title: Combination therapy of tiotropium and ciclesonide attenuates airway inflammation and remodeling in a guinea pig model of chronic asthma.
abstract: BACKGROUND
  The long-acting anticholinergic tiotropium has recently been registered for the treatment of asthma, and its use is associated with a reduction in exacerbation frequency. Anti-inflammatory and anti-remodeling effects of tiotropium have been demonstrated in in vitro and in vivo models. Because tiotropium treatment is used in combination with inhaled corticosteroids, potential additive effects between the two would be clinically relevant. Therefore, the aim of this study was to investigate additive effects between tiotropium and ciclesonide on airway inflammation and remodeling in guinea pig models of asthma.
  
  
  METHODS
  Guinea pigs (n = 3-8/group) were sensitized and challenged with ovalbumin in an acute (single challenge) and a chronic model (12 weekly challenges) of allergic asthma. Animals were treated with vehicle, nebulized tiotropium (0.01-0.3 mM) and/or intranasally instilled ciclesonide (0.001-1 mg/kg) before each challenge. Bronchoalveolar lavage fluid and lungs were collected for analysis of airway inflammation and remodeling.
  
  
  RESULTS
  Tiotropium and ciclesonide treatment, alone or in combination, did not inhibit airway inflammation in the acute asthma model. In a dose-finding study, low doses of tiotropium and ciclesonide inhibited airway eosinophilia and airway smooth muscle thickening in the chronic asthma model. Threshold doses of 0.01 mM tiotropium (nebulizer concentration) and 0.01 mg/kg ciclesonide were selected to investigate potential additive effects between both drugs. At these doses, tiotropium and ciclesonide did not inhibit airway eosinophilia or airway smooth muscle thickening when administered alone, but significantly inhibited these allergen-induced responses when administered in combination.
  
  
  CONCLUSIONS
  Combined treatment with low doses of tiotropium and ciclesonide inhibits airway inflammation and remodeling in a guinea pig model of chronic asthma, suggesting that combined treatment with anticholinergics and corticosteroids may have anti-inflammatory and anti-remodeling activity in allergic airway diseases. Since tiotropium is registered as a therapy for asthma added on to corticosteroid treatment, these beneficial effects of the combination therapy may be clinically relevant.
authors: Department of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. l.e.m.kistemaker@rug.nl.|GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. l.e.m.kistemaker@rug.nl.
authors: Loes E M
authors: LE
authors: Kistemaker
authors: Department of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: I Sophie T
authors: IS
authors: Bos
authors: Department of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Mark H
authors: MH
authors: Menzen
authors: Department of Pharmaceutical Sciences, Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, FL, USA.
authors: Harm
authors: H
authors: Maarsingh
authors: Department of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Herman
authors: H
authors: Meurs
authors: Department of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.|GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Reinoud
authors: R
authors: Gosens
mesh_terms: D000280:Administration, Inhalation; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D001993:Bronchodilator Agents / Q000008:administration & dosage; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000379:methods; D006168:Guinea Pigs; D008297:Male; D010047:Ovalbumin; D011282:Pregnenediones / Q000008:administration & dosage*; D000069447:Tiotropium Bromide / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D018926:Anti-Allergic Agents; D001993:Bronchodilator Agents; D011282:Pregnenediones; D010047:Ovalbumin; C120481:ciclesonide; D000069447:Tiotropium Bromide