- Email: [email protected]
Salmeterol, FP Alone or FP Plus Montelukast
S92 Abstracts
Budesonide prevents Cytokine-induced Decrease of the Relaxant Response to 2-agonists in Mouse Trachea M. Adner1, L. Cardell1, A. Miller-Larsson2; 1ENT, Lab Clin Exp Allergy Research, Malmö University Hospital, Malmö, SWEDEN, 2Medical Science, AstraZeneca R&D Lund, Lund, SWEDEN. RATIONALE: During asthma exacerbation periods, increased levels of pro-inflammatory cytokines in asthmatic airways may impair bronchodilating effects of 2-adrenoceptors agonists but this process may be counteracted by corticosteroid-treatment. The aim of this study was to investigate how the relaxant effects of 2-agonists in cultured mouse tracheal segments are affected by pro-inflammatory cytokines and concomitant treatment with corticosteroid. METHODS: BALB/cJ mice tracheal segments were cultured for 4 days in absence/presence of TNF (100ng/mL)+IL1 (10ng/mL) and a glucocorticoid, budesonide (1M). After the culture period, segments were moved to a myograph and pre-contracted with carbachol. Cumulative concentration-effect curves to formoterol, terbutalin and salmeterol were obtained with estimates of potency (logEC50) and maximal relaxation (Rmax; % decrease of pre-contraction). RESULTS: Formoterol relaxed tracheal segments with a higher potency and efficacy than both terbutalin and salmeterol; logEC50= -8.25±0.22, -6.15±0.23 and -7.60±0.17, and Rmax = 95.0±1.3%, 88.0±2.0% and 79.3±5.6% for formoterol, terbutalin and salmeterol, respectively (mean±SEM). Treatment with TNF+IL1 did not affect potency for any of the relaxant agonists but decreased Rmax by 14% for formoterol, by 33% for terbutalin and by 58% for salmeterol (p<0.05 versus formoterol). Budesonide completely prevented the cytokine-induced impairment of response to formoterol, terbutalin and salmeterol. CONCLUSIONS: Formoterol was more efficacious than both terbutalin and salmeterol to induce relaxation of trachea, especially in the presence of TNF+IL1. The decrease of the relaxant response to 2-agonists induced by cytokines was prevented by budesonide. These results highlight the value of combination treatment with budesonide and formoterol in maintaining optimal 2-adrenoceptor efficacy in periods with increased inflammation. Funding: AstraZeneca
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Inhaled Corticosteroids and the Risk of Oropharyngeal Adverse Events: Results from a Meta-Analysis G. S. Rachelefsky1, H. Li2, N. Liao2, Y. Liao2, N. J. Combates2, R. Faruqi2, S. T. Varghese2; 1Allergy Research Foundation, Inc, Los Angeles, CA, 2Aventis Pharmaceuticals, a member of the sanofi-aventis Group, Bridgewater, NJ. RATIONALE: Oropharyngeal adverse events (AEs) are common among inhaled corticosteroid (ICS) users; however, the extent of their incidence is not clear. METHODS: A computerized MEDLINE (January 1966 to June 2004) and EMBASE (January 1974 to June 2004) search was conducted using indexed MedDRA terms for AEs and ICS available in 2004 (English only). Only studies emphasizing single entity or combination ICS for adolescents and adults with asthma were included. Studies were characterized by robust study designs that were randomized, double-blinded and placebo-controlled with clearly delineated study objectives, treatments and diagnostic criteria. Odds ratios (OR) were used to determine the AE incidence rate for ICS according to dose, device and propellant. RESULTS: A total of 23 studies (59 ICS arms and 23 placebo arms) were evaluated. The incidences of ICS-induced oral candidiasis (P0.0006), dysphonia (P0.0007) and pharyngitis (P0.0228) increased significantly with dose versus placebo (at all dose levels and combined, regardless of actuator device). For all ICS, doses and devices combined, ICS had a greater risk of oral candidiasis (OR=3.6), dysphonia (OR=5.2) and pharyngitis (OR=2.2) versus placebo (P<0.0001 for each event). When analyzing by device used, budesonide (BUD) metered dose inhaler (MDI; OR=19.29) and fluticasone propionate (FP) dry powder inhaler (DPI; OR=4.73) posed the greatest risk of oral candidiasis at all doses combined
