This research project was initiated in 1967 and completed in approximately 18 months. The purpose for the project was to identify what antigens may be allergic triggers for the patients' asthma. Based on the results, we intended to make environmental control suggestions and to provide a formula for immunotherapy. In the late 1960s, the challenge methodology and the allergen solutions were not standardized as they are now. Even considering the antiquated challenge testing, the results were quite spectacular. The study clearly supported that puncture skin testing showed a greater sensitivity than intradermal testing, the latter being considered the more specific method at that time in diagnosing allergic causes of asthma. The bronchial challenge testing showed an excellent correlation between positive puncture testing and allergic asthma. The study resulted in a rapid decrease in the use of intradermal testing in many allergy offices. Noteworthy was the negative correlation. When properly done, it was rare to see a positive bronchial challenge in the presence of a negative skin test. Three of 7 positive challenges to Endo dust, which showed a negative skin reaction, may have been due to an irritant effect of the antigen rather than an allergic reaction. The irritant effect was suggested in the literature of the time. Pulmonary function was evaluated by a peak flow meter rather than using the more laborious spirometry of the era. With the equipment at the time of the study, not only was the use of spirometry extremely labor intensive for patients and physicians, but also the methodology rapidly resulted in exhaustion for the children, and it was obvious that this would not enable the study to be completed with a significant number of patients. The peak flow meter was chosen as the children used the meter 3 times a day for their entire residence at National Jewish Hospital. Repeated usage on the day of challenge did not lead to exhaustion, and each patient was able to complete the session until a positive result or the end of the testing occurred. The peak flow is not as sensitive as spirometry, which was potentially a difficulty. Over the subsequent decades, we have seen a dramatic improvement of allergy testing and bronchial provocation. Bronchial challenge testing has become more standardized, as well as standardization of pollen, dander, and other allergens. The big shortfall in technique 3-plus decades ago was the use of solutions of allergen as opposed to current the use of allergens in a more natural form. Allergen challenge rooms using pollens and dander have offered a much more natural setting for determining sensitivity. This has eliminated or reduced reliance on unintended alteration of the allergens, which in effect was not consistent with natural exposure.

Objective: To assess the peak inspiratory flow rate (PIFR) and forced inspiratory vital capacity (FIVC) through the formoterol (Foradil*) Aerolizer* in patients with mild, moderate and severe asthma.Research design and methods: PIFR and FIVC were assessed in 33 adults and 32 children using a spirometer alone (baseline), a spirometer with an adaptor, and a spirometer with an adaptor and the Aerolizer inhaler (placebo loaded).Results: Of adult patients using the Aerolizer inhaler, 73% had PIFR values of > 100 l/min and 91% had values of > 60 l/min. PIFR in adults was reduced from a mean baseline of 283 l/min to 118 l/min through the loaded Aerolizer inhaler Similarly, 75% of children using the Aerolizer inhaler had PIFR values > 80 l/min and 91% had values of > 60 l/min. The mean PIFR in children was reduced from a baseline of 154 l/min to 100 l/min through the loaded Aerolizer inhaler. Only small mean decreases from baseline were observed in FIVC through the loaded Aerolizer inhaler: 8.4% in adults and 3.8% in children. FIVC values of > 2.0 litre were achieved in 82% of adults, and 81% of children achieved FIVC values of > 1.5 litre.Conclusion: This study, albeit in a relatively small patient population, suggests that most children and adults with asthma can generate PIFRs of > 60 l/min and FIVCs of > 1.5 litre through the Aerolizer inhaler regardless of their disease severity. Such findings compare extremely favourably with other dry powder inhalers.

Background. Inhaled corticosteroids are the agents of choice for treating persistent asthma. Objective. To evaluate the long-term efficacy and safety of budesonide inhalation powder (Pulmicort Turbuhaler((R))) in patients with mild to severe persistent asthma. Methods. Patients (n = 1133) received open-label budesonide (dose range, 100-800 mug b.i.d.) for 52 weeks following 2 weeks to 5 months of treatment in one of four double-blind, placebo-controlled studies. Patients, identified before the double-blind studies, included adults (n = 249) not receiving corticosteroids, adults (n = 384) and children (n = 356) previously maintained on inhaled corticosteroids, and adults (n = 144) previously maintained on oral corticosteroids. Results. Mean forced expiratory volume in I see was 68.2% of predicted normal (n = 1133) at baseline (mean from two visits before randomization), 74.4% (n = 1132) at the end of double-blind treatment, 81.3% (n = 97 1) at week 52, and 80.1% (n = 1125) at last observation (including patients who discontinued early). Sixty-four patients maintained on oral corticosteroids before double-blind treatment entered the open-label study off oral corticosteroids, 58 of whom (91%) remained oral corticosteroid-free throughout the study. There was no evidence of basal or cosyntropin-stimulated hypothalamic-pituitary-adrenal axis function suppression, and the most commonly occurring adverse events were respiratory infection, sinusitis, and pharyngitis. Conclusions. During this 52-week, open-label study, budesonide maintained the improved pulmonary function and decreased oral corticosteroid use observed during previous double-blind treatment and was well tolerated, supporting its long-term use in adults and children with mild to severe persistent asthma.

