Pharmacological evidence of beneficial interactions in asthma
To better understand the complementary interactions between LABAs and ICSs, data have been recently produced about the non-bronchodilator effects of β₂-agonists and the possible influence of a combined administration with a corticosteroid.

A recent study confirmed that corticosteroids and long-acting β₂-agonists may have a complementary and synergistic mode of action on the inflammatory processes in asthma.¹⁶ In fact, induced sputum cells (ISC) from 20 mild asthmatic patients have been cultured for 24 h with beclomethasone dipropionate (BDP), salbutamol and formoterol either alone or in combination (BDP plus salbutamol and BDP plus formoterol). The release of specific inflammatory mediators (GM-CSF, RANTES and IL-8) in ISC has been significantly reduced by BDP plus salbutamol or formoterol as compared with either drug alone (p<0.0001). β₂-receptor expression has increased after 30 min of incubation with BDP and continued to increase over a time period of 4 h (p<0.0001). Furthermore after 30 min of incubation, nuclear translocation of GR was greater with BDP plus salbutamol or formoterol than with any of the drugs alone (p<0.0001). Therefore, this ex vivo study demonstrated a complementary mode of action between BDP and salbutamol or formoterol leading to an enhanced anti-inflammatory activity.

Pharmacological evidence of beneficial interactions in COPD
So far there are no available treatments which can reduce the exaggerated airway wall inflammation of COPD. A recent study has been performed to test the hypothesis that inhaled combined LABA/ICS will reduce the inflammatory component in COPD.¹⁷ Bronchial biopsies and induced sputum were taken from current and former smokers with moderate-to-severe COPD, who were randomised for 13 weeks to either placebo or salmeterol plus fluticasone (50/500 mcg) twice daily. Combination therapy was associated with a reduction in biopsy CD8⁺ cells (p=0.02) of 36% over placebo (p=0.001), and this is particularly interesting since CD8⁺ cells are predominant in COPD inflammation at all airway levels, including lung parenchyma. There was also a progressive reduction in sputum differential neutrophils (but not total), which was statistically significant at the end of the treatment (p=0.04) (Fig. 11). Neutrophils represent another class of inflammatory cells which undergoes a great increase in sputum and bronchoalveolar lavage fluid in COPD patients. On the contrary, CD68⁺ cells (monocytes/macrophages), whose number is increased in the bronchial sub-epithelium and alveoli of COPD patients, were unaffected by the combination treatment.

Figure 11: Sputum neutrophils differential count (%).

The identified anti-inflammatory effects were accompanied by a mean treatment difference at the end of the study of 173 mL (p<0.001) in prebronchodilator FEV₁ (Fig. 12).

Figure 12: Adjusted mean change in prebronchodilator FEV₁.

In conclusion, the administration of the salmeterol/fluticasone combination provided a broad-spectrum anti-inflammatory effect in both current and former smokers COPD patients, besides inducing clinical benefits.