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versus placebo. Likewise, BUD MDI (OR=11.45) and FP DPI (OR=5.70) had the greatest risk of dysphonia versus placebo, while BUD MDI (OR=5.08) and BUD DPI (OR=5.11) had the greatest risk of pharyngitis. CONCLUSIONS: Older ICS present a significant risk of oropharyngeal AEs. Funding: Aventis Pharmaceuticals, a member of the sanofi-aventis Group, and ALTANA Pharma Genome-Scale Analysis of Posttranscriptional Effects of Glucocorticoids (GC) J. Fan1, S. L. Curry1, U. X. Atasoy2, K. G. Becker3, M. Gorospe3, C. Stellato1; 1Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, 2University of Missouri-Columbia, Columbia, MO, 3National Institute of Aging, NIH, Baltimore, MD. RATIONALE: Modulation of gene expression by GC is increasingly recognized to occur through post-transcriptional regulation (PTR). However, the impact of PTR in GC anti-inflammatory activity is poorly understood. We aim to define the proportion and nature of the genes regulated by GCs mainly through PTR. METHODS: We compared GC effects on the expression of total RNA versus newly transcribed RNAs isolated in parallel samples using a modified nuclear run-on protocol. RNA pools were identified by cDNA arrays of the human airway epithelial cell line BEAS-2B, challenged or not with TNF alpha, following treatment with the GC budesonide (BUD). We used an established scoring system to calculate the ratio between fold-changes (expressed as z-ratio) induced by GCs in the levels of total and newly generated transcripts in untreated and TNFalpha-stimulated cells. By revealing genes whose transcription is only partially affected, or uninfluenced, by GC despite parallel changes in steady-state RNA levels, this method uncovers the involvement of PTR. Genes were classified as: posttranscriptionally upregulated (mRNA-stability score (SS) > 1.0), posttranscriptionally downregulated (mRNA-SS <-1.0) or transcriptionally regulated (mRNA-SS between 1 and -1). RESULTS: Transcriptional regulation accounted for ~ 50% of GC-mediated changes in total mRNA levels. Among the genes affected by GC predominantly by PTR, we identified the chemokine CCL-2/MCP-1, which is both highly inducible by TNFalpha and strongly inhibited by GC through PTR. Validation experiments are ongoing. CONCLUSIONS: Changes in PTR account for a significant proportion of the effect of GCs on gene expression. Identification of the pathways involved could uncover novel targets of anti-inflammatory therapy. Funding: NIH
359
Control of Airway Inflammation in Asthma Patients Receiving Fluticasone Propionate (FP)/Salmeterol, FP Alone or FP Plus Montelukast N. Jarjour1, P. Dorinsky2, J. Stauffer2, D. Reilly2, S. Yancey2, L. Edwards2, L. Sutton2; 1University of Wisconsin School of Medicine, Madison, WI, 2GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: To evaluate asthma control and control of airway inflammation after various treatments in patients symptomatic on ICS or shortacting beta2-agonists. METHODS: We combined data from two randomized, double-blind studies evaluating: (Study 1) FP/salmeterol (FSC) 100/50mcgBID (n=40) vs. FP 250mcgBID (n=48) or (Study 2) FP 100mcgBID vs. FP 100mcgBID (n=53) + montelukast (MON) 10mgQD (n=50). Subjects underwent biopsy/BAL prior to randomization and after 24 weeks of treatment (Study 1) or 12 weeks of treatment (Study 2). RESULTS: Measures of clinical efficacy were maintained or improved in subjects receiving FSC vs. FP250, whereas there were no improvements in clinical efficacy with FP+MON vs. FP100. Consistent with these clinical observations, no significant differences in bronchial mucosal eosinophils were found at 24 weeks for FSC vs. FP250 (95% CI: -0.64, 1.67) or at 12 weeks for FP100 vs. FP100+MON (95% CI: -6.61, 8.82) Similar results were noted for neutrophils, CD3+, CD4+, CD8+ and CD25+ lymphocytes in biopsies as well as BAL percentages of
