Exercise-induced bronchoconstriction is common among adults with mild-to-severe asthma, limiting activity and worsening the quality of life.
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The presence of airway hyperresponsiveness to exercise ...suggests a lack of control of asthma. Accordingly, the degree of protection afforded by a drug against exercise-induced bronchoconstriction may be used to assess therapeutic benefit in patients with mild asthma who have near-normal airway function and minimal symptoms.
The cause of exercise-induced bronchoconstriction is incompletely understood, although airway cooling and drying are hypothesized to stimulate the release of inflammatory mediators such as the cysteinyl leukotrienes (leukotriene C
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Pain is a common complaint, often occurring in conjunction with inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesic agents in ambulatory patients. In ...recent studies, the cyclooxygenase-2 (COX-2) inhibitor rofecoxib demonstrated analgesic effects similar to those of NSAIDs in the treatment of acute pain and primary dysmenorrhea. The present randomized, single-dose, double-blind, doubledummy, placebo- and active-comparator-controlled, parallel-group study was undertaken to compare the analgesic efficacy of the COX-2 inhibitors rofecoxib 50 mg and celecoxib 200 mg with that of ibuprofen 400 mg and placebo in patients with postoperative dental pain. Two hundred and seventy-two patients experiencing pain after the removal of ≥ 2 third molars were randomized according to pain severity (moderate vs severe) to receive a single dose of placebo (n = 45), rofecoxib 50 mg (n = 90), celecoxib 200 mg (n = 91), or ibuprofen 400 mg (n = 46). Using a patient diary, patients recorded pain intensity, pain relief, and global evaluations throughout the 24-hour period after dosing. The overall analgesic effect, onset of action, peak effect, and duration of effect were evaluated, with the primary end point being total pain relief over 8 hours (TOPAR8). The safety profile was assessed on the basis of physical findings, laboratory results, and spontaneous reports of adverse experiences. The results showed that compared with celecoxib, rofecoxib had superior analgesic effects on all measures of analgesic efficacy, including overall analgesic effect (TOPAR8, 18.3 vs 12.5;
P < 0.001), time to onset of effect (30 vs 60 minutes;
P = 0.003), peak pain relief (score, 2.8 vs 2.3;
P < 0.05), and duration of effect (> 24 vs 5.1 hours;
P < 0.001). In addition, rofecoxib's analgesic efficacy was similar to that of ibuprofen (TOPAR8, 18.3 vs 17.0;
P = 0.460), but the duration was longer (
P < 0.05); with ibuprofen, the time to onset was 24 minutes, peak pain relief score was 2.9, and duration of analgesic effect was 8.9 hours. The safety profile was similar across all treatment groups. Thus rofecoxib provided analgesic efficacy superior to that of celecoxib and comparable to that of ibuprofen in the treatment of patients with acute postoperative dental pain.
CONTEXT.— Leukotrienes are important mediators of asthma by causing bronchoconstriction,
mucous secretion, and increased vascular permeability. Studies using compounds
that block leukotrienes have ...demonstrated improvement in asthma control in
adults and adolescents, but children younger than 12 years, for whom asthma
is the most common chronic disease, have not been studied. OBJECTIVE.— To determine the clinical effect of montelukast, a leukotriene receptor
antagonist, in 6- to 14-year-old children with asthma. DESIGN.— Eight-week, multicenter, randomized, double-blind study. SETTING.— Forty-seven outpatient centers at private practices and academic medical
centers in the United States and Canada. PATIENTS.— A total of 336 children with forced expiratory volume in 1 second (FEV1) between 50% to 85% of the predicted value, at least 15% reversibility
after inhaled β-agonist administration, a minimal predefined level of
daytime asthma symptoms, and daily β-agonist use. Concomitant inhaled
corticosteroids at a constant daily dose were used by 39% of patients receiving
montelukast and 33% receiving placebo. INTERVENTION.— After a 2-week placebo run-in period, patients received either montelukast
(5-mg chewable tablet) or matching-image placebo once daily at bedtime for
8 weeks. MAIN OUTCOME MEASURE.— Morning FEV1 percent change from baseline. RESULTS.— Mean morning FEV1 increased from 1.85 L to 2.01 L in the
montelukast group and from 1.85 L to 1.93 L in the placebo group. This represents
an 8.23% (95% confidence interval CI, 6.33% to 10.13%) increase from baseline
in the montelukast group and a 3.58% (95% CI, 1.29% to 5.87%) increase from
baseline in the placebo group (P<.001 for montelukast
vs placebo). CONCLUSION.— Montelukast improves morning FEV1 in 6- to 14-year-old children
with chronic asthma.
