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Exercise-induced Bronchodilation Equalizes Exercise Ventilatory Mechanics despite Variable Baseline Airway Function in Asthma.
Rossman, MJ, Petrics, G, Klansky, A, Craig, K, Irvin, CG, Haverkamp, HC
Medicine and science in sports and exercise. 2022;(2):258-266
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Abstract
PURPOSE We quantified the magnitude of exercise-induced bronchodilation in adult asthmatics under conditions of narrowed and dilated airways. We then assessed the effect of the bronchodilation on ventilatory capacity and the extent of ventilatory limitation during exercise. METHODS Eleven asthmatics completed three exercise bouts on a cycle ergometer. Exercise was preceded by no treatment (trialCON), inhaled β2 agonist (trialBD), or a eucapnic voluntary hyperpnea challenge (trialBC). Maximal expiratory flow-volume maneuvers (MEFV) were performed before and within 40 s of exercise cessation. Exercise tidal flow-volume loops were placed within the preexercise and postexercise MEFV curve and used to determine expiratory flow limitation and maximum ventilatory capacity (V˙ECap). RESULTS Preexercise airway function was different among the trials (forced expiratory volume 1 s during trialCON, trialBD, and trialBC = 3.3 ± 0.8 L, 3.8 ± 0.8 L, and 2.9 ± 0.8 L, respectively; P < 0.05). Maximal expired airflow increased with exercise during all three trials, but the increase was greatest during trialBC (delta forced expiratory volume 1 s during trialCON, trialBD, and trialBC = +12.2% ± 13.1%, +5.2% ± 5.7%, +28.1% ± 15.7%). Thus, the extent of expiratory flow limitation decreased, and V˙ECap increased, when the postexercise MEFV curve was used. During trialCON and trialBC, actual exercise ventilation exceeded V˙ECap calculated with the preexercise MEFV curve in seven and nine subjects, respectively. CONCLUSIONS These findings demonstrate the critical importance of exercise bronchodilation in the asthmatic with narrowed airways. Of clinical relevance, the results also highlight the importance of assessing airway function during or immediately after exercise in asthmatic persons; otherwise, mechanical limitations to exercise ventilation will be overestimated.
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Nigella sativa Supplementation Improves Asthma Control and Biomarkers: A Randomized, Double-Blind, Placebo-Controlled Trial.
Koshak, A, Wei, L, Koshak, E, Wali, S, Alamoudi, O, Demerdash, A, Qutub, M, Pushparaj, PN, Heinrich, M
Phytotherapy research : PTR. 2017;(3):403-409
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Poor compliance with conventional asthma medications remains a major problem in achieving asthma control. Nigella sativa oil (NSO) is used traditionally for many inflammatory conditions such as asthma. We aimed to investigate the benefits of NSO supplementation on clinical and inflammatory parameters of asthma. NSO capsules 500 mg twice daily for 4 weeks were used as a supplementary treatment in a randomized, double-blind, placebo-controlled trial in asthmatics (clinicaltrials.gov: NCT02407262). The primary outcome was Asthma Control Test score. The secondary outcomes were pulmonary function test, blood eosinophils and total serum Immunoglobulin E. Between 1 June and 30 December 2015, 80 asthmatics were enrolled, with 40 patients in each treatment and placebo groups. After 4 weeks, ten patients had withdrawn from each group. Compared with placebo, NSO group showed a significant improvement in mean Asthma Control Test score 21.1 (standard deviation = 2.6) versus 19.6 (standard deviation = 3.7) (p = 0.044) and a significant reduction in blood eosinophils by -50 (-155 to -1) versus 15 (-60 to 87) cells/μL (p = 0.013). NSO improved forced expiratory volume in 1 second as percentage of predicted value by 4 (-1.25 to 8.75) versus 1 (-2 to 5) but non-significant (p = 0.170). This randomized, double-blind, placebo-controlled trial demonstrated that NSO supplementation improves asthma control with a trend in pulmonary function improvement. This was associated with a remarkable normalization of blood eosinophlia. Future studies should follow asthmatics for longer periods in a multicentre trial. Copyright © 2017 John Wiley & Sons, Ltd.
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A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.
Birring, SS, Wijsenbeek, MS, Agrawal, S, van den Berg, JWK, Stone, H, Maher, TM, Tutuncu, A, Morice, AH
The Lancet. Respiratory medicine. 2017;(10):806-815
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BACKGROUND Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. METHODS This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. FINDINGS Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. INTERPRETATION This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation. FUNDING Patara Pharma.
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Genome-wide association study of leukotriene modifier response in asthma.
Dahlin, A, Litonjua, A, Irvin, CG, Peters, SP, Lima, JJ, Kubo, M, Tamari, M, Tantisira, KG
The pharmacogenomics journal. 2016;(2):151-7
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Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.
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Effects of mometasone, fluticasone, and montelukast on bone mineral density in adults with asthma.
