sample [53% (n=27,654) salmeterol/fluticasone propionate, 23% (n=11,762) tiotropium, and 15% (n=7755) combination therapy]. Patients treated with salmeterol/fluticasone propionate (p<0.001), formoterol fumarate (p=0.032), salmeterol (p=0.004), or with combination therapy (p<0.001) had higher COPD-related costs and a greater risk of inpatient admission (p<0.01 for all) versus tiotropium. Limitations: These data are based on administrative claims and as such do not include clinical information or information on risk factors, like smoking status, that are relevant to this population. Conclusions: Patients treated with tiotropim had lower COPD-related expenditures and risk of hospitalisation than patients treated with other LABDs.
  • Author:
    Goossens LMA; Nivens MC; Sachs P; Monz BU; Rutten-van Moelken MPMH
    Title:
    Is the EQ-5D responsive to recovery from a moderate COPD exacerbation?
    Source:
    Respir Med 105 (8), 1195-1202 (2011)
    Abstract:
    Background: To correctly estimate the cost-effectiveness of treatments that reduce COPD exacerbations, the utility gains from preventing exacerbations need to be measured. This requires utility measurement during exacerbations. Aim: To assess the ability of the EQ-5D to detect the recovery from moderate COPD exacerbations. Methods: In the US, 65 COPD and/or chronic bronchitis patients (?40 years old smokers or ex-smokers with a history of 10 pack-years) were enrolled within 48 h of symptom onset of the exacerbation. Patients completed the EQ-5D at enrollment and after 7, 14 and 42 days. Symptoms and medication use were recorded in diaries. Change over time and loss of quality-adjusted life years (QALYs) due to the exacerbation was estimated. Using standardized response mean (SRM) as the metric of responsiveness, we compared the responsiveness of the EQ-5D to the responsiveness of morning peak expiratory flow rate, rescue medication use and symptom scores. SRMs were also used to assess whether patients with greater improvements in peak expiratory flow rate, rescue medication use, symptom scores, clinician global impression of change, and patient global impression of change had a greater improvement in EQ-5D than patients with smaller improvement. Results: Mean utility index scores (standard deviation) using the US value set were 0.683 (0.209), 0.726 (0.216), 0.768 (0.169) and 0.760 (0.181) at days 1, 7, 14 and 42, respectively. The mean of each patient's lowest index score, either at visit 1 or visit 2, was 0.651 (0.213). Over the course of 6 weeks there was a highly significant improvement in mean utility. The greatest improvement was seen between day 7 and day 14. Patients lost on average 0.00896 QALY (0.0086) or 3.27 (3.13) quality-adjusted life days during the exacerbation. The EQ-5D (SRM: 0.653) was more responsive to change than peak expiratory flow (0.269), rescue medication use (0.343) and sputum symptom scores (0.322) and equally responsive as cough (0.587) and dyspnea (0.638) symptom scores. Conclusion: The EQ-5D is responsive to the recovery from a moderate COPD exacerbation.
  • Author:
    Fabbri LM; Vogelmeier C; Hederer B; Glaab Th; Schmidt H; Beeh KM; van-Rutten Molken MPMH; Rabe KF
    Title:
    Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
    Source:
    N Engl J Med 364 (12), 1093-1103 (2011)
    Abstract:
    BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-tovery- severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a beta(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the beta(2)-agonist salmeterol in preventing exacerbations of COPD. METHODS In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 mu g of tiotropium once daily with that of 50 mu g of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. RESULTS A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P = 0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. CONCLUSIONS These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. - DERWENT Abstract - This randomized, double-blind, double-dummy, parallel-group study (NCT00563381) compared the effects of tiotropium (Spiriva, Boehr.Ingelheim) vs. salmeterol (Serevent, GlaxoSmithKline) on incidence of exacerbations in 7376 patients with moderate-to-severe COPD. Tiotropium (18 ug/day), as compared with salmeterol (50 ug b.i.d.), increased the time to the 1st exacerbation, with a 17% reduction in risk. Tiotropium also increased the time to the 1st severe exacerbation, reduced the annual number of moderate or severe exacerbations, and reduced the annual number of severe exacerbations. Overall, the incidence of serious adverse events (AE) and of AE leading to the discontinuation of treatment was similar in the 2 study groups. There were 64 deaths in the tiotropium group and 78 in the salmeterol group. Thus, tiotropium is more effective than salmeterol in preventing exacerbations.
