Werte schaffen durch Innovation

Main navigation

jump to content jump to meta navigation

Page content

jump to main navigation jump to meta navigation

Wissenschaftliche Publikationen

Boehringer Ingelheim bietet auf den folgenden Seiten eine Übersicht der wissenschaftlichen Publikationen der letzten drei Jahre, an denen Mitarbeiter des Unternehmens weltweit beteiligt waren.

Thema auswählen

87 Veröffentlichungen zu Atemwegserkrankungen
  • Autor(en):
    Sattah MV; Aye SS; Azen C; Kort JJ; Jones BE; Escalante P
    Titel:
    Interferon-gamma release assay T-SPOT.RTM..TB and HIV-related tuberculosis.
    Quelle(n):
    Int J Tuberc Lung Dis 16 (2), 281-282 (2012)
  • Autor(en):
    Schmidt M; Michel MC
    Titel:
    How can 1 + 1 = 3? .beta.2.-adrenergic and glucocorticoid receptor agonist synergism in obstructive airway diseases.
    Quelle(n):
    Mol Pharmacol 80 (6), 955-958 (2011)
  • Autor(en):
    Tsuyusaki J; Kuroda F; Kasuya Y; Ishizaki S; Yamauchi K; Sugimoto H; Kono T; Iwamura C; Nakayama T; Tatsumi K
    Titel:
    Cigarette smoke-induced pulmonary inflammation is attenuated in CD69-deficient mice.
    Quelle(n):
    J Recept Signal Transduct 31 (6), 434-439 ( 2011)
  • Autor(en):
    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
    Titel:
    Genotyping non-small cell lung cancer (NSCLC) in latin America.
    Quelle(n):
    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.
  • Autor(en):
    Bleecker ER; Busse WW; Donohue JF; Garfinkel S; Lystig T; Manuel RC; Schlenker-Herceg R; Wise RA
    Titel:
    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.
    Quelle(n):
    J Allergy Clin Immunol 127 (2) (Supp.[S]), AB83 (2011)
  • Autor(en):
    Kesten St; Celli B; Decramer M; Liu D; Tashkin D
    Titel:
    Adverse helth consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial.
    Quelle(n):
    Respir Res 12, 129 (2011)
  • Autor(en):
    Kariyawasam S; Strait E; Jordan D; Kroll J
    Titel:
    Development of a real-time polymerase chain reaction assay for detection of actinobacillus suis in porcine lung.
    Quelle(n):
    J Vet Diagn Invest 23 (5), 885-889 (2011)
  • Autor(en):
    Miravitlles M; Llor C; Calvo E; Diaz S; Diaz-Cuervo H
    Titel:
    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.
    Quelle(n):
    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.
  • Autor(en):
    Berard E; Bongard V; Roche N; Perez T; Broquires D; Taraszkiewicz D; Fieves S; Denis F; Escamilla R; Ferries J
    Titel:
    Undiagnosed airflow limitation in patients at cardiovascular risk.
    Quelle(n):
    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.
  • Autor(en):
    Dalby RN; Eicher J; Zierenberg B
    Titel:
    Development of Respimat soft mist inhaler and its clinical utility in respiratory disorders.
    Quelle(n):
    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.
  • Autor(en):
    Onoue S; Sato H; Ogawa K; Kojo Y; Aoki Y; Kawabata Y; Wada K; Mizumoto T; Yamada S
    Titel:
    Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats.
    Quelle(n):
    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.
  • Autor(en):
    Dellweg D; Hohn E; Barchfeld Th; Kohler D; Wachtel H; Pieper MP; Glaab Th
    Titel:
    In vitro validation of a respimat.RTM. adapter for delivery of inhaled bronchodilators during mechanical ventilation.
    Quelle(n):
    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.
  • Autor(en):
    Bosnjak B; Stelzmueller B; Epstein MM; Erb K
    Titel:
    Treatment of allergic asthma: Modulation of Th2 cells and their responses.
    Quelle(n):
    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.
  • Autor(en):
    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
    Titel:
    Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.
    Quelle(n):
    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.)
  • Autor(en):
    van Noord JA; Smeets JJ; Drenth BM; Rascher J; Pivovarova A; Hamilton AL; Cornelissen PJG
    Titel:
    24-hour bronchodilation following a single dose of the novel beta2-agonist olodaterol in COPD.
    Quelle(n):
    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.
  • Autor(en):
    Deschl U; Vogel J; Aufderheide M
    Titel:
    Development of an in vitro exposure model for investigating the biological effects of therapeutic aerosols on human cells from the respiratory tract.
    Quelle(n):
    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.
  • Autor(en):
    Disse B; Metzdorf N; Bender H
    Titel:
    Tiotropium mist inhaler manufacturer's reply to letter by seed and colleagues - art. No. d5365
    Quelle(n):
    Br Med J 343 (7821), PD5365-D5365 (2011)
  • Autor(en):
    Nieves D; Isla D; Gonzalez-Rojas N; Brosa M; Finnern HW
    Titel:
    Treatment patterns, use of resources, and costs of advanced non-small-cell lung cancer patients in Spain: results from a Delphi panel.
    Quelle(n):
    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.
  • Autor(en):
    Fabbri LM; Bateman ED; Kornmann O; Schmidt P; Pivovarova A; Engel M
    Titel:
    Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma.
    Quelle(n):
    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.
  • Autor(en):
    Beaumont JL; Victorson D; Wortman K; Cella D; Su J; Shah H; Baker ChL
    Titel:
    Examining web equivalence and risk faktor sensitivity of the COPD population screener.
    Quelle(n):
    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.
  • Autor(en):
    Choi SW; Victorsen DE; Yount S; Cella D; Anton S
    Titel:
    Development of a conceptual framework and calibrated item banks to measure patient-reported dyspnea severity and related functional limitations.
    Quelle(n):
    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.
  • Autor(en):
    Yount SF; Choi SW; Victorson D; Cella D; Ruo B; Anton S; Hamilton A
    Titel:
    Brief, valid measures of dyspnea and related functional limitations in chronic obstructive pulmonary disease (COPD).
    Quelle(n):
    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.
  • Autor(en):
    Breitenbuecher F; Hoffarth S; Gauler ThC; Stergar SL; Kasper St; Koehler J; Schuler M; Worm K; Schmid KW; Maerten A
    Titel:
    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.
    Quelle(n):
    J Thorac Oncol 6 (6) (Supp.(S)), S956-S957 ( 2011)
  • Autor(en):
    Vogelmeier C; Glaab T; Fabbri LM
    Titel:
    Tiotropium versus Salmeterol in COPD REPLY. The authors reply.
    Quelle(n):
    N Engl J Med 364 (26), 2553-2554 (2011)
  • Autor(en):
    Halpin DMG; Decramer M; Celli B; Kesten S; Leimer I; Tashkin DP
    Titel:
    Risk of nonlower respiratory serious adverse events following COPD exacerbations in the 4-year UPLIFT trial.
    Quelle(n):
    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.
  • Autor(en):
    Profita M; Bonanno A; Montalbano AM; Ferraro M; Siena L; Bruno A; Girbino S; Albano GD; Casarosa P; Pieper MP; Gjomarkaj M
    Titel:
    Cigarette smoke extract activates human bronchial epithelial cells affecting non-neuronal cholinergic system signaling in vitro.
    Quelle(n):
    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.
  • Autor(en):
    Kerstjens HAM; Disse B; Schroeder-Babo W; Bantje TA; Gahlemann M; Sigmund R; Engel M; van Noord JA
    Titel:
    Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial.
    Quelle(n):
    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.
  • Autor(en):
    Reck M; Kaiser R; Eschbach C; Stefanic M; Love J; Gatzemeier U; Stopfer P; von Pawel J
    Titel:
    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.
    Quelle(n):
    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.
  • Autor(en):
    Walter-Kroker A; Kroker A; Mattiucci-Guehlke M; Glaab Th
    Titel:
    A practical guide to bioelectrical impedance analysis using the example of chronic obstructive pulmonary disease.
    Quelle(n):
    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.
  • Autor(en):
    Frith P; Crockett A; Beilby J; Marshall D; Attewell R; Ratnanesan A; Gavagna G
    Titel:
    Simplified COPD screening: validation of the PiKo-6 in primary care.
    Quelle(n):
    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.
  • Autor(en):
    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
    Titel:
    Inappropriate overuse of inhaled corticosteroids for COPD patients: impact on health costs and health status.
    Quelle(n):
    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.
  • Autor(en):
    Kocks JWH; Asijee GM; Tsiligianni IG; Kerstjens HA; van der Molen T
    Titel:
    Functional status measurement in COPD: a review of available methods and their feasibility in primary care.
    Quelle(n):
    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.
  • Autor(en):
    Decramer M; Molenberghs G; Liu D; Celli B; Kesten S; Lystig T; Tashkin DP
    Titel:
    Premature discontinuation during the UPLIFT study.
    Quelle(n):
    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.
  • Autor(en):
    Bogatkevich GS; Ludwicka-Bradley A; Nietert PJ; Akter T; Silver RM; van Ryn J
    Titel:
    Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstital lung disease.
    Quelle(n):
    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.
  • Autor(en):
    Casarosa P; Kollak I; Kiechle T; Ostermann A; Schnapp A; Kiesling R; Pieper M; Sieger P; Gantner F
    Titel:
    Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol.
    Quelle(n):
    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.
  • Autor(en):
    Barbara C; Moita J; Cardoso J; Costa R; Redondeiro R; Gaspar M
    Titel:
    The importrance of dyspnoea in the diagnosis of chronic obstructive pulmonary disease - a descriptive analysis of a stable cohort in Portugal (SAFE Trial).
    Quelle(n):
    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.
  • Autor(en):
    Takada Y; Gresh L; Bozec A; Ikeda E; Kamiya K; Watanabe M; Kobayashi K; Asano K; Toyama Y; Wagner EF; Matsuo K
    Titel:
    Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1.
    Quelle(n):
    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.
  • Autor(en):
    Cao Z; Zou KH; Baker CL; Su J; Paulose-Ram R; Durden E; Shi N; Shah N
    Titel:
    Respiratory-related medical expenditure and inpatient utilisation among COPD patients receiving long-acting bronchodilator therapy.
    Quelle(n):
    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.
  • Autor(en):
    Goossens LMA; Nivens MC; Sachs P; Monz BU; Rutten-van Moelken MPMH
    Titel:
    Is the EQ-5D responsive to recovery from a moderate COPD exacerbation?
    Quelle(n):
    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.
  • Autor(en):
    Fabbri LM; Vogelmeier C; Hederer B; Glaab Th; Schmidt H; Beeh KM; van-Rutten Molken MPMH; Rabe KF
    Titel:
    Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
    Quelle(n):
    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.