Improvement in patient daily functioning and well-being resulting from disease-related symptom relief is increasingly viewed as a clinically relevant therapeutic outcome. The objective of this study was to evaluate the health-related quality of life (HRQL) effects, safety and efficacy of cetirizine in the treatment of seasonal allergic rhinitis, and impact on self-reported work/school-related productivity and activity impairment (WPAI). This was a double-blind, placebo-controlled, parallel-group study. Adult patients (n = 865) were randomized to daily treatment for 2 weeks with cetirizine or placebo. Patient disease-specific HRQL and WPAI were assessed at baseline and weeks 1 and 2 of treatment using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Allergy-Specific Work Productivity and Activity Impairment (WPAI-AS) Instrument, respectively. Treatment with cetirizine resulted in greater (p < 0.001) improvement in overall RQLQ and individual domain scores (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, emotional), as compared with placebo. Cetirizine therapy produced a 28.9% mean reduction in total symptom severity complex (TSSC) score versus 12.7% with placebo at study end. Work/school productivity and activity impairment were significantly (p < 0.001) decreased from baseline for cetirizine-treated patients compared with placebo. The incidence of treatment-related side effects was similar between groups. Cetirizine provides safe and effective symptomatic relief in adults with SAR while significantly improving HRQL and providing a positive impact on work/school-related productivity and activity impairment. These results provide a more comprehensive assessment of cetirizine, indicating that its benefits extend beyond conventional measures of clinical outcome.

Background: Montelukast, an oral, once-daily leukotriene receptor antagonist, provides protection against exercise-induced bronchoconstriction.Objective: To evaluate the effect of 8 weeks of therapy with salmeterol aerosol or montelukast on exercise-induced bronchoconstriction in adults with asthma.Design: 8-week multicenter, randomized, double-blind study.Setting: 17 asthma treatment centers in the United States.Patients: 191 adults with asthma who had documented exercise-induced bronchoconstriction.Intervention: qualified patients were randomly assigned to double-blind treatment with montelukast (10 mg once in the evening) or salmeterol (50 mu g [2 puffs] twice daily).Measurements: Changes in pre-exercise and postexercise challenge values; percentage inhibition in the maximal percentage decrease in FEV,; the area above the FEV1-time curve; and time to recovery of FEV, at days 1 to 3, week 4, and week 8 of treatment.Results: By day 3, similar and statistically significant reductions in maximal percentage decrease in FEV, were seen with both therapies. Sustained improvement occurred in the montelukast group at weeks 4 and 8; at these time points, the bronchoprotective effect of salmeterol decreased significantly. At week 8, the percentage inhibition in the maximal percentage decrease in FEV, was 57.2% in the montelukast group and 33.0% in the salmeterol group (P = 0,002), By week 8, 67% of patients receiving montelukast and 46% of patients receiving salmeterol had a maximal percentage decrease in FEV, of less than 20%,Conclusions: The bronchoprotective effect of montelukast was maintained throughout 8 weeks of study. In contrast, significant loss of bronchoprotection at weeks 4 and was seen with salmeterol. Long-term administration of montelukast provided consistent inhibition of exercise- induced bronchoconstriction at the end of the 8-week dosing interval without tolerance.