360
Abstracts S93
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Budesonide and Montelukast Once Daily Inhibits ExerciseInduced Bronchoconstriction in 6- to 18-Year-Old Children with Asthma T. Grzelewski, J. Jerzynska, I. Stelmach; Department of Pediatrics and Allergy, Medical University of Lodz, M Curie Hospital, Zgierz, POLAND. RATIONALE: To determine whether budesonide and montelukast attenuate exercise-induced bronchoconstriction (EIB) in 6- to 18-year-old children with asthma. METHODS: Randomized, double blind, placebo controlled, single center trial. Children (n = 25) with forced expiratory volume in 1 second (FEV1) 70% of the predicted value and a fall in FEV1 20% after exercise on 2 occasions. Patients received budesonide 200 g/dose one puff and montelukast 5 mg tablets in children aged 6-14 or 10 mg tablets in children over 14 years old (n=12) or placebo (n=13) once daily for 4 weeks. Standardized exercise challenges were performed 24 hours after the last dose. End points included area above the postexercise percent fall in FEV1 versus time curve (AAC0-20min), maximum percent fall in FEV1 from pre-exercise baseline, and time to recovery of FEV1 to within 5% of pre-exercise baseline. RESULTS: Budesonide and montelukast significantly reduced AAC0-20min ( 171 vs 610 % x min for budesonide with montelukast and placebo, respectively, P < 0.05 ) and the maximum percent fall (11% vs 36% for budesonide with montelukast and placebo, respectively, P < 0.05). Budesonide and montelukast treatment resulted in a shorter time to recovery (6 vs 19 minutes for budesonide with montelukast and placebo, respectively, P <0.05 ). CONCLUSIONS: Budesonide and montelukast attenuate EIB in 6- to 18-year-old children with asthma.
361
Treatment of Inhaled Corticosteroid and Leukotriene Receptor Antagonistin Korean Young Cough-Variant Asthma Children J. Jung1, J. Lee2, J. Kim3; 1Dong-A University Hospital, Busan, REPUBLIC OF KOREA, 2Masan Samsung Hospital, Masan, REPUBLIC OF KOREA, 3Ulsa University Hospital, Ulsan, REPUBLIC OF KOREA. RATIONALE: Cough-variant asthma (CVA) is a common cause of chronic cough in young children. Some children who have CVA eventually become classic asthma. We evaluated the effect of inhaled corticosteroid and leukotriene receptor antagonist in young children who are suspected as CVA. METHODS: Forty cough-variant asthma patients who were younger than 5-years-old were enrolled in study. Fifteen were treated with pulmicort nebulization (500g, bid) for 4 weeks (Group A). Fourteen were treated with leukotriene receptor antagonist (Singulair, 4mg) for 4 weeks (Group B). Eleven were treated with intermittent short-acting 2-agonist nebulization (control). We evaluated the mean change of symptom score in night cough and sleep disturbance. RESULTS: There were no differences in age, sex, total IgE, total eosinophil count, duration of cough among 3 groups. Group A and B showed significant improvement of night cough and sleep disturbance after treatment. (p<0.05) In Group A and B, night cough was significantly improved after treatment more than in control. (P<0.05) But the improvement of sleep disturbance didn’t have no signigicant differences between three groups. (P=1.0) CONCLUSIONS: Inhaled corticosteroid and leukotriene receptor antagonist are effective to control of chronic cough in CVA children who are younger than 5-years-old.