  • Autor(en):
    Song X; Varker H; Eichelbaum M; Stopfer P; Shahidi M; Wilson K; Kaiser R; Finnern HW
    Titel:
    Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome p450 isoenzymes.
    Quelle(n):
    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.
  • Autor(en):
    Yang C; Su W; Hsia T; Sequist LV; Chang G; Calvo R; Cong XJ; Shahidi M; Miller V; Shih J
    Titel:
    A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR/HER1 mutations (LUX-Lung 2).
    Quelle(n):
    35th European Society for Medical Oncology, ESMO Congress, Milan (Italy), Oct 8-12,2010Ann Oncol 21 (Supp.[8]), 123 (2010)
    Abstract:
    This phase-II study evaluated the safety and efficacy of BIBW-2992 in the treatment of 461 patients with a stage IIIB/IV or recurrent lung adenocarcinoma and EGF receptor (EGFR) mutations in exons 18-21. The most common drug-related adverse events (AEs) were diarrhea and rash/acne. Administration of BIBW-2992 resulted in similarly high objective response rate (ORR), disease control rate (DCR) and PFS in NSCLC patients with either del19 or L858R mutations. Thus BIBW-2992 was effective with manageable GI and skin disorders in lung adenocarcinoma patients. Methods 461 Patients with a stage IIIB/IV or recurrent lung adenocarcinoma and EGFR mutations in exons 18-21 received BIBW-2992 (50 or 40 mg, every day) until progression. RECIST was used to assess response at 4, 8 and 12 wk and at 8-wkly intervals thereafter; images were centrally reviewed. Analysis included primary endpoint objective response rate (ORR) assessed by independent review and the secondary endpoints PFS and overall survival (OS), among others. Results 129 Patients received at least 1 dose of BIBW-2992. Among the 129 patients, the investigators reported an ORR of 67%, disease control rate (DCR) of 86%, median PFS of 14 mth and median OS of 24 mth. Comparable efficacy was observed in the first- and second-line settings. Overall, the confirmed ORR (60%) was similar to that by independent review (57%). A similar confirmed ORR, DCR, and median PFS in the 54 patients with L858R mutations was observed (59%, 83%, and 16.1 mth, respectively). and in 52 patients with del19 mutations (69%, 93%, and 13.7 mth, respectively). The most common drug-related AEs were diarrhea and rash/acne in 95% and 91% of patients, respectively, with common terminology criteria for adverse events (CTCAE) grade of 3 in 19% and 21% of patients, respectively.
  • Autor(en):
    Song X; Helen V; Eichelbaum M; Kaiser R; Stopfer P; Shahidi M; Wilson K; Finnern HW
    Titel:
    Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome P450 isoenzymes.
    Quelle(n):
    Ann Oncol 21 (Supp.[8]), 134 (2010)
  • Autor(en):
    Shih J; Su W; Hsia T; Graziano SL; Calvo R; Cong XJ; Shahidi M; Miller V; Yu C; Yang C
    Titel:
    Activity of BIBW 2992, an irreversible EGFR/HER1 and HER2 TKI, in lung adenocarcinoma patients harboring less common EGFR mutations.
    Quelle(n):
    Ann Oncol 21 (Supp.[8]), 138 (2010)
  • Autor(en):
    Sally L
    Titel:
    Introduction - Examples of chronic care models.
    Quelle(n):
    Chronic Respir Dis 8 (1), 41 (2011)
  • Autor(en):
    Hanania NA; Sharafkhaneh A; Celli B; Decramer M; Lystig T; Kesten S; Tashkin D
    Titel:
    Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial - art. no. 6
    Quelle(n):
    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.
  • Autor(en):
    Fernandez L; Kesten St; Liu D; Decramer M; Tashkin D; Celli B; Fukuchi Y
    Titel:
    Efficacy of tiotropium in COPD patients from ASIA: A subgroup analysis from the UPLIFT trial.
    Quelle(n):
    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).
  • Autor(en):
    De Geer A; Eriksson J; Finnern HW
    Titel:
    A review of data collected on non-small cell lung cancer (NSCLC) patients in cancer registries, databases, retrospective and non-randomized prospective studies.
    Quelle(n):
    Ann Oncol 21 (Supp.[8]), 340 (2010)
  • Autor(en):
    Miller VA; Hirsch V; Cadranel J; Chen Y; Park K; Kim S; Lorence R; Cong J; Shaidi M; Yang C
    Titel:
    Subgroup analysis of LUX-Lung 1: A randomized phase III trial of afatinib (BIBW 2992) + best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1-2 lines of chemotherapy and erlotinib or gefitinib.
    Quelle(n):
    Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago (United States), Dec 9-11, 2010J Thorac Oncol 5 (12) (Supp.[7]), S557-S558 (2010 )
    Abstract:
    This randomized, phase III trial compared the safety and efficacy of afatinib (BIBW-2992) + best supportive care (BSC) vs. placebo + BSC in 585 patients with NSCLC failing 1-2 of chemotherapy and erlotinib or gefitinib. PFS improvement for afatinib was high. Diarrhea and rash/acne were the most common side effects of afatinib. Thus the addition of afatinib to BSC did not improve overall survival (OS) but improved PFS and was associated with a higher objective response rate (ORR) and disease control rate (DCR). Methods 585 Adenocarcinoma NSCLC patients (mean age 58 yr, 60% women and stage IIIB/IV) were randomized double-blind 2:1 to BSC + either p.o. afatinib (50 mg, every day) or placebo. The primary endpoint was OS with secondary endpoints that included PFS, ORR, and DCR. Results At primary analysis, median OS was 10.8 mth with BSC + afatinib vs. 12.0 mth with BSC + placebo. Afatinib lead to improvement in key secondary efficacy endpoints: PFS by independent review (3-fold increase in median PFS from 1.1 to 3.3 mth), confirmed DCR at 8 wk (58% vs. 19%) and confirmed ORR (11% vs. 0.5% and 7.4% vs. 0.5%). Median PFS was improved from 0.97 to 3.7 mth in the patients who had CR/PR to prior erlotinib/gefitinib. In the 214 patients with clinical benefit on prior erlotinib/gefitinib and short interval after prior erlotinib/gefitinib and randomization, PFS improvement for afatinib was as good if not better than the whole study population: Median PFS of 4.5 mth for afatinib vs. 10 mth for Diarrhea (87% all grades; 17% grade 3) and rash/acne (78% all grade; 14% grade 3) were the 2 most common side effects of afatinib and effectively managed by supportive care and dose modification.
  • Autor(en):
    Duechs MJ; Hahn C; Benediktus E; Werner-Klein M; Braun A; Hoymann HG; Gantner F; Erb KJ
    Titel:
    TLR-agonist mediated suppression of allergic responses is associated with increased innate inflammation in the aiways.
    Quelle(n):
    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.
  • Autor(en):
    van Ryn J; Bogatkevich GS; Ludwicka-Bradley A; Silver RM
    Titel:
    Inhibition of thrombin as a novel strategy in the treatment of scleroderma-associated interstitial lung disease.
    Quelle(n):
    Clin Exp Rheumatol 28 (5) (Supp.[62]), S57 ( 2010)
  • Autor(en):
    DiBonaventura M; Wagner JS; Paulose-Ram R; McDonald M; Zou KH; Su J; Shah H
    Titel:
    Quality of life, productivity loss, and resource use among employed adults aged 40 to 64 years with chronic obstructive pulmonary disease (COPD) in the United States (US) workforce.
    Quelle(n):
    Value Health 13 (7), A326 (2010)
  • Autor(en):
    Goossens LM; Rutten-van Molken MP; Baker CL; Zou KH; Monz BU
    Titel:
    Adjusting for chronic obstructive pulmonary disease (COPD) severity in database research: Feasibility of developing and validating an algorithm.
    Quelle(n):
    Value Health 13 (7), A327 (2010)
  • Autor(en):
    Kogler H; Metzdorf N; Glaab Th; Welte T
    Titel:
    Preselection of patients at risk for COPD by two simple screening questions.
    Quelle(n):
    Respir Med 104 (7), 1012-1019 (2010)
    Abstract:
    Background: The Burden of Obstructive Lung Disease study showed that in Germany, to confirm the diagnosis of chronic obstructive lung disease (COPD) in one subject, eight people =40 years of age have to be screened. The number-needed-to-screen (NNS) increased to 18 for identifying a patient with COPD = GOLD stage II. These high numbers limit the cost-effectiveness of COPD screening by population spirometry. We investigated in a primary care setting whether using two simple questions regarding smoking status and presence of cough and/or dyspnea may help to preselect patients for proper diagnosis of COPD. Methods: A total of 1088 patients aged =40 yrs without a history of chronic lung disease, who were either current or ex-smokers and complained of cough and/or dyspnea, were examined by respiratory physicians. Spirometry was carried out to confirm COPD diagnosis and severity. Results: A total of 61.6% of patients were male. Mean smoking history was 31.8 pack-yrs. In 516 patients (47.4%), a diagnosis of COPD was confirmed. Among these, 379 (34.8% of total) had at least GOLD stage II COPD, while 89 (8.2% of total) had advanced disease (GOLD stages III/IV). COPD prevalence was significantly associated with age and the extent of cigarette smoke exposure. Conclusions: Two questions regarding smoking status and presence of cough and/or dyspnea enabled general practitioners to select patients at risk for COPD for subsequent spirometry. This preselection reduced the NNS to 2.1 for identifying a COPD patient, and to 2.9 for identifying a patient of at least GOLD stage II.
  • Autor(en):
    Stepanyan IE; Khmelkova NG; Belin-Atarac B
    Titel:
    The efficacy of thiotropium bromide (Spiriva) in the treatment of patients with chronic obstructive pulmonary disease of varying severity: Results of the Russian trial.
    Quelle(n):
    Ter Arkh 82 (10), 46-51 (2010)
    Abstract:
    Aim. To evaluate the efficacy and safety of Spiriva (thiotropium bromide 18 µg for inhalation via a HandiHaler device) in patients with chronic obstructive pulmonary disease (COPD) of all severities in routine clinical practice in Russia. Subjects and methods. The study enrolled 407 patients (68 women and 339 men) with COPD who used thiotropium bromide (Spiriva) for 8 weeks. Most (72.3%) of the patients were aged 50-70 years; active smokers were 64.9%; ex-smokers were 27%; smoking duration averaged 38.6pack-years; Severe, moderate, very severe, and mild COPD was observed in 38.6, 37.3, 18.4, and 5.7%, respectively. By the start of the trial, 305 (74.5%) had received concomitant therapy. Results. After 8-week thiotropium bromide therapy, there was a significant increase in bronchial patency, as suggested by considerable increments in the postbronchial indices: forced expiratory volume in one second (FEV1) by an average of 290 ml (20.4%) of the baseline level during treatment and forced vital capacity (FVC) by 310 ml (12.1%). By the end of the trial, the mean increase in inspiratory capacity (IC) by 180 ml (8.07%) of the baseline value was indicative of decreased lung hyperinflation in the treated patients. The significant increment in mean FEV1, FVC, and IC was observed in patients with any severity of COPD. Conclusion. The RUSSE study has indicated that there may be very good results in patients with COPD of any severity and a steady-state positive effect just after 8-week thiotropium bromide treatment. This treatment improves bronchial patency and diminishes lung hyperinflation, thus improving the patients' health status and exercise endurance.
