Effects of oral and inhaled corticosteroid on lymphocyte beta2-adrenoceptor function in asthmatic patients.
OBJECTIVE
We have previously demonstrated that a single dose of oral prednisolone but not single doses of inhaled fluticasone had facilitatory effects on lymphocyte beta2-adrenoceptor (AR) function. To address possible differences in steady-state time-course, the aim of this study was to determine if repeated dosing with inhaled fluticasone would have facilitatory effects on lymphocyte beta2-AR. Plasma cortisol was also evaluated as a measure of systemic bioactivity.


METHODS
Ten asthmatic subjects, mean (s.e.mean) age 29 (3) years, FEV1 89 (5) % predicted, were randomised in a double-blind crossover study to receive inhaled placebo (PL), inhaled fluticasone 1000 microg day-1 (F1000) and inhaled fluticasone 2000 microg day-1, each for 4 days and also a single dose of oral prednisolone 50 mg (PRED). Prednisolone was given as open medication. The last dose of study drug was taken at 22.00 h and subjects attended the laboratory at 08.00 h the following day.


RESULTS
beta2-AR density (Bmax; fmol/10[6] cells) was significantly increased after PRED compared with PL and inhaled fluticasone. Bmax (geometric mean) after each treatment were: PL 1.51, F1000 1.20, F2000 1.20 and PRED 2.14 (a 1.4 fold difference PRED vs PL; 95% CI 1.05 to 1.95; P < 0.001). There was significant (P < 0.001) suppression of plasma cortisol (nmol l-1) following F2000 and PRED compared with PL: 393.8, F1000 302.1, F2000 205.0 (95% CI F2000 vs PL 58.1 to 319.4) and PRED 87.0 (95% CI PRED vs PL 176.2 to 437.5). The estimated milligram equivalence ratio for adrenal suppression was calculated at 1:11 for fluticasone vs prednisolone.


CONCLUSIONS
Repeated dosing with high-dose inhaled fluticasone did not up-regulate lymphocyte beta2-AR as compared with a single dose of oral prednisolone, despite having significantly suppressed early morning plasma cortisol. This study confirms our previous finding of a dissociation in sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte beta2-AR regulation, at least for doses up to 2 mg day-1 of fluticasone.
Tan
K S
KS
Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Scotland, UK.
McFarlane
L C
LC
Lipworth
B J
BJ
D000280:Administration, Inhalation; D000284:Administration, Oral; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D000068298:Fluticasone; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D011239:Prednisolone / Q000008:administration & dosage / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D018343:Receptors, Adrenergic, beta-2; D011239:Prednisolone; D000068298:Fluticasone; D006854:Hydrocortisone