362
Early Intervention with High-Dose Inhaled Corticosteroids for Control of Acute Asthma Exacerbations and Improved Outcomes; A Randomized Controlled Trial E. W. Skorpinski1,2, E. Yousef1,2, S. J. McGeady1,2; 1Division of Allergy/Immunology, A.I. duPont Hospital for Children, Wilmington, DE, 2Thomas Jefferson University, Philadelphia, PA. RATIONALE: To investigate the effectiveness of inhaled corticosteroids (ICS) in controlling acute asthma exacerbations in children at home. Previous studies regarding the efficacy of increased ICS in these instances have provided conflicting results. METHODS: Data was collected on asthmatic children, aged 2 to 17 years, who have been maintained on ICS for at least 3 months. Fifty-seven children were randomized to twice (2X), 4X and 8X maintenance ICS sick-day protocols, and were provided written instructions to contact our office and initiate therapy within 72 hours of onset of increased symptoms. Physicians, blinded to the patients’ dosing assignments, assessed their clinical status with symptom scores via telephone on the initial day and on days 3, 7 and 14 following the start of therapy. RESULTS: Fifteen patients completed the study. There were no differences in the average rates of improvement, based on symptom scores, between the 2X, 4X and 8X maintenance ICS therapy groups. None of these subjects required systemic corticosteroids (SCS), ED visits or hospitalizations. Two of seven 2X assignees and one of five 4X assignees were taken to their primary physicians’ offices for sick-day evaluations during their trials; however, they did not require further intervention. CONCLUSIONS: Our data indicates that acute asthma exacerbations in children can be controlled at home with increased doses of ICS. This intervention may reduce the need for SCS, but a larger patient sample is needed to clarify the role of greater vs. lesser dose increases in ICS in the home management of these exacerbations.
363
Effect of Once-Daily Evening Administration of Low-Dose Mometasone Furoate on Peak Expiratory Flow in Subjects With Mild-to-Moderate Persistent Asthma B. Prenner1, R. Yao2, B. N. Lutsky2; 1Allergy Associates Medical Group, Inc., San Diego, CA, 2Schering-Plough Research Institute, Kenilworth, NJ. RATIONALE: The ability of inhaled corticosteroid (ICS) therapy to improve peak expiratory flow (PEF) throughout the day is an important measure of asthma control. It was decided to analyze the effects on PEF measurements observed with once-daily evening (QD PM) dosing of mometasone furoate dry powder inhaler (MF-DPI) in different populations of asthma patients. METHODS: Two randomized, double-blind studies evaluated treatment with MF-DPI 220 mcg QD PM (n = 177) or placebo (n = 178) in 12 weeks of therapy for persistent asthma. Subjects in one study were ICS-naïve. Subjects in the other study were previously maintained on daily ICS therapy (75% were using fluticasone propionate), and completed a pre-baseline ICS reduction period. As a result, subjects in both studies were comparable at baseline with respect to lung function and were pooled for analysis. The analysis compared MF-DPI with placebo for changes from baseline in AM and PM PEF at endpoint. RESULTS: Treatment with MF-DPI 200 QD PM significantly improved AM and PM PEF. The mean change from baseline in AM PEF at endpoint was 28.01 L/min in the MF-DPI group, compared with 3.12 L/min in the placebo group (p < 0.0001). For PM PEF, the mean change from baseline was 21.06 L/min with MF-DPI, and 5.92 with placebo (p = 0.0022). CONCLUSIONS: Treatment with MF-DPI 220 mcg QD PM significantly improved both AM and PM PEF in patients with persistent asthma who were either ICS-naïve or previously maintained on daily ICS therapy. Funding: Schering-Plough Research Institute