BACKGROUND Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

OBJECTIVE:Intranasal corticosteroids are used widely for the treatment of allergic rhinitis because they are effective and well tolerated. However, their potential to suppress growth of pediatric subjects with allergic rhinitis continues to be a concern, particularly in light of reports of growth suppression after treatment with intranasal beclomethasone dipropionate or intranasal budesonide (see the article by Skoner et al in this month's issue). A 1-year study of prepubertal patients between 3 and 9 years of age with perennial allergic rhinitis was conducted to assess the effects on growth of mometasone furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal corticosteroid with negligible bioavailability.METHODS:This was a randomized, placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were randomized to treatment with either MFNS 100 microg QD or placebo for 1 year. Each subject's height was required to be between the 5th and 95th percentile at baseline, and skeletal age at screening was required to be within 2 years of chronological age, as determined by left wrist x-rays. Washout periods for medications that affect either childhood growth or allergic rhinitis symptoms were established based on estimated period of effect, and these medications were prohibited during the study. However, short courses of either oral prednisone lasting no longer than 7 days or low-potency topical dermatologic corticosteroids lasting no longer than 10 days were permitted if necessary. Height was measured with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks, and the primary safety variable was the change in standing height. The rate of growth was also calculated for each subject as the slope (linear regression) of the change in height from baseline using data from all visits of subjects who had at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks. All analyses were based on all randomized subjects (intent-to-treat principle). The change from baseline in standing height was analyzed by a 2-way analysis of variance that extracted sources of variation attributable to treatment, center, and treatment-by-center interaction.RESULTS:Demographic characteristics were similar at baseline. Eighty-two subjects completed the study (42 in the MFNS group and 40 in the placebo group), and 93% of subjects achieved at least 80% compliance with therapy. After 1 year of treatment, no suppression of growth was seen in subjects treated with MFNS, and mean standing heights were similar for both treatment groups at all time points. For the primary safety variable (change in height from baseline), both treatment groups were similar at all time points except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean increase in height than subjects treated with placebo at these time points: the change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However, the rate of growth (.018 cm/day) averaged for all time points over the course of the study was similar for both treatment groups. Additional analyses found that MFNS did not retard growth in any sex or age subgroup of subjects. The use of exogenous corticosteroids other than the study drug was also similar among the 2 treatment groups. Results from cosyntropin stimulation testing confirmed the absence of systemic effects of MFNS. The change from baseline in the difference between prestimulation and poststimulation levels was similar for both treatment groups after 1 year of treatment, with no evidence of HPA-axis suppression in MFNS-treated subjects at any time point. Incidences of treatment-related adverse events were similar for both treatment groups, with 16% of MFNS-treated subjects reporting adverse events, compared with 22% of placebo-treated subjects.CONCLUSIONS:(ABSTRACT TRUNCATED)

Background: The efficacy and safety of mometasone furoate aqueous nasal spray (MFNS; Nasonex) 200 mu g once daily for the treatment and prophylaxis of seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been demonstrated in adults. However, the dose response of MFNS in pediatric patients has not yet been characterized. Objective: This study was conducted to determine the dose-response relationship of 3 different doses of MFNS in a pediatric population.Methods: This was a multicenter, double-blind, active- and placebo-controlled study of 679 children 6 to 11 years of age with histories of SAR and documented positive skin test responses. Patients were randomized to one of the following treatment groups for 4 weeks: MFNS 25 mu g once daily, MFNS 100 mu g once daily, MFNS 200 mu g once daily, beclomethasone dipropionate 84 mu g twice daily (168 mu g/day), or placebo. Physician evaluations were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed for days 1 to 15 and 16 to 29.Results: The mean reduction from baseline in physician-evaluated total nasal symptom scores at day 8 (the primary efficacy variable) was significantly greater in the MFNS and beclomethasone dipropionate groups than in the placebo group (P less than or equal to.02). No significant differences were observed among the 3 MFNS groups. However, as treatment continued, symptoms in patients treated with MFNS 100 or 200 mu g once daily continued to improve, whereas those treated with MFNS 25 mu g once daily demonstrated little further improvement. By day 29, MFNS 100 and 200 mu g once daily both were significantly more effective than MFNS 25 mu g once daily in relieving symptoms of SAR, but MFNS 200 mu g provided no additional benefit over MFNS 100 mu g. All doses of MFNS were well tolerated, and cosyntropin stimulation tests performed before and after treatment found no evidence of hypothalamic-pituitary-adrenal axis suppression.Conclusion: These results indicate that the most appropriate therapeutic dosage of MFNS in the treatment of SAR in children 6 to 11 years of age is 100 mu g once daily. In addition, MFNS at doses up to 200 mu g once daily for 4 weeks was well tolerated and had no detectable effects on hypothalamic-pituitary-adrenal axis function.

