Concomitant administration of low-dose prednisolone protects against in vivo beta2-adrenoceptor subsensitivity induced by regular formoterol.
OBJECTIVE
To assess whether concomitant administration of low-dose prednisolone (PRED) with regular inhaled formoterol (FM) might prevent the occurrence of beta2-adrenoceptor (beta2-AR) tachyphylaxis.


METHODS
Eleven healthy male subjects (mean age, 29 years) were randomized to receive 1 week with either inhaled FM, 24 microg bid, and placebo tablets (PL), or inhaled FM, 24 microg bid, and oral PRED, 15 mg daily, in double-blind, crossover fashion, with a 2-week washout between treatments. A dose-response curve (DRC) for systemic beta2-responses to inhaled salbutamol (800 to 3,200 microg) was constructed before and after each treatment period (ie, FM + PL or FM + PRED). Lymphocyte beta2-AR density (Bmax) and maximal cyclic adenosine monophosphate response to isoproterenol (isoprenaline) (Emax) were evaluated ex vivo at each visit; 8 AM serum cortisol level was also evaluated as a marker of systemic glucocorticoid activity. Comparisons for DRC were made as peak responses and area under curve (AUC).


RESULTS
There was significant (p < 0.05) subsensitivity of systemic beta2-AR responses (as AUC) following FM + PL: for heart rate (before vs after), 760 vs 340 beats (95% confidence interval [CI], 160 to 680), for tremor 0.39 vs 0.19 log units/h (95% CI, 0.01 to 0.41), and for potassium, -0.34 vs -0.19 mmol x h/L (95% CI, -0.04 to -0.28). With PRED, there was protection against subsensitivity induced by FM with no significant difference in values before vs after FM: heart rate, 740 vs 640; tremor, 0.35 vs 0.34; and potassium, -0.30 vs -0.25. FM + PL induced significant downregulation of lymphocyte beta2-AR density (log Bmax; fmol/10(6) cells) (before vs after): 0.25 vs 0.11 (95% CI, 0 to 0.22; p < 0.05) and this was not altered by PRED (before vs after): 0.21 vs 0.10 (95% CI, 0.01 to 0.27; p < 0.05). FM + PL also caused desensitization of Emax (pmol/10(6) cells) (before vs after): 6.21 vs 2.29 (95% CI, 1.19 to 6.64; p < 0.05) and this was attenuated by PRED with no significant difference between before and after values: 4.60 vs 3.28.


CONCLUSIONS
Concomitant administration of a low dose of PRED produced protection against FM-induced subsensitivity of systemic beta2-AR, as assessed by the response to inhaled salbutamol. In contrast, prednisolone did not prevent ex vivo beta2-AR downregulation despite causing significant cortisol suppression. This, in turn, suggests that there is a dissociation in the dose of PRED required to protect against beta2-AR downregulation and subsensitivity, following continuous exposure to long-acting beta2-agonist.
Tan
K S
KS
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Scotland.
McFarlane
L C
LC
Lipworth
B J
BJ
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage* / Q000627:therapeutic use; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D018655:Lymphocyte Count / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage* / Q000627:therapeutic use; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013618:Tachyphylaxis
D000318:Adrenergic beta-Agonists; D015415:Biomarkers; D004983:Ethanolamines; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D011239:Prednisolone; D000420:Albuterol; D000068759:Formoterol Fumarate; D006854:Hydrocortisone