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  • Journal article
    O'Byrne PM, FitzGerald JM, Zhong N, Bateman E, Barnes PJ, Keen C, Almqvist G, Pemberton K, Jorup C, Ivanov S, Reddel HKet al., 2017,

    The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials

    , Trials, Vol: 18, ISSN: 1745-6215

    Background: In many patients with mild asthma, the low frequency of symptoms and the episodic nature ofexacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance onshort-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poorcontrol of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol ‘as needed’ inresponse to symptoms may represent an alternative treatment option for patients with mild asthma.Methods/design: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week,double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with aclinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaledcorticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid)plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-neededbudesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthmaweeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versusmaintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, orbudesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate thenoninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured bythe annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recordedelectronically using Turbuhaler® Usage Monito

  • Journal article
    Barnes PJ, 2016,

    Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

    , Pharmacological Reviews, Vol: 68, Pages: 788-815, ISSN: 1521-0081

    Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation, and proliferation. For this reason there has been great interest in the development of kinase inhibitors as anti-inflammatory therapies, particular where corticosteroids are less effective, as in severe asthma and COPD. However, it has proven difficult to develop selective kinase inhibitors that are both effective and safe after oral administration and this has led to a search for inhaled kinase inhibitors, which would reduce systemic exposure. Although many kinases have been implicated in inflammation and remodeling of airway disease, very few classes of drug have reached the stage of clinical studies in these diseases. The most promising drugs are p38 MAP kinases, isoenzyme-selective PI3-kinases, Janus-activated kinases, and Syk-kinases, and inhaled formulations of these drugs are now in development. There has also been interest in developing inhibitors that block more than one kinase, because these drugs may be more effective and with less risk of losing efficacy with time. No kinase inhibitors are yet on the market for the treatment of airway diseases, but as kinase inhibitors are improved from other therapeutic areas there is hope that these drugs may eventually prove useful in treating refractory asthma and COPD.

  • Journal article
    Barnes PJ, 2016,

    Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

    , Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 16-27, ISSN: 1097-6825

    Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.

  • Journal article
    Barnes PJ, 2015,

    Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes

    , JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 136, Pages: 531-545, ISSN: 0091-6749
  • Journal article
    Barnes PJ, 2015,

    Identifying Molecular Targets for New Drug Development for Chronic Obstructive Pulmonary Disease: What Does the Future Hold?

    , SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 36, Pages: 508-522, ISSN: 1069-3424
  • Journal article
    Barnes PJ, 2015,

    Mechanisms of development of multimorbidity in the elderly

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 790-806, ISSN: 0903-1936
  • Journal article
    Mortaz E, Adcock IM, Tabarsi P, Masjedi MR, Masjedi MR, Mansouri D, Velayati AA, Casanova J-L, Barnes PJet al., 2015,

    Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.

    , Journal of clinical immunology, Vol: 35, Pages: 1-10, ISSN: 0271-9142

    Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities.

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