Objective: To determine the effects of zafirlukast on exercise-induced bronchoconstriction in children. Study design: Exercise challenges were done 4 hours after single oral doses of zafirlukast or placebo were administered in asthmatic children (6 to 14 years) treated with β2 -agonists alone. Subjects randomized to treatment had a ≥20% decrease in forced expiratory volume in 1 second (FEV1 ) after a screening challenge. In a randomized, double-blind, 3-way, crossover design, group 1 (n = 20) received placebo and 5 and 20 mg zafirlukast, and group 2 (n = 19) received placebo and 10 and 40 mg zafirlukast. Maximal percentage fall in FEV1 , area under the curve, and time to recovery of FEV1 to within 5% of baseline after the challenge were compared with analysis of variance. Results: Mean values for maximal fall in FEV1 ranged from –8.7% ± 1.7% to –11.1% ± 1.9% after zafirlukast compared with –17.1% ± 1.8% and –16.3% ± 1.9% after placebo. Differences from placebo for fall in FEV1 and area under the curve were significant (P ≤ .05) after 5, 20, and 40 mg zafirlukast and approached significance (P ≤ .08) after 10 mg zafirlukast. After all zafirlukast doses, recovery times (means of 5 to 7 minutes) decreased significantly (P ≤ .05) and by approximately half compared with placebo (11 and 14 minutes). Safety assessments did not differ among treatments. Conclusion: Four hours after dosing, zafirlukast attenuated exercise-induced bronchoconstriction in children. (J Pediatr 1999;134:273-9)

The objective of this study was to compare the efficacy and safety of Claritin-D 24 Hour (once daily) with that of Claritin-D 12 Hour (twice daily) and placebo in the treatment of patients with seasonal allergic rhinitis (SAR). In this double-blind, placebo-controlled, multicenter study, 469 patients with moderate-to-severe SAR symptoms were treated for 2 weeks with one of the following: Claritin-D 24 Hour (a combination tablet formulation of loratadine 10 mg in the coating and pseudoephedrine sulfate 240 mg in an extended-release core), Claritin-D 12 Hour (a combination tablet formulation of loratadine 5 mg in the tablet coating and 120 mg pseudoephedrine sulfate, 60 mg in the coating and 60 mg in the core), or placebo. Claritin-D 24 Hour and Claritin-D 12 Hour were consistently superior to placebo (P < 0.01) in reducing total, nasal, and nonnasal symptom scores. Patients in the Claritin-D 24 Hour and Claritin-D 12 Hour groups also had significantly greater (P lE 0.05) relief of rhinorrhea and nasal stuffiness as compared with placebo. Insomnia was reported significantly more often (P < 0.01) in Claritin-D 12 Hour (15%) patients compared with Claritin-D 24 Hour (4%) and placebo (2%) patients. Dry mouth was reported significantly more often (P < 0.05) in Claritin-D 24 Hour (13%) and Claritin-D 12 Hour (13%) groups compared with placebo (4%). Claritin-D 24 Hour has efficacy comparable to Claritin-D 12 Hour in relieving allergic rhinitis symptoms while producing significantly less insomnia.

BACKGROUND:Patients with mild asthma frequently have only exercise-induced bronchoconstriction, a symptom of inadequate control of asthma. We evaluated the ability of montelukast, a leukotriene-receptor antagonist, to protect such patients against exercise-induced bronchoconstriction. METHODS:We randomly assigned 110 patients (age, 15 to 45 years) with mild asthma and a decrease in the forced expiratory volume in one second (FEV1) of at least 20 percent after exercise on two occasions during a placebo run-in period to receive 10 mg of montelukast (54 patients) or placebo (56 patients) once daily at bedtime for 12 weeks in a double-blind study. Treatment was followed by a two-week, single-blind washout period during which all patients received placebo. Exercise challenges were performed at base line; 20 to 24 hours after dosing at weeks 4, 8, and 12; and at the end of the washout period. The primary end point was the area under the curve for FEV1 (expressed as the percent change from base-line values) in the first 60 minutes after exercise. This measure summarized the extent and duration of bronchoconstriction after exercise. RESULTS:At 12 weeks, montelukast therapy offered significantly greater protection against exercise-induced bronchoconstriction than placebo therapy (expressed as the percentage of inhibition of the end points), as evidenced by the improvement in the area under the FEV1 curve (degree of inhibition, 47.4 percent; P=0.002). Montelukast therapy was also associated with a significant improvement in the maximal decrease in FEV1 after exercise (P=0.003) and the time from the maximal decrease in FEV1 to the return of lung function to within 5 percent of pre-exercise values (P=0.04). The differences between groups in the various measures of lung function were similar at 4, 8, and 12 weeks; there was no evidence of rebound worsening of lung function in the montelukast group after the washout period. After 12 weeks of treatment, patients in the montelukast group were more likely to rate their asthma control as better and less likely to require rescue therapy with a beta-agonist during or after exercise challenge. The rates of adverse events were similar in the two groups. CONCLUSIONS:As compared with placebo, once-daily treatment with montelukast provided significant protection against exercise-induced asthma over a 12-week period. Tolerance to the medication and rebound worsening of lung function after discontinuation of treatment were not seen.

