The effect of zafirlukast on repetitive exercise-induced bronchoconstriction: the possible role of leukotrienes in exercise-induced refractoriness

BACKGROUND: Single doses of zafirlukast attenuate exercise-induced bronchoconstriction (EIB), but previous studies have not measured zafirlukast's effects after regular dosing or its duration of effect beyond 4 hours. OBJECTIVE: The purpose of this study was to assess the effects of zafirlukast 20 mg and 80 mg twice daily compared with placebo on exercise challenges performed at 2 and 8 hours after the last dose of regular administration. METHODS: Twenty-four adult patients with stable asthma taking beta(2)-agonists, inhaled corticosteroids, or both received treatment with zafirlukast (20 mg and 80 mg) and placebo. The patients were treated twice daily for 14 days in a randomized, double-blind, 3-way cross-over fashion, with a 7-day washout period between each treatment. Exercise challenges were performed at 2 and 8 hours after the morning dose on day 14. FEV(1) was measured before exercise and at set intervals after exercise until it returned to within 7% of its baseline value. RESULTS: Both zafirlukast treatments significantly reduced EIB, as measured by the area under the FEV(1) time curve after the 2-hour (P <.001) and 8-hour (P <.001) exercise challenges and maximum fall in FEV(1) at the 2-hour challenge (P <.001). The comparison at 8 hours between treatments was affected by the unexpected finding that EIB was less in the placebo group after the 8-hour challenge than after the 2-hour challenge, as measured by the within-group change in the maximum fall in FEV(1) (P <.001) and the area under the FEV(1) time curve (P =.0023). CONCLUSION: Regular zafirlukast treatment protects against EIB for at least 8 hours after regular dosing. A refractory period, which may be caused by exercise-induced leukotriene release, may last for up to 6 hours after the initial response to exercise.     

Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma

Background: Few studies have compared the efficacy of inhaled corticosteroids and leukotriene modifiers for the treatment of persistent asthma. Objective: Our purpose was to compare the efficacy of a low dose of inhaled fluticasone propionate (FP) with that of oral zafirlukast in the treatment of persistent asthma previously treated with short-acting β₂-agonists alone. Methods: A 12-week, randomized, double-blind, double-dummy, multicenter study was conducted in 451 patients aged 12 years and older with asthma who were symptomatic on short-acting β₂-agonists alone. After an 8- to 14-day run-in period, patients were randomized to treatment with FP 88 μg twice daily or zafirlukast 20 mg twice daily. Results: Treatment with FP was more effective than treatment with zafirlukast in increasing morning FEV₁ (by 0.42 L vs 0.20 L over baseline, P < .001), morning peak expiratory flow (by 49.94 L/min vs 11.68 L/min over baseline, P < .001), and evening PEF (by 38.91 L/min vs 10.50 L/min over baseline, P < .001). Statistically significant differences between the two treatments in FEV₁ were noted after the first observation (week 4) and in morning and evening peak expiratory flow by week 2. Mean change in percentage of symptom-free days was greater with FP than with zafirlukast (28.5% of days vs 15.6% of days, P < .001) and FP significantly increased the percentage of rescue-free days by 40.4% of days compared with 24.2% of days with zafirlukast (P < .001). Treatment with FP significantly reduced albuterol use by 2.39 puffs per day compared with 1.45 puffs per day (P < .001) and increased the percentage of nights with no awakenings by 21.2% of nights compared with 8.0% of nights with zafirlukast (P < .001). Conclusion: The clinical effectiveness of a low dose of FP as first-line therapy in patients with persistent asthma who are symptomatic on β₂-agonists alone is superior to that of zafirlukast. (J Allergy Clin Immunol 2000;105:1123-9.)     

