Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis

Radboud University Nijmegen Medical Centre, Department of General Practice, Nijmegen, The Netherlands.
Respiratory medicine (Impact Factor: 3.09). 02/2009; 103(4):542-51. DOI: 10.1016/j.rmed.2008.11.003
Source: PubMed


Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD.
To investigate whether treatment with the inhaled corticosteroid fluticasone propionate (FP) or the anti-oxidative agent N-acetylcysteine (NAC) are effective in primary care patients.
The study was a 3-year placebo-controlled randomised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment. Patients were (ex-)smokers with chronic bronchitis or COPD. Interventions were inhaled FP 500microg b.i.d., oral NAC 600mg o.d., or placebo. Exacerbation rate and quality of life measured with the Chronic Respiratory Questionnaire (CRQ) were the primary outcomes, FEV(1) decline and respiratory symptoms secondary outcomes.
286 patients recruited from 44 general practices were randomised. Exacerbation rate was 1.35 times higher for NAC (p=0.054) and 1.30 times higher for FP (p=0.095) compared with placebo. CRQ total scores did not differ between NAC (p=0.306) or FP (p=0.581) treatment compared to placebo. Annual postbronchodilator FEV(1) decline was 64mL [SD 5.4] for NAC [p=0.569 versus placebo], 59mL [SD 5.7] for FP [p=0.935], and 60mL [SD 5.4] for placebo.
No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis.

Download full-text


Available from: Niels Chavannes,
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The oral prednisolone test is widely used to distinguish chronic obstructive pulmonary disease (COPD) patients who might benefit from inhaled steroid treatment. Previous studies used selected patient groups that did not represent the large COPD population in primary care. The study included smokers and exsmokers with chronic bronchitis or COPD from primary care, who underwent prednisolone testing (30 mg for 14 days) before randomization in a three-year follow-up randomized controlled trial (COOPT Study). Spirometry was performed before and after the test. Responders and nonresponders were classified according to international criteria. Effectiveness of inhaled fluticasone relative to placebo was compared in terms of health status (Chronic Respiratory Disease Questionnaire), exacerbations, and postbronchodilator forced expiratory volume in one second (FEV(1)), using repeated measurement analysis. Two hundred eighty-six patients recruited from 44 primary care practices were randomized. Nine percent to 16% of the COPD population was classified as responder, depending on the international guideline criteria used. On average, responders did not reach the minimum clinically important difference in health status (0.29 points/year, P = 0.05), although a borderline significant effect of inhaled fluticasone was noted. Possible clinically relevant reductions in exacerbation rate (rate ratio 0.67) and FEV(1) decline (39 mL/year) occurred in responders, but did not reach statistical significance. Oral steroid testing identifies a limited proportion of COPD patients, but does not reveal any clinically relevant benefit from inhaled steroid treatment on health status. No significant effects on exacerbation rate and lung function decline occurred.
    International Journal of COPD 11/2009; 4:431-6. DOI:10.2147/COPD.S8196 · 3.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Samenvatting Chavannes NH, Schermer TRJ, Wouters EFM, Akkermans RP, Dekhuijzen PNR, Muris JWM, et al. Het nut van de orale prednisontest bij de behandeling van COPD in de eerste lijn. Huisarts Wet 2010;5:272-6.
    Huisarts en wetenschap 05/2010; 53(5):1-5. DOI:10.1007/s12445-010-0118-0
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a considerable and growing unmet medical need in respiratory disease concerning effective anti-inflammatory therapies for conditions such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis. These diseases share a predominant characteristic of an enhanced and uncontrolled inflammatory response in the lungs, which contributes to disease progression, hospitalization and mortality. These diseases are poorly controlled by current anti-inflammatory therapies including glucocorticoids, which are otherwise effective in many other inflammatory conditions or in milder disease such as asthma. The exact cause of this apparent impairment of glucocorticoid function remains largely unclear; however, recent studies have now implicated a number of possible mechanisms. Central among these is an elevation of the oxidant burden in the lungs and the resulting reduction in the activity of histone deacetylase (HDAC)-2. This contributes to both the enhancement of proinflammatory mediator expression and the impaired ability of the glucocorticoid receptor (GR)-alpha to repress proinflammatory gene expression. The oxidant-mediated reduction in HDAC-2 activity is, in part, a result of an elevation in the phosphoinositol 3-kinase (PI3K) delta/Akt signalling pathway. Blockade of the PI3Kdelta pathway restores glucocortiocoid function in both in vitro and in vivo models, and in primary cells from disease. In addition, inhibition of the PI3Kdelta and PI3Kgamma isoforms is anti-inflammatory in both innate and adaptive immune responses. Consequently, selective inhibition of this pathway may provide a therapeutic strategy both as a novel anti-inflammatory and in combination therapy with glucocorticoids to restore their function. However, a number of other oxidant-related and -unrelated mechanisms, including altered kinase signalling and expression of the dominant negative GRbeta, may also play a role in the development of glucocorticoid insensitivity. Further elucidation of these mechanisms and pathways will enable novel therapeutic targeting for alternative anti-inflammatory drugs or combination therapies providing restoration for the anti-inflammatory action of glucocorticoids.
    Drugs 05/2010; 70(8):929-48. DOI:10.2165/10898520-000000000-00000 · 4.34 Impact Factor
Show more