Objectives: To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more.Design: Randomized, multicenter, double-blind, placebocontrolled, parallel-group study. A 2-week, singleblind, placebo run-in period was followed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg, or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period.Setting/Patients: Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled ␤-agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled ␤-agonist use. Twenty-three percent of the patients used concomitant inhaled corticosteroids.Primary End Points: Forced expiratory volume in 1 second and daytime asthma symptoms.Results: Montelukast improved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, "as-needed" ␤-agonist use, nocturnal awakenings) (PϽ.001 compared with placebo). Montelukast provided nearmaximal effect in these end points within the first day of treatment. Tolerance and rebound worsening of asthma did not occur. Montelukast improved outcome end points, including asthma exacerbations, asthma control days (PϽ.001 compared with placebo), and decreased peripheral blood eosinophil counts (PϽ.001 compared with placebo). The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups.Conclusions: Montelukast, compared with placebo, significantly improved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo.

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To elucidate the role of leukotrienes (LT) in allergic asthma in humans the effect of MK-886, an LT biosynthesis inhibitor, was evaluated on antigen-induced early (EAR) and late (LAR) asthmatic reactions and bronchial responsiveness to histamine. Eight atopic men participated in a two-part, double-blind, placebo-controlled, crossover trial. MK-886 was administered in two oral doses of 500 mg and 250 mg, 1 h before and 2 h after allergen inhalation, respectively. Biochemical effects of MK-886 were evaluated by the inhibition of urinary LTE4 excretion and calcium ionophore-stimulated LTB4 biosynthesis in whole blood ex vivo. MK-886 significantly inhibited the EAR by 58.4% (AUC0-3 h) and the LAR by 43.6% (AUC3-7 h) when compared with placebo (p < 0.01). There was no difference in PC20 histamine 30 h post allergen challenge between MK-886 and placebo (0.33 and 0.27 doubling doses, p > 0.1). MK-886 inhibited calcium ionophore-stimulated LTB4 production in whole blood (54.2 +/- 25.6%) for up to 6 h post allergen challenge. LTE4 excretion in urine was inhibited by 51.5% during the EAR by as much as 80% during the LAR. This indicates that LT play a role in allergen-induced asthmatic reactions in humans in vivo and that LT synthesis inhibitors such as MK-886 should be further explored for the treatment of asthma.

These data indicate a tolerability profile for montelukast similar to placebo during both short-term and long-term administration, even at doses substantially higher than the recommended clinical dose of 10 mg once daily for adults and 5 mg once daily for children aged 6-14 years.

This 2-part, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of etoricoxib, a COX-2 selective inhibitor, for the treatment of hemophilic arthropathy. In part 1 (6 weeks), 102 patients (> 12 years old) with hemophilic arthropathy were randomized to receive 90 mg etoricoxib once daily or placebo (1:1 ratio). In part 2 (6 months), 51 patients taking placebo in part 1 were randomized to receive 90 mg etoricoxib or 25 mg rofecoxib once daily; patients taking etoricoxib in part 1 continued the same treatment. Efficacy end points included