title: Comparison of Symbicort® versus Pulmicort® on steroid pharmacodynamic markers in asthma patients.
abstract: BACKGROUND
  Combination therapy with inhaled corticosteroids (ICS) and long-acting β(2)-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophages.
  
  
  METHODS
  In a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis(®) 12 μg), budesonide (Pulmicort(®) 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort(®)) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose. Sputum macrophages were separated by plate adhesion from induced sputum. GR binding to the glucocorticoid-response elements on oligonucleotides (GR-GRE binding) was evaluated by ELISA. mRNA expression of MAP-kinase phosphatase (MKP)-1 and IL-8 were measured by quantitative RT-PCR.
  
  
  RESULTS
  GR-GRE binding was significantly increased after treatment with SYM100 (3.5 OD/10 μg protein, median, p < 0.05) versus placebo (1.3) and BUD200 (1.6), and the induction was higher than that of BUD800 (2.4). MKP-1 mRNA was increased and IL-8 mRNA was significantly inhibited by BUD800, SYM100 and SYM200 versus placebo.
  
  
  CONCLUSIONS
  The effects of SYM100 and SYM200 on GR activation were not different from that of BUD800 and superior to BUD200. Thus, it has been confirmed at a molecular level that inhaled combination therapy with a lower dose of budesonide has an equivalent effect to a high dose of budesonide alone. In addition, GR-GRE binding is found to be a valuable pharmacodynamic marker for steroid efficacy in clinical studies.
authors: Airway Disease, National Heart and Lung Institute, Imperial College, Dovehouse street, London SW3 6LY, UK.
authors: Sarah
authors: S
authors: Essilfie-Quaye
authors: Kazuhiro
authors: K
authors: Ito
authors: Misako
authors: M
authors: Ito
authors: Sergei A
authors: SA
authors: Kharitonov
authors: Peter J
authors: PJ
authors: Barnes
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019819:Budesonide / Q000494:pharmacology / Q000627:therapeutic use*; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D020218:Response Elements / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013183:Sputum / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D001993:Bronchodilator Agents; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D004338:Drug Combinations; D004983:Ethanolamines; D005938:Glucocorticoids; D016209:Interleukin-8; D019819:Budesonide; D054638:Dual Specificity Phosphatase 1