Study objectives: To assess whether concomitant administration of low-dose prednisolone (PRED) with regular inhaled formoterol (FM) might prevent the occurrence of β2-adrenoceptor (β2-AR) tachyphylaxis.
Design: Eleven healthy male subjects (mean age, 29 years) were randomized to receive 1 week with either inhaled FM, 24 µg bid, and placebo tablets (PL), or inhaled FM, 24 µg 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 β2-responses to inhaled salbutamol (800 to 3,200 µg) was constructed before and after each treatment period (ie, FM+PL or FM+PRED). Lymphocyte β2-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 β2-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 · 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 β2-AR density (log Bmax; fmol/106 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/106 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 β2-AR, as assessed by the response to inhaled salbutamol. In contrast, prednisolone did not prevent ex vivo β2-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 β2-AR downregulation and subsensitivity, following continuous exposure to long-acting β2-agonist.