title: Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits.
abstract: 1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen-induced increase in total lung resistance (RL); however, both drugs prevented the antigen-induced reduction in dynamic compliance (Cdyn). CDP840 and budesonide also prevented antigen-induced AHR and eosinophilia in the immunised rabbit.
authors.affiliation: Celltech Therapeutics Ltd., Slough, London.
authors.forename: N
authors.initials: N
authors.lastname: Gozzard
authors.forename: A
authors.initials: A
authors.lastname: el-Hashim
authors.forename: C M
authors.initials: CM
authors.lastname: Herd
authors.forename: S M
authors.initials: SM
authors.lastname: Blake
authors.forename: M
authors.initials: M
authors.lastname: Holbrook
authors.forename: B
authors.initials: B
authors.lastname: Hughes
authors.forename: G A
authors.initials: GA
authors.lastname: Higgs
authors.forename: C P
authors.initials: CP
authors.lastname: Page
mesh_terms: D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy; D016535:Bronchial Hyperreactivity; D001992:Bronchoalveolar Lavage Fluid; D016084:Bronchoconstriction / Q000187:drug effects; D019819:Budesonide; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D012130:Respiratory Hypersensitivity / Q000209:etiology / Q000276:immunology; D014132:Trachea / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D006633:Histamine Antagonists; D010726:Phosphodiesterase Inhibitors; D011282:Pregnenediones; D011725:Pyridines; C102660:CDP 840; D019819:Budesonide