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ABSTRACT: The aims were to determine the effect of an oral inhibitor of the signaling mediator p38 mitogen-activated protein kinase (GW856553, losmapimod) on sputum neutrophils, pulmonary function, and blood biomarkers of inflammation in chronic obstructive pulmonary disease (COPD). Three hundred and two individuals with GOLD stage II COPD were randomized to oral losmapimod 7.5 mg twice daily, inhaled salmeterol/fluticasone propionate 50 µg/500 µg combination (SFC), or placebo in a 12-week, randomized, double-blind, double-dummy study (MKI102428/NCT00642148). Neither losmapimod nor SFC had an effect on the primary end point of sputum neutrophils. Losmapimod was well tolerated and reduced plasma fibrinogen by 11% (-0.4 g/L, ratio of effect of losmapimod/placebo 0.89; 95% confidence interval, 0.83-0.96; P = .002) with nonsignificant reductions in interleukin-6, interleukin-8, and C-reactive protein. There was evidence of improvement in hyperinflation with losmapimod compared with placebo (overall P = .02). Inhaled SFC significantly improved lung function and reduced serum CC-16 (ratio of effect of SFC/placebo 0.87; 95% confidence interval, 0.82-0.93; P < .001). It was concluded that oral losmapimod significantly reduced plasma fibrinogen in patients with COPD.
The Journal of Clinical Pharmacology 11/2011; 52(3):416-24. · 2.91 Impact Factor
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ABSTRACT: Most patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However the value of their use remains uncertain. Some controlled trials of antibiotics have shown benefit (Berry 1960; Pines 1972) while others have not (Elmes 1965b; Nicotra 1982).
To conduct a systematic review of the literature estimating the value of antibiotics in the management of acute COPD exacerbations.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2005, issue 4) which contains the Acute Respiratory Infections Group's Specialized Register; MEDLINE (1966 to December 2005); EMBASE (1974 to December 2005); Web of Science (December 2005), and other electronically available databases.
Randomised controlled trials (RCTs) in patients with acute COPD exacerbations comparing antibiotic (for a minimum of five days) and placebo.
Data were analysed using Review Manager software. Continuous data were analysed using weighted mean differences (WMD) and 95% confidence intervals (CI). Relative risks (RR) (and 95% CI) were calculated for all dichotomous data. Where appropriate, number needed to treat to benefit (NNT) and 95% CI were calculated.
Eleven trials with 917 patients were included. Ten trials used increased cough, sputum volume and purulence diagnostic criteria for COPD exacerbation. Eight-hundred and fifty-seven patients provided data for outcomes including mortality, treatment failure, increased sputum volume, sputum purulence, PaCO(2), PaO(2), peak flow and adverse events. Antibiotic therapy regardless of antibiotic choice significantly reduced mortality (RR 0.23; 95% CI 0.10 to 0.52 with NNT of 8; 95% CI 6 to 17), treatment failure (RR 0.47; 95% CI 0.36 to 0.62 with NNT of 3; 95% CI 3 to 5) and sputum purulence (RR 0.56; 95% CI 0.41 to 0.77 with NNT of 8; 95% CI 6 to 17). There was a small increase in risk of diarrhoea with antibiotics (RR 2.86; 95% CI 1.06 to 7.76). Antibiotics did not improve arterial blood gases and peak flow.
This review shows that in COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short-term mortality by 77%, decrease the risk of treatment failure by 53% and the risk of sputum purulence by 44%; with a small increase in the risk of diarrhoea. These results should be interpreted with caution due to the differences in patient selection, antibiotic choice, small number of included trials and lack of control for interventions that influence outcome, such as use of systemic corticosteroids and ventilatory support. Nevertheless, this review supports antibiotics for patients with COPD exacerbations with increased cough and sputum purulence who are moderately or severely ill.
Cochrane database of systematic reviews (Online) 01/2011; · 5.72 Impact Factor
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ABSTRACT: Budesonide/formoterol maintenance and reliever therapy maintains asthma control and reduces exacerbation frequency compared with higher fixed-dose combination regimens. Its effects on eosinophilic airway inflammation and structure are unknown.
We sought to compare the effects of budesonide/formoterol 200/6 microg twice daily plus as-needed with budesonide/formoterol 800/12 microg twice daily on airway eosinophils and remodeling.
This 52-week, parallel-group, randomized, double-blind study of 127 asthma patients who were symptomatic despite therapy compared (1) the change between induced sputum percent eosinophils at baseline and the geometric mean of 4 on-treatment values and (2) the change in endobronchial biopsy eosinophil counts pre- and post-treatment.