  • Autor(en):
    Peter D; Goeggel R; Colbatzky F; Nickolaus P
    Titel:
    Inhibition of cyclooxygenase-2 prevents adverse effects induced by phosphodiesterase type 4 inhibitors in rats.
    Quelle(n):
    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.
  • Autor(en):
    Byron PR; Hindle M; Lange CF; Longest PW; McRobbie D; Oldham MJ; Olsson B; Thiel CG; Wachtel H; Finlay WH
    Titel:
    In vivo-in vitro correlations: Predicting pulmonary drug deposition from pharmaceutical aerosols.
    Quelle(n):
    J Aerosol Med Pulm Drug Deliv 23 (2), S59-S69 (2010)
    Abstract:
    In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo-in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.
  • Autor(en):
    Rau-Berger H; Mitfessel H; Glaab Th
    Titel:
    Tiotropium Respimat.RTM. improves physical functioning in chronic obstructive pulmonary disease.
    Quelle(n):
    Int J Chronic Obstruct Pulm Dis 5, 367-373 ( 2010)
    Abstract:
    This observational study with tiotropium Respimat® was performed in a real-life setting to investigate its effectiveness with regard to physical functioning and tolerability. Patients with chronic obstructive pulmonary disease (COPD; n = 1,230; mean age, 65.5 years) received tiotropium 5 ?g once daily via Respimat® Soft Inhaler for 6 weeks in an open-label observational study. At baseline and week 6, patients completed the Physical Function subdomain [PF-10] of the Short Form (SF) 36 questionnaire. Improvement in standardized PF-10 score of ?10 points was achieved by 61.5% of patients. Mean (SD) standardized PF-10 scores improved by 13.4 (15.9) points, from 49.0 (24.5) to 62.3 points (23.5; P < 0.001). Results in smokers (n = 435) were not significantly different to those in nonsmokers. The general condition of patients improved during treatment. Adverse events were reported by 4.0% of patients and were chiefly respiratory symptoms and dry mouth. In COPD patients receiving tiotropium Respimat® in daily practice, physical function improved rapidly within 6 weeks of treatment, irrespective of smoking status.
  • Autor(en):
    Mauskopf JA; Baker CL; Monz BU; Juniper MD
    Titel:
    Cost effectiveness of tiotropium for chronic obstructive pulmonary disease: A systematic review of the evidence.
    Quelle(n):
    J Med Econ 13 (3), 403-417 (2010)
    Abstract:
    Background: Tiotropium has been shown to reduce exacerbations and improve quality of life for patients with chronic obstructive pulmonary disease (COPD), a lung disease characterized by a persistent and progressive airflow limitation. Objectives: To present a systematic literature review of the cost effectiveness of treatment with tiotropium compared with other currently used treatments for COPD. Methods: A systematic search was performed via PubMed, the Cochrane database, and EMBASE from 2002 to 2009. Methods and results by study design and by country were compared. Results: Seventeen studies were included in the review. Study designs were characterized as follows: modeling based on clinical trial data, and empirical analysis based on either clinical trial or observational data. Comparing monotherapy regimens (12 studies), all study designs found that treatment with tiotropium was associated with lower costs for hospitalisation and other non-drug services. Total costs, including the costs of maintenance drugs, were lower with tiotropium in some, but not all, of the studies. Tiotropium was shown to be cost effective based on commonly accepted benchmark values. Limitations of the review included the wide variety of outcome measures used in different studies, the limited number of observational database studies for monotherapy, and limited data for combination therapy regimens. Conclusions: The main conclusions of the economic evaluations derived from clinical trial data at the time of product approval and from later observational data reflecting clinical use are similar: use of tiotropium monotherapy is associated with lower hospital and other non-drug costs and better health outcomes and is either cost saving or cost effective compared with other maintenance monotherapies.
  • Autor(en):
    Tashkin D; Celli B; Kesten S; Lystic T; Decramer M
    Titel:
    Effect of tiotropium in men and women with COPD: Results of the 4-year UPLIFT trial.
    Quelle(n):
    Respir Med 104 (10), 1495-1504 (2010)
    Abstract:
    Background: Gender differences may occur in many chronic diseases. We have examined the influence of gender in chronic obstructive pulmonary disease (COPD) on long-term responses to tiotropium. Methods: Subgroup analysis of data from the Understanding the Potential Long-term Impact of Tiotropium (UPLIFT (R)) trial (4-year, randomized, double-blind, placebo-controlled trial of tiotropium in patients with COPD). Results: Of 5992 patients, 75% were men and 25% women. Mean age was 65 and 63 years, respectively. Baseline post-bronchodilator forced expiratory volume in 1 s (FEV1) = 47% predicted(men) and 49% predicted(women). St George's Respiratory Questionnaire (SGRQ) total score was 44.9 and 48.7 units, respectively. At 48 months, improvement in trough FEV1 over control was 92 mL(men) and 77 mL(women) (p < 0.001 for both), with no differences in the rate of decline (trial primary endpoint). Hazard ratio (HR) (95% confidence interval [CI]) for first exacerbation (tiotropium/placebo) was 0.87(0.81, 0.93)(men) and 0.83(0.74, 0.94)(women). Number of exacerbations (per patient-year) was reduced with tiotropium in men (from 0.82 to 0.71) and women (from 0.92 to 0.77) (p < 0.005 for both). HR (95% CI) for a hospitalized exacerbation was 0.89(0.79, 0.99) and 0.77(0.62, 0.94), respectively. HR (95% CI) for mortality during treatment was 0.85(0.72, 0.99)(men) and 0.85(0.62, 1.18)(women). Improvements in SGRQ total score (tiotropium control) at 1, 2, 3 and 4 years were: -2.8, -2.3, -3.6, -2.4(men) and -2.7, -2.6, -2.6, -2.1(women) (p < 0.05 for all). Conclusion: Long-term treatment of COPD with tiotropium improves lung function, exacerbations and health status in men and women, with similar magnitudes of benefit. - DERWENT Abstract - The Authors examined the influence of gender on long-term responses to tiotropium in a subgroup analysis of data from the Understanding the Potential Long-term Impact of Tiotropium (UPLIFT) 4-yr, randomized, double-blind, placebo-controlled trial of 5992 patients with COPD. At 48 mth, improvement in trough FEV1 over control was 92 ml (men) and 77 ml (women), with no differences in the rate of decline. Hazard ratio (HR) for 1st exacerbation (tiotropium/placebo) was 0.87 (men) and 0.83 (women). Number of exacerbations was reduced with tiotropium in men and women. HR for a hospitalized exacerbation was 0.89 and 0.77, respectively. HR for mortality during treatment was 0.85 (men) and 0.85 (women). Results suggest that long-term treatment of COPD with tiotropium improves lung function, exacerbations, and health status in men and women, with similar magnitudes of benefit. Methods 5992 Patients with COPD were randomized to receive tiotropium (n=2986: 2251 male, mean age 65 yr; 735 female, mean age 63 yr) or placebo (n=3006: 2222 male, mean age 65 yr; 784 female, mean age 62 yr). Results While women had moderately lower baseline values for FEV1, similar improvements with tiotropium relative to control were observed in both groups, with the absolute improvements in FEV1 being slightly less in women but the percent predicted improvements are fairly comparable in men and women. Similar findings were observed for changes in FVC. In each treatment group, rates of decline in both pre- and postbronchodilator FEV1 and FVC were slightly lower for women than for men in absolute terms, but similar when expressed as the yearly decline in the percent of predicted. The tiotropium-placebo differences in the rates of decline were comparable for men and women. There was no evidence of an interaction with treatment by gender. The rate of decline in prebronchodilator percent predicted FEV1 and postbronchodilator FEV1 was similar in men and women. Both men and women showed a benefit of tiotropium with respect to a reduction in the risk for an exacerbation and an exacerbation leading to a hospitalization. The rate of exacerbations was lower in the tiotropium group compared to the placebo group. Both men and women had improvements in St. George's Respiratory Questionnaire total scores during the trial. While women had slightly worse (higher) total St. George's Respiratory Questionnaire scores than men at baseline, in general, they showed similar tiotropium-related improvements in overall health-related QOL.
  • Autor(en):
    De Greve J; Decoster L; De Mey J; In 't Veld P; Geers C; Tatzon M; Shahidi M; Galdermans D
    Titel:
    CLINICAL ACTIVITY OF BIBW 2992, AN IRREVERSIBLE INHIBITOR OF EGFR/HER1 AND HER2 IN ADENOCARCINOMA OF THE LUNG WITH MUTATIONS IN THE KINASE DOMAIN OF HER2NEU.
    Quelle(n):
    J Thorac Oncol 5 (5) (Supp.[1]), S90-S91 ( 2010)
  • Autor(en):
    Morice AH; Celli B; Kesten S; Lystig T; Tashkin D; Decramer M
    Titel:
    COPD in young patients: A pre-specified analysis of the four year trial of tiotropium (UPLIFT).