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macrophages, lymphocytes, eosinophils and neutrophils and inflammatory mediators. There were no significant differences in basement membrane thickness between FSC and FP250 (95% CI: -2.11, 0.63) or FP100 and FP100+MON (95% CI: -1.97, 0.99). CONCLUSIONS: FSC allowed a 60% reduction in ICS dose while maintaining control of underlying airway inflammation; confirming that treatment with low dose ICS+LABA is as effective as higher dose ICS. However, the addition of montelukast to FP100 offered no additional benefit on control of airway inflammation compared with FP100 alone. (SAS40026/FPD40014) Funding: GlaxoSmithKline
Budesonide prevents Cytokine-induced Decrease of the Relaxant Response to 2-agonists in Mouse Trachea M. Adner1, L. Cardell1, A. Miller-Larsson2; 1ENT, Lab Clin Exp Allergy Research, Malmö University Hospital, Malmö, SWEDEN, 2Medical Science, AstraZeneca R&D Lund, Lund, SWEDEN. RATIONALE: During asthma exacerbation periods, increased levels of pro-inflammatory cytokines in asthmatic airways may impair bronchodilating effects of 2-adrenoceptors agonists but this process may be counteracted by corticosteroid-treatment. The aim of this study was to investigate how the relaxant effects of 2-agonists in cultured mouse tracheal segments are affected by pro-inflammatory cytokines and concomitant treatment with corticosteroid. METHODS: BALB/cJ mice tracheal segments were cultured for 4 days in absence/presence of TNF (100ng/mL)+IL1 (10ng/mL) and a glucocorticoid, budesonide (1M). After the culture period, segments were moved to a myograph and pre-contracted with carbachol. Cumulative concentration-effect curves to formoterol, terbutalin and salmeterol were obtained with estimates of potency (logEC50) and maximal relaxation (Rmax; % decrease of pre-contraction). RESULTS: Formoterol relaxed tracheal segments with a higher potency and efficacy than both terbutalin and salmeterol; logEC50= -8.25±0.22, -6.15±0.23 and -7.60±0.17, and Rmax = 95.0±1.3%, 88.0±2.0% and 79.3±5.6% for formoterol, terbutalin and salmeterol, respectively (mean±SEM). Treatment with TNF+IL1 did not affect potency for any of the relaxant agonists but decreased Rmax by 14% for formoterol, by 33% for terbutalin and by 58% for salmeterol (p<0.05 versus formoterol). Budesonide completely prevented the cytokine-induced impairment of response to formoterol, terbutalin and salmeterol. CONCLUSIONS: Formoterol was more efficacious than both terbutalin and salmeterol to induce relaxation of trachea, especially in the presence of TNF+IL1. The decrease of the relaxant response to 2-agonists induced by cytokines was prevented by budesonide. These results highlight the value of combination treatment with budesonide and formoterol in maintaining optimal 2-adrenoceptor efficacy in periods with increased inflammation. Funding: AstraZeneca
357
SUNDAY
Inhaled Corticosteroids and the Risk of Oropharyngeal Adverse Events: Results from a Meta-Analysis G. S. Rachelefsky1, H. Li2, N. Liao2, Y. Liao2, N. J. Combates2, R. Faruqi2, S. T. Varghese2; 1Allergy Research Foundation, Inc, Los Angeles, CA, 2Aventis Pharmaceuticals, a member of the sanofi-aventis Group, Bridgewater, NJ. RATIONALE: Oropharyngeal adverse events (AEs) are common among inhaled corticosteroid (ICS) users; however, the extent of their incidence is not clear. METHODS: A computerized MEDLINE (January 1966 to June 2004) and EMBASE (January 1974 to June 2004) search was conducted using indexed MedDRA terms for AEs and ICS available in 2004 (English only). Only studies emphasizing single entity or combination ICS for adolescents and adults with asthma were included. Studies were characterized by robust study designs that were randomized, double-blinded and placebo-controlled with clearly delineated study objectives, treatments and diagnostic criteria. Odds ratios (OR) were used to determine the AE incidence rate for ICS according to dose, device and propellant. RESULTS: A total of 23 studies (59 ICS arms and 23 placebo arms) were evaluated. The incidences of ICS-induced oral candidiasis (P0.0006), dysphonia (P0.0007) and pharyngitis (P0.0228) increased significantly with dose versus placebo (at all dose levels and combined, regardless of actuator device). For all ICS, doses and devices combined, ICS had a greater risk of oral candidiasis (OR=3.6), dysphonia (OR=5.2) and pharyngitis (OR=2.2) versus placebo (P<0.0001 for each event). When analyzing by device used, budesonide (BUD) metered dose inhaler (MDI; OR=19.29) and fluticasone propionate (FP) dry powder inhaler (DPI; OR=4.73) posed the greatest risk of oral candidiasis at all doses combined
