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[A PHASE III STUDY TO EVALUATE SAFETY AND EFFICACY OF FLUTICASONE/FORMOTEROL COMBINATION (FLUTIFORM® AEROSOL) IN LONG-TERM ADMINISTRATION (24 WEEKS) IN JAPANESE PEDIATRIC PATIENTS WITH BRONCHIAL ASTHMA].
Katsunuma, T, Kamata, M, Ishikawa, Y
Arerugi = [Allergy]. 2020;(5):341-352
Abstract
BACKGROUND The combination drug of inhaled corticosteroid (ICS)/long-acting β2 agonist is being used as a long-term control medication for pediatric asthma patients for those who are poorly controlled by ICS alone. Long-term efficacy and safety of Fluticasone propionate/formoterol fumarate hydrate (FP/FM) was evaluated in pediatric patients with bronchial asthma. METHODS Two inhales of FP/FM (50/5μg) at one time, twice daily were administered for 24 weeks to Japanese asthma patients aged 5 to <16 years who had asthma symptoms during the observation period while using the same dosage of ICS during a certain period of time. Adverse drug reactions, morning peak flow (mPEF) and asthma symptoms were evaluated 24 weeks after administration. RESULTS FP/FM was administered to 53 subjects. 52 subjects completed the 24 week administration. The incidence of adverse drug reactions was 9.4% (5 of 53), and all of the adverse drug reactions were mild. The mPEF increased from the starting value and was maintained through the treatment period. The average change from baseline in the mPEF after 24 weeks of treatment was 21.39±2.93L/min (Least squares mean±standard error). Changes in asthma symptoms were similar to that of morning peak flow. CONCLUSION It was considered that FP/FM could be useful for long-term control of pediatric asthma.
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Dietary fats, olive oil and respiratory diseases in Italian adults: A population-based study.
Cazzoletti, L, Zanolin, ME, Spelta, F, Bono, R, Chamitava, L, Cerveri, I, Garcia-Larsen, V, Grosso, A, Mattioli, V, Pirina, P, et al
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(6):799-807
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BACKGROUND Fat intake has been associated with respiratory diseases, with conflicting results. OBJECTIVE We studied the association between asthma and rhinitis with dietary fats, and their food sources in an Italian population. METHODS Clinical and nutritional information was collected for 871 subjects (aged 20-84) from the population-based multi-case-control study Genes Environment Interaction in Respiratory Diseases (GEIRD): 145 with current asthma (CA), 77 with past asthma (PA), 305 with rhinitis and 344 controls. Food intake was collected using the EPIC (European Investigation into Cancer and Nutrition) Food Frequency Questionnaire. The associations between fats and respiratory diseases were estimated by multinomial models. Fats and their dietary sources were analysed both as continuous variables and as quartiles. RESULTS Monounsaturated fatty acids and oleic acid were associated with a reduced risk of CA in both continuous (RRR = 0.68, 95%CI: 0.48; 0.96; RRR = 0.69; 95%CI: 0.49; 0.97, per 10 g, respectively) and per-quartile analyses (p for trend = 0.028 and 0.024, respectively). Olive oil was associated with a decreased risk of CA (RRR = 0.80; 95%CI: 0.65; 0.98 per 10 g). An increased risk of rhinitis was associated with moderate total fat and SFA intake. CONCLUSIONS High dietary intakes of oleic acid and of olive oil are associated with a lower risk of asthma but not of rhinitis.
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Carotenoids, fatty acids and disease burden in obese minority adolescents with asthma.