To determine the minimal perceptible clinical improvement (MPCI) in patients with osteoarthritis (OA) with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, ...and patient and investigator global assessment of disease status in randomized clinical trials for treatment of OA.
Subjects with OA of the knee or hip were randomized to receive either rofecoxib 12.5 or 25 mg once daily, ibuprofen 800 mg 3 times daily, or placebo for 6 weeks. The WOMAC and global assessments were completed at baseline and Weeks 2, 4, and 6. A patient global assessment of response to therapy (0 to 4 scale) was used to "anchor" the WOMAC scores. MPCI was defined as the difference in mean change from baseline in WOMAC (100 mm normalized visual analog scale, VAS) between patients with 0 = "None" global response to therapy and patients with 1 = "Poor" global response to therapy.
MPCI was determined to be 9.7, 9.3, and 10.0 mm for the WOMAC pain, physical function and stiffness subscales, respectively, and 11.1 mm for WOMAC question 1: Pain walking on a flat surface. The MPCI for the investigator was 0.4 with investigator assessment of disease status reported on a 0 to 4 Likert scale. Of note, the estimated MPCI for the WOMAC and investigator globals were similar irrespective of treatment, sex, age, or geographic region.
In this analysis, mean changes of roughly 9 to 12 mm (100 mm normalized VAS) on WOMAC scales were perceptible changes to patients with hip and knee OA. A mean decrease of 0.4 in global disease status (0 to 4 Likert scale) as assessed by the investigator corresponded to the patients' MPCI. Understanding the minimal perceptible differences may permit a better assessment of the clinical relevance of therapeutic interventions in OA.
OBJECTIVE The Pediatric Asthma Diary was developed and validated to assess efficacy of interventions in children with asthma. DESIGN, PATIENTS, AND SETTING Diary validation was performed in a three ...week, prospective study of 106 children aged 6–14 years with asthma. Children were classified at baseline as either stable (requiring no additional asthma treatment) or new onset/worse (requiring either addition of or increase in anti-inflammatory treatment). RESULTS A daytime symptom scale and “day without asthma” were defined from diary questions. Both measures demonstrated significant validity and responsiveness to anti-inflammatory treatment. The stable group experienced a higher percentage of days without asthma during week 1 compared with the new onset/worse group (39.6%v 11.6%, respectively). The new onset/worse patients experienced significant improvement in days without asthma (24.5%) compared with stable patients (6.4%). CONCLUSIONS The Pediatric Asthma Diary daytime symptom scale and day without asthma are acceptable measures for use in asthma intervention studies of children aged 6–14 years.
Abstract Objective: To determine the ability of montelukast, a leukotriene receptor antagonist, to allow tapering of inhaled corticosteroids in clinically stable asthmatic patients. Design: Double ...blind, randomised, placebo controlled, parallel group study. After a single blind placebo run in period, during which (at most) two inhaled corticosteroids dose decreases occurred, qualifying, clinically stable patients were allocated randomly to receive montelukast (10 mg tablet) or matching placebo once daily at bedtime for up to 12 weeks. Setting: 23 academic asthma centres in United States, Canada, and Europe. Participants: 226 clinically stable patients with chronic asthma receiving high doses of inhaled corticosteroids (113 randomised to montelukast and 113 to placebo). Interventions: Every 2 weeks, the inhaled corticosteroids dose was tapered, maintained, or increased (rescue) based on a standardised clinical score. Main outcome measures: Last tolerated dose of inhaled corticosteroids. Results: Compared with placebo, montelukast allowed significant (P=0.046) reduction in the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square mean difference 17.6%, 95% confidence interval 0.3 to 34.8). Fewer patients on montelukast (18 (16%) v 34 (30%) placebo, P=0.01) required discontinuation because of failed rescue. Conclusions: Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control. Key messages Leukotriene receptor antagonists have complementary action to inhaled corticosteroids in asthma Many patients receive higher doses of inhaled corticosteroids than clinically required In this placebo controlled trial, montelukast allowed significant reduction of inhaled corticosteroid doses Fewer patients receiving montelukast had failed rescue than patients receiving placebo
Objective: To determine whether montelukast, a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction (EIB) in 6- to 14-year-old children with asthma.