Background: The efficacy and safety of salmeterol powder have not previously been evaluated in children with asthma in the United States.Objective: The efficacy and safety of salmeterol powder versus placebo were compared in children between the ages of 4 and 11 years with chronic persistent asthma.Methods: A randomized, double-blind, placebo-controlled, parallel group trial was performed at 11 clinical centers, Two hundred seven patients were randomly assigned to receive 50 mu g salmeterol powder or placebo (and albuterol as needed) twice daily via a breath-actuated device for 12 weeks. Twelve-hour serial pulmonary function assessments were conducted on day 1 and at week 12. Daily recordings of morning and evening peak expiratory flow (PEF), supplemental albuterol use, asthma symptoms, and nocturnal awakenings were assessed.Results: On day 1 and at week 12, weighted mean percent of predicted PEF (P <.001, day 1 and P =.008, week 12) and weighted mean forced expiratory volume in one second (P <.001, day 1 and week 12) were significantly higher at all timepoints evaluated over the 12-hour postdosing period in patients treated with salmeterol powder compared with placebo. Overall reductions in supplemental albuterol use and mean asthma symptom scores were also significantly greater in children administered salmeterol compared with placebo (P =.004 and P =.006, respectively). The frequency of adverse events was similar in the two treatment groups.Conclusion: Salmeterol powder (50 mu g twice daily) is effective and safe in producing bronchodilation and relieving symptoms in children with chronic persistent asthma during 12 weeks of treatment.

Objective: To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma.Study design: In a double-blind, randomized, parallel-group, multicenter study, 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 mu g or 100 mu g administered twice daily by a breath-actuated device for 1 year. Growth was evaluated monthly, whereas other safety variables and pulmonary function were evaluated periodically.Results: The prepubescent patients showed no statistically significant differences in mean height, mean growth velocity, or mean skeletal age between any of the treatment groups at any time. Over a period of 1 year, mean height (+/- SE) increased 6.15 +/- 0.17 cm in the placebo group, 5.94 +/- 0.16 cm in the fluticasone propionate 50 mu g group, and 5.73 +/- 0.13 cm in the fluticasone propionate 100 mu g group (p = 0.308, overall).Conclusions: Prepubescent children treated with fluticasone propionate 50 mu g and 100 mu g administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age.

Objective: To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler (Turbuhaler) in children with moderate to severe persistent asthma. Study design: In our randomized, double-blind, placebo-controlled, parallel-group, multicenter study, a total of 404 children with asthma, who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy, were randomly assigned to receive either 100, 200, or 400 μg of budesonide or placebo twice daily for 12 weeks. At baseline, mean forced expiratory volume in 1 second (FEV1) was 74.6% (range, 30.7% to 123.3%) of the predicted normal value. Results: Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function (morning peak expiratory flow and FEV1), in asthma symptoms, and with a significant decrease in inhaled β2-agonist use in comparison with placebo. Improvements were evident within 2 weeks and were maintained throughout the 12 weeks. Budesonide treatment had no significant effect on hypothalamic–pituitary–adrenal axis function, and the incidence of reported adverse events was similar in all treatment groups. Conclusion: Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children (6 to 18 years of age) with moderate to severe persistent asthma. (J Pediatr 1998;132:976-82.)

Fexofenadine HCl is a new, nonsedating H1-receptor antagonist approved for treatment of seasonal allergic rhinitis (SAR). In a double-blind, randomized, placebo-controlled, multicenter trial, 588 patients with fall SAR rated the severity of their symptoms using a scoring system at a screening visit and during a 3-day placebo lead-in period. Patients who did not respond to placebo and met symptom severity criteria were randomized to receive placebo or fexofenadine HCl at 40, 60, or 120 mg bid at 7:00 a.m. and 7:00 p.m. for 14 days. Patients continued to rate the severity of their symptoms immediately before receiving each dose (at trough). A total of 545 patients were included in an intent-to-treat analysis. The change from baseline in the primary efficacy variable (average daily 7:00 p.m. reflective symptom scores) was significantly greater in patients receiving all dosages of fexofenadine HCl than placebo (p < 0.01). All active dosages produced significant decreases (p < 0.05) in secondary end points: 7:00 a.m. reflective symptom scoring; 7:00 a.m. and 7:00 p.m. scoring 1-hour before dose; and bedtime scoring 1-3 hours after the 7:00 p.m. dose. All dosages of fexofenadine HCl were well tolerated, and no effect on QTc was observed. In conclusion, fexofenadine HCl is safe and effective in the treatment of fall SAR, with 60 mg bid being the optimal therapeutic dosage.