    Quelle(n):
    Respir Med 104 (11), 1659-1667 (2010)
    Abstract:
    Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease (COPD), relatively little is known about the effect in younger patients. We report a pre-specified post-hoc analysis of 356 patients with COPD ? 50 years old from the four year randomised, double blind placebo controlled Understanding Potential Long Term Impact on Function with Tiotropium (UPLIFT) trial. Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s (FEV<sub>1</sub>) of ?70%, FEV<sub>1</sub>/FVC &lt; 0.70, age ?40 years, and smoking history of ?10 pack years. Younger patients had a mean FEV<sub>1</sub> of 1.24 L (39% predicted) and an impaired health-related quality of life (St. George's Respiratory Questionnaire (SGRQ)) compared to the entire UPLIFT population. There were 40.2% women and 51.1% current smokers in the younger age group. Tiotropium was associated with a sustained improvement in spirometry and SGRQ. Mean decline in post-bronchodilator FEV<sub>1</sub> was 58 ml/year (placebo) vs. 38 ml/year (tiotropium) (p = 0.01). Corresponding values for pre-bronchodilator FEV<sub>1</sub> were 41 ml/year (placebo) compared with 34 ml/year (tiotropium) (p = 0.34). The hazard ratio (95%CI) for an exacerbation in the younger age group was 0.87(0.68, 1.13)). The rate of exacerbations was reduced by tiotropium (rate ratio (95%CI) = 0.73(0.56, 0.95)). Tiotropium resulted in sustained bronchodilation, improved quality of life, and a decreased exacerbation rate in younger patients. Tiotropium also resulted in a significant reduction in the decline in post-bronchodilator FEV<sub>1</sub>, suggesting possible disease modification by tiotropium in younger patients with COPD. - DERWENT Abstract - In this study (NCT00144339), the Authors investigated the 4-yr progression of COPD and the effect of tiotropium (TP) in 356 patients with COPD aged 50 yr and younger from the 4-yr randomized, double-blind, placebo-controlled Potential Long Term Impact on Function with TP (UPLIFT) Trial. TP was associated with a sustained improvement in spirometry and St. George's Respiratory Questionnaire (SGRQ) total score. TP decreased the rate of exacerbation and was insignificantly associated with a decreased mortality rate. These findings provide a justification and rationale for the early diagnosis and treatment in young patients with COPD. Methods The 4-yr progression of COPD and the effect of TP (18 ug/day) were investigated in 356 patients with COPD aged 50 yr and younger from the UPLIFT Trial. Results The co-primary endpoints of rate of decline in pre- and post-bronchodilator FEV1 tended to be improved by TP. In the case of post-bronchodilator change in FEV1, this was significant at 58 ml/yr vs. 38 ml/yr. TP was associated with improvements in the SGRQ total score throughout the study period, with this improvement being significant at half of the clinic visits. The mean differences (TP-control) were -3.3, -3.0, and -4.1 U at 1, 2, and 3 yr in favor of TP. The rate of exacerbation was diminished by TP, with a rate ratio of 0.73. The hazard ratio (TP/control) for the 1st exacerbation was 0.87. Mortality was relatively low in patients aged 50 yr or younger, being 7% or less in both treatment groups. TP was associated with a lower mortality rate, but this did not reach statistical significance. There was a significant interaction by age for pre-bronchodilator FEV1 (until mth 36) and for pre-bronchodilator FVC (throughout the study), which could be suggestive of a difference in the magnitude of treatment benefit across age groups.
  • Autor(en):
    Laforest L; Denis F; van Ganse E; Ritling C; Saussier C; Passante N; Devouassoux G; Chatte G; Freymond N; Pacheco Y
    Titel:
    Correlates of adherence to respiratory drugs in COPD patients.
    Quelle(n):
    Prim Care Respir J 19 (2), 148-154 (2010)
    Abstract:
    Aims: To identify the correlates of accidental omissions and intentional interruptions of respiratory therapy in COPD. Methods: COPD patients (GOLD stages II-IV) were recruited by general practitioners or respiratory physicians. Patients reported in self-report questionnaires their adherence to respiratory drugs (over the past three months) and their perception of therapy. Results: 179 patients were included (mean age 63 years, 24% females). 45% forgot their respiratory therapy, while 30% interrupted it in the absence of any perceived benefit. The risks of accidental omissions were significantly higher when patients complained about having too many medications to take on a daily basis (OR=2.35; 95%CI=1.13-4.89), and among current smokers (OR=2.14; 95%CI=1.07-4.29). Females were more likely to interrupt therapy intentionally (OR=2.40; 95%CI=1.04-5.53). Surprisingly, there was no significant relationship with the number of drugs actually taken by patients. Conclusions: Adherence to respiratory drugs is inadequate in COPD patients. In order to improve adherence, patients' perception of the burden of therapy should not be overlooked.
  • Autor(en):
    Troosters T; Celli B; Lystig T; Kesten S; Mehara S; Tashkin DP; Decramer M
    Titel:
    Tiotropium as a first maintenance drug in COPD: Secondary analysis of the UPLIFT trial.
    Quelle(n):
    Eur Respir J 36 (1), 65-73 (2010)
    Abstract:
    The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease (COPD). A 4-yr, randomised, multicentre, double-blind, parallel-group, placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®)) was conducted. Analysis focused on the effect of tiotropium versus matching placebo in the 810 (13.5%) COPD patients not on other maintenance treatment (long-acting b-agonists, inhaled corticosteroids, theophyllines or anticholinergics) at randomisation. Spirometry, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) score), exacerbations of COPD and mortality were also analysed. 403 patients (mean±SD age 63±8 yrs, post-bronchodilator forced expiratory volume in 1 s (FEV<sub>1</sub>) 53±12% predicted) received tiotropium and 407 (64±8 yrs of age, post-bronchodilator FEV<sub>1</sub> 51±12% pred) received placebo. Post-bronchodilator FEV<sub>1</sub> decline was 42±4 mL·yr<sup>-1</sup> in the tiotropium group and 53±4 mL·yr<sup>-1</sup> in the placebo group (p=0.026). At 48 months, the morning pre-dose FEV<sub>1</sub> was 134 mL higher in the tiotropium group compared to the placebo group (p&lt;0.001). SGRQ total score declined more slowly in the tiotropium group (difference of 1.05±0.34 units·yr<sup>-1</sup>; p=0.002). This was particularly significant for the impact (difference of 1.08±0.37 units·yr <sup>-1</sup>; p=0.004) and activity (1.44±0.40 units·yr <sup>-1</sup>; p&lt;0.001) domains, but not for symptoms (0.26±0.50 units·yr<sup>-1</sup>; p=0.6). At 48 months, the difference in total score was 4.6 units (p&lt;0.001) with tiotropium compared to placebo. In patients with COPD who are not on maintenance therapy, tiotropium is associated with significant benefits in disease progression.
  • Autor(en):
    Tashkin DP; Celli B; Kesten S; Lystig T; Mehra S; Decramer M
    Titel:
    Complete smoking cessation is beneficial in older and more advanced COPD patients.
    Quelle(n):
    Eur Respir J 36 (1), 217-218 (2010)
  • Autor(en):
    Bateman ED; Tashkin D; Siafakas N; Dahl R; Towse L; Massey D; Pavia D; Zhong NS
    Titel:
    A one-year trial of tiotropium Respimat<sup>@</sup> plus usual therapy in COPD patients.
    Quelle(n):
    Respir Med 104 (10), 1460-1472 (2010)
    Abstract:
    In this randomised double-blind study, patients ?40 years old with COPD, a smoking history of ?10 pack-years, a pre-bronchodilator FEV<sub>1</sub> of ?60% predicted and an FEV<sub>1</sub>/FVC of ?70% received tiotropium 5 ?g or placebo via Respimat® inhaler once daily for 48 weeks. Other medications were permitted except inhaled anticholinergics. Co-primary endpoints were trough FEV<sub>1</sub> and the time to first exacerbation. Adverse events were followed and vital status regularly assessed. In all, 3991 patients (mean age, 65 years [SD, 9 years]) were evaluable. Mean baseline FEV<sub>1</sub> was 1.11 L (0.40 L) or 40% (12%) of predicted normal. Adjusted mean differences in trough FEV<sub>1</sub> and trough FVC at Week 48 (tiotropium minus placebo) were 102 and 168 ml respectively (p &lt; 0.0001, both). Tiotropium delayed time to first exacerbation relative to placebo (hazard ratio [HR], 0.69 [95% CI, 0.63-0.77]) and time to first hospital-treated exacerbation (HR, 0.73 [0.59-0.90]). SGRQ score at Week 48 was 2.9 units lower with tiotropium (p &lt; 0.0001). Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials. The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 (0.67-1.86). By the end of planned treatment (Day 337) 52 patients on tiotropium (incidence rate per 100 years, 2.94) and 38 on placebo (2.13) had died (HR = 1.38 [0.91-2.10]; p = 0.13). Lung function, exacerbations and quality of life were improved by tiotropium 5 ?g Respimat® but a numerical imbalance was seen in all-cause mortality. The protocol is registered on the European Clinical Trials Database as trial number 2006-001009-27 and in the ClinicalTrials.gov database as NCT00387088. - DERWENT Abstract - The Authors assessed clinical efficacy and safety of 1-yr treatment with tiotropium 5 ug delivered via Respimat, particularly its effect on exacerbations, in a randomized double-blind study of 3917 COPD patients. Tiotropium delayed time to 1st exacerbation relative to placebo and time to 1st hospital-treated exacerbation. St. George's Respiratory Questionnaire score at wk 48 was 2.9 units lower with tiotropium. Adverse and serious adverse events were balanced across treatment groups and similar in profile to tiotropium trials. Lung function, exacerbations, and QOL were improved by tiotropium 5 ug Respimat, but a numerical imbalance was seen in all-cause mortality. Once/day tiotropium delivered via the Respimat inhaler to patients who continued to take their usual maintenance therapy for COPD produces improvements in lung function, exacerbation risk, and QOL after 48 wk treatment. Methods 3917 Patients 40 yr or older with COPD, a smoking history of 10 or more pack-yr, a prebronchodilator FEV1 of less than 60% predicted, and an FEV1/FVC of 70% or less received tiotropium 5 ug (n=1952, mean age 64.8 yr, 78.1% male) or placebo (n=1965, mean age 64.8 yr, 77% male) via Respimat inhaler once/day for 48 wk. Results After 48 wk, the adjusted mean increase from baseline trough FEV1 was greater in the tiotropium group (119 ml) than the placebo group (18 ml). The adjusted mean difference between treatments was 102 ml. The time to first exacerbation was delayed by treatment with tiotropium. During the treatment period, 685 (35.3%) patients in the tiotropium group and 842 (43.1%) in the placebo group had at least 1 exacerbation, representing a risk reduction with tiotropium. A difference was also found in a sensitivity analysis, in which time to 1st exacerbation was calculated using life-table analysis. The proportion of adverse events and serious adverse events reported by patients in the 2 treatment groups during the on-treatment period was similar. Most of the frequently-reported adverse events were reported by similar proportions of patients in the 2 treatment groups. The notable exceptions to this were COPD exacerbation, which was reported by 641 (32.8%) in the tiotropium group and 759 (38.6%) in the placebo group, and dry mouth, reported by 60 (3.1%) and 27 (1.4%), respectively. After COPD exacerbations, the most common adverse events across both groups were balanced between groups, e.g., nasopharyngitis (8.0 and 7.7% respectively), dyspnea (7.0 and 7.7%), upper respiratory tract infection (6.4 and 7.3%), and cough (6.4 and 5.5%).
  • Autor(en):
    Laviolette L; Sava F; O'Donnell DE; Webb KA; Hamilton AL; Kesten S; Maltais F
    Titel:
    Effect of obesity on constant workrate exercise in hyperinflated men with COPD.
