title: 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.
authors.affiliation: Department of System Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Laboratory of Systems Approaches and Non Communicable Diseases, IRCCS San Raffaele Pisana, Via di Val Cannuta 247 , 00166 Rome, Italy. Electronic address: luigicalz@gmail.com.
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King׳s College London, London, UK.
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.affiliation: Department of System Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rogliani
authors.affiliation: Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facciolo
authors.affiliation: Almirall, Respiratory Therapeutic Area - Discovery, R&D Center Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Matera
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000368:Aged; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D055745:Bronchioles / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D009126:Muscle Relaxation / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D014326:Tropanes / Q000008:administration & dosage*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D018727:Muscarinic Antagonists; D014326:Tropanes; C542859:aclidinium bromide; D000068759:Formoterol Fumarate
keywords: Aclidinium bromide; COPD; Formoterol fumarate; Human bronchi; LABA; LAMA; Synergistic interaction