title: A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses.
abstract: BACKGROUND
  Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids.
  
  
  OBJECTIVE
  We evaluated the effect of an inhaled nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses.
  
  
  METHODS
  Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 μg) once daily, budesonide 200 μg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6.
  
  
  RESULTS
  FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 μg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 μg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated.
  
  
  CONCLUSIONS
  Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).
authors.affiliation: 1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gail M
authors.initials: GM
authors.lastname: Gauvreau
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Boulet
authors.forename: Richard
authors.initials: R
authors.lastname: Leigh
authors.forename: Donald W
authors.initials: DW
authors.lastname: Cockcroft
authors.forename: Kieran J
authors.initials: KJ
authors.lastname: Killian
authors.forename: Beth E
authors.initials: BE
authors.lastname: Davis
authors.forename: Francine
authors.initials: F
authors.lastname: Deschesnes
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watson
authors.forename: Veronica
authors.initials: V
authors.lastname: Swystun
authors.forename: Carina Kärrman
authors.initials: CK
authors.lastname: Mårdh
authors.forename: Peter
authors.initials: P
authors.lastname: Wessman
authors.forename: Carin
authors.initials: C
authors.lastname: Jorup
authors.forename: Magnus
authors.initials: M
authors.lastname: Aurivillius
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Byrne
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000187:drug effects* / Q000502:physiology; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy*; D018592:Cross-Over Studies; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011965:Receptors, Glucocorticoid / Q000008:administration & dosage / Q000819:agonists* / Q000627:therapeutic use; D013183:Sputum / Q000166:cytology; D055815:Young Adult
chemical_list: D000485:Allergens; D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011965:Receptors, Glucocorticoid
keywords: AZD5423; airway hyperresponsiveness; allergen inhalation challenge; late asthmatic response; sputum eosinophils