Effect of Symbicort ® on GR in Sputum in COPD
Condition: Chronic Obstructive Lung Disease
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of the research (or "knowledge gap" this research is designed to fill) is to
      understand the science of how the combination therapy of 2 drugs (inhaled longacting
      beta-agonists(LABA) and inhaled corticosteroids (ICS), which are commonly used in chronic
      obstructive pulmonary disease (COPD) patients, is better than each drug alone. ICS and LABA
      both have antiinflammatory properties; that is, they dampen the inflammation in the cells of
      the airways in the lungs. The combination of LABA and ICS has also been shown to improve
      clinical effectiveness in asthma patients. The addition of a LABA to LOW doses of ICS has
      been shown to be more clinically beneficial in asthma than the use of HIGH doses of ICS
      alone. This has allowed a reduction in the total ICS dose and minimised the adverse side
      effects of inhaled corticosteroids. Recent evidence suggests that the use of combination
      therapy of LABA and ICS may also improve clinical effectiveness in COPD patients.

      Investigators will address this hypothesis by examining the inflammation cells of COPD direct
      from the site of disease (the airways) by looking at sputum/mucus. This research will build
      on the existing knowledge of the science of how these drugs work in asthma and COPD and
      allows us to understand the molecular science, which may support new future drug targets for
      patients with COPD, which are greatly needed.
    

Detailed description: 
      Corticosteroids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR).
      The inactive GR is bound to a protein complex that includes heat shock protein hsp90, acting
      as molecular chaperones to prevent the nuclear localisation of unoccupied GR.

      GR binding to the palindromic promotor induces the transcriptional induction of
      anti-inflammatory genes such as mitogen-activated protein kinase phosphatase-1 (MKP-1) and
      secretory leukocyte protease inhibitor (SLPI). GR-steroid complex also binds to negative GRE
      sequences, resulting in inhibition of pro-inflammatory mediators, such as IL-6. More
      importantly, GR binds transcription factor with recruitment of histone deacetylase (HDAC) and
      inhibits wide range of pro-inflammatory cytokines. By this process of transrepression,
      corticosteroids reduce such pro-inflammatory cytokines as tumour necrosis-alpha (TNF-alpha)
      and interleukin-8 (IL-8) in asthmatic patients whereas they are far less effective in chronic
      obstructive pulmonary disease (COPD) patients.

      The combination of inhaled corticosteroids (ICS) and long acting beta 2-agonists (LABAs) has
      been shown to improve clinical effectiveness and anti-inflammatory properties in asthma. The
      addition of a LABA to low dose ICS has been shown to be more clinically beneficial in asthma
      than the use of high dose ICS, allowing a reduction in ICS dose and minimising and adverse
      side effects of corticosteroids. Recent evidence suggests that this may also be the case in
      COPD.

      ICS such as budesonide, beclomethasone and fluticasone have been used in combination with
      LABA's such as formoterol and salmeterol. These combination treatments are established in
      national guidelines for treating patients with asthma and also, COPD. The combination of
      formoterol and budesonide (Symbicort ®, Astra Zeneca) will be studied in this project.

      Evidence suggests that LABAs enhance GR function in vitro. In an asthmatics study, the
      combination of formoterol and budesonide (Symbicort ®, Astra Zeneca) was as effective as high
      dose ICS on GR activation, gene transactivation and transrepression. However, the precise
      mechanisms for this enhanced effectiveness are unknown, although priming of the steroid
      receptor (GR) by LABAs may be important.

      Investigators have developed a novel method of measuring GR-GRE binding activity in sputum
      using an enzyme immunosorbent assay system. This method, together with the measurements of
      some functional readouts, will help us to understand some of the mechanisms of steroid and GR
      interactions using non-invasive methods of assessment of the airways. This may provide
      insight into the mechanisms of corticosteroid action and whether the addition of a LABA to
      ICS can alter molecular patterns, which may explain the observed beneficial action of
      combination therapy seen in patient studies in vivo. This may allow a scientific basis to
      explore future drug interactions that may be helpful in patients, particularly those patients
      whose disease tends to be severe and may be unresponsive to standard therapies for COPD
      and/or where high dose ICS have little beneficial clinical effect and have led to
      side-effects.
    

Intervention name(s): Symbicort® total dose 400ug/12ug; Symbicort® total dose 800ug/24ug; Formoterol 24ug; BUD total dose 800ug
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Symbicort® is combination of formoterol 400ug and budesonide 12ug. Single dose; Symbicort® is combination of formoterol 800ug and budesonide 24ug. Single dose; Turbuhaler; Turbuhaler
Intervention MeSH terms: Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Chronic Obstructive Lung Disease