Comparison of once- and twice-daily dosing of fluticasone propionate 200 micrograms per day administered by Diskus device in patients with asthma treated with or without inhaled corticosteroids

Background: There are limited published data regarding the efficacy of once- versus twice-daily administration of flutica-sone propionate. Objective: Our purpose was to evaluate the effectiveness of fluticasone propionate powder 200 μg/d administered as a once- or twice-daily dosage regimen in patients who were currently being treated with bronchodilators only (BD patients) and in patients who required inhaled corticosteroids for maintenance treatment of asthma (ICS patients). Methods: Five hundred seventy patients were randomly assigned to receive one of the following inhaled treatments through the Diskus device (Glaxo Wellcome, Research Triangle Park, NC) for 12 weeks: fluticasone propionate 100 μg twice daily (FP100BID) or 200 μg once daily (FP200QD) or placebo. Results: BD patients treated with FP100BID, FP200QD, and placebo had mean increases in FEV₁ from baseline to end point of 0.49 L, 0.37 L, and 0.21 L, respectively (P < .001, FP100BID vs placebo; P = .05, FP200QD vs placebo). ICS patients treated with FP100BID and FP200QD had mean increases in FEV₁ of 0.27 L and 0.11 L, respectively, compared with a decrease in FEV₁ of –0.08 L with placebo (P < .001, FP100BID vs placebo; P = .023, FP200QD vs placebo). BD patients treated with FP100BID and FP200QD had mean increases in morning peak expiratory flow from baseline to end point of 31 L/min and 27 L/min, respectively, compared with a 1 L/min increase in patients treated with placebo. ICS patients treated with FP100BID had a mean increase in morning peak expiratory flow (from baseline to end point) of 18 L/min compared with mean decreases of –3 L/min and –12 L/min in the FP200QD and placebo groups, respectively. More patients were withdrawn from placebo (26% and 48%, in BD and ICS patients, respectively) than from fluticasone propionate (7%-9% [BID-QD] and 18%-32% [BID-QD], in BD and ICS patients, respectively) because of failure to meet predetermined asthma stability criteria. Conclusion: The efficacies of FP100BID and FP200QD were comparable with regard to improvement in pulmonary function and asthma stability in BD patients. In ICS patients, asthma control was maintained with FP200QD, whereas FP100BID provided greater improvements in pulmonary function and asthma stability. (J Allergy Clin Immunol 2000;105:1153-61.)     

Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction

BACKGROUND: Airway obstruction induced by physical exercise is a common feature in asthma, and conventional treatments do not offer optimal protection. There is thus a need for additional therapies for optimal control of exercise-induced bronchoconstriction (EIB). OBJECTIVE: The influence of treatment with the antihistamine loratadine and the antileukotriene zafirlukast alone and in combination on EIB was investigated. This combination has previously shown beneficial additive effects in allergen-induced bronchoconstriction. METHODS: In a double-blind cross-over study loratadine (10 mg twice daily) and zafirlukast (80 mg twice daily) were evaluated alone and in combination in 16 nonsmoking patients with mild asthma, previously documented EIB, and airways hyperresponsiveness to histamine. RESULTS: The mean +/- SE maximum decrease in FEV1 after a standardized exercise provocation was 21.6% +/- 3% after placebo, 22.8% +/- 3% after loratadine, 13.9% +/- 2% after zafirlukast (P <.05 vs placebo), and 10.3% +/- 2% after the combination of loratadine and zafirlukast (P <.05 vs placebo). Expressed as the area under the FEV1 percentage change versus time curve, the mean protection produced by zafirlukast and the combination of zafirlukast and loratadine was 57% and 65%, respectively, whereas loratadine alone had no significant protective effect. There was also no significant difference between the effect of zafirlukast alone or in combination with loratadine. CONCLUSION: The study confirmed the beneficial effect of a leukotriene receptor antagonist in EIB but failed to obtain evidence that H1-receptor antagonism alone or together with the cysteinyl-leukotriene 1 receptor antagonist zafirlukast offers a protective effect.     

Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma

Background: Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A₂ receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear. Objective: We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release. Methods: We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. Results: After treatment, significant improvements in symptom score (P < .05), PEF (P < .01), diurnal variation of PEF (P < .01), and bronchial responsiveness (P < .01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2⁺ eosinophils (P < .05). There was also a reduction in the number of cells expressing RANTES (P < .05) and macrophage inflammatory protein (MIP)-1α (P < .05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P < .01), RANTES (P < .05), MIP-1α (P < .01), and eotaxin (P < .01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2⁺ eosinophils and numbers of monocyte chemotactic protein-3⁺ (r_s = 0.52, P < .005), MIP-1α⁺ (r_s = 0.34, P < .05), and eotaxin⁺ cells (r_s = 0.47, P < .01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2⁺ cells (r_s = –0.65, P < .001). Conclusions: These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues. (J Allergy Clin Immunol 1999;103:1054-61.)     

