Interaction between aclidinium bromide and formoterol fumarate in small human airways

Abstract

Background

Combining a long-acting β₂-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) may improve chronic obstructive pulmonary disease therapy.

Aim

To investigate the synergistic interaction of aclidinium (LAMA) and formoterol (LABA) in small human bronchi.

Methods

Precision cut lung slices (PCLSs) from 8 patients were incubated inKrebs-Henseleit solution (37°C) aerated with O₂/CO₂ (95:5%). The concentration response to aclidinium and formoterol, administered alone and in combination, at isoeffective concentrations, was assessed at sub-maximal contraction (70% maximum, EC₇₀) induced by acetylcholine (ACh).

PCLS relaxation was expressed as % of maximal response (lumen area enhancement) induced by papaverine (E_max) and potency as the negative logarithm of IC₅₀ or EC₅₀ (pD₂). Drug mixture effects were analyzed by Bliss Independence theory. Values (n=3) are mean±SEM.

Results

Aclidinium and formoterol induced potent concentration-dependent relaxation of PCLSs (pD₂: aclidinium 7.9±0.3, formoterol 8.4±0.3). Only formoterol eliminated ACh-induced bronchiolar contraction (E_max: formoterol 99.0±5.6%, aclidinium 68.1±4.5%; p<0.05).

Aclidinium and formoterol at low-to-high concentrations (aclidinium 3.2 nM–1.0 µM, formoterol 1.0–63.0 nM) had a synergistic relaxant response on PCLSs, enhancing relaxation by +19.7±0.8% compared with the expected response (p<0.05).

Low concentrations (EC₃₀) of aclidinium with formoterol induced significant (p<0.05) lumen area enhancement; 69.9±2.3% compared with the expected response (51.0±5.6%).

Conclusions

Aclidinium and formoterol had a synergistic interaction on the lumen area enhancement of bronchioles, mainly at low concentrations.