Tobias, TAM, Wood, LG, Rastogi, D
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(6):838-846
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BACKGROUND Paediatric obesity-related asthma causes high disease burden, is associated with metabolic abnormalities, has few therapeutic options, and disproportionately affects urban minority children. Although poor diet quality is linked to asthma, the association of nutritional status with disease burden among children with obesity-related asthma is not well understood. OBJECTIVE To quantify nutritional status, defined as concentrations of serum carotenoids and n-3 fatty acids, and its association with pulmonary function and metabolic markers among obese asthmatic children. METHODS We quantified serum carotenoids and fatty acids in a study cohort of 158 urban minority adolescents including 39 obese asthmatics, 39 healthy weight asthmatics, 38 obese controls and 42 healthy weight controls and compared between the groups. We correlated carotenoid and fatty acid levels with pulmonary function indices and with insulin resistance and dyslipidemia. RESULTS Mean total carotenoids were lowest in obese asthmatic children (0.41 μg/mL), lower than healthy weight asthmatics (0.52 μg/mL, P < 0.05) and healthy weight controls (0.60 μg/mL, P < 0.001). n-6/n-3 polyunsaturated fatty acid (PUFA) ratio also differed between the groups (P < 0.05). Total carotenoids positively correlated with per cent-predicted FEV1 and inversely correlated with insulin resistance among obese asthmatics only. n-6/n-3 PUFA ratio inversely correlated with per cent-predicted FEV1 in obese asthmatics. CONCLUSIONS & CLINICAL RELEVANCE Our findings suggest that carotenoids, which are lowest in obese asthmatic children, may have protective effects on metabolic health and pulmonary function among obese asthmatic children. Similarly, n-3 PUFA appear to be protective for pulmonary function.
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Maternal and neonatal 25-hydroxyvitamin D concentrations and school-age lung function, asthma and allergy. The Generation R Study.
Mensink-Bout, SM, van Meel, ER, de Jongste, JC, Voortman, T, Reiss, IK, De Jong, NW, Jaddoe, VWV, Duijts, L
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(6):900-910
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BACKGROUND Vitamin D deficiency in early life might affect the developing lung and immune system, and subsequently influence the risk of asthma and allergy in later life. OBJECTIVE We examined the associations of 25-hydroxyvitamin D concentrations in mid-gestation and at birth with lung function, asthma, inhalant allergic sensitization and inhalant allergy at school-age. METHODS This study among 4951 children and their mothers was embedded in a population-based prospective cohort in Rotterdam, the Netherlands. Maternal venous blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D concentrations. At age 10 years, lung function was measured by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. We used multivariable regression models to examine associations. RESULTS Higher 25-hydroxyvitamin D concentrations in mid-gestation were associated with a higher forced vital capacity (FVC), but a lower forced expiratory volume in 1 second/FVC (FEV1 /FVC) and a lower forced expiratory flow after exhaling 75% of FVC (FEF75 ) (Z-score differences [95% CI] 0.02 [0.00, 0.03], -0.02 [-0.03, -0.01] and -0.01 [-0.03, -0.00], respectively, per 10 nmol/L 25-hydroxyvitamin D), but not with asthma. Furthermore, higher 25-hydroxyvitamin D concentrations in mid-gestation were associated with an increased risk of inhalant allergy (Odds Ratio [95% CI] 1.07 [1.02, 1.12]), but not with inhalant allergic sensitization. After additional adjustment for child's 25-hydroxyvitamin D concentrations at the age of 6 years, only the associations of 25-hydroxyvitamin D concentrations in mid-gestation with FEV1 /FVC and FEF75 remained. We did not find consistent associations of 25-hydroxyvitamin D concentrations at birth with respiratory or allergy outcomes. CONCLUSION AND CLINICAL RELEVANCE Our results suggest that maternal 25-hydroxyvitamin D concentrations in mid-gestation may influence lung development. The clinical implications of the observed associations remain unclear.
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Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients.
Vogelberg, C, Szefler, SJ, Vrijlandt, EJLE, Boner, AL, Engel, M, El Azzi, G, Vulcu, SD, Moroni-Zentgraf, PM, Eickmeier, O, Hamelmann, EH
The European respiratory journal. 2019;(6)
Abstract
There remains an unmet need for effective, well-tolerated therapeutic options in paediatric patients with not fully controlled asthma, for whom safety is of paramount importance.Data were pooled from five randomised, double-blind, placebo-controlled studies evaluating tiotropium 5 or 2.5 µg versus placebo add-on therapy in patients with symptomatic asthma aged 1-17 years. Analysis included adverse events (AEs) and serious AEs (SAEs) reported throughout and for 30 days following treatment.Of 1691 patients treated, 1119 received tiotropium. Reporting of AEs was low and comparable across all groups: tiotropium 5 µg (51%), tiotropium 2.5 µg (51%) and placebo (54%). Reporting of drug-related AEs, those leading to discontinuation and SAEs was also low and balanced between treatment groups, irrespective of age, disease severity or sex. The number of AEs related to asthma symptoms and exacerbations was lower with tiotropium (5 µg) than with placebo, particularly during the seasonal peaks of these AEs.This comprehensive analysis of a large safety database allowed subgroup analyses that are often impractical with individual trials and provides further support for the safety of once-daily tiotropium Respimat add-on therapy in paediatric patients with symptomatic asthma.