Tolerance to the bronchoprotective effect of β2 -agonists: Comparison of the enantiomers of salbutamol with racemic salbutamol and placebo

Background: Regular use of racemic salbutamol results in the partial loss of its bronchoprotective effect. The 2 enantiomers of salbutamol, the bronchodilator R-salbutamol and nonbronchodilator S-salbutamol, are now available. Objective: We sought to compare the effect of regular use of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the bronchoprotective effect of a single dose of racemic salbutamol against methacholine-induced bronchoconstriction. Methods: Eleven of 13 well-controlled β₂ -agonist–free asthmatic subjects completed a double-blind, randomized study comparing racemic salbutamol 2.5 mg, S-salbutamol 1.25 mg, R-salbutamol 1.25 mg, and diluent placebo nebulized and inhaled 3 times daily for 6 days (≥6-day washout period). Ten to 12 hours after the last dose, the subjects performed measurement of FEV₁ , methacholine PC₂₀ , and a repeat methacholine PC₂₀ done 1 hour after the first methacholine test and 10 minutes after 2 puffs (200 μg) of racemic salbutamol administered from a metered-dose inhaler. The primary endpoint was the methacholine PC₂₀ dose shift (Δlog PC₂₀ ÷ log 2) from before to after administration of 200 μg of racemic salbutamol. Results: The methacholine dose shift was 3.2 doubling doses (9-fold increase in methacholine PC₂₀ after 200 μg of racemic salbutamol) during the placebo treatment and was unaltered (3.2) after administration of S-salbutamol. The dose shift was significantly lower after both the R-salbutamol and racemic salbutamol treatments (2.2 and 2.6 doubling doses, respectively); there was no significant difference between R-salbutamol and racemic salbutamol. There was no treatment effect on baseline FEV₁ , baseline methacholine PC₂₀ , or bronchodilation. Conclusion: Regular treatment with racemic salbutamol or R-salbutamol, but not S-salbutamol, results in a partial loss of bronchoprotection, without loss of bronchodilation, compared with placebo. (J Allergy Clin Immunol 1999;103:1049-53.)     

Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma

Background: Racemic albuterol is an equal mixture of (R)-albuterol (levalbuterol), which is responsible for the bronchodilator effect, and (S)-albuterol, which provides no benefit and may be detrimental. Objective: We sought to compare 2 doses of a single enantiomer, levalbuterol (0.63 mg and 1.25 mg), and equivalent amounts of levalbuterol administered as racemic albuterol with placebo in patients with moderate-to-severe asthma. Methods: This was a randomized, double-blind, parallel-group trial. Three hundred sixty-two patients 12 years of age or older were treated with study drug administered by means of nebulization 3 times daily for 28 days. The primary endpoint was peak change in FEV₁ after 4 weeks. Results: The change in peak FEV₁ response to the first dose in the combined levalbuterol group was significantly greater compared with the combined racemic albuterol group (0.92 and 0.82 L, respectively; P = .03), with similar but nonsignificant results after 4 weeks (0.84 and 0.74 L, respectively). Improvement in FEV₁ was similar for levalbuterol 0.63 mg and racemic albuterol 2.5 mg and greatest for levalbuterol 1.25 mg. Racemic albuterol 1.25 mg demonstrated the weakest bronchodilator effect, particularly after chronic dosing. The greatest increase in FEV₁ was seen after levalbuterol 1.25 mg, especially in subjects with severe asthma. All active treatments were well tolerated, and β-adrenergic side effects after administration of levalbuterol 0.63 mg were reduced relative to levalbuterol 1.25 mg or racemic albuterol 2.5 mg. At week 4, the predose FEV₁ value was greatest in patients who received levalbuterol or placebo when compared with those who received racemic albuterol. The difference was more evident and was statistically significant in patients who were not receiving inhaled corticosteroids. Conclusion: Levalbuterol appears to provide a better therapeutic index than the standard dose of racemic albuterol. These results support the concept that (S)-albuterol may have detrimental effects on pulmonary function. (J Allergy Clin Immunol 1998;102:943-52.)     