  • Author:
    Song X; Varker H; Eichelbaum M; Stopfer P; Shahidi M; Wilson K; Kaiser R; Finnern HW
    Title:
    Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome p450 isoenzymes.
    Source:
    Lung Cancer (Neth) 74 (1), 103-111 (2011)
    Abstract:
    Objective: The majority of anticancer medicines used in the therapy of lung cancer patients are metabolized by cytochrome P450 (CYP450) enzymes, but little is known about the frequency of prescribed concomitant medicines interacting via the same enzyme system. This study analyzed the use of medications that could cause drug-drug interactions (inhibition or induction) in lung cancer patients before and during anticancer treatment. Research design and methods: In this retrospective cross sectional study, all lung cancer patients (ICD-9 codes 162.2-162.9, 231.2) aged ?18 years who received any anticancer medicines between 1/1/2004 and 6/30/2008 were identified in the US Thomson Reuters MarketScan® Claims Database. Patients had to have data for at least 12 months prior to (pre-period) and during their treatment, had no other cancer or use of other anticancer treatment in the pre-period. Patients with renal disease, renal failure, or liver failure were excluded. Drugs known to induce or inhibit P450 enzymes and used before and during lung cancer treatment were categorized with respect to their potency (strong, moderate, low). Results: Out of 144,959 lung cancer patients, 6647 (4.6%) patients met the study entry criteria. Mean age was 67 years, 53% were men, and mean Charlson combordity index was 3.5. 99% of patients received at least one drug known as a substrate, inhibitor or inducer of P450 (98% inhibitors, 93% inducers, 98% substrates) during the patient's anticancer treatment episode. Mean co-treatment duration with any CYP450 agent was 99 days (76% of the episode length); ?2 different CYP450 agents were prescribed during 98% of episodes, and ?10 different CYP450 agents were prescribed during 44% of episodes. Use of CYP450 agents was similar in the pre-treatment period: at least one CYP450 agent was prescribed during 99% of episodes (99% inhibitors, 79% inducers, 98% substrates). Conclusions: Drugs which may cause drug-drug interactions while affecting the CYP 450 enzymes are frequently prescribed both before and during anticancer treatment of lung cancer patients.
  • Author:
    Sally L
    Title:
    Introduction - Examples of chronic care models.
    Source:
    Chronic Respir Dis 8 (1), 41 (2011)
  • Author:
    Hanania NA; Sharafkhaneh A; Celli B; Decramer M; Lystig T; Kesten S; Tashkin D
    Title:
    Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial - art. no. 6
    Source:
    Respir Res 12, 6 (2011)
    Abstract:
    Background: Debate continues as to whether acute bronchodilator responsiveness (BDR) predicts long-term outcomes in COPD. Furthermore, there is no consensus on a threshold for BDR. Methods: At baseline and during the 4-year Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT (R)) trial, patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg. Patients were split according to three BDR thresholds: >= 12% + >= 200 mL above baseline (criterion A), >= 15% above baseline (criterion B); and >= 10% absolute increase in percent predicted FEV1 values (criterion C). Several outcomes (pre-dose spirometry, exacerbations, St. George's Respiratory Questionnaire [SGRQ] total score) were assessed according to presence or absence of BDR in the treatment groups. Results: 5783 of 5993 randomized patients had evaluable pre- and post-bronchodilator spirometry at baseline. Mean age (SD) was 64 (8) years, with 75% men, mean post-bronchodilator FEV1 1.33 +/- 0.44 L (47.6 +/- 12.7% predicted) and 30% current smokers. At baseline, 52%, 66%, and 39% of patients had acute BDR using criterion A, B, and C, respectively. The presence of BDR was variable at follow-up visits. Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used. Conclusions: A large proportion of COPD patients demonstrate significant acute BDR. BDR in these patients is variable over time and differs according to the criterion used. BDR status at baseline does not predict long-term response to tiotropium. Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD.
  • Author:
    Fernandez L; Kesten St; Liu D; Decramer M; Tashkin D; Celli B; Fukuchi Y
    Title:
    Efficacy of tiotropium in COPD patients from ASIA: A subgroup analysis from the UPLIFT trial.
