Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma.
Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function, surrogate markers of airway inflammation, and tests of adrenal function. After a 10-day placebo run-in, we evaluated the effects of 200 microg, 400 microg, and 800 microg of inhaled budesonide, each dose given twice daily sequentially for 3 weeks in 26 patients, aged 35 +/- 12 years (mean +/- SD), with mild-to-moderate asthma. Measurements were made of bronchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor. For measurements of pulmonary function and exhaled nitric oxide, there was a plateau in the mean response to budesonide between 400 microg (low dose) and 800 microg (medium dose) per day, whereas for eosinophilic cationic protein and bronchial challenge, maximal benefits occurred between 800 and 1,600 microg (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway response (fourfold decrease in bronchial hyperreactivity) and minimal systemic response (overnight urinary cortisol greater than 20 nmol), was similar at low-dose (46%) and at high-dose (52%) budesonide. The proportion of patients with a suboptimal therapeutic index, a good airway response with a marked systemic response (overnight urinary cortisol greater than 20 nmol), increased from 4% at low dose to 38% at high dose. In patients with mild-to-moderate atopic asthma, there were dose-related effects of budesonide on surrogate markers of inflammation (bronchial hyperreactivity and serum eosinophilic cationic protein), although higher doses were associated with adrenal suppression and a decrease in the therapeutic index.