Inhalation challenge testing of latex-sensitive health care workers and the effectiveness of laminar flow HEPA–filtered helmets in reducing rhinoconjunctival and asthmatic reactions

Background: There are few data relating latex aeroallergen concentrations to biologic responses in latex-sensitized persons. Objectives: We sought to investigate acceptable latex aeroallergen concentrations below which latex-sensitive health care workers do not experience symptoms and to study the effect of high-efficiency particle arrest (HEPA)–filtered laminar flow helmets in preventing latex-induced symptoms. Methods: Under challenge chamber conditions, latex-sensitive health care workers underwent 7 sequential inhalation challenge tests by donning and discarding either vinyl gloves (challenge 1), low latex–allergen powder-free gloves (challenge 2), or high latex–allergen powdered gloves (challenges 3 to 7) for up to 1 hour. Volunteers wore a laminar flow helmet during all challenges; HEPA filters in the helmet were in place only during challenges 3 and 4. Flow-volume loops, symptom scores, and latex aeroallergen concentrations were measured before and during each test. Results: At 60 minutes, latex aeroallergen concentrations during challenges 3 to 7 (mean, 7600 ng/m³ ; range, 93 to 54,000 ng/m³ ) were significantly higher than during challenges 1 or 2 (mean, 65 ng/m³ ; range, nondetectable to 100 ng/m³ ) (P < .001). During challenges 5 and 6, mean maximum percent falls in FEV₁ (–16% and –11%, respectively) were significantly greater compared with those measured during challenges 3 and 4 (–3% and –1%, respectively) (P = .03). Mean maximum change from baseline symptom scores during challenges 5 and 6 was significantly higher than that during challenges 3 and 4 (P = .006). During challenges with high latex–allergen gloves, 4 volunteers had reproducible FEV₁ falls of 20% or greater at cumulative inhaled latex aeroallergen doses ranging from less than 100 ng to 1500 ng. Conclusion: The laminar flow helmets were effective in reducing latex-induced symptoms. Only 1 volunteer exhibited a fall in FEV₁ of 20% or greater after a cumulative inhaled latex aeroallergen dose of less than 100 ng, and no volunteer showed a decline in FEV₁ after exposure to powder-free low allergen gloves. (J Allergy Clin Immunol 1998;102:998-1004.)     

The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils

Background: Viral respiratory tract infections are the most frequent cause of asthma exacerbations. Of the respiratory viruses associated with these exacerbations, rhinovirus (RV) is the most common. It is proposed that these RV infections may enhance airway inflammation and thus provoke asthma. Objective: It is our hypothesis that RV infections generate nasal proinflammatory mediators that are associated with an initial increase in circulating leukocytes and may contribute to later development of neutrophilic airway inflammation. Methods: To evaluate this hypothesis, subjects with a history of allergic asthma were experimentally inoculated with strain 16 RV (RV16). The effect of this experimental infection was evaluated on circulating leukocytes, nasal-derived mediators, and markers of bronchial inflammation that were obtained by bronchoscopy and lavage. Results: RV16 inoculation was associated with an initial increase in circulating neutrophils. Paralleling these acute changes in circulating neutrophils was an increase in nasal concentrations of IL-8 and granulocyte–colony-stimulating factor (G-CSF). The RV16-associated changes in circulating and nasal G-CSF correlated with increases in peripheral blood neutrophils (r_s = 0.874, P < .001 and r_s = 0.898, P < .001, respectively). Bronchial lavage samples showed no increase in neutrophils 48 hours after RV16 inoculation; however, 96 hours after RV inoculation there was a significant increase in bronchial neutrophils compared with preinoculation values. Conclusions: These results suggest that the production of nasal mediators associated with the RV infection, particularly G-CSF, may be important to the eventual development of neutrophilic bronchial inflammation and thus contribute to asthma exacerbations. (J Allergy Clin Immunol 2000;105:1169-77.)     

Comparison of once-daily ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, and placebo in the treatment of seasonal allergic rhinitis