    Quelle(n):
    BMC Pulm Med 10 art. no. 33 (2010)
    Abstract:
    Background: Chronic obstructive pulmonary disease (COPD) and a high body mass index (BMI) can both affect pulmonary volumes as well as exercise tolerance, but their combined effect on these outcomes is not well known. The aim of this study was to investigate the effects of increased BMI during constant workrate cycle ergometry in patients with COPD.Methods: Men with COPD and hyperinflation were divided according to World Health Organization BMI classification: 84 normal BMI (NBMI), 130 overweight (OW) and 64 obese (OB). Patients underwent spirometric and lung volumes assessment and an incremental cycling exercise test. This was followed by a constant workrate exercise test (CET) at 75% of peak capacity. Inspiratory capacity and Borg dyspnea scores were measured at baseline, during and at the end of CET.Results and discussion: FEV1 % predicted was not different across BMI classes. Total lung capacity and functional residual capacity were significantly lower in OB and OW compared to NBMI patients. Peak VO2 in L.ovrhdot.min-1 was significantly higher in OB and OW patients than in NBMI patients. CET time was not different across BMI classes (p = 0.11). Changes in lung volumes and dyspnea during CET were not different between BMI categories.Conclusions: OB and OW patients with COPD had a higher peak VO2 than their lean counterparts. Endurance time, dyspnea and changes in lung volumes during CET were similar between BMI categories.
  • Autor(en):
    Sebastian M; Reck M; Waller CF; Kortsik C; Frickhofen N; Schuler M; Fritsch H; Gaschler-Markefski B; Hanft G; Munzert G; von Pawel J
    Titel:
    The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: Results from an open-label, randomiozed phase II clinical trial.
    Quelle(n):
    J Thorac Oncol 5 (7), 1060-1067 (2010)
    Abstract:
    OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer. METHODS: Ninety-five patients were randomized to intravenous BI 2536 on day 1 (200 mg) or days 1 to 3 (50 or 60 mg) of a 21-day treatment course. BI 2536 doses were escalated beyond course 2 if well tolerated. The primary objective was response, and the secondary objectives were progression-free survival (PFS) and overall survival (OS), quality of life, safety, and pharmacokinetics. Primary statistical aim was to demonstrate the difference in objective response rate to historical placebo for both treatment groups. RESULTS: Four patients (4.2%) had a partial response; two were confirmed by independent review. Median PFS was 8.3 weeks (58 days 95% confidence interval [CI]: 48-85) and 7 weeks (49 days 95% CI: 46-70) assessed by investigator and independent review, respectively. Median OS was 28.7 weeks (201 days 95% CI: 180-305). No statistically significant difference was observed between the two treatment schedules regarding clinical benefit, PFS, or OS. Grade 4 neutropenia occurred in 37% of patients; common nonhematologic adverse events were fatigue (31%) and nausea (27%). Two deaths (pulmonary hemorrhage and sepsis) were considered drug related. There was a trend in favor of the days 1 to 3 dosing schedule in quality of life. BI 2536 displayed moderate interpatient variability. CONCLUSIONS: BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication.
  • Autor(en):
    Bouyssou T; Casarosa P; Naline E; Pestel S; Konetzki I; Devillier P; Schnapp A
    Titel:
    Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models.
    Quelle(n):
    J Pharmacol Exp Ther 334 (1), 53-62 (2010)
    Abstract:
    The preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1hydroxy-2-[[2-(4-methoxyphenyl)-1,1- dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human beta(2)-adrenoceptor (h beta(2)-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the beta(2)-AR (EC50 = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (219- and 1622-fold against the h beta(1)- and h beta(3)-ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel beta(2)-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile. - DERWENT Abstract - This study discussed the pharmacological characterization of olodaterol (OX) in-vitro. In-vitro, OX showed a potent, nearly full agonistic response at the human beta2-adrenoceptor (hbeta2-AR) and a significant selectivity profile. Likewise, OX was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In-vivo, antagonistic effects of single doses of OX and formoterol (FX) were measured against Ach challenges in anesthetized guinea pigs and dogs. OX showed a rapid onset of action in guinea pigs and dogs comparable with FX. The preclinical behavior of OX suggests that this novel beta2-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile. OX shows the highest potency for the hbeta2-AT among the tested drugs (EC50-0.1 nM) and the profile of an almost full agonist with an IA of 88%, not different from the reference full agonist isoprenaline and FX. OX and FX potently relaxed the human bronchi with differences in potency and efficacy. In-vivo, OX induced a dose-dependent bronchoprotection when applied at doses from 0.1 to 3 ug/kg in anesthetized guinea pigs and dogs. Only OX protected the animals against Ach-induced bronchospasm when administered at a dose of 3 ug/kg and a lower dose (1 ug/kg) after 24 hr. OX and FX exerted a rapid onset of action and achieved a full bronchoprotection within 3 to 6 min after inhalation. OX (1.2 ug/kg) inhibited the Ach-induced bronchoconstriction in dogs in a dose-dependent manner. OX (0.6 ug/kg) induced a maximal bronchoprotection of approximately 60% after 0.5 hr. Intraduodenal administration of OX induced only a small increase in HR of maximally 10% and 20% when given 2- and 4-fold above the rate maximum effective dose , respectively.
  • Autor(en):
    Adams SG; Anzueto A; Briggs Jr. DD; Leimer I; Kesten S
    Titel:
    Response to Dr. Tsakok's letter to the editor entitled "Comment on tiotropium".
    Quelle(n):
    Respir Med 104 (9), 1389-1389 (2010)
  • Autor(en):
    Brosa M; Diaz-Cerezo S; Miravitlles M; Gonzalez-Rojas N; Nieves D
    Titel:
    Analysis of the cost-effectiveness of tiotropium in the treatment of chronic obstructive pulmonary disease in Spain.
    Quelle(n):
    Pharmacoeconomics 7 (1), 3-12 (2010)
    Abstract:
    Objective: The aim of this study is to assess whether if tiotropium bromide is an efficient alternative versus ipratropium bromide and standard therapy, in the management of chronic obstructive pulmonary disease (COPD) patients in Spain. Methods: Tiotropium bromide was compared to ipratropium bromide and standard therapy by means of a cost-effectiveness analysis that estimates life years gained (LYG) with tiotropium versus alternatives. The time horizon of the study was 13 years, the mean life expectancy in COPD patients included in the clinical trials with tiotropium. Uncertainty was studied by successive univariant sensitivity analysis of key parameters of the model and a probabilistic sensitivity analysis. All costs were expressed in 2,008 Euros and a 3% discount rate was applied to costs and effects. The analysis took the perspective of the Spanish National Health System (NHS). Results: Incremental cost-effectiveness ratio (ICER) when treating COPD patients with tiotropium versus standard therapy was 2,873 (euro)/LYG, and in patients treated with tiotropium versus ipratropium bromide it was 4,208 (euro)/LYG. Univariant sensitivity analysis showed that results where most sensitive to COPD severity and to the future costs of surviving patients. Conclusions: Treating COPD patients with tiotropium is an efficient alternative respect ipratropium bromide or standard therapy for the Spanish NHS.
  • Autor(en):
    Deschl U; Vogel J; Aufderheide M
    Titel:
    Development of an in vitro exposure model for investigating the biological effects of therapeutic aerosols on human cells from the respiratory tract.
    Quelle(n):
    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.
  • Autor(en):
    Ellis PM; Kaiser R; Zhao Y; Stopfer P; Gyorffy S; Hanna N
    Titel:
    Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor and premetrexed in pretreated non-small cell-lung cancer patients.
    Quelle(n):
    Clin Cancer Res 16 (10), 2881-2889 (2010)
    Abstract:
    Introduction: BIBF 1120 (planned brand name Vargatef) is a novel, oral, triple angiokinase inhibitor targeting three receptor classes involved in blood vessel formation. The objectives of this phase I, openlabel dose-escalation study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of BIBF 1120 with pemetrexed in patients with recurrent advanced-stage non-small cell lung carcinoma. Patients and Methods: Patients harboring a tumor of any non-small cell lung carcinoma histology, previously treated with one first-line platinum-based chemotherapy regimen, received a BIBF 1120 starting dose of 100 mg bid (days 2-21) with pemetrexed 500 mg/m2 (day 1) over a 21-day cycle. Previous pemetrexed treatment was not permitted. BIBF 1120 dose was escalated until the MTD was determined. Results: Twenty-six patients were treated. During treatment cycle (TC) 1, dose-limiting toxicities were experienced by one patient receiving 100 mg bid, one patient receiving 150 mg bid, one patient receiving 200 mg bid, and two patients receiving 250 mg bid BIBF 1120. Two additional dose-limiting toxicities were observed in TC 1 in an expanded patient cohort receiving 200 mg bid. Gastrointestinal disorders (84.6%), general disorders, and administration site conditions (76.9%) were the most frequent drug-related adverse events. One patient had a complete response 44 days after initiating trial medication; 50% had stable disease as the best overall response. No clinically relevant pharmacokinetic interactions between BIBF 1120 and pemetrexed were observed. Conclusion: The MTD of BIBF 1120 in combination with standard-dose pemetrexed was 200 mg bid. Continuous daily treatment with BIBF 1120 in this combination was tolerable, with promising signs of efficacy. - DERWENT Abstract - This phase I, open-label, dose-escalation, multicenter study determined the MTD of p.o. BIBF-1120 in combination with standard-dose i.v. pemetrexed (PEM) in 26 patients with recurrent, advanced-stage NSCLC who had previously been treated with 1 prior platinum-based chemotherapy regimen. BIBF-1120 200 mg b.i.d. + standard-dose PEM was the recommended dose for continuous daily treatment. Grade 3 fatigue was the most frequently observed dose-limiting toxicity (DLT). GI adverse events and reversible liver enzyme elevations were the predominant adverse events associated with BIBF-1120. No clinically relevant pharmacokinetic interactions between BIBF-1120 and PEM were observed. BIBF-1120 + PEM induced 1 CR, while half of the patients had stable disease as the best overall response. Thus, continuous daily treatment with BIBF-1120 have promising signs of efficacy. Methods 26 Patients (mean age 62.5yr, 13 male) harboring a tumor of any NSCLC histology, previously treated with 1 1st-line platinum-based chemotherapy regimen, received a p.o. BIBF-1120 starting dose of 100 mg b.i.d. (days 2-21) with i.v. PEM (500 mg/sq.m, day 1) over a 21-day cycle. Results 1 Patients with a CR completed the study and has remained on 100 mg b.i.d. BIBF-1120 monotherapy for more than 3 yr. The most common reasons for study discontinuation were disease progression (57.7%) and DLT (19.2%). During the first TC, 7 patients on study medication (26.9%) experienced a DLT. These DLT events included elevated ALT and AST, GI events including vomiting, esophageal pain, and nausea, fatigue, confusion and anorexia. All DLT were of CTCAE grade 3. All patients experienced an adverse event throughout the course of the study. GI disorders (84.6%; consisting of mainly nausea, vomiting, abdominal pain, and diarrhea), general disorders, and administration site conditions (76.9%; predominantly rash) were the most frequently reported drug-related adverse events. The most frequent individual dmgrelated adverse events reported across all dose groups were fatigue (65.4%), nausea (61.5%), anorexia (53.8%), rash (38.5%), diarrhea (34.6%), and vomiting (34.6%). All bleeding events were reversible and of mild to moderate intensity. 13 Patients (50%) had stable disease as the best overall response. 8 Patients showed progressive disease as best response. Median PFS was approximately 5.4 mth. No clinically relevant pharmacokinetic interactions between BIBF-1120 and PEM were observed.