Mean daily doses of budesonide/formoterol were 604/18 microg in the maintenance and reliever therapy group and 1,600/24 microg in the high fixed-dose group. In the former, the geometric mean percent sputum eosinophils remained unchanged (1.6% to 1.9%), whereas biopsy specimen subepithelial eosinophils increased (6.2 to 12.3 cells/mm(2)). Sputum and biopsy eosinophil counts decreased with high fixed-dose treatment (2.2% to 1.2% and 7.7 to 4.8 cells/mm(2), respectively), resulting in significant treatment differences of 0.7% (ratio, 1.8; 95% CI, 1.2-2.8; P = .0038) and 7.5 cells/mm(2) (ratio, 2.9; 95% CI, 1.6-5.3; P < .001), respectively. There were no between-treatment differences in reticular basement membrane thickness, exhaled nitric oxide, exacerbation frequency, or FEV(1).
Compared with fixed-dose combination treatment containing a 4-fold higher maintenance dose of budesonide, budesonide/formoterol maintenance and reliever therapy is associated with higher eosinophil counts, but these remain within the range associated with stable clinical control.
The Journal of allergy and clinical immunology 04/2009; 123(5):1083-9, 1089.e1-7. · 9.17 Impact Factor
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Patrick Flood-Page,
Cheri Swenson,
Isidore Faiferman,
John Matthews,
Michael Williams,
Lesley Brannick,
Douglas Robinson,
Sally Wenzel,
William Busse,
Trevor T Hansel, Neil C Barnes
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ABSTRACT: Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans.
To investigate the effect of three intravenous infusions of mepolizumab, 250 or 750 mg at monthly intervals, on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400-1,000 mug of beclomethasone or equivalent).
Multicenter, randomized, double-blind, placebo-controlled study.
Morning peak expiratory flow, forced expiratory volume in 1 second, daily beta(2)-agonist use, symptom scores, exacerbation rates, and quality of life measures. Sputum eosinophil levels were also measured in a subgroup of 37 individuals. Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups (blood, P < 0.001 for both doses; sputum, P = 0.006 for 250 mg and P = 0.004 for 750 mg). There were no statistically significant changes in any of the clinical end points measured. There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group (P = 0.065).
Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.
American Journal of Respiratory and Critical Care Medicine 12/2007; 176(11):1062-71. · 11.08 Impact Factor
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ABSTRACT: Cigarette smoking worsens asthma and is associated with reduced response to corticosteroid therapy. As cigarette smoke is known to have immunomodulatory effects, we hypothesized that one mechanism by which smoking mediates its adverse effect is by reduction of the numbers of bronchial mucosal dendritic cells (DCs), which control B-cell growth and T-cell responses.
We set out to sample the bronchial mucosa in smoking and never-smoking patients with asthma and to count DCs, B cells, and cells expressing genes for two key T-lymphocyte regulatory cytokines.
Twenty-one never-smoker patients with asthma (6 steroid naive), 24 smoker patients with asthma (9 steroid naive), and 10 healthy never-smokers (control subjects) were recruited and their endobronchial biopsy samples were immunostained for detection of mature DCs (CD83(+)), Langerhans cells (CD1a(+)), B lymphocytes (CD20(+)), and helper T-cell type 1 (IFN-gamma) and helper T-cell type 2 (IL-4) cytokine-expressing cells.
The number (per square millimeter) of CD83(+) mature DCs was significantly lower in smoker patients with asthma (median [range]: 37 [0, 131]) in comparison with never-smoker steroid-naive and steroid-treated patients with asthma (76 [24, 464]; p = 0.006) or control subjects (85 [40, 294]; p = 0.004). Moreover, B cells were fewer in smoker (26 [4, 234]) versus never-smoker steroid-naive and steroid-treated patients with asthma (45 [10, 447]; p = 0.01) and in smoker steroid-naive patients with asthma (23 [4, 111]) versus control subjects (34 [10, 130]; p = 0.05). The number of cells expressing IFN-gamma showed a trend toward fewer in smoker (70 [6, 24]) versus never-smoker steroid-naive patients with asthma (144 [44, 323]; p = 0.10).
There are important and statistically significant differences in the number of CD83(+) mature DCs and B cells in the large airways of smokers with asthma. We speculate that their reductions may render patients with asthma less responsive to corticosteroids and more susceptible to infection.
American Journal of Respiratory and Critical Care Medicine 06/2007; 175(9):919-25. · 11.08 Impact Factor
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ABSTRACT: No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease.