358
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
versus placebo. Likewise, BUD MDI (OR=11.45) and FP DPI (OR=5.70) had the greatest risk of dysphonia versus placebo, while BUD MDI (OR=5.08) and BUD DPI (OR=5.11) had the greatest risk of pharyngitis. CONCLUSIONS: Older ICS present a significant risk of oropharyngeal AEs. Funding: Aventis Pharmaceuticals, a member of the sanofi-aventis Group, and ALTANA Pharma Genome-Scale Analysis of Posttranscriptional Effects of Glucocorticoids (GC) J. Fan1, S. L. Curry1, U. X. Atasoy2, K. G. Becker3, M. Gorospe3, C. Stellato1; 1Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, 2University of Missouri-Columbia, Columbia, MO, 3National Institute of Aging, NIH, Baltimore, MD. RATIONALE: Modulation of gene expression by GC is increasingly recognized to occur through post-transcriptional regulation (PTR). However, the impact of PTR in GC anti-inflammatory activity is poorly understood. We aim to define the proportion and nature of the genes regulated by GCs mainly through PTR. METHODS: We compared GC effects on the expression of total RNA versus newly transcribed RNAs isolated in parallel samples using a modified nuclear run-on protocol. RNA pools were identified by cDNA arrays of the human airway epithelial cell line BEAS-2B, challenged or not with TNF alpha, following treatment with the GC budesonide (BUD). We used an established scoring system to calculate the ratio between fold-changes (expressed as z-ratio) induced by GCs in the levels of total and newly generated transcripts in untreated and TNFalpha-stimulated cells. By revealing genes whose transcription is only partially affected, or uninfluenced, by GC despite parallel changes in steady-state RNA levels, this method uncovers the involvement of PTR. Genes were classified as: posttranscriptionally upregulated (mRNA-stability score (SS) > 1.0), posttranscriptionally downregulated (mRNA-SS <-1.0) or transcriptionally regulated (mRNA-SS between 1 and -1). RESULTS: Transcriptional regulation accounted for ~ 50% of GC-mediated changes in total mRNA levels. Among the genes affected by GC predominantly by PTR, we identified the chemokine CCL-2/MCP-1, which is both highly inducible by TNFalpha and strongly inhibited by GC through PTR. Validation experiments are ongoing. CONCLUSIONS: Changes in PTR account for a significant proportion of the effect of GCs on gene expression. Identification of the pathways involved could uncover novel targets of anti-inflammatory therapy. Funding: NIH
359
Control of Airway Inflammation in Asthma Patients Receiving Fluticasone Propionate (FP)/Salmeterol, FP Alone or FP Plus Montelukast N. Jarjour1, P. Dorinsky2, J. Stauffer2, D. Reilly2, S. Yancey2, L. Edwards2, L. Sutton2; 1University of Wisconsin School of Medicine, Madison, WI, 2GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: To evaluate asthma control and control of airway inflammation after various treatments in patients symptomatic on ICS or shortacting beta2-agonists. METHODS: We combined data from two randomized, double-blind studies evaluating: (Study 1) FP/salmeterol (FSC) 100/50mcgBID (n=40) vs. FP 250mcgBID (n=48) or (Study 2) FP 100mcgBID vs. FP 100mcgBID (n=53) + montelukast (MON) 10mgQD (n=50). Subjects underwent biopsy/BAL prior to randomization and after 24 weeks of treatment (Study 1) or 12 weeks of treatment (Study 2). RESULTS: Measures of clinical efficacy were maintained or improved in subjects receiving FSC vs. FP250, whereas there were no improvements in clinical efficacy with FP+MON vs. FP100. Consistent with these clinical observations, no significant differences in bronchial mucosal eosinophils were found at 24 weeks for FSC vs. FP250 (95% CI: -0.64, 1.67) or at 12 weeks for FP100 vs. FP100+MON (95% CI: -6.61, 8.82) Similar results were noted for neutrophils, CD3+, CD4+, CD8+ and CD25+ lymphocytes in biopsies as well as BAL percentages of
