SUBSENSITIVITY TO BRONCHOPROTECTION AGAINST ADENOSINE-MONOPHOSPHATE CHALLENGE FOLLOWING REGULAR ONCE-DAILY FORMOTEROL

Regular treatment with inhaled long-acting beta(2)-agonists leads to s ubsensitivity to their bronchoprotective effects, although the effect of dosing frequency on this subsensitivity is not known. The aim of th is study was to assess whether a once-daily dosing regimen with formot erol might be associated with a lesser degree of subsensitivity. In a randomized placebo-controlled double-blind, double-dummy crossover stu dy 10 asthmatics treated with inhaled steroids (mean age 31 yrs, force d expiratory volume in one second (FEV1) 82% predicted) received 1 wee k of treatment with: formoterol dry powder 24 mu g twice daily (08:00 and 20:00 h); formoterol 24 mu g once daily (20:00 h); or identical pl acebo. Adenosine monophosphate (AMP) bronchial challenge was performed 12 h after the first and the last dose of each treatment. There was s ignificant loss of protection with formoterol twice daily between the first and last dose (geometric mean provocative concentration causing a 20% fall in FEV1 (PC20)): 475 versus 129 mg.mL(-1) (a 3.7-fold loss, p=0.006) and with formoterol once daily: 367 versus 127 mg.mL(-1) (a 2.9-fold loss, p=0.005), compared with placebo: 71 versus 75 mg.mL(-1) (nonsignificant), There was no significant difference in the degree o f loss of protection between formoterol once and twice daily, For firs t-dose protection there was a significant difference between active tr eatments and placebo, but after the last dose the residual protection between active treatments and placebo was not significant. Thus, in pa tients taking inhaled corticosteroids, regular formoterol 24 mu g once daily induces a similar degree of subsensitivity to adenosine monopho sphate bronchial challenge as with formoterol 24 mu g twice daily. Thi s in turn suggests that even with a 24-h dosing interval there is the development of tolerance to formoterol by prolonged occupancy of airwa y beta(2)-adrenoceptors.