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 micrograms and 42 micrograms administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral beta-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vital signs, electrocardiogram (ECG), and 24-hr ECG (Holter) monitoring. Both the 21-micrograms and 42-micrograms doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV1) (p < or = 0.02) and PEFR (p < or = 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-micrograms dosage producing consistently higher serial FEV1 and PEFR than did the 21-micrograms dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p < or = 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECGs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 micrograms or 42 micrograms twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 micrograms twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 micrograms.

The dose-related protective effects of montelukast, a potent and selective cysteinyl leukotriene-receptor antagonist, against exercise-induced bronchoconstriction were investigated in a five-period, randomized, incomplete-block, crossover study with montelukast (0.4, 2, 10, 50 mg) and placebo. The study subjects were 27 nonsmoking, healthy stable patients with asthma (mean forced expiratory volume in 1 second [FEV1], 82.0% predicted) who demonstrated a a greater than or equal to 20% decrease in FEV1 while beta-agonist was withheld for 6 hours before treadmill exercise. The standard exercise challenge was performed 20 to 24 hours, and again 32 to 36 hours, after the second of two once-daily doses. The effect of oral montelukast on exercise was measured by the area above the postexercise percentage decrease in FEV1 versus time curve from 0 to 60 minutes [AUC(0-60)], the maximal percentage decrease in FEV1 after exercise, and time after maximal decrease to recovery of FEV1, to within 5% of the preexercise baseline. Twenty to 24 hours after administration, montelukast caused dose-related protection, while providing similar protection against exercise-induced bronchoconstriction at the two highest doses. The AUC(0-60) values (mean +/-SD) were 637 +/- 898, 715 +/- 870, 988 +/- 1147, and 927 +/- 968 min % for 50, 10, 2, and 0.4 mg montelukast, respectively, and 1193 +/- 1097 min % for placebo (p = 0.003). No important clinical effect was present 36 hours after dosing. Montelukast was generally well tolerated at all dose levels. In conclusion, montelukast caused dose-related protection against exercise-induced bronchoconstriction at the end of a once-daily dosing interval. Protection against exercise-induced bronchoconstriction can be used to determine appropriate dose selection.

Objective: The purpose of this study was to evaluate the feasibility of switching to once-daily (qd) administration of flunisolide in patients with asthma that was controlled by twice-daily (bid) dosing of this inhaled steroid.Methods: Three hundred sixty-six adults and children with bronchial asthma that was controlled with inhaled steroids were recruited for this prospective, double-blind, parallel-group study. After a 4-week, stable baseline period of flunisolide administration, 2 inhalations (500 mu g) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 mu g) bid; group 2, 4 inhalations (1000 mu g) qd in the morning; group 3, 4 inhalations (1000 mu g) qd in the evening; or group 4, 2 inhalations (500 mu g) qd in the morning. Outcome measures included morning and evening asthma symptoms (scale of 0 to 3), daytime and nighttime albuterol use, morning and evening peak expiratory flow rate (PEFR), FEV(1), and methacholine PC20. In addition, a subset of patients in each group had 24-hour urinary cortisol levels measured before and after randomization.Results: Outcome measures in the four groups mere not significantly different at baseline before randomization. The three groups that received maintenance therapy with flunisolide, 1000 mu g daily, did not show significant changes from baseline values and remained comparable in all outcome areas. Asthma control in the group randomized to flunisolide 500 mu g qd, however, deteriorated significantly: morning symptoms increased by 0.21 units (48%), evening symptoms increased by 0.15 units (31%), daytime albuterol use increased by 0.42 inhalations per day (37%), nighttime albuterol use increased by 0.48 inhalations per night (91%), morning PEFR decreased by 17.1 L/min (4%), and evening PEFR decreased by 12.6 L/min (3%). There were no significant changes in PC20 or 24-hour urinary cortisol levels in any group.Conclusions: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 mu g) bid, switching to 4 inhalations (1000 mu g) gd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 mu g) qd in the morning, however, leads to a deterioration in asthma control.