We tested the hypothesis that inhaled combined long-acting beta2-agonist (salmeterol) and corticosteroid (fluticasone propionate) will reduce inflammation.
Bronchial biopsies and induced sputum were taken from 140 current and former smokers (mean age, 64 yr) with moderate to severe disease, randomized in a 13-wk double-blind study to placebo (n = 73) or salmeterol/fluticasone propionate 50/500 microg (n = 67) twice daily. Biopsies were repeated at 12 wk and sputa at 8 and 13 wk. After adjustment for multiplicity, comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8+ and CD68+ cells/mm2 and sputum neutrophils.
Combination therapy was associated with a reduction in biopsy CD8+ cells of -118 cells/mm2 (95% confidence interval [CI], -209 to -42; p = 0.02), a reduction of 36% over placebo (p = 0.001). CD68+ cells were unaffected by combination treatment. Sputum differential (but not total) neutrophils reduced progressively and, at Week 13, significantly with combination treatment (median treatment difference, 8.5%; 95% CI, 1.75%-15.25%; p = 0.04). The combination also significantly reduced biopsy CD45+ and CD4+ cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils (all p < or = 0.03). These antiinflammatory effects were accompanied by a 173-ml (95% CI, 104-242; p < 0.001) improvement in prebronchodilator FEV1.
The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease, which may contribute to clinical efficacy.
American Journal of Respiratory and Critical Care Medicine 05/2006; 173(7):736-43. · 11.08 Impact Factor
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Elizabeth Gamble,
Diana C Grootendorst,
Christopher E Brightling,
Susannah Troy,
Yusheng Qiu,
Jie Zhu,
Debbie Parker,
Dean Matin,
Swati Majumdar,
Antonio M Vignola, [......],
Trevor T Hansel,
Stephen I Rennard,
Christopher Compton,
Ohad Amit,
Tri Tat,
Jeffrey Edelson,
Ian D Pavord,
Klaus F Rabe, Neil C Barnes,
Peter K Jeffery
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ABSTRACT: Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.
American Journal of Respiratory and Critical Care Medicine 10/2003; 168(8):976-82. · 11.08 Impact Factor
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ABSTRACT: Bronchoscopy with biopsy and BAL is being performed increasingly in patients with COPD as a research tool. Previous reports have shown these procedures to be safe in asthmatic patients, but there is little safety data specific to COPD.
We studied 57 patients with COPD (11 women and 46 men; median FEV(1), 1.2 L [range, 0.64 to 2.69 L]; percent predicted FEV(1), 44.5% [range, 25 to 74.8%]). Eleven patients had mild disease, 28 patients had moderate disease, and 18 patients had severe disease according to British Thoracic Society classification. Ninety-eight bronchoscopies were performed according to American Thoracic Society guidelines: 68 procedures with endobronchial biopsy and BAL and 30 procedures with biopsy alone. Controlled oxygen was administered via nasal cannula, and pulse oximetry and vital signs were monitored.
Five adverse events occurred. One patient in the moderate-disease group had severe bronchospasm requiring 4 days of inpatient treatment. One patient in the severe-disease group had a pneumothorax requiring 7 days of inpatient treatment. There were three episodes of hemoptysis, two with pleuritic pain (in the BAL group) that settled without intervention. No deaths or prolonged morbidity were observed. We found a 2.0% incidence of adverse events requiring hospital treatment and a 3.1% incidence of minor hemoptysis requiring no intervention.
Bronchoscopy, biopsy, and BAL can be performed safely in patients with COPD, including those with severe disease, provided careful assessment is performed and guidelines are adhered to.
Chest 01/2003; 122(6):1909-12. · 5.25 Impact Factor
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ABSTRACT: Inhaled corticosteroids (ICS) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies. However, the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease (COPD) is unknown. We have performed a double-blind, placebo-controlled, randomized study to compare fluticasone propionate (FP) 500 microg twice daily via a dry powder inhaler and placebo (P) over a 3-month period in subjects with COPD. Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment. Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis. Compared with P (n = 14), subjects on inhaled FP (n = 16) had no significant reductions in the primary endpoints: CD8+, CD68+ cells, or neutrophils, considered to be of importance in COPD. However, there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group. CD4+ cells were significantly raised in the P group in both subepithelium and epithelium. Symptoms significantly improved, and there were significantly fewer exacerbations in subjects on FP, compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD, and this may explain, in part, the decrease in exacerbations seen in long-term studies with fluticasone propionate.
American Journal of Respiratory and Critical Care Medicine 07/2002; 165(12):1592-6. · 11.08 Impact Factor