360
Abstracts S93
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Budesonide and Montelukast Once Daily Inhibits ExerciseInduced Bronchoconstriction in 6- to 18-Year-Old Children with Asthma T. Grzelewski, J. Jerzynska, I. Stelmach; Department of Pediatrics and Allergy, Medical University of Lodz, M Curie Hospital, Zgierz, POLAND. RATIONALE: To determine whether budesonide and montelukast attenuate exercise-induced bronchoconstriction (EIB) in 6- to 18-year-old children with asthma. METHODS: Randomized, double blind, placebo controlled, single center trial. Children (n = 25) with forced expiratory volume in 1 second (FEV1) 70% of the predicted value and a fall in FEV1 20% after exercise on 2 occasions. Patients received budesonide 200 g/dose one puff and montelukast 5 mg tablets in children aged 6-14 or 10 mg tablets in children over 14 years old (n=12) or placebo (n=13) once daily for 4 weeks. Standardized exercise challenges were performed 24 hours after the last dose. End points included area above the postexercise percent fall in FEV1 versus time curve (AAC0-20min), maximum percent fall in FEV1 from pre-exercise baseline, and time to recovery of FEV1 to within 5% of pre-exercise baseline. RESULTS: Budesonide and montelukast significantly reduced AAC0-20min ( 171 vs 610 % x min for budesonide with montelukast and placebo, respectively, P < 0.05 ) and the maximum percent fall (11% vs 36% for budesonide with montelukast and placebo, respectively, P < 0.05). Budesonide and montelukast treatment resulted in a shorter time to recovery (6 vs 19 minutes for budesonide with montelukast and placebo, respectively, P <0.05 ). CONCLUSIONS: Budesonide and montelukast attenuate EIB in 6- to 18-year-old children with asthma.
361
Treatment of Inhaled Corticosteroid and Leukotriene Receptor Antagonistin Korean Young Cough-Variant Asthma Children J. Jung1, J. Lee2, J. Kim3; 1Dong-A University Hospital, Busan, REPUBLIC OF KOREA, 2Masan Samsung Hospital, Masan, REPUBLIC OF KOREA, 3Ulsa University Hospital, Ulsan, REPUBLIC OF KOREA. RATIONALE: Cough-variant asthma (CVA) is a common cause of chronic cough in young children. Some children who have CVA eventually become classic asthma. We evaluated the effect of inhaled corticosteroid and leukotriene receptor antagonist in young children who are suspected as CVA. METHODS: Forty cough-variant asthma patients who were younger than 5-years-old were enrolled in study. Fifteen were treated with pulmicort nebulization (500g, bid) for 4 weeks (Group A). Fourteen were treated with leukotriene receptor antagonist (Singulair, 4mg) for 4 weeks (Group B). Eleven were treated with intermittent short-acting 2-agonist nebulization (control). We evaluated the mean change of symptom score in night cough and sleep disturbance. RESULTS: There were no differences in age, sex, total IgE, total eosinophil count, duration of cough among 3 groups. Group A and B showed significant improvement of night cough and sleep disturbance after treatment. (p<0.05) In Group A and B, night cough was significantly improved after treatment more than in control. (P<0.05) But the improvement of sleep disturbance didn’t have no signigicant differences between three groups. (P=1.0) CONCLUSIONS: Inhaled corticosteroid and leukotriene receptor antagonist are effective to control of chronic cough in CVA children who are younger than 5-years-old.
