CONCOMITANT ADMINISTRATION OF LOW-DOSE PREDNISOLONE PROTECTS AGAINST IN-VIVO BETA(2)-ADRENOCEPTOR SUBSENSITIVITY INDUCED BY REGULAR FORMOTEROL

Study objectives: To assess whether concomitant administration of low- dose prednisolone (PRED) with regular inhaled formoterol (FM) might pr event the occurrence of beta(2)-adrenoceptor (beta(2)-AR) tachyphylaxi s. Design: Eleven healthy male subjects (mean age, 29 years) were rand omized to receive 1 week with either inhaled FM, 24 mu g bid, and plac ebo tablets (PL), or inhaled FM, 24 mu g bid, and oral PRED, 15 mg dai ly, in double-blind, crossover fashion, with a 2-week washout between treatments. A dose-response curve (DRC) for systemic beta(2)-responses to inhaled salbutamol (800 to 3,200 mu g) was constructed before and after each treatment period (ie, FM+PL or FM+PRED). Lymphocyte beta(2) -AR density-(Bmax) and maximal cyclic adenosine monophosphate response to isoproterenol (isoprenaline) (Emax) mere evaluated ex vivo at each visit; 8 AM serum cortisol level was also evaluated as a marker of sy stemic glucocorticoid activity. Comparisons for DRC were made as peak responses and area under curve (AUG). Results: There was significant ( p<0.05) subsensitivity of systemic beta(2)-AR responses (as AUG) follo wing FM+PL: for heart rate (before vs after), 760 vs 340 beats (95% co nfidence 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 subs ensitivity induced by FM with no significant difference in values befo re vs after FM: heart rate, 740 vs 640; tremor, 0.35 vs 0.34; and pota ssium, -0.30 vs -0.25. FM+PL induced. significant downregulation of ly mphocyte beta(2)-AR density (log Bmax; fmol/10(6) cells) (before vs af ter): 0.25 vs 0.11 (95% CI, 0 to 0.22; p<0.05) and this was not altere d by PRED (before vs after): 0.21 vs 0.10 (95% CI, 0.01 to 0.27; p<0.0 5). FM+PL also caused desensitization of Emax (pmol/10(6) cells) (befo re 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 subsensitiv ity of systemic beta(2)-AR, as assessed by the response to inhaled sal butamol. In contrast, prednisolone did not prevent ex vivo beta(2)-AR downregulation despite causing significant cortisol suppression. This, in turn, suggests that there is a dissociation in the dose of PRED re quired to protect against beta(2)-AR downregulation and subsensitivity , following continuous exposure to long-acting beta(2)-agonist.