  • Autor(en):
    Taskin D; Celli B; Kesten S; Lystic T; Decramer M
    Titel:
    Effect of tiotropium in men and women with COPD: Results of the 4-year UPLIFT<sup>R</sup>trial.
    Quelle(n):
    Respir Med 104 (10), 1495-1504 (2010)
  • Autor(en):
    Escamilla R; Grignet J-P; Bourcereau J; Mueser M
    Titel:
    The profile of the patients referred by general practitioners to respiratory physicians for assessment of undiagnosed bronchial disease.
    Quelle(n):
    Rev Mal Respir 27 (5), 463-471 (2010)
    Abstract:
    Introduction. - In general practice, COPD is often under-diagnosed and inappropriate pharmacological treatment given. Objectives. - To determine the profile of patients over 40 years old, smokers or ex-smokers, referred by general practitioners to respiratory physicians for assessment of undiagnosed bronchial disease. Methods. - Observational study carried-out among 103 respiratory physicians in France in 2007. Results. - The diagnosis of COPD was confirmed by the respiratory physicians in 433/486 (89%) patients. COPD patients were aged 61 years on average, male (63%) and often current smokers (46%). Most of them had more than three respiratory symptoms. The diagnosis of COPD was made after a long history of symptoms. We found 148 (34.2%) COPD patients with a FEV1/FVC greater than 0.7 and were classified as mild (61 patients), moderate (77 patients) or severe (10 patients). Conclusions. - In patients at risk, smokers or ex-smokers with respiratory symptoms, COPD was the diagnosis most often confirmed by the respiratory physician. A significant proportion of respiratory physicians diagnosed and assessed the severity of COPD, not strictly on the basis of national recommendations, but rather on the association of risk factors, respiratory symptoms and even isolated changes in FEV1.
  • Autor(en):
    van Noord JA; Aumann J-L; Janssens E; Smeets JJ; Zaagsma J; Mueller A; Cornelissen PJG
    Titel:
    Combining tiotroopium and salmeterol in COPD: Effects on airflow obstruction and symptonms.
    Quelle(n):
    Respir Med 104 (7), 995-1004 (2010)
    Abstract:
    Background: Clinical information on 24-h spirometric efficacy of combining tiotropium and salmeterol compared to single-agent therapy is lacking in patients with COPD. Methods: A randomized, double-blind, four-way crossover study of 6-week treatment periods comparing combination therapy of tiotropium 18 ?g plus qd or bid salmeterol 50 ?g versus single-agent therapy. Serial 24-h spirometry (FEV<sub>1</sub>, FVC), effects on dyspnea (TDI focal score) and rescue salbutamol use were evaluated in 95 patients. Results: Tiotropium plus qd salmeterol was superior to tiotropium or salmeterol alone in average FEV<sub>1</sub> (0-24 h) by 72 mL and 97 mL (p &lt; 0.0001), respectively. Compared to this qd regimen, combination therapy including bid salmeterol provided comparable daytime (0-12 h: 12 mL, p = 0.38) bronchodilator effects, but significantly more bronchodilation during the night-time (12-24 h: 73 mL, p &lt; 0.0001). Clinically relevant improvements in TDI focal score were achieved with bronchodilator combinations including salmeterol qd or bid (2.56 and 2.71; p &lt; 0.005 versus components). Symptom benefit of combination therapies was also reflected in less need for reliever medication. All treatments were well tolerated. Conclusion: Compared to single-agent therapy, combination therapy of tiotropium plus salmeterol in COPD provided clinically meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication. - DERWENT Abstract - This randomized, double-blind, 4-way crossover study characterized the 24-hr bronchodilating profile of tiotropium (TIO) in combination with salmeterol (SAL) to evaluate symptom relief in 95 patients with COPD. Both combination regimens were superior to single-agent therapy in terms of 24-hr lung function improvement, Transition Dyspnea Index (TDI) focal score and use of reliever medication. The superior bronchodilator effects were not only restricted to the relevant period of daily activities, but were also observed during the night-time and did not increase the incidence of side effects. Thus, combination therapy of TIO + SAL in COPD provided clinically meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication. Methods 95 Patients (mean age 64 yr, 76 male) with COPD received TIO (18 ug + once-daily or b.i.d. SAL (50 ug) vs. single agent therapy. Results Combination treatment with TIO + once-daily SAL provided greater bronchodilation compared with the individual components as measured by the average FEV1 (0-24 hr). In terms of average FEV1 (0-24 hr), coadministration of TIO + b.i.d. SAL was superior to the once-daily combination as a result of an additional increase in FEV1 after the evening salmeterol dose. TIO treatment resulted in greater bronchodilation compared with SAL in terms of average FEV1 (0-24 hr), mainly due to the superior daytime (0-12 hr) spirometric efficacy of TIO. Both combination therapies provided higher FVC values at all time points during the 24-hr observation period compared to each of the single agents, resulting in a better performance of combination therapy in all FVC-derived endpoints. Both combination regimens provided additional improvements in morning and evening PEFR compared with single-agent therapy. The proportion of patients who achieved a clinically meaningful improvement in TDI focal score was greater during treatment with TIO + once-daily SAL (67%) or b.i.d. SAL (72%) than for the SAL (48%) or TIO (57%) periods. The improvement in TDI focal score is associated with less need of salbutamol. Although the incidence of adverse events was generally balanced between the treatment periods, during combination therapy a lower incidence was noted for COPD exacerbations and complaints of dyspnea.
  • Autor(en):
    Woodruff PG; Wolff M; Hohlfeld JM; Krug N; Dransfield MT; Sutherland ER; Criner GJ; Kim V; Prasse A; Nivens MC; Tetzlaff K; Heilker R; Fahy JV
    Titel:
    Safety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease.
    Quelle(n):
    Am J Respir Crit Care Med 181 (5), 438-445 ( 2010)
    Abstract:
    Rationale: Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD). Objectives: To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD. Methods: Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium(Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings. Measurements and Main Results: Inhaled BIBW 2948 induced a dose-related inhibition ofEGFRinternalization (reflecting decreasedEGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV<sub>1</sub>. The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 ± 7.11 vs. 0.47 ± 8.06 µm<sup>3</sup>/µm <sup>2</sup>; P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71-0.99). Conclusions: Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected. Clinical trial registered with www.clinicaltrials.gov (NCT00423137). - DERWENT Abstract - This multicenter, double-blind, randomized, parallel- placebo-controlled study (NCT00423137) investigated the safety and efficacy of an inhaled EGF receptor (EGFR) antagonist (BIBW-2948 BS, Boehr.Ingelheim) in 48 patients with COPD. Inhaled BIBW-2948 BS induced a dose-related inhibition of EGFR internalization in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n - 2), and reduction in FEV1. In the high-dose BIBW-2948 subgroup, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition. Thus, higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but adverse events should be expected. Methods 48 Patients with COPD randomly received placebo (n=23) (15 (n=11, mean age 56 yr, 73% male) or 30 (n=12, mean age 56 yr, 75% male) mg b.i.d.) or inhaled BIBW-2948 BS (n=25) (15 (n=13, mean age 54 yr, 46% male) or 30 (n=12, mean age 59 yr, 75% male) mg b.i.d.). Results Images from brushing cells displayed AF647 tagged EGF in perinuclear compartments. In contrast, brushing cells collected from BIBW-2948 BS-treated patients at the end of treatment showed cell surface EGF localization and decreased perinuclear EGF localization compared with baseline, consistent with a lack of EGFR internalization. Treatment with 30 mg b.i.d. BIBW-2948 BS caused a 4-fold inhibition of EGF-induced receptor internalization compared with a 1.7-fold average inhibition for a 15 mg b.i.d. dose. EGFR internalization correlated with plasma levels of BIBW-2948 BS only in the 30-mg b.i.d. group. Treatment was discontinued because of adverse events in 1/23 (4.3%) subjects in the placebo group vs. 6/25 (24%) subjects in the BIBW-2948 BS group. 1 Subject suffered unstable angina early in the active treatment phase. Another subject had a MI 3 wk after completion of the study. The principal adverse events considered related to study drug were declines in FEV1 and abnormalities in liver function. There was a correlation between reduction in Vs mu,bala and inhibition of EGFR internalization, which was driven by a reduction in the 30-mg subgroup and was not present in the 15-mg group. The change in Vs mu,bala correlated with mean plasma AUC for BIBW-2948 BS at steady state in the 30-mg subgroup. There was a trend for increased MPO and IL-8 levels in the BIBW-2948 BS subgroups.
  • Autor(en):
    Gani R; Griffin J; Kelly St; Rutten-van Molken M
    Titel:
    Economic analyses comparing tiotropium with ipratropium or salmeterol in UK patients with COPD.
    Quelle(n):
    Prim Care Respir J 19 (1), 68-74 (2010)
    Abstract:
    AIMS: This study presents a cost-effectiveness and budget impact analysis comparing cost and outcomes for UK patients with COPD treated with either tiotropium, ipratropium or salmeterol. METHODS: A previously-published COPD cost-effectiveness model was adapted for the UK, then used to estimate the cost-effectiveness of tiotropium compared to salmeterol and ipratropium. Additional epidemiological data were used to estimate the budget impact of switching patients from ipratropium or salmeterol to tiotropium. RESULTS: In England, the estimated annual cost per patient on tiotropium was pound1350, on salmeterol was pound1404, and on ipratropium was pound1427; in Scotland/Wales/Northern Ireland (S/W/NI) these costs were pound1439, pound1565, and pound1631, respectively. Tiotropium patients experienced better quality-adjusted life-years (QALYs) across all comparisons, and this option was therefore dominant compared to salmeterol and ipratropium. The probability of tiotropium being dominant ranged from 72% to 87% across comparisons. At a willingnessto- pay threshold of pound20,000 per QALY, tiotropium had at least a 97% chance of being cost-effective. The estimated annual saving per primary care trust (PCT) of switching patients from salmeterol and ipratropium to tiotropium in England was pound230,000 and in S/W/NI was pound160,000. CONCLUSIONS: Tiotropium is a cost-effective alternative to ipratropium and salmeterol, and switching COPD patients from ipratropium and salmeterol to tiotropium could result in considerable cost savings for PCTs along with improvements in quality-of-life.