362
Early Intervention with High-Dose Inhaled Corticosteroids for Control of Acute Asthma Exacerbations and Improved Outcomes; A Randomized Controlled Trial E. W. Skorpinski1,2, E. Yousef1,2, S. J. McGeady1,2; 1Division of Allergy/Immunology, A.I. duPont Hospital for Children, Wilmington, DE, 2Thomas Jefferson University, Philadelphia, PA. RATIONALE: To investigate the effectiveness of inhaled corticosteroids (ICS) in controlling acute asthma exacerbations in children at home. Previous studies regarding the efficacy of increased ICS in these instances have provided conflicting results. METHODS: Data was collected on asthmatic children, aged 2 to 17 years, who have been maintained on ICS for at least 3 months. Fifty-seven children were randomized to twice (2X), 4X and 8X maintenance ICS sick-day protocols, and were provided written instructions to contact our office and initiate therapy within 72 hours of onset of increased symptoms. Physicians, blinded to the patients’ dosing assignments, assessed their clinical status with symptom scores via telephone on the initial day and on days 3, 7 and 14 following the start of therapy. RESULTS: Fifteen patients completed the study. There were no differences in the average rates of improvement, based on symptom scores, between the 2X, 4X and 8X maintenance ICS therapy groups. None of these subjects required systemic corticosteroids (SCS), ED visits or hospitalizations. Two of seven 2X assignees and one of five 4X assignees were taken to their primary physicians’ offices for sick-day evaluations during their trials; however, they did not require further intervention. CONCLUSIONS: Our data indicates that acute asthma exacerbations in children can be controlled at home with increased doses of ICS. This intervention may reduce the need for SCS, but a larger patient sample is needed to clarify the role of greater vs. lesser dose increases in ICS in the home management of these exacerbations.
363
Effect of Once-Daily Evening Administration of Low-Dose Mometasone Furoate on Peak Expiratory Flow in Subjects With Mild-to-Moderate Persistent Asthma B. Prenner1, R. Yao2, B. N. Lutsky2; 1Allergy Associates Medical Group, Inc., San Diego, CA, 2Schering-Plough Research Institute, Kenilworth, NJ. RATIONALE: The ability of inhaled corticosteroid (ICS) therapy to improve peak expiratory flow (PEF) throughout the day is an important measure of asthma control. It was decided to analyze the effects on PEF measurements observed with once-daily evening (QD PM) dosing of mometasone furoate dry powder inhaler (MF-DPI) in different populations of asthma patients. METHODS: Two randomized, double-blind studies evaluated treatment with MF-DPI 220 mcg QD PM (n = 177) or placebo (n = 178) in 12 weeks of therapy for persistent asthma. Subjects in one study were ICS-naïve. Subjects in the other study were previously maintained on daily ICS therapy (75% were using fluticasone propionate), and completed a pre-baseline ICS reduction period. As a result, subjects in both studies were comparable at baseline with respect to lung function and were pooled for analysis. The analysis compared MF-DPI with placebo for changes from baseline in AM and PM PEF at endpoint. RESULTS: Treatment with MF-DPI 200 QD PM significantly improved AM and PM PEF. The mean change from baseline in AM PEF at endpoint was 28.01 L/min in the MF-DPI group, compared with 3.12 L/min in the placebo group (p < 0.0001). For PM PEF, the mean change from baseline was 21.06 L/min with MF-DPI, and 5.92 with placebo (p = 0.0022). CONCLUSIONS: Treatment with MF-DPI 220 mcg QD PM significantly improved both AM and PM PEF in patients with persistent asthma who were either ICS-naïve or previously maintained on daily ICS therapy. Funding: Schering-Plough Research Institute
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macrophages, lymphocytes, eosinophils and neutrophils and inflammatory mediators. There were no significant differences in basement membrane thickness between FSC and FP250 (95% CI: -2.11, 0.63) or FP100 and FP100+MON (95% CI: -1.97, 0.99). CONCLUSIONS: FSC allowed a 60% reduction in ICS dose while maintaining control of underlying airway inflammation; confirming that treatment with low dose ICS+LABA is as effective as higher dose ICS. However, the addition of montelukast to FP100 offered no additional benefit on control of airway inflammation compared with FP100 alone. (SAS40026/FPD40014) Funding: GlaxoSmithKline