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Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma.
Bjermer, L, Abbott-Banner, K, Newman, K
Pulmonary pharmacology & therapeutics. 2019;:101814
Abstract
INTRODUCTION This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma. METHODS In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV1) 60-90% predicted and ≥1.5 L, with post-salbutamol FEV1 increase ≥15%. The co-primary objectives were peak and average FEV1 over 12 h for ensifentrine vs placebo and salbutamol. Secondary endpoints included: peak and average systolic and diastolic blood pressure, pulse rate and ECG heart rate; and safety and tolerability (adverse events [AEs], and serum potassium). ClinicalTrials.gov: NCT02427165. RESULTS A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of ensifentrine resulted in a dose-related increase in plasma exposure. CONCLUSIONS Single-dose ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All ensifentrine doses were similarly well tolerated, and did not show the characteristic β2-agonist systemic adverse effects.
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Evaluation of Bioequivalence Between the New Procaterol Hydrochloride Hydrate Dry Powder Inhaler and the Approved Dry Powder Inhaler in Patients With Asthma in a Randomized, Double-Blind, Double-Dummy, Crossover Comparison Study: A Phase 3 Study.
Shirai, R, Suzaki, Y, Sato, K, Takeuchi, Y, Tokimatsu, I, Koga, N, Kadota, J, Ohashi, K
Clinical pharmacology in drug development. 2018;(4):392-399
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Procaterol hydrochloride hydrate (procaterol) is a β2 -adrenergic receptor agonist that induces a strong bronchodilatory effect. The procaterol dry powder inhaler (DPI) has been frequently used in patients with bronchial asthma or chronic obstructive pulmonary disease. We evaluated the bioequivalence and safety between the new procaterol DPI (new DPI) and the approved procaterol DPI (approved DPI). This study was a randomized, double-blind, double-dummy, crossover comparison to evaluate the pharmacodynamic equivalence of the new DPI and the approved DPI in patients with bronchial asthma. Primary efficacy variables were area under the concentration-time curve (AUC) forced expiratory volume in the first second (FEV1 )/h and maximum FEV1 during the 480-minute measurement period. Patients were divided into 2 groups, New-DPI-First (n = 8) and Approved-DPI-First (n = 8), according to the investigational medical product that was administered first. Patients inhaled 20 μg of procaterol in each period. FEV1 was measured by a spirometer at predose and at 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after each investigational medical product administration. Equivalence was evaluated by confirming that the 2-sided 90%CIs for the difference between the new and the approved DPI in means of AUC (FEV1 )/h and maximum FEV1 were within the acceptance criteria of -0.15 to 0.15 L. The difference in means of AUC (FEV1 )/h and maximum FEV1 was 0.041 L and 0.033 L, respectively, and the 90%CI was 0.004 to 0.078 L and -0.008 to 0.074 L, respectively. These CIs were both within the acceptance criteria. The new DPI was assessed as being bioequivalent to the approved DPI.
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A Randomized, Multicenter, Double-blind, Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis.
Kim, MK, Lee, SY, Park, HS, Yoon, HJ, Kim, SH, Cho, YJ, Yoo, KH, Lee, SK, Kim, HK, Park, JW, et al
Clinical therapeutics. 2018;(7):1096-1107.e1
Abstract
PURPOSE The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone. METHODS This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n = 112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n = 116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, asthma control test score, and the frequency of rescue medication used during the treatment period. FINDINGS Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, -0.98 [0.06] vs -0.81 [0.06]; P = 0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV1, FVC, FEV1/FVC, and asthma control test score changes from baseline for the 2 treatment groups. Montelukast/levocetirizine was well tolerated, and the safety profile was similar to that observed in the montelukast group. IMPLICATIONS The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667.
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Vitamin D Receptor Gene Polymorphisms in Serbian Patients With Bronchial Asthma: A Case-Control Study.
