A proof of concept study to evaluate putative benefits of montelukast in moderate persistent asthmatics.

AIMS: Whether chronic dosing with montelukast confers benefit in patients with moderate to severe asthma remains to be fully established. A proof of concept study was performed evaluating putative benefits with montelukast in moderate persistent asthmatics who were taken off inhaled corticosteroids (ICS) and switched to salmeterol. The latter was done to dissociate the effects of montelukast from ICS. METHODS: Twenty moderate to severe persistent asthmatics completed a randomized double-blind crossover study. Subjects received montelukast 10 mg daily or placebo for 2 weeks each. This was preceded by a 2-week run-in when ICS were discontinued and salmeterol started, and used on a regular basis throughout the study. Measurements were made after run-in and after both randomized treatments. RESULTS: There were no significant sequence effects for responses as to whether placebo or montelukast were given first or second. Methacholine PD20 values after run-in, first and second placebo were 63 micro g, 60 micro g and 64 micro g, respectively (corresponding to 2, 4 and 6 weeks of ICS washout, respectively). Lung function deteriorated pre vs post run-in, which was significant (P < 0.05) for FEF25-75 % predicted. Montelukast conferred significant (P < 0.05) improvements as change from post run-in compared with placebo in methacholine PD20, FEV1 % predicted, FEF25-75 % predicted, diurnal peak expiratory flow, symptoms and salbutamol use. For the primary outcome of methacholine PD20, this amounted to a 1.6-fold difference (95% CI 1.1, 2.5). CONCLUSIONS: In moderate persistent asthmatics switched from taking ICS to salmeterol alone, adding montelukast conferred significant benefits on all parameters of asthma control. Further studies are indicated to evaluate whether montelukast exhibits additive effects to ICS/long-acting beta2-adrenoceptor agonist combination inhalers upon clinically important outcomes.

Effects of high-dose inhaled fluticasone propionate on the hypothalamic-pituitary-adrenal axis in asthmatic patients with severely impaired lung function.

BACKGROUND: The effects of high-dose fluticasone propionate therapy on dynamic cortisol stimulation in severe asthma are unknown. OBJECTIVE: To evaluate the human corticotropin-releasing factor (hCRF)-stimulated plasma cortisol response to fluticasone propionate therapy in severe asthmatic patients with impaired airway caliber (forced expiratory volume in 1 second [FEV1] < 60% of predicted) and in control subjects. METHODS: Ten severe asthmatic patients (mean FEV1, 47% of predicted) and 10 controls (mean FEV1, 104% of predicted) received fluticasone propionate, 2,000 microg/d, via a 750-mL primed spacer for 2 weeks. Plasma cortisol levels before and after hCRF stimulation and overnight 10-hour urinary cortisol excretion corrected for creatinine concentration (OUCC) were measured at baseline after washout and 12 hours after the last dose of fluticasone propionate. RESULTS: Baseline values before fluticasone propionate use were not significantly different in asthmatic patients vs controls for plasma cortisol before and after hCRF stimulation and OUCC. Comparing values at baseline vs after fluticasone propionate use, there was no significant suppression of plasma cortisol levels before (378.2 vs 357.4 nmol/L) or after (510.5 vs 507.9 nmol/L) hCRF stimulation or OUCC (8.2 vs 7.5 nmoL/mmoL) in asthmatic patients. In controls, all outcomes were significantly suppressed comparing values before vs after fluticasone propionate therapy: plasma cortisol levels before (423.5 vs 200.2 nmol/L; P = .002) and after (503.5 vs 291.1 nmol/L; P = .001) hCRF stimulation and OUCC (6.5 vs 2.4 nmol/mmol; P = .002). CONCLUSION: Patients with severe persistent asthma and impaired airway caliber seem to be protected from developing systemic adverse effects with high-dose fluticasone propionate therapy, as evaluated by basal and dynamic measures of hypothalamic-pituitary-adrenal axis activity.