Anti-inflammatory effects of salmeterol, fluticasone propionate and the combination in epithelial cells from Japanese COPD patients

Trial description: Chronic obstructive pulmonary disease (COPD) is a long-term multifaceted inflammatory disease state that consists pathologically of chronic bronchitis, small airways disease and emphysema, which may occur alone or together in varying proportion. In exacerbations of COPD, there are increases in neutrophils and eosinophils in sub-epithelial tissue and sputum. The worldwide/local guidelines emphasize the functional consequences of the disease and the fundamental underlying inflammatory process, defining COPD, as “an inflammatory disease characterised by progressive development of airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases”. Salmeterol/Fluticasone propionate combination product has been approved as a treatment for COPD. It was significantly more effective than its individual components in improving lung function, and more effective than one or both components in terms of improvements in symptoms and health status in many clinical studies in COPD patients. It produced clinically important improvement in all of these COPD endpoints as well as a significant reduction in COPD exacerbation rate compared to placebo.The mechanism of action of salmeterol/fluticasone propionate combination product is complementary and could account for additive or synergistic effects relevant to the treatment of COPD. Hence it is possible that their combined use should result in better disease control than with the agents used alone. The presence of airway inflammation in COPD and its implication in the pathophysiology of the disease provides a rationale for the use of inhaled corticosteroids. Although the inflammatory profiles in COPD and asthma differ, the anti-inflammatory effects of corticosteroids suggest they can be beneficial in both diseases. A 6-month study with fluticasone propionate (FP) has been shown to reduce CD68, and BMK13+, markers for macrophages and eosinophils respectively, in biopsies from patients with COPD. Neutrophil numbers have been shown to be reduced in a biopsy study in patients with COPD following a 3-month course of FP. Inhaled corticosteroids have also been shown to reduce neutrophil numbers in the sputum of COPD patients, possibly through suppression of neutrophil chemotaxis, although shorter-term studies of 2-4 weeks duration have failed to show an effect on induced sputum parameters. Corticosteroids increase the ß2-receptor transcription and expression in human lung in-vitro and in rat lung in-vivo, doubling the rate of transcription. Similarly, in normal human subjects, ß2-receptor density in the nasal mucosa is doubled after 3 days of treatment with a topical corticosteroid. Inflammation may lead to uncoupling of ß2-receptors from adenylate cyclase and thus reduce the responses to ß2-agonists. Long-acting ß2-agonists prime the glucocorticoid receptor for subsequent corticosteroid binding and increase the translocation of the receptor from the cell cytosol to the nucleus. Hence there is potential for a synergistic interaction between salmeterol and FP. The use of long-acting beta2-agonists and inhaled corticosteroids, either singly or in combination, is therefore supported by an increasing body of data on their mechanisms of action in COPD. The combination of SALM and FP showed additive or synergistic anti-inflammatory effects on both cigarette smoke extract and virus-induced cytokine and chemokine production form human cells (primary cells, BEAS2-B cells). However, there is no data with SALM/FP in primary cells from Japanese COPD patients.Taken together with the existing in vitro and clinical data on salmeterol and FP in COPD inflammation from overseas studies, there is a sound rationale for anti-inflammatory effects of SALM/FP in the cells from Japanese COPD patients.