GR Activity in Induced Sputum Macrophages, and a Change in Inflammatory Biomarkers 2-hours After a Single Dose of Either Symbicort®/Budesonide/Formoterol or in Chronic Obstructive Pulmonary Disease (COPD)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 1
- 主要终点
- GR-GRE Binding (Relative to Baseline)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 35 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients (n=30) with chronic obstructive pulmonary disease (COPD) with mild-to-moderate disease severity (GOLD 1 and 2 guidelines). The post-bronchodilator FEV1 will be used in the criteria to define GOLD severity (reference 7/Table 1).
- •Aged 38-80 years inclusive
- •FEV1 <15% reversibility (not % predicted) and/or an increase of <200 ml after inhaled β2-agonists (400 μg salbutamol)
- •Patients will be allowed to use their current short-acting β2-agonists (SABA) and long-acting β2-agonists (LABA) and short-acting muscarinic-antagonist (SAMA) and long-acting muscarinic-antagonists (LAMA). However they should refrain from short-acting β2-agonists (SABA) and short-acting muscarinic-antagonist (SAMA) for 6 hours before the study visit and for long-acting β2-agonists (LABA) and long-acting muscarinic-antagonists (LAMA) at least 12 hours before the study visit, unless needed by the patient's clinical condition.
- •Theophylline (an oral tablet bronchodilator) will be required to be stopped at least 3 days prior to start of Study Visit one, and patients will not be allowed this treatment during the study as it may affect the GR response and the bronchodilator (lung function, spirometry) responses.
- •Capable of giving informed consent.
排除标准
- •As a result of the medical interview, physical examination or screening investigations, the Physician Responsible considers the volunteer unfit for the study.
- •Patients who have a clinical diagnosis of Asthma, as decided by the Study Investigators, as this does not fulfil the diagnosis of chronic obstructive pulmonary disease (COPD).
- •Patients who have had a history of an upper or lower respiratory infection (including sinusitis) within 4 weeks prior to study entry, as this can affect the breathing response.
- •Patients who have received oral or parenteral steroids within 4 weeks prior to study entry, as this can affect the breathing response and signifies that their condition needs to be controlled better.
- •Patients who have been hospitalised for a COPD exacerbation within 1 month of study entry and/or has received antibiotics within 4 weeks of study entry, as this signifies that their condition needs to be controlled better.
- •Patients taking any regular medication that is contraindicated (as indicated in the British National Formulary) in those about to receive the study medications listed in this protocol; other than the oral contraceptive pill.
- •Any evidence of a positive pregnancy urine test for female volunteers or females who are pregnant or lactating or are likely to become pregnant during the trial. Women of child-bearing potential may be included in the study if, in the opinion of the investigator, they are taking adequate contraceptive precautions (which will be directly enquired at the screening visit).
- •Patients who have a history of drug allergy which, in the opinion of the Unit Physician, contraindicates his/her participation in the study.
- •Patients with a known or suspected allergy to corticosteroids or any component of the formulations and/or suspected hypersensitivity to inhaled corticosteroid (this will be asked directly at the screening visit).
- •Patients who regularly, or on average, drink more than 21 units of alcohol (males) and 14 units of alcohol (female) per week (this will be asked directly at the screening visit).
研究组 & 干预措施
COPD
Participants with COPD
干预措施: Formoterol 24ug (Drug)
Symbicort® total dose 400ug/12ug
Symbicort® total dose 400ug/12ug: is a combination of FORM (6ug) and ICS (Budesonide, (BUD) 200ug)
干预措施: Symbicort® total dose 400ug/12ug (Drug)
Symbicort® total dose 800ug/24ug
Symbicort® total dose 800ug/24ug: is a combination FORM (12ug) and BUD (400ug) at a higher-dose
干预措施: Symbicort® total dose 800ug/24ug (Drug)
BUD total dose 800ug
BUD total dose 800ug: is an intermediate dose of ICS
干预措施: BUD total dose 800ug (Drug)
结局指标
主要结局
GR-GRE Binding (Relative to Baseline)
时间窗: Screening visit and 2 hours post inhalation of treatment
Enzyme immunosorbent assay system
次要结局
- Changes in IL-6 Levels(Screening visit and 2 hours post inhalation of treatment)
- Changes in CXCL8 Levels(Screening visit and 2 hours post inhalation of treatment)
- Changes in Lung Function Parameter FEV1(Baseline and 2 hours post inhalation)
- Changes in TNF Alpha(Screening visit and 2 hours post inhalation of treatment)