  • Autor(en):
    ZuWallack R; De Salvo MC; Kaelin T; Bateman ED; Park CS; Abrahams R; Fakih R; Sachs P; Pudi K; Zhao Y; Wood CC
    Titel:
    Efficacy and safety of ipratropium bromide/albuterol delivered via Respimat<sup>R</sup>inhaler versus MDI.
    Quelle(n):
    Respir Med 104 (8), 1179-1188 (2010)
    Abstract:
    We compared the efficacy and safety of ipratropium bromide/albuterol delivered via Respimat<sup>®</sup> inhaler, a novel propellant-free inhaler, versus chlorofluorocarbon (CFC)-metered dose inhaler (MDI) and ipratropium Respimat<sup>®</sup> inhaler in patients with COPD. This was a multinational, randomized, double-blind, double-dummy, 12-week, parallel-group, active-controlled study. Patients with moderate to severe COPD were randomized to ipratropium bromide/albuterol (20/100 mcg) Respimat<sup>®</sup> inhaler, ipratropium bromide/albuterol MDI [36 mcg/206 mcg (Combivent<sup>®</sup> Inhalation Aerosol MDI)], or ipratropium bromide (20 mcg) Respimat<sup>®</sup> inhaler. Each medication was administered four times daily. Serial spirometry was performed over 6 h (0.15 min, then hourly) on 4 test days. The primary efficacy variable was forced expiratory volume in 1 s (FEV<sub>1</sub>) change from test day baseline at 12 weeks. A total of 1209 of 1480 randomized, treated patients completed the study; the majority were male (65%) with a mean age of 64 yrs and a mean screening pre-bronchodilator FEV<sub>1</sub> (percent predicted) of 41%. Ipratropium bromide/albuterol Respimat<sup>®</sup> inhaler had comparable efficacy to ipratropium bromide/albuterol MDI for FEV<sub>1</sub> area under the curve at 0-6 h (AUC<sub>0-6</sub>), superior efficacy to ipratropium Respimat<sup>®</sup> inhaler for FEV<sub>1</sub> AUC<sub>0-4</sub> and comparable efficacy to ipratropium Respimat<sup>®</sup> inhaler for FEV<sub>1</sub> AUC<sub>4-6</sub>. All active treatments were well tolerated. This study demonstrates that ipratropium bromide/albuterol 20/100 mcg inhaler<sup>®</sup> administered four times daily for 12 weeks had equivalent bronchodilator efficacy and comparable safety to ipratropium bromide/albuterol 36 mcg/206 mcg MDI, and significantly improved lung function compared with the mono-component ipratropium bromide 20 mcg Respimat<sup>®</sup> inhaler. [Clinical Trial Identifier Number: NCT00400153]. - DERWENT Abstract - This multinational, randomized, double-blind, double-dummy, 12-wk, parallel-group, active-controlled study determined the efficacy and safety of ipratropium bromide/albuterol (IB, Boehr.Ingelheim/A) delivered via the Respimat inhaler vs. IB/A by metered-dose inhaler (MDI, Combivent) and IB alone via the Respimat inhaler in 1460 patients with moderate to severe COPD. IB/A Respimat inhaler and IB/A MDI produced equivalent bronchodilation which was greater than that by IB Respimat inhaler. IB/A delivered by Respimat inhaler and MDI similarly reduced the median time to onset of therapeutic response and median time to peak FEV1 response and prolonged the median duration of therapeutic response. Overall adverse event frequencies were comparable across groups. Thus, IB/A Respimat inhaler is as effective and safe as the reference MDI for use in patients with moderate to severe COPD. Methods 1460 Patients with moderate to severe COPD were randomized to IB/A (20/100 mcg) Respimat inhaler (n=486, mean age 63.8 yr, 65% male), IB/A MDI (36 mcg/206 mcg) Combivent Inhalation Aerosol MDI) (n=491, mean age 64.23 yr, 65.6% male), or IB (20 mcg) Respimat inhaler (n=483, mean age 64.3 yr, 65.5% male). Each medication was administered q.i.d. Results The withdrawal rates were similar for the 3 treatment groups (12.6% IB Respimat inhaler; 11.2% IP/A MDI; 9.9% IB/A Respimat inhaler). Comparable bronchodilation was achieved with IB/A Respimat inhaler and IB/A MDI, and both were superior to IB Respimat inhaler. IB/A Respimat inhaler improved FEV1 compared IB Respimat inhaler at 0-4 and 0-6 hr on all test days. Peak FEV1, peak FEV1 response, and peak FVC response were comparable between IB/A Respimat inhaler and IB/A MDI and superior to IB Respimat inhaler. Median duration of a therapeutic response was comparable between IP/A Respimat inhaler (165-189 min) and MDI (172-219 min) overall test days, which was longer compared with IB Respimat inhaler (70-122 min). The total incidence of adverse events was comparable across treatment groups. Respiratory events were the most frequently reported adverse events and were predominately comprised of COPD exacerbations. Potential class adverse events included dry mouth and tremor. The occurrences of headache, dizziness, nausea and hypertension were the most frequent possible beta-agonist adverse events across all treatment groups. The percentage of patients who discontinued due to an adverse event was lower in the IB/A Respimat inhaler group.
  • Autor(en):
    Wollin L; Pieper MP
    Titel:
    Tiotropium bromid exerts anti-inflammatory activity in a cigarette smoke mouse model of COPD
    Quelle(n):
    DGP Meeting, Hannover (Germany), 2010.Pulm Pharmacol Ther 23 (4), 345-354 (2010)
    Abstract:
    Tiotropium bromide is a long acting muscarinic antagonist (LAMA), marketed under the brand name Spiriva<sup>®</sup>, for the treatment of chronic obstructive pulmonary disease (COPD). Besides its proven direct bronchodilatory activity, recent clinical studies demonstrated that tiotropium is able to reduce the exacerbation rate and impact the clinical course of COPD. One significant pathological feature believed to be causative for the progressive nature of COPD is chronic pulmonary inflammation. The aim of the present study was to investigate the anti-inflammatory activity of tiotropium on cigarette smoke-induced pulmonary inflammation in mice. C57Bl/6 mice were exposed to cigarette smoke (CS) for four days with increasing exposure time for up to 6 h per day to elicit pulmonary inflammation and mediator release. One hour before smoke exposure, animals were treated with tiotropium by inhalation (0.01-0.3 mg/mL) for 5 min; 18 h after the last CS exposure a bronchoalveolar lavage was performed. Tiotropium concentration-dependently inhibited pulmonary neutrophilic inflammation with an IC<sub>50</sub> of 0.058 mg/mL and a maximum inhibition of 60% at 0.3 mg/mL. Furthermore, the CS-induced pulmonary release of leukotriene B<sub>4</sub>, interleukin-6, keratinocyte-derived chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha and -2, and tumor necrosis factor alpha was dose-dependently reduced. The bronchodilatory activity of tiotropium against acetycholine-induced bronchoconstriction was found to be in the same dose range as the anti-inflammatory activity with an IC<sub>50</sub> of 0.045 mg/mL and a maximum bronchodilation of 90% at 0.3 mg/mL. Our data suggest that the beneficial effects of tiotropium on the course of COPD shown in patients may be associated with an anti-inflammatory activity. - DERWENT Abstract - This study investigated the antiinflammatory activity of inhaled tiotropium bromide (TIO, Boehr.Ingelheim) on cigarette smoke (CS)-induced pulmonary inflammation in mice. TIO concentration-dependently inhibited pulmonary neutrophilic inflammation. TIO reduced CS-induced pulmonary release of LTB4, IL-6, keratinocyte-derived chemokine, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-alpha and -2, and TNF-alpha. TIO had a bronchodilatory activity against ACh-induced bronchoconstriction. P.o. dexamethasone (Sigma-Aldrich) did not induce any reduction in CS-induced pulmonary inflammation. P.o. roflumilast (Boehr.Ingelheim) reduced CS-induced pulmonary neutrophilia. Thus, the beneficial effects of TIO on the course of COPD shown in patients may be associated with an anti-inflammatory activity. After CS exposure, 87%-94% of all accumulated cells in the airways were neutrophils in female C57BBl/6 mice (18-23 g). Depending on the experiment, total cell count in CS-exposed animals increased 2.9-3.9-fold while neutrophilic cell count increased 21-22-fold compared to room air-exposed control animals. Inhaled TIO (0.3 mg/ml) administered once daily as an aerosol for 5 min 1 hr before CS exposure concentration-dependently inhibited CS-induced pulmonary neutrophil accumulation. At the highest tested concentration of tiotropium (0.3 mg/ml) maximum inhibition for LTB4, IL-6, TNF-alpha, MCP-1, MIP-1alpha and, MIP-2 was 94%, 79%, 79%, 56%, 90%, and 89%, respectively. For KC the maximum inhibition of 65% was already achieved at a tiotropium concentration of 0.1 mg/ml. Only at 0.01 mg/ml at day 4 of CS exposure a reduction of the body weight was noticed. TIO concentration-dependently inhibited ACh-induced bronchoconstriction in mice. The calculated IC50 was 0.045 mg/ml. P.o. dexamethasone (3 and 10 mg/kg) did not induce any reduction in CS-induced pulmonary inflammation. In contrast, p.o. roflumilast (5 mg/kg) reduced CS-induced pulmonary neutrophilia by 46%. TIO administered once daily or administered for 4 days did not have a suppressive effect on pulmonary neutrophil influx. However, there was a dose-dependent trend in reducing the total cell number with a maximum effect of 23%-24%. TIO administered for 4 days dose-dependently reduced IL-6 concentrations by 49% and 68% at concentrations of 0.1 and 0.3 mg/ml, respectively.
  • Autor(en):
    Tashkin DP; Celli B; Kesten S; Lystic T; Mehra S; Decramer M
    Titel:
    Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial.