Study design: ...Double-blind, multicenter, 2-period crossover study. Children (n = 27) with forced expiratory volume in 1 second (FEV
1 ) ≥70% of the predicted value and a fall in FEV
1 ≥ 20% after exercise on 2 occasions. Patients received montelukast (5-mg chewable tablet) or placebo once daily in the evening for 2 days in crossover fashion (at least 4 days between treatment periods). Standardized exercise challenges were performed 20 to 24 hours after the last dose in each period. End points included area above the postexercise percent fall in FEV
1 versus time curve (AAC
0-60min ), maximum percent fall in FEV
1 from pre-exercise baseline, and time to recovery of FEV
1 to within 5% of pre-exercise baseline.
Results: Montelukast significantly reduced AAC
0-60min (265 vs 590 % · min for montelukast and placebo, respectively,
P ≤ .05; ~59% protection relative to placebo) and the maximum percent fall (18% vs 26% for montelukast and placebo, respectively,
P ≤ .05). Montelukast treatment resulted in a shorter time to recovery (18 vs 28 minutes for montelukast and placebo, respectively,
P = .079).
Conclusions: Montelukast attenuates EIB at the end of the dosing interval in 6- to 14-year-old children with asthma. (J Pediatr 1998;133:424-8)
Montelukast, an oral leukotriene‐receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once‐daily 10 mg dose (film‐coated tablet) was ...selected as the optimal adult dose based on dose‐ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film‐coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose‐ranging studies in children. Therefore, the dose of montelukast for 6‐ to 14‐ year‐old children was selected by identifying the chewable tablet dose of montelukast yielding a single‐dose area under the plasma concentration‐time curve (AUC) comparable to that achieved with the adult 10 mg film‐coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6‐ to 14‐year‐old children with asthma.
BACKGROUND Montelukast sodium, a potent, oral, specific leukotriene-receptor antagonist, has demonstrated clinical efficacy in the treatment of chronic asthma. Loratadine, a selective histamine type ...1 (H1)-receptor antagonist, has demonstrated antiallergic properties. Leukotriene-receptor antagonists given concomitantly with H1-receptor antagonists have been shown to have additive effects in the prevention of bronchospasm in antigen-challenge models. OBJECTIVE To determine whether montelukast plus loratadine provides improved efficacy to montelukast alone in the treatment of chronic asthma. METHODS The efficacy of montelukast alone vs montelukast-loratadine was studied in a 10-week, multicenter, randomized, double-blind, 2 × 2 crossover study. After a 2-week placebo run-in period, patients received montelukast sodium (10 mg) plus loratadine (20 mg), or montelukast sodium (10 mg) plus placebo once daily for 2 weeks. After a 2-week placebo washout period, patients were crossed over to receive 2 weeks of the other active treatment regimen, followed by another 2-week placebo washout period. RESULTS Montelukast given concomitantly with loratadine caused significant improvement in percentage of change from baseline in forced expiratory volume in 1 second (FEV1) compared with montelukast alone (13.86% vs 9.72%; P = .001). The average additional effect of loratadine (least square mean difference in percentage of change from baseline in FEV1) was 4.15% (95% confidence interval, 1.65%-6.65%). Key secondary end points (mean daily β-agonist use, daytime and nighttime symptom scores, morning and evening peak expiratory flow rate, and the Patient Global Evaluation) all showed significant improvement with montelukast-loratadine (P<.05). CONCLUSION Montelukast-loratadine significantly improved end points of asthma control during a 2-week treatment period.Arch Intern Med. 2000;160:2481-2488-->
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