    Source:
    Respirology 16 (5), 825-835 (2011)
    Abstract:
    This subgroup analysis of a 4-yr, placebo-controlled study (Uplift) evaluated the efficacy of tiotropium (TIO) in 362 COPD patients. In TIO treated patients, discontinuations were less when compared to the placebo group. Pre-bronch forced expiratory volume in 1 sec (lung airflow measure; FEV1) increased at all timepoints. Higher annual FEV1 decline was observed in TIO treated patients when compared to the placebo group. Thus, in COPD patients, tiotropium improves lung function, improves health-related quality of life, and reduces exacerbations over 4 yr of treatment. Methods 362 COPD patients (median age 66 yr; males 95%) were randomized to receive TIO (n=184) or placebo (n=178). The outcomes evaluated were the rate of FEV1 decline, changes in FEV1 and forced vital capacity (lung function test; FVC), St. Georges respiratory questionnaire (SGRQ), exacerbations, and mortality. Results Discontinuations were 38% in the TIO group and 47% in the placebo group. Annual FEV1 decline (TIO vs. placebo) were 20 vs. 18 ml/yr (pre-bronch) and 26 vs. 31 ml/yr (post-bronch). Pre-bronch FEV1 increased by 63-120 ml at all timepoints. Mean pre-bronch FEV1 over time: SGRQ total score improved by 1.5-6.1 units for mth 6, 12, 42, and 48. Number of exacerbations were reduced with TIO vs. placebo (0.68/patient-yr vs. 0.92/patient-yr). Death occurred in 34 (TIO) and 42 (placebo) patients during planned treatment (vital status to day 1440).
  • Author:
    Duechs MJ; Hahn C; Benediktus E; Werner-Klein M; Braun A; Hoymann HG; Gantner F; Erb KJ
    Title:
    TLR-agonist mediated suppression of allergic responses is associated with increased innate inflammation in the aiways.
    Source:
    Pulm Pharmacol Ther 24 (2), 203-214 (2011)
    Abstract:
    Toll-like receptor (TLR) mediated signaling induces pro-inflammatory responses and can both suppress and exacerbate allergic responses in the airways. The aim of our study was to directly compare the efficacy of different TLR agonists in inhibiting or exacerbating the development of Th2-mediated responses in the airways and investigate if the suppressive effects were associated with increased pro-inflammatory responses. Mice were immunized on day 0, 14 and 21 by intraperitoneal injection of ovalbumin/alum and exposed to ovalbumin aerosol on day 26 and 27. TLR2, TLR3, TLR4, TLR7 and TLR9 agonists (0.001, 0.01, 0.1, or 1 mg/kg) were administered intratracheally 1 h before each allergen exposure. Both the TLR7 and TLR9 agonists dose dependently reduced airway eosinophilia, while the TLR3 agonist only reduced airway eosinophilia at a dose of 1.0 mg/kg. The TLR2 and TLR4 agonists potentiated eosinophilia. All TLR agonists enhanced neutrophil numbers at doses as low as 0.01 mg/kg, in particular TLR2 and TLR4 agonists. TLR7 and TLR9 agonists also significantly reduced IL-4 and IL-5 levels and all TLR agonists, with the exception of TLR7, enhanced the amount IL-1?, IL-6, and TNF-? detected in the whole lung lavage. Only application of TLR9 agonist induced detectable levels of IL-10 in the lung. Suppressive effects of the TLR agonists were not dependent upon IFN-? and IL-10 or associated with increased numbers of Foxp3<sup>+</sup>CD4<sup>+</sup> Tr cells in the lavage fluid. Airway resistance was reduced significantly only when TLR7 agonist was administered. When applied therapeutically 2 days after allergen exposure, all TLR agonists, except TLR2, similarly reduced airway eosinophilia and IL-4 levels. Taken together our results show that TLR7 agonists had the strongest anti-asthmatic effects with the lowest pro-inflammatory potential, suggesting that activating TLR7 may have the greatest potential to treat allergic disorders in humans.
  • Author:
    Peter D; Goeggel R; Colbatzky F; Nickolaus P
    Title:
    Inhibition of cyclooxygenase-2 prevents adverse effects induced by phosphodiesterase type 4 inhibitors in rats.
