title: Bronchoprotection by olodaterol is synergistically enhanced by tiotropium in a guinea pig model of allergic asthma.
abstract: The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Smit
authors.forename: Annet B
authors.initials: AB
authors.lastname: Zuidhof
authors.forename: Sophie I T
authors.initials: SI
authors.lastname: Bos
authors.forename: Harm
authors.initials: H
authors.lastname: Maarsingh
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.forename: Johan
authors.initials: J
authors.lastname: Zaagsma
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D021461:Animals, Outbred Strains; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage / Q000627:therapeutic use*; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000627:therapeutic use*; D000069447:Tiotropium Bromide
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018926:Anti-Allergic Agents; D048588:Benzoxazines; D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D020011:Protective Agents; D012602:Scopolamine Derivatives; D006632:Histamine; C549647:olodaterol; D000069447:Tiotropium Bromide