Mario Cazzola1, Luigino Calzetta2, Paola Rogliani3, Ermanno Puxeddu4, Francesco Facciolo5, Maria Gabriella Matera6. 1. University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy; University of Rome Tor Vergata, Department of Systems Medicine, Respiratory Pharmacology Research Unit, Rome, Italy; University Hospital Tor Vergata, Division of Respiratory Medicine, Rome, Italy. 2. University of Rome Tor Vergata, Department of Systems Medicine, Respiratory Pharmacology Research Unit, Rome, Italy. Electronic address: luigicalz@gmail.com. 3. University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy; University Hospital Tor Vergata, Division of Respiratory Medicine, Rome, Italy. 4. University Hospital Tor Vergata, Division of Respiratory Medicine, Rome, Italy. 5. Regina Elena National Cancer Institute, Thoracic Surgery Unit, Rome, Italy. 6. Second University of Naples, Department of Experimental Medicine, Unit of Pharmacology, Naples, Italy.
Abstract
BACKGROUND: To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone. METHODS: We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method. RESULTS: The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα--cyclic adenosine monophosphate (cAMP)--protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations. CONCLUSIONS: Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.
BACKGROUND: To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone. METHODS: We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method. RESULTS: The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα--cyclic adenosine monophosphate (cAMP)--protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations. CONCLUSIONS: Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.
Authors: Cynthia Koziol-White; Timothy B Johnstone; Maia L Corpuz; Gaoyuan Cao; Sarah Orfanos; Vishal Parikh; Brian Deeney; Omar Tliba; Rennolds S Ostrom; Ian Dainty; Reynold A Panettieri Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-11-20 Impact factor: 5.464