Background: Ebastine and loratadine are 2 nonsedating second-generation H₁ antihistamines with once-daily dosing. Objective: We compared the efficacy and safety of ebastine 20 mg and 10 mg, loratadine 10 mg, and placebo administered once daily for 4 weeks in controlling the symptoms of seasonal allergic rhinitis (SAR). Methods: In a double-blind, placebo-controlled, randomized, parallel-group study, 565 patients with ragweed SAR, ages 12 to 70 years, received either ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, or placebo once daily for 4 weeks. Patients recorded morning and evening reflective scores (past 12 hours) as well as snapshot scores (at time of recording) for nasal discharge, congestion, sneezing, itching, and total eye symptoms. Total symptom score (TSS) is the sum of these 5 scores. Results: Ebastine 20 mg produced significantly greater (P < .05) reductions from baseline compared with loratadine 10 mg over the entire treatment period in the mean daily reflective (42.5% vs 36.3%) and mean morning snapshot (40.3% vs 31.3%) TSS. The overall improvement in daily reflective and morning snapshot TSS was comparable between ebastine 10 mg and loratadine 10 mg and significantly better than placebo (P < .05). The total percent of patients with adverse events was similar among all 4 treatment groups (P = .78). Conclusion: Ebastine 20 mg given once daily was significantly superior to loratadine 10 mg given once daily at improving the rhinitis total symptom score throughout the day and at awakening over a 4-week period. Ebastine 20 mg and 10 mg doses were both efficacious and well tolerated in the treatment of SAR. (J Allergy Clin Immunol 2000;105:1101-7.)     

Effect of formoterol fumarate treatment on exercise-induced bronchoconstriction in children.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is common, particularly in children. OBJECTIVES: To compare the protective effect of single doses of formoterol fumarate via Aerolizer with placebo and albuterol in children with EIB. METHODS: In this randomized, double-blind, double-dummy, crossover trial, 23 children (aged 4-11 years) received formoterol, 12 or 24 microg; albuterol, 180 microg; or placebo at 4 separate visits. Protection against EIB was evaluated as the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) from the preexercise value after exercise challenge tests (6-minute treadmill) conducted 15 minutes and 4, 8, and 12 hours after administration of the dose. RESULTS: The maximum percentage decrease in FEV1 after the 4-hour exercise test (primary efficacy variable) was significantly less for formoterol, 12 and 24 microg, vs placebo (P < .001 for both) or albuterol (P = .016 and .010, respectively); albuterol was not significantly different from placebo. Formoterol, 12 and 24 microg, differed from placebo at 8 hours (P = .002 and .001, respectively), with a smaller difference between albuterol and placebo (P = .045). Rescue medication use and a high dropout rate may have biased treatment differences at later time points. Protection against EIB (<20% maximum decrease in FEV1) across all time points was observed for 17 (77%) of 22 and 17 (74%) of 23 children with formoterol, 12 and 24 microg, respectively, compared with 8 (35%) of 23 with albuterol and 6 (27%) of 22 with placebo. CONCLUSIONS: Single doses of formoterol, 12 or 24 microg, are effective in protecting against EIB in children, affording a statistically significantly greater protective effect than placebo or albuterol.     

Effect of FPL57787 in exercise-induced asthma

In ten patients with extrinsic asthma the effects of a new oral chromone FPL57787 and placebo were studied in a random double-blind fashion to assess the effect of FPL57787 in preventing exercise-induced asthma (EIA). Exercise testing consisted of steady state running on an inclined treadmill for up to 8 min. FPL57787 gave significant protection (P < 0.01) compared to placebo from the maximum percentage fall in FEV₁, FVC and MMEF after exercise. FPL57787 also produced a small but significant (P < 0.01) percentage increase in FEV₁, 2 hr after the drug compared to placebo, whereas no significant increase was seen in FVC or in MMEF.     

Exercise-induced bronchoconstriction in children with asthma: An observational cohort study

Background/purposeThe diagnosis of exercise-induced bronchoconstriction (EIB) was established by changes in lung function after exercise challenge. The prevalence of EIB and factors related to EIB were not fully described in children with asthma. The aim of this study was to investigate the prevalence and predictors of EIB in children with asthma.MethodsA total of 149 children with physician-diagnosed asthma above 5 years of age underwent standardized treadmill exercise challenge for EIB and methacholine challenge for airway hyper-responsiveness from October 2015 to December 2016.ResultsEIB presented in 52.5% of children with asthma. Compared with children without EIB, there were more patients with atopic dermatitis in children with EIB (p = 0.038). Allergic to Dermatohagoides pteronyssinus and Dermatophagoides farinae were also found more in children with EIB (p = 0.045 and 0.048 respectively). Maximal decrease in forced expiratory volume in 1 s (FEV₁) were highest in patients who were most sensitive to methacholine provocation (provocation concentration causing 20% fall in FEV1 [PC₂₀] ≤ 1 mg/mL). Patients, who were more sensitive to methacholine challenge (with lower PC₂₀ levels), develop EIB with more decline in FEV₁ after exercise challenge (p = 0.038). Among patients with EIB, airflow limitation development in patient with methacholine-induced airway hyper-responsiveness was more abrupt and severe compared with patients without airway hyper-responsiveness (p = 0.045 and 0.033 respectively).ConclusionEIB presented in 52.5% of children with asthma. The more severe methacholine-induced hyper-responsiveness, the higher prevalence of EIB as well as the severity.     

Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled trial

Background: Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control. Objective: Our purpose was to compare the efficacy and safety of salmeterol 50 μg combined with fluticasone 100 μg (in a combination dry powder product) with that of placebo, fluticasone, or salmeterol alone. Methods: A 12-week randomized, double-blind, multicenter study was conducted in 356 patients aged 12 years or older with asthma. After a 14-day screening period, patients were randomized to treatment with salmeterol 50 μg combined with fluticasone 100 μg (combination product), salmeterol 50 μg, fluticasone 100 μg, or placebo administered in the Diskus dry powder inhaler (GlaxoWellcome, UK) twice daily. Results: Mean change in FEV₁ at end point was significantly (P ≤ .003) greater with the combination product (0.51 L) compared with placebo (0.01 L), salmeterol (0.11 L), and flutica-sone (0.28 L). The combination product significantly increased (P ≤ .013) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo, salmeterol, and fluticasone at week 1 and week 12. Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups (P ≤ .020). The combination product significantly increased (P ≤ .012) morning PEF (combination, 52.5 L/min; placebo, –23.7 L/min; salmeterol, –1.7 L/min; fluticasone, 17.3 L/min) and evening PEF at end point compared with the other groups. The combination product significantly (P ≤ .025) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol. All treatments were equally well tolerated. Conclusion: Salmeterol 50 μg and fluticasone 100 μg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses. (J Allergy Clin Immunol 2000;105:1108-16.)     

Application de la spectroscopie infrarouge (NIRS) dans l’évaluation des adaptations musculaires périphériques chez l’enfant cardiaque

Objective. – The purpose of this work is to study the muscular responses in children with congenital heart disease using near infrared spectroscopy during isometric exercise.Materials and methods. – Twelve healthy children and eight children with congenital heart disease (class II and III NYHA) performed an isometric knee extension on Cybex Norm. For every subject, maximal voluntary contraction (MVC) and endurance time (TE) at 50% of MVC was assessed. The near infrared spectroscopy (NIRS) has been used to assess muscular oxygenation (SmO₂) and of blood volume (VS) during exercise and recovery. Half time recovery of the SmO₂ (1/2 Trec) has been also measured.Results. – Cardiac subjects developed MVC and TE weaker than healthy subjects (MVC: 96.1 ±5.0 vs 125.1 ±6.7 N·m; P <0.01) and (TE: 60.88 ±5.7 vs 116.5 ±8.7 secondes; P <0.001). No significant difference of the SmO₂ and the VS has been noted at rest. The SmO₂ decrease rapidly to reach a plateau at 25% of TE in the healthy subjects, whereas the cardiac subjects reach this plateau at 50% of TE. During recovery, 1/2 Trec is significantly higher in cardiac subjects compared to healthy subjects (26.6 ±1.8 secondes vs 18.9 ±1.9 secondes; respectively, P <0.05).Conclusion. – A decreased muscular performance accompanied with oxygenation and blood volume abnormalities has been found in children with congenital heart diseases. The NIRS is a valuable non-invasive technique for assessment of oxygenation and blood volume during exercise.     

Effect of inhaled indomethacin in asthmatic patients taking high doses of inhaled corticosteroids

Background: Cyclooxygenase products of arachidonic acid may play a part in bronchoconstriction and airway inflammation in asthma. Objective: We sought to determine the effect of inhaled indomethacin on asthma control and asthma exacerbations during reduction of inhaled corticosteroids in patients with moderate-to-severe steroid-dependent asthma. Methods: We conducted a double-blind, randomized, parallel-group, multicenter study in 38 patients with asthma taking high doses (≥1500 μg/d) of beclomethasone dipropionate (BDP). After a run-in period, patients were assigned inhaled indomethacin (50 mg/d) or placebo for 6 weeks, during which the daily doses of BDP were reduced to half at week 2 and then to one third of the baseline dose at week 4. Results: Data were available from 34 patients. After the reduction of BDP doses, FEV₁, peak expiratory flow, asthma symptoms, and exhaled nitric oxide concentrations deteriorated in both treatment groups, but these effects were less pronounced in the indomethacin group compared with the placebo group. During the 6-week treatment period, 89% of the patients receiving placebo had relapse of asthma, whereas only 38% of those receiving inhaled indomethacin did so (P = .003). Conclusion: Inhalation of indomethacin can reduce asthma exacerbations induced by reduction of high-dose inhaled corticosteroid in steroid-dependent asthma. (J Allergy Clin Immunol 2000;105:1134-9.)     