Maspero, J, Backer, V, Yao, R, Staudinger, H, Teper, A
The journal of allergy and clinical immunology. In practice. 2013;(6):649-55.e1
Abstract
BACKGROUND Associations of inhaled corticosteroids (ICS) with bone mineral density (BMD) loss have not been characterized consistently. OBJECTIVE This randomized, double-blind study assessed effects of mometasone furoate (MF) administered via dry powder inhaler on BMD of patients with persistent asthma. METHODS Adults with mild-moderate persistent asthma who did not receive ICS for ≥3 months were randomized to MF 400 μg once daily (QD) in the evening (pm), MF 200 μg QD pm, montelukast sodium (ML) 10 mg QD pm, or fluticasone propionate (FP) 250 μg twice daily. Included patients had 25-hydroxy vitamin D levels ≥15 ng/mL at baseline. All the patients received calcium and vitamin D supplements for daily use during the trial. Duplicate BMD scans were done at baseline, 6 months, and 1 year. The mean percentage change in lumbar spine (LS) BMD from baseline to end point for MF 400 μg versus ML 10 mg was the primary analysis. Changes from baseline in left total femur BMD and femoral neck BMD were secondary assessments. RESULTS At the end point, mean LS BMD increased 0.9% (MF 400 μg), 1.2% (ML), 0.7% (MF 200 μg), and 1.1% (FP), with no significant differences for MF 400 μg versus ML (-0.3% [95% CI, -1.01 to 0.27]) for LS BMD. No significant differences among treatments occurred for changes in left total femur BMD; all were slight increases. Changes in femoral neck BMD were 0.4% (MF 400 μg), -0.2% (ML), -0.2% (MF 200 μg), and -0.4% (FP); only the difference between MF 400 μg and FP was statistically significant (P = .044). CONCLUSION No detrimental effects on lumbar BMD were observed after up to 1 year of treatment with MF in comparison with ML for patients who received calcium and vitamin D supplements.
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Montelukast as an add-on therapy to inhaled corticosteroids in the treatment of severe asthma in elderly patients.
Bozek, A, Warkocka-Szoltysek, B, Filipowska-Gronska, A, Jarzab, J
The Journal of asthma : official journal of the Association for the Care of Asthma. 2012;(5):530-4
Abstract
BACKGROUND Severe asthma remains a worldwide medical problem. However, this disease has not been adequately explored in the elderly. This study was performed to determine how the addition of montelukast to antiasthmatic therapy improves the control of severe asthma in elderly patients. METHODS Elderly patients (>60 years old) with diagnoses of severe asthma were observed over 24 months of therapy: the first 12 months using inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) and the second 12 months with oral montelukast added in two-thirds of the patients, with the remaining third representing the control group. The primary efficacy endpoint of the study was the percentage of days without asthma symptoms in the first 12 months of treatment compared with the percentage after adding montelukast therapy. RESULTS A total of 512 elderly, asthmatic patients were included in the study: seventy-one (13.9%) patients had well-controlled asthma, 211 (41.2%) had partly controlled asthma, and 230 (44.9%) had uncontrolled asthma. During the first year of treatment using ICS and LABA, an increase in the median percentage of days without asthma was observed from 50.1% to 62.1%, as well as a decrease in the percentage of days with short beta-receptor agonist use, from 52.2% to 46.8%. These differences were significantly greater after 12 months, when montelukast was added to the therapy (78.4% and 39.5%, respectively). This improvement was not observed in the control group. After 2 years of observation, the median number of asthma exacerbation incidents per patient decreased from 1.6 per year to 1.2 per year when montelukast was added. CONCLUSION Severe asthma in elderly patients is very poorly treated, with this population exhibiting very low compliance with antiasthmatic therapy. Adding montelukast provides benefits and improved control; however, it does not resolve severe asthma control problems.
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CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast.
Karonen, T, Neuvonen, PJ, Backman, JT
British journal of clinical pharmacology. 2012;(2):257-67
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AIM: According to product information, montelukast is extensively metabolized by CYP3A4 and CYP2C9. However, CYP2C8 was also recently found to be involved. Our aim was to study the effects of selective CYP2C8 and CYP3A4 inhibitors on the pharmacokinetics of montelukast. METHODS In a randomized crossover study, 11 healthy subjects ingested gemfibrozil 600 mg, itraconazole 100 mg (first dose 200 mg) or both, or placebo twice daily for 5 days, and on day 3, 10 mg montelukast. Plasma concentrations of montelukast, gemfibrozil, itraconazole and their metabolites were measured up to 72 h. RESULTS The CYP2C8 inhibitor gemfibrozil increased the AUC(0,∞) of montelukast 4.3-fold and its t(1/2) 2.1-fold (P < 0.001). Gemfibrozil impaired the formation of the montelukast primary metabolite M6, reduced the AUC and C(max) of the secondary (major) metabolite M4 by more than 90% (P < 0.05) and increased those of M5a and M5b (P < 0.05). The CYP3A4 inhibitor itraconazole had no significant effect on the pharmacokinetic variables of montelukast or its M6 and M4 metabolites, but markedly reduced the AUC and C(max) of M5a and M5b (P < 0.05). The effects of the gemfibrozil-itraconazole combination on the pharmacokinetics of montelukast did not differ from those of gemfibrozil alone. CONCLUSIONS CYP2C8 is the dominant enzyme in the biotransformation of montelukast in humans, accounting for about 80% of its metabolism. CYP3A4 only mediates the formation of the minor metabolite M5a/b, and is not important in the elimination of montelukast. Montelukast may serve as a safe and useful CYP2C8 probe drug.
