title: Pharmacological assessment of the onset of action of aclidinium and glycopyrronium versus tiotropium in COPD patients and human isolated bronchi.
abstract: Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, glycopyrronium 50μg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1μM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1μM: 6.4±0.5min) and tiotropium (1μM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, University Hospital "Tor Vergata", Rome, Italy; Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rogliani
authors.affiliation: Research Unit of Respiratory Clinical Pharmacology, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address: luigicalz@gmail.com.
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, University Hospital "Tor Vergata", Rome, Italy.
authors.forename: Josuel
authors.initials: J
authors.lastname: Ora
authors.affiliation: Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lipsi
authors.affiliation: Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Segreti
authors.affiliation: Section of Pharmacology L. Donatelli, Department of Experimental Medicine, Second University of Naples, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Matera
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, University Hospital "Tor Vergata", Rome, Italy; Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Research Unit of Respiratory Clinical Pharmacology, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000280:Administration, Inhalation; D001980:Bronchi / Q000187:drug effects* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006024:Glycopyrrolate / Q000008:administration & dosage*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D000069447:Tiotropium Bromide / Q000008:administration & dosage*; D016896:Treatment Outcome; D014326:Tropanes / Q000008:administration & dosage*
chemical_list: D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D014326:Tropanes; C542859:aclidinium bromide; D006024:Glycopyrrolate; D000069447:Tiotropium Bromide
keywords: Aclidinium; COPD; Glycopyrronium; Onset of action; Tiotropium