Effects of a thromboxane-receptor antagonist, BAY u 3405, on prostaglandin D2- and exercise-induced bronchoconstriction

In the pathogenesis of exercise-induced bronchoconstriction ('EIB), prostaglandin D₂, (PGD₂) may play a role as a newly generated, mast cell-derived mediator. As the bronchoconstrictor effects of PGD₂ are predominantly mediated via stimulation of thromboxane receptors in the lung, we studied a novel, orally effective, thromboxane-receptor antagonist, BAY u 3405, on EIB in 12 male subjects with mild asthma. On 4 study days, we determined, in a randomized. double-blind, placebo-controlled, crossover fashion, the effects of 20 mg of BAY u 3405 administered orally 1 hour before PGDZ and exercise challenges, respectively. Increasing dosages of PGDZ were inhaled to establish dose-response curves that allowed determination of the provocative concentration necessary to decrease FEV, by at least 20% (PC₂₀) and to increase specific airway resistance (SR_aw) by 100% (PC₁₀₀). EIB was measured as a maximal fall/increase in postexertional FEV₁/SR_aw after bicycle exercise and cold-air breathing. Prechallenge lung function values were similar on all four occasions. BAY a 3405 did not elicit any effect on resting bronchial tone. After placebo, the geometric means (SD) of PC₂₀ and PC₁₀₀ were 0.0380 (2.6) and 0.0266 (2.4) mglml, increasing to 0.554 (5.9) and 0.143 (8.1) mg/ml after BAY u 3405 (p = 0.0002). Mean (SD) maximal postexertional decrease in FEV, and increase in SR_aw after placebo was 29.4% (16.4%) and 280% (135%), and after BAY u 3405, 31.4% (18.1%) and 379% (281%) (not significant). No clinically relevant BAY a 3405-related side effects were observed. From these results we conclude that BAY u 3405 is highly effective in attenuating PGDZ-induced bronchoconstriction. However, BAY u 3405 does not modulate EIB, suggesting that the mast cell-derived mediator, PGD₂, does not play an important role in the pathogenesis of exercise-induced asthma.     

TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma

Background Thromboxane A2 receptor (TBXA2R) gene polymorphism has been associated with atopy and asthma, but few studies have reported the effect of this gene polymorphism on asthma‐related phenotype or responsiveness to leukotriene receptor antagonist (LTRA) in asthmatic children. This study investigated associations between asthma‐related phenotypes and TBXA2R polymorphism, and also analysed whether the TBXA2R polymorphism has an effect on the efficacy of the LTRA, montelukast, in asthmatic children with exercise‐induced bronchoconstriction (EIB). Methods Asthmatic children (n=695) and control children (n=159) were evaluated for asthma‐related phenotypes including total IgE, pulmonary function test, and bronchial hyperresponsiveness to methacholine or exercise. Genotypes were detected by PCR‐RFLP. In the montelukast study, exercise challenge was performed before and after an 8‐week montelukast treatment. Results The TBXA2R polymorphism was not associated with asthma susceptibility and the clinical parameters of asthma. However, asthmatic children with combinations of the TBXA2R+795T>C and +924T>C risk alleles had significantly higher total IgE levels (P=0.01), total eosinophil counts (P<0.01) and lower forced expiratory volume in 1 s (FEV₁) (P=0.02) and forced expiratory rates at 25–75% of vital capacity (P=0.02) than those carrying the common alleles. When compared with individuals with the common alleles, patients with the TBXA2R+924T>C TT homozygote and TBXA2R+795T>C hetero‐ or homozygote (CT or CC) had a 3.67‐fold poor response to 8‐week montelukast treatment with respect to maximum percent fall in FEV₁ after exercise (odds ratio, 3.67; 95% confidence interval, 1.15–11.15). Conclusions A combined effect of TBXA2R+795T>C and +924T>C risk alleles may be linked to IgE production, eosinophilic inflammation, and severity of asthma. In addition, the TBXA2R+795T>C genotype may be a predictive marker of a clinical response to the LTRA in Korean asthmatic children with EIB.     

