Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi

Abstract

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2-adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine (Emax: 97.5±2.6% and 96.4±1.1%; pEC50 8.5±0.1 and 8.8±0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles (Emax: 68.1±4.5% and 99.0±5.6%; pEC50 7.9±0.3 and 8.4±0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4±2.7%; P<0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7±0.9%; P<0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6h post-treatment (+55.1±9.4%; P<0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic.

Assessing the clinical value of fast onset and sustained duration of action of long-acting bronchodilators for COPD

“…more than additive) bronchodilator effect of a LABA and LAMA has been demonstrated in airway preparations in vitro and in patients with COPD [39,40]. These preliminary studies support the scientific rationale for combining the two types of drugs but preclinical data investigating synergy are limited and further work is required.…”

Aclidinium bromide inhalation powder for the long-term, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease including chronic bronchitis and emphysema

“…In human bronchial tissue, it has a similar potency at M 3 receptors to that of tiotropium and ipratropium, although its onset of action is significantly faster than tiotropium and its duration of action is significantly longer than ipratropium [5]. Moreover, aclidinium induces a potent concentration-dependent relaxation of human precision-cut lung slices submaximally pre-contracted with acetylcholine and its potency is not significantly different from that of formoterol [6].…”

“…Actually, the combination of aclidinium and formoterol induces moderate to strong synergistic interaction in relaxing human isolated bronchi [6] that has a role also in the clinic setting [39]. However, there is evidence that the regular addition of formoterol to aclidinium improved the SGRQ total score more than formoterol (-6.57 units, and -4.70 units mean changes from baseline at week 24, respectively), but not more than aclidinium (-6.44 units) [40].…”

Progress and Prospects for Long-Acting Β 2 -Agonists in the Treatment of Chronic Obstructive Pulmonary Disease

“…За последние 3 года, помимо наших оригиналь-ных публикаций, сфокусированных, прежде всего, на значении двойной бронходилатации [7][8][9][10][11][12], в кото-рой, безусловно, β 2 -агонисты играют фундаменталь-ную роль, мы изучили и описали развитие одного ультра-ДДБА, применяемого теперь в повседневной практике в качестве монотерапии или в сочетании с мускариновым антагонистом длительного действия (ДДАХ), или с ингаляционным кортикостероидом (ИГКС) [13][14][15][16][17][18][19][20][21].…”