title: Comparison of the bronchodilating effects of inhaled β₂-agonists after methacholine challenge in a human lung reperfusion model.
abstract: The aim of the present investigation was to compare the onset of action and intrinsic activity of the long-acting β(2)-agonist GW597901 with the fast- and short-acting salbutamol as model compounds using an isolated human lung reperfusion model. Twelve resected human lung lobes were challenged with methacholine (MCh) and subsequently nebulised with either GW597901 or salbutamol. Prostaglandin E(2) (PGE(2)) concentrations in the perfusion fluid were compared with the dose of MCh that was required to induce a bronchoconstriction. After successful MCh provocation, nebulisation of GW597901 and salbutamol fully reversed any observed bronchoconstriction. The bronchodilating effect was more pronounced for GW597901. Salbutamol revealed an immediate onset of action while the effect of GW597901 was observed with an approximate delay of 6 min. Higher doses of MCh were required for a successful bronchial challenge in the presence of elevated PGE(2) levels (r=0.8171, p ≤ 0.05). For the first time, an isolated perfused human lung model has been established for comparing the onset of action and potency of a short- and long-acting β(2)-agonist. We therefore conclude that it is an alternative for determination of drug effect characteristics and suitable for supplementing or predicting clinical data.
authors.affiliation: Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Würzburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Gnadt
authors.forename: Beatrice
authors.initials: B
authors.lastname: Trammer
authors.forename: Boris
authors.initials: B
authors.lastname: Kardziev
authors.forename: Martin K
authors.initials: MK
authors.lastname: Bayliss
authors.forename: Chris D
authors.initials: CD
authors.lastname: Edwards
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Petra
authors.initials: P
authors.lastname: Högger
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology; D015424:Reperfusion; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; C576936:GW597901; D013449:Sulfonamides; D016210:Methacholine Chloride; D015232:Dinoprostone; D000420:Albuterol