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Concomitant Administration of Low-Dose Prednisolone Protects Against In Vivo β2-Adrenoceptor Subsensitivity Induced by Regular Formoterol

Kia Soong Tan; Lesley C. McFarlane; Brian J. Lipworth
Author and Funding Information

From the Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland


1998 by the American College of Chest Physicians


Chest. 1998;113(1):34-41. doi:10.1378/chest.113.1.34
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Abstract

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.


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