Clinical trial NCT00671151: Effects of Low-Dose Theophylline During Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Official title: Molecular Mechanisms of COPD Exacerbations. Effect of Low-Dose Theophylline
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COPD
Keywords: COPD exacerbation
histone
steroid resistance
inflammation
theophylline
Lead sponsor: Hospital Universitari Son Dureta
Sponsor class: OTHER
Collaborators: name: Fondo de Investigación Sanitaria (FIS)
name: Sociedad Española de Neumología y Cirugía Torácica
First posted: 2008-05-05
Enrollment: 35
Sex: MALE
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Molecular mechanisms of COPD exacerbations and the modulating effect of low dose theophylline on that inflammation are elucidated in this project. NF-kappa B-dependent pathway and acetylation status of nuclear histones are to be studied.Design: controlled, prospective and randomized study with or without theophylline, a potent HDAC activator.Objectives: 1) To determine NF-kB activation, histone deacetylase (HDAC) and histone acetyl-transferase (HAT) activity in sputum macrophages and blood monocytes during an episode of exacerbation and 3 months later, once stability is achieved. To correlate these measurements with inflammatory and oxidative stress markers and with pulmonary function and clinical variables. 2) To assess the effect of theophylline on previous molecular, functional and clinical data. Method: 25 patients with COPD will be recruited during an episode of exacerbation requiring hospitalization. NF-kB activation, HDAC and HAT activity, markers of inflammation and oxidative stress will be determined with specific assays. These determinations will be repeated once the patient is stable and compared with smokers and non smoker controls with normal lung function


Eligibility criteria: Inclusion Criteria:

* Severe COPD according to GOLD guidelines
* Age between 40 and 75
* Admission to hospital due to COPD exacerbation

Exclusion Criteria:

* History of asthma
* Pulmonary embolism
* Pneumonia
* Other chronic inflammatory disease
* Patient on theophylline at the time of admission
* Patient on oral steroids at the time of admission

Primary outcomes:
measure: HDAC activity in alveolar macrophages
timeFrame: 3 months
Secondary outcomes:
measure: Lung function
timeFrame: 3 months
measure: Inflammatory cytokine release in sputum and serum
timeFrame: 3 months
Other outcomes:
Locations:
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Dureta
state: Baleares
Study officials:
affiliation: Hospital Universitario Son Dureta
name: Borja G Cosio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004 Sep 6;200(5):689-95. doi: 10.1084/jem.20040416. Epub 2004 Aug 30.
citation: Cosio BG, Iglesias A, Rios A, Noguera A, Sala E, Ito K, Barnes PJ, Agusti A. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax. 2009 May;64(5):424-9. doi: 10.1136/thx.2008.103432. Epub 2009 Jan 21.