Effect of rush immunotherapy on airway inflammation and airway hyperresponsiveness after bronchoprovocation with allergen in asthma

Background: Rush immunotherapy (RIT) has been shown to be effective in allergic asthma. Objective: We investigated the mechanisms of RIT on the basis of cytokine production by T-cell lines and airway inflammation and responsiveness. Methods: Subjects were 8 patients with house dust mite–allergic asthma treated with dust mite extract RIT for 6 months and 6 RIT-untreated control patients. IL-5 production by Dermatophagoides farinae –specific T-cell lines, eosinophil percentages, and eosinophil cationic protein (ECP) in induced sputum and airway responsiveness to allergen and histamine were evaluated before and after treatment. Changes in eosinophil percentages and ECP in induced sputum and responsiveness to histamine 24 hours after allergen inhalation were also studied. Results: After 6 months of RIT, percentages of total eosinophils (43.0% ± 6.90% to 16.8% ± 2.48%; P < .01), percentages of EG2⁺ eosinophils (32.6% ± 6.39% to 19.7% ± 4.68%; P < .01) and ECP (362.7 ± 125.3 ng/mL to 26.2 ± 5.15 ng/mL; P < .05) decreased in induced sputum, and IL-5 production by T-cell lines decreased (617 ± 93.2 pg/mL to 200.0 ± 34.1 pg/mL; P < .01). RIT decreased both early- and late-phase bronchoconstriction (early phase: 33.2% ± 3.46% to 25.4% ± 1.42%; P < .03; late phase: 16.2% ± 3.52% to 6.2% ± 1.96%; P < .03) and suppressed increases in the percentages of total (61.8% ± 4.89% to 42.0% ± 4.67%; P < .01) and EG2-positive eosinophils (55.54% ± 7.21% to 36.5% ± 6.43%; P < .01) and ECP (685.6 ± 217.0 ng/mL to 85.4 ± 23.4 ng/mL; P < .05) in induced sputum after allergen inhalation. RIT also decreased airway responsiveness to dust mite (1:303.7 ± 123.7 wt/vol to 1:65.0 ± 13.2 wt/vol; P < .03) and to histamine before (397.1 ± 206.9 μg/mL to 1391.3 ± 283.3 μg/mL; P < .03) and after allergen inhalation (139.2 ± 36.5 μg/mL to 629.1 ± 196.3 μg/mL; P < .03). Conclusion: RIT decreases airway inflammation and airway hyperresponsiveness before and after bronchial provocation with allergen, possibly by inhibiting both allergen-specific T-cell– and mast cell-dependent pathways. RIT is an effective antiinflammatory treatment in allergic asthma. (J Allergy Clin Immunol 1998;102:927-34.)     

Effects of nedocromil sodium on bronchospasm and HS-NCA release induced by allergen inhalation in asthmatic patients

The aim of this study was to assess the ability of nedocromil sodium (NS) to prevent the immediate asthmatic reaction and the increase in the scrum level of heal stable neutrophil chemotactie activity (HS-NCA) induced by antigen inhalation. In a double-blind, cross-over study. 13 atopic subjects affected with seasonal asthma underwent a bronchial provocation lest with a preselected dose of grass pollen allergen (enough to cause a decrease of ≥ 20% in FEV₁:FEV₁ PD20) after pre-treatment with 4 mg NS or placebo. Serum samples were withdrawn from 11 subjects for HS-NCA determination. After NS administration the decrease in FEV₁ was significantly less than after placebo administration at all lime points after challenge (2 min P= 0.0004; 7 min, P= 0.0005; 17 min P= 0.0002 and 27 min P= 0.0005). The percentage increase in HS-NCA was significantly higher after placebo than after NS inhalation, both 10 (P= 0.0048) and 2d (P= 0.0068) min after challenge. Our study confirms previous investigations, showing that NS inhibits the immediate asthmatic response to allergen inhalation in atopic, asthmatic subjects and moreover it shows that this drug prevents in vivo the increase of the serum HS-NCA. This last finding has not been previously reported.