    Quelle(n):
    Eur Respir J 35 (2), 287-294 (2010)
    Abstract:
    UPLIFT (Understanding Potential Long-Term Improvements in Function with Tiotropium), a 4-yr trial of tiotropium in chronic obstructive pulmonary disease, allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy. 5,993 patients were randomised (tiotropium/placebo). Lung function, St George's Respiratory Questionnaire, exacerbations and adverse events were followed. Patients were characterised as continuing smokers (CS), continuing ex-smokers (CE), or intermittent smokers (IS) based on self-reporting smoking behaviour. 60%, 14% and 26% of patients were CE, CS and IS, respectively. The rate of forced expiratory volume in 1 s (FEV1) decline for placebo patients was most rapid in CS (-51 +/- 4, -36 +/- 2 and -23 +/- 2 mL.yr(-1) in CS, IS, and CE, respectively). Tiotropium did not alter FEV1 decline, but was associated with significant improvements in pre- and post-bronchodilator FEV1 over placebo that persisted throughout the 4-yr trial for each smoking status (pre-bronchodilator: 125, 55 and 97 mL at 48 months in CS, IS and CE, respectively; p <= 0.0003). Tiotropium reduced exacerbation risk in CS (HR (95%CI) 0.81 (0.68-0.97)), in CE (0.86 (0.79-0.93)) and trended towards significance in IS (0.89 (0.80-1.01)). At 4 yrs, St George's Respiratory Questionnaire for tiotropium patients improved the most in CS (-4.62 units, p=0.0006) and the least in IS (-0.54 units, p=0.55), compared with control. Tiotropium provided long-term benefits irrespective of smoking status, although differences among categories were observed. - DERWENT Abstract - The Authors assessed long-term responses to maintenance bronchodilator therapy tiotropium and smoking status in a 4-yr randomized placebo-controlled trial of 5925 patients with COPD. A total of 60%, 14%, and 26% of patients were continuing ex-smokers (CE), continuing smokers (CS), and intermittent smokers (IS), respectively. The rate of forced expiratory volume in 1 sec (FEV1) decline for placebo patients was most rapid in CS. Tiotropium did not alter FEV1 decline but was associated with improvements in pre- and post-bronchodilator FEV1 over placebo. Tiotropium reduced exacerbation risk in CS, in CE, and trended toward significance in IS. At 4 yr, St. George's Respiratory Questionnaire for tiotropium patients improved the most in CS and the least in IS. Tiotropium provides long-term benefits irrespective of smoking status, although differences among categories are observed. Methods 5925 Patients with COPD randomly received tiotropium or placebo. 3534, 846, And 1545 patients were CE (mean age 66.4 yr, 77.1% male), CS (mean age 60.7 yr, 66.5% male), and IS (mean age 62.3 yr, 73.3% male), respectively. Results Irrespective of treatment assignment, CS had the most rapid rate of FEV1 decline and the CE the slowest rate of decline, with the IS exhibiting an intermediate decline. For each smoking category the rate of lung function decline (FEV1) showed similar differences between the tiotropium and control arms. Although the primary end-point was rate of change in FEV1 from 30 days through 48 mth postrandomization and was similar between treatment groups within each of the 3 smoking behavior categories, improvements in lung function (FEV1, FVC, and SVC) were observed with tiotropium compared with the control group within each of the 3 smoking behavior categories throughout the trial. The improvements in the CS were numerically larger than in either the ex-smoking or the intermittent smoking group. This was evident at both 1 mth and 48 mth after the initiation of treatment. Tiotropium was associated with a reduced risk of an exacerbation by 19% and 14% in CS and CE, respectively and, to a lesser extent, in IS. Tiotropium was associated with improved St. George's Respiratory Questionnaire scores at both 6 and 48 mth in both CS and CE, the effect being largest in the CS. CS had the highest mortality rate followed by CE and then IS. There were reductions in mortality in CE and IS related to tiotropium that were significant in the CE both on treatment and during the protocol-defined treatment period.
  • Autor(en):
    Koegler H; Metzdorf N; Glaab T; Welte T
    Titel:
    Preselection of patients at risk for COPD by two simple screening questions.
    Quelle(n):
    Respir Med 104 (7), 1012-1019 (2010)
    Abstract:
    Background: The Burden of Obstructive Lung Disease study showed that in Germany, to confirm the diagnosis of chronic obstructive lung disease (COPD) in one subject, eight people ?40 years of age have to be screened. The number-needed-to-screen (NNS) increased to 18 for identifying a patient with COPD ? GOLD stage II. These high numbers limit the cost-effectiveness of COPD screening by population spirometry. We investigated in a primary care setting whether using two simple questions regarding smoking status and presence of cough and/or dyspnea may help to preselect patients for proper diagnosis of COPD. Methods: A total of 1088 patients aged ?40 yrs without a history of chronic lung disease, who were either current or ex-smokers and complained of cough and/or dyspnea, were examined by respiratory physicians. Spirometry was carried out to confirm COPD diagnosis and severity. Results: A total of 61.6% of patients were male. Mean smoking history was 31.8 pack-yrs. In 516 patients (47.4%), a diagnosis of COPD was confirmed. Among these, 379 (34.8% of total) had at least GOLD stage II COPD, while 89 (8.2% of total) had advanced disease (GOLD stages III/IV). COPD prevalence was significantly associated with age and the extent of cigarette smoke exposure. Conclusions: Two questions regarding smoking status and presence of cough and/or dyspnea enabled general practitioners to select patients at risk for COPD for subsequent spirometry. This preselection reduced the NNS to 2.1 for identifying a COPD patient, and to 2.9 for identifying a patient of at least GOLD stage II.
  • Autor(en):
    Soler N; Ballester E; Martin A; Gobartt E; Miravitlles M; Torres A
    Titel:
    Changes in management of chronic obstructive pulmonary disease (COPD) in primary care: EMMEPOC study.
    Quelle(n):
    Respir Med 104 (1), 67-75 (2010)
    Abstract:
    Background: Changes in management of COPD in primary care were studied following a training exercise among Spanish general practitioners (GPs). The exercise involved dissemination of the Spanish Society for Pulmonology and Thoracic Surgery (SEPAR) guidelines. The use of a portable device to perform spirometry tests was evaluated to adequately categorize COPD and reduce other diagnostic interventions. Methods: A representative sample of GPs from general practices in Spain was recruited for the study. In phase I, GPs performed an initial evaluation of 5 patients with COPD. In phase II, GPs were randomly allocated to the following groups: 1) control group-G1 (GPs managing COPD according to usual clinical practice); 2) training group-G2 (dissemination of SEPAR guidelines); and 3) training group-G3 (dissemination of SEPAR guidelines and distribution of the Koko Peak Pro to measure FEV1, FEV6, and FEV1/FEV6). Results: Phase-I included 3254 physicians, who selected 16,024 patients. In phase II, 301 physicians in G1, 1182 in G2, and 1141 in G3 selected 1481, 5798, and 5556 patients respectively. Evaluation of the changes in COPD stratification according to the SEPAR guidelines showed that physicians in G1 adequately classified 60% of patients, compared to 69% in G2 and 88.5% in G3 (p < 0.0001). On comparing groups G1 and G3, a significant reduction was seen in chest X-rays (from 42% to 32%, p = 0.0002) and arterial blood gas studies performed (from 34% to 22%, p < 0.0001). Conclusions: The dissemination of the SEPAR guidelines and the utilization of the portable device for spirometry may improve management of COPD in primary care.
  • Autor(en):
    Wagner J; Kneucker A; Liebler-Tenorlo E; Fachinger V; Glaser M; Pesch S; Murtaugh MP; Reinhold P
    Titel:
    Respiratory function and pulmonary lesions in pigs infected with porcine reproductive and respiratory syndrome virus.
    Quelle(n):
    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.
  • Autor(en):
    Decramer M; Kesten St; Celli B; Tashkin DP
    Titel:
    How much lift to the UPLIFT study? - Authors' reply.
    Quelle(n):
    Lancet 375 (9710), 198 (2010)
  • Autor(en):
    Yamamoto N; Tamura T; Takahashi T; Murakami H; Nokihara H; Naito T; Nishio K; Seki Y; Sarashina A; Shahidi M
    Titel:
    Phase I open-label trial of continuous dose of BIBW 2992 in patients with advanced non-small cell lung cancer failing chemotherapy and/or erlotinib and/or gefitinib (LUX-Lung 4).
    Quelle(n):
    IASLC-ESMO Conference, Geneva (Switzerland), Apr 28-May 1, 2010.J Thorac Oncol 5 (5), 91-91 Abs230 (2010)
    Abstract:
    This phase I, open-label trial evaluated the safety, tolerability, pharmacokinetics (PK), tumor response and recommended dose of p.o. BIBW-2992 in the treatment of 12 patients with advanced NSCLC. Mucositis was the only DLT. Adverse events (AEs) were diarrhea, dry skin, stomatitis, rash, paronychia, and anorexia. Peak plasma concentrations of BIBW-2992 were reached 3-4 hr after administration and the half life was reached after 30-40 hr. The safety and PK profile of BIBW-2992 in Japanese patients were similar to non-Japanese patients. Thus continuous p.o. BIBW-2992 at a starting dose of 50 mg, once daily was well tolerated with acceptable safety profile in NSCLC patients. Methods 12 NSCLC patients (median age 62.5 yr, who had either failed standard chemotherapy and/or treatment with gefitinib or erlotinib, or those with no other appropriate therapy available, were treated with p.o. BIBW-2992 (20 mg, every day); doses were increased to 50 mg, every day until 33.3% or more Grade >2 toxicity occurred. PK sampling was performed on days 1-2 and at steady state of the initial treatment course. Tumor response was assessed by RECIST. EGFR mutation analysis in serum and tumor specimens was performed where possible. Results 1 DLT was seen in course 1 patient developed grade 3 mucositis at 50 mg, which subsided following dose reduction. Most AEs were mild (grade 1 or 2) and included diarrhea, dry skin, stomatitis, rash, paronychia, and anorexia. Peak plasma concentrations of BIBW-2992 were reached 3-4 hr after administration; the half life was 30-40 hr. 6/12 Patients had tumor size reductions, with 3 achieving prolonged stable disease (SD). EGFR mutation status was wild-type (n=4) and EGFR exon 19 deletion and T790M
  • Autor(en):
    Monz BU; Sachs P; McDonald J; Crawford B; Nivens MC; Tetzlaf K
    Titel:
    Responsiveness of the cough and sputum assessment questionnaire in exacerbations of COPD and chronic bronchitis.
    Quelle(n):
    Respir Med 104 (4), 534-541 (2010)
    Abstract:
    Background: To assess the responsiveness of the Cough and Sputum Assessment Questionnaire (CASA-Q) in COPD and chronic bronchitis patients recovering from an acute exacerbation. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings. The four domains (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. Methods: Outpatients were enrolled within 48 h of symptom onset of their exacerbation. Treatment was initiated at the discretion of the investigator, and patients observed for 6 weeks. During study visits, 59 eligible patients completed the CASA-Q at enrolment, week 1, 2 and 6. Responsiveness was assessed by calculating standardized effect sizes. Results: Of the 19 male and 40 female patients with a mean (standard deviation, SD) age of 61.1 (10.5) years, all were classified by their physician to have improved or recovered after six weeks. The mean (SD) CASA-Q sores for the cough symptom, cough impact, sputum symptom and sputum impact domains increased from 32.6 (21.0), 40.7 (22.4), 37.4 (20.1), 47.1 (24.2) at enrolment to 54.0 (19.8), 63.7 (21.3), 55.1 (19.0), 65.5 (20.5) at week 6, respectively. Standardized effect sizes for patients improved or recovered from their exacerbation at week 6 were above 1.0 for the cough domains and at least 0.77 for the sputum domains. Conclusions: The CASA-Q was responsive to symptom changes in patients recovering from an exacerbation.
nach oben