    Source:
    Br J Pharmacol 162 (2), 415-427 (2011)
    Abstract:
    BACKGROUND AND PURPOSE Phosphodiesterase type 4 (PDE4) inhibitors such as roflumilast are currently being developed as anti-inflammatory treatments for chronic airway disorders. However, high doses of PDE4 inhibitors have also been linked to several side effects in different animal species, including pro-inflammatory effects in the rat. Here, we analysed PDE4-related toxicological findings in a rat model and how these side effects might be therapeutically prevented. EXPERIMENTAL APPROACH Wistar rats were treated orally once daily with 10 mg·kg<sup>-1</sup> roflumilast for 4 days. Macroscopic changes were monitored throughout the study and further parameters were analysed at the end of the experiment on day 5. In addition, the effects of concomitant treatment with cyclooxygenase (COX) inhibitors were assessed. KEY RESULTS Supratherapeutical treatment with roflumilast induced marked body and spleen weight loss, diarrhea, increased secretory activity of the harderian glands, leukocytosis, increased serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels, and histopathological changes in thymus, spleen, mesentery and mesenteric lymph nodes. All these toxicological findings could be prevented by the non-steroidal anti-inflammatory drug (NSAID) and non-selective COX inhibitor, diclofenac, given orally. Similar protective effects could be achieved by the COX-2 selective inhibitor lumiracoxib, whereas the COX-1 selective inhibitor SC-560 was generally not effective. CONCLUSIONS AND IMPLICATIONS Treatment with an NSAID inhibiting COX-2 prevents the major effects found after subchronic overdosing with the PDE4-specific inhibitor roflumilast. If this effect translates into humans, such combined treatment may increase the therapeutic window of PDE4 inhibitors, currently under clinical development.
  • Author:
    Deschl U; Vogel J; Aufderheide M
    Title:
    Development of an in vitro exposure model for investigating the biological effects of therapeutic aerosols on human cells from the respiratory tract.
    Source:
    Exp Toxicol Pathol 63 (6), 593-598 (2011)
    Abstract:
    Respiratory diseases like asthma or COPD are gaining more and more importance worldwide due to an increased exposure of humans to inhalable compounds such as cigarette smoke, diesel exhaust or other forms of environmental pollution. Therefore, a high impact on national health systems is expected, meaning long-term treatment, with periodic examinations accompanied by high costs. Although a number of efficient drugs for these disease patterns, like Tiotropium (antimuscarinic), Salmetron (ß-antagonist) or corticosteroids, are already available, a great deal of effort has to be put into the development of new drugs and therapy concepts. In this context, in vitro methods may be useful to establish more efficient prescreening procedures to analyze, for example, the toxicity of new compounds during the research and development process. These studies should aim to achieve a better selection of substances relevant for further development and a final reduction in the number of animal experiments. Therefore, we established an in vitro exposure device that allows the analysis of inhalable compounds for their pharmacological and toxicological effects. This CULTEX® device is composed of an exposure entity representing the in vivo respiratory air compartment and a basal feeding compartment representing the subepithelium. Both compartments are connected by porous transwells on which cells form an epithelium-like cell layer. We have used this system for exposing human lung cells directly to liquid aerosols and present the first data with regard to aerosolized model substances.
  • Author:
    Wagner J; Kneucker A; Liebler-Tenorlo E; Fachinger V; Glaser M; Pesch S; Murtaugh MP; Reinhold P
    Title:
    Respiratory function and pulmonary lesions in pigs infected with porcine reproductive and respiratory syndrome virus.
    Source:
    Vet J (Lond) 187 (3), 310-319 (2011)
    Abstract:
    Pulmonary dysfunction was evaluated in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV, isolate VR-2332) and compared to clinical and pathological findings. Infected pigs developed fever, reduced appetite, respiratory distress and dullness at 9. days post-inoculation (dpi). Non-invasive pulmonary function tests using impulse oscillometry and rebreathing of test gases (He, CO) revealed peripheral airway obstruction, reduced lung compliance and reduced lung CO-transfer factor. PRRSV-induced pulmonary dysfunction was most marked at 9-18 dpi and was accompanied by a significantly increased respiratory rate and decreased tidal volume. Expiration was affected more than inspiration. On histopathological examination, multifocal areas of interstitial pneumonia (more severe and extensive at 10 dpi than 21 dpi) were identified as a possible structural basis for reduced lung compliance and gas exchange disturbances.
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