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Lung function changes in asthmatic children treated with HFA-BDP.
Eid, N, Morton, R
Pediatric pulmonology. 2011;(9):837-41
Abstract
STUDY OBJECTIVES Asthma guidelines suggest that normal or near normal lung function should be one of the goals for good asthma control. Therefore, children with chronic persistent asthma and reduced peripheral airway function were assessed after the replacement of conventional inhaled corticosteroids (ICS) with an extrafine aerosol formulation, hydrofluoroalkane-134a beclomethoasone diproprionate (HFA-BDP). DESIGN AND SETTING Lung function and clinical details were studied in children with moderate persistent asthma who regularly attended the pediatric pulmonary outpatient clinic at Kosair Children's Hospital, Louisville, Kentucky, USA. SUBJECTS A total of 20 children, 7 girls and 13 boys, with stable asthma but reduced forced expiratory flows between 25% and 75% of vital capacity (FEF(25-75) ) were included in the study. INTERVENTION After the initial assessment, each subject was switched from conventional ICS to HFA-BDP. All other medications remained the same. Reassessment of lung function and clinical status was performed at least 3 weeks after the intervention. RESULTS FEF(25-75) increased from a mean of 50.75% to 68.85% predicted (P < 0.001). Forced expiratory volume in 1 sec (FEV(1)) also increased significantly from 84.6% to 93.8% predicted (P = 0.001). No changes asthma symptoms were observed. CONCLUSION Compared to conventional ICS, the use of HFA-BDP in asthmatic children significantly improves airflow in both the large and the peripheral airways without loss of asthma control.
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Montelukast therapy and psychological distress in chronic obstructive pulmonary disease (COPD): a preliminary report.
Gueli, N, Verrusio, W, Linguanti, A, De Santis, W, Canitano, N, Ippoliti, F, Marigliano, V, Cacciafesta, M
Archives of gerontology and geriatrics. 2011;(1):e36-9
Abstract
Chronic obstructive pulmonary disease (COPD) is an alteration in which ventilatory function, exercise capacity and health status of patients progressively decline and it is characterized by an increase of inflammatory cytokines such as TNF-α, LTB4, IL-8, etc. In this study we considered twenty patients (15 males and 5 females; mean age: 72.8 ± 6.3) with stable COPD. All patients were performed evaluation of psychological stress at enrollment and were treated with leukotriene receptor antagonists (montelukast tablets) 10mg/day for 12 months. After 12 months we observed a significant decrease of serum levels of LTB4, IL-8 and also a decrease of the number of outpatient clinic visits, of the number of hospitalizations and of the duration of hospitalization.
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Conjugated linoleic acid improves airway hyper-reactivity in overweight mild asthmatics.
MacRedmond, R, Singhera, G, Attridge, S, Bahzad, M, Fava, C, Lai, Y, Hallstrand, TS, Dorscheid, DR
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2010;(7):1071-8
Abstract
BACKGROUND Conjugated linoleic acids (CLA) are naturally occurring fatty acids that have multiple biological properties including the regulation of metabolic, proliferative and immune processes. OBJECTIVE The aim of this study was to investigate the efficacy and safety of CLA as a dietary supplement in mild asthma. METHODS This was a prospective, randomized, double-blind, placebo-controlled study. Twenty-eight adult subjects (aged 19-40 years) with mild asthma (FEV(1)>70% predicted) were randomized to CLA 4.5 g/day or placebo for 12 weeks in addition to usual treatment. On average, subjects were overweight with a mean body mass index (BMI) of 27.9 kg/m(2). RESULTS Subjects in the CLA group had a significant improvement in airway hyperresponsiveness (AHR) at week 12 compared with week 0 [PC(20) 6.6 (2.1) mg/mL vs. 2.2 (0.7) mg/mL; P<0.05]. The CLA group had a significant reduction in weight and BMI compared with placebo and this was associated with a reduction in leptin/adiponectin ratio. There were no differences in systemic cytokine levels, induced sputum cell counts, quality-of-life scores or adverse events. CONCLUSIONS CLA treatment as an adjunct to usual care in overweight mild asthmatics was well tolerated and was associated with improvements in AHR and BMI.