Despotovic, M, Jevtovic Stoimenov, T, Stankovic, I, Basic, J, Pavlovic, D
Journal of cellular biochemistry. 2017;(11):3986-3992
Abstract
Vitamin D and single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene are potentially involved in the pathogenesis of bronchial asthma (BA); however, precise mechanisms by which vitamin D reduces the inflammation and the role of VDR SNPs in BA are not completely understood. The aim of this study was to examine the possible associations of FokI, BsmI, ApaI, and TaqI SNPs with BA. A total of 168 subjects were screened for VDR SNPs using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The obtained results showed statistically significant differences in the distribution of FokI genotypes (df = 2; P = 0.008) and alleles (P = 0.002; OR = 0.446; 95%CI = 0.264-0.752) between patients and controls. Distributions of BsmI, ApaI, and TaqI genotypes and alleles did not show statistical differences. BsmI, ApaI, and TaqI SNPs are in linkage disequilibrium (LD) in the whole studied group, as well as in BA patients and controls. The strongest LD was observed between BsmI and TaqI (r2 = 0.69 for all subjects in the study; r2 = 0.75 in BA; r2 = 0.64 in controls), while lower values of LD were observed for BsmI and ApaI, and ApaI and TaqI SNPs. This is the first study that examined the association of VDR SNPs (FokI, BsmI, ApaI, and TaqI) in Serbian patients with BA indicating protective effect of FF genotype and F allele of FokI SNP on BA development. J. Cell. Biochem. 118: 3986-3992, 2017. © 2017 Wiley Periodicals, Inc.
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[Optimization of acupoint application scheme in the treatment of bronchial asthma based on the orthogonal design method].
Shi, K, Wu, W, Liu, L, Wang, H, Chen, D, Liu, C, Zhang, C
Zhongguo zhen jiu = Chinese acupuncture & moxibustion. 2017;(6):571-575
Abstract
OBJECTIVE To study the primary and secondary factors of the allergic history, the frequency of acupoint application and the time of acupoint application in the treatment of bronchial asthma and optimize its scheme. METHODS Eighty patients of bronchial asthma were selected as the subjects in the orthogonal trial. The herbal medicines were the empirical formula of acupoint application (prepared at the ratio as 2:2:1:1:1:1:1:1:1 of semen brassicae, rhizome corydalis, unprocessed radix kansui, asarum sieboldii, ephedra, semen lepidii, syzygium aromaticum, cortex cinnamomi and fructus gleditsiae) and used on bilateral Feishu (BL 13), Xinshu (BL 15), Geshu (BL 17) and Shenshu (BL 23). Firstly, two groups were divided according to allergic history (40 cases with allergic history and 40 cases without allergic history), and then four subgroups were divided on the basis of the two main groups, 10 cases in each one. Through studying three factors and two levels, i.e. allergic history (Factor A:AⅠ:with allergic history; AⅡ:without allergic history), the frequency of acupoint application (Factor B:BⅠ:4 times; BⅡ:10 times, in which, in the group of 4-time applications, the application was given once every 10 days; in the group of 10-time applications, the application was given once every 4 days); and the time of application (Factor C:CⅠ:4 h; CⅡ:8 h), the optimal scheme was screened on the basis of the attack frequency before and after treatment and the score of the asthma quality life questionnaire (AQLQ) before treatment and 6 months after treatment in the patients of each group. RESULTS ① The orthogonal trial indicated that the best optimal scheme was AⅠBⅡCⅠ, meaning the patients with allergic history were treated with acupoint application for 10 times, remained for 4 h. ②Factor B (frequency of acupoint application) and C (time of acpoint application) were the significant influential factors of AQLQ scores (both P<0.05). ③The comparison of the attack frequency and AQLQ score before and after treatment in all of the patients showed that the different combinations of factor levels induced the different impacts on the asthma attack frequency and AQLQ scores. Except in the group No.1 and the group No.5, the improvements were all significant in the rest groups, indicating the significant differences (P<0.05, P<0.01). CONCLUSIONS Acupoint application reduces apparently the attack frequency of asthma in the patients and improves the living quality. The primary and secondary relationship among the allergic history, the frequency of acupoint application and the time of acupoint application for the impacts on the therapeutic effects are:the frequency of acupoint application > the time of acupoint application > the allergic history. The best optimal scheme is AⅠBⅡCⅠ, meaning the patients with allergic history are treated with acupoint application for 10 times, remained for 4h.