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Randomised clinical trial to determine the safety of quercetin supplementation in patients with chronic obstructive pulmonary disease.
Han, MK, Barreto, TA, Martinez, FJ, Comstock, AT, Sajjan, US
BMJ open respiratory research. 2020;(1)
Abstract
INTRODUCTION Quercetin is a plant flavonoid and has potent antioxidant and anti-inflammatory properties. In a preclinical model of chronic obstructive pulmonary disease (COPD), quercetin reduced markers of both oxidative stress and lung inflammation and also reduced rhinovirus-induced progression of lung disease. Although quercetin appears to be an attractive natural alternative to manage COPD, the safety of quercetin supplementation in this population is unknown. METHODS We recruited COPD patients with mild-to-severe lung disease with FVE1 ranging between >35% and <80% and supplemented with either placebo or quercetin at 500, 1000 or 2000 mg/day in a dose-escalation manner. The duration of quercetin supplementation was 1 week. RESULTS Patients had no study drug-related severe adverse events based on blood tests, which included both complete blood counts and evaluation of comprehensive metabolic panel. One of the patients reported mild adverse events included gastro-oesophageal reflux disease, which was observed in both placebo and quercetin groups. CONCLUSIONS Quercetin was safely tolerated up to 2000 mg/day as assessed by lung function, blood profile and COPD assessment test questionnaire. TRIAL REGISTRATION NUMBER NCT01708278.
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A phase II, open-label clinical trial on the combination therapy with medium-chain triglycerides and ghrelin in patients with chronic obstructive pulmonary disease.
Miki, K, Kitada, S, Miki, M, Hui, SP, Shrestha, R, Yoshimura, K, Tsujino, K, Kagawa, H, Oshitani, Y, Kida, H, et al
The journal of physiological sciences : JPS. 2019;(6):969-979
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The aim of this study was to investigate the effect of activated ghrelin with dietary octanoic acids or medium-chain triglyceride (MCT) administration to underweight patient with chronic obstructive pulmonary disease (COPD). Eleven severe and very severe COPD patients received a 5-day treatment with edible MCT. Sequentially, 10 patients received a 3-week combination treatment with MCT and intravenous acyl ghrelin. Five-day MCT treatment increased endogenous acyl ghrelin (p = 0.0049), but the total ghrelin level was unchanged. MCT-ghrelin combination treatment improved the peak oxygen uptake (p = 0.0120) during whole treatment course. This effect was attributed to the resultant improvements in cardiac function by O2 pulse, and to the difference between inspired and expired oxygen concentration rather than minute ventilation. Addition of dietary MCT to ghrelin treatment improved the aerobic capacity of underweight COPD patients, likely by mechanisms of increased O2 delivery through improvements in primary cardiocirculatory and muscular crosstalk.
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Current Status of Forest Medicine Research in China.
Huang, QD, Wu, Q, Mao, GX, Wang, SY, Jia, BB, Wang, GF
Biomedical and environmental sciences : BES. 2018;(7):551-554
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Efficacy and safety of four doses of glycopyrrolate/formoterol fumarate delivered via a metered dose inhaler compared with the monocomponents in patients with moderate-to-severe COPD.
Reisner, C, Pearle, J, Kerwin, EM, Rose, ES, Darken, P
International journal of chronic obstructive pulmonary disease. 2018;:1965-1977
Abstract
PURPOSE To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 µg) using innovative co-suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 µg and formoterol fumarate (FF) MDI 9.6 µg, in patients with moderate-to-severe COPD. METHODS In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0-12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7. Safety was assessed. RESULTS All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 µg (all P≤0.0137). For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 µg. No significant differences were observed between GFF MDI and FF MDI 9.6 µg for primary and secondary endpoints. The incidence of adverse events was similar between treatments. CONCLUSION While all doses of GFF MDI were superior to GP MDI 36 µg for the primary end-point, in this study neither superiority of GFF MDI to FF MDI 9.6 µg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings.
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Assessment of energy intake in women with chronic obstructive pulmonary disease: a doubly labeled water method study.
Farooqi, N, Slinde, F, Håglin, L, Sandström, T
The journal of nutrition, health & aging. 2015;(5):518-24
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OBJECTIVES To maintain energy balance, reliable methods for assessing energy intake and expenditure should be used in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to validate the diet history and 7-day food diary methods of assessing energy intake (EI) using total energy expenditure (TEE) with the doubly labeled water (DLW) method (TEEDLW) as the criterion method in outpatient women with COPD. METHODS EI was assessed by diet history (EIDH) and a 7-day food diary (EIFD) in 19 women with COPD, using TEEDLW as the criterion method. The three methods were compared using intra-class correlation coefficients (ICC) and Bland-Altman analyses. The participants were classified according to their reporting status (EI/TEE) as valid-reporters 0.79-1.21, under-reporters < 0.79 or over-reporters > 1.21. RESULTS Diet history underestimated reported EI by 28%, and 7-day food diary underestimated EI by approximately 20% compared with TEEDLW. The ICC analysis showed weak agreement between TEEDLW and EIDH (ICC=-0.01; 95%CI-0.10 to 0.17) and between TEEDLW and EIFD (ICC=0.11; 95%CI -0.16 to 0.44). The Bland-Altman plots revealed a slight systematic bias for both methods. For diet history, six women (32%) were identified as valid-reporters, and for the 7-day food diary, twelve women (63%) were identified as valid-reporters. The accuracy of reported EI was only related to BMI. CONCLUSION The diet history and 7-day food diary methods underestimated energy intake in women with COPD compared with the DLW method. Individuals with higher BMIs are prone to underreporting. Seven-day food diaries should be used with caution in assessing EI in women with COPD.
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Pneumothorax risk factors in smokers with and without chronic obstructive pulmonary disease.
Hobbs, BD, Foreman, MG, Bowler, R, Jacobson, F, Make, BJ, Castaldi, PJ, San José Estépar, R, Silverman, EK, Hersh, CP, ,
Annals of the American Thoracic Society. 2014;(9):1387-94
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RATIONALE The demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined. OBJECTIVES We evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema. METHODS The study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report. MEASUREMENTS AND MAIN RESULTS Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08-2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34-2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03-1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01-1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09-1.33). CONCLUSIONS Among smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
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A new class of bronchodilator improves lung function in COPD: a trial with GSK961081.
Wielders, PL, Ludwig-Sengpiel, A, Locantore, N, Baggen, S, Chan, R, Riley, JH
The European respiratory journal. 2013;(4):972-81
Abstract
GSK961081 is a bifunctional molecule demonstrating both muscarinic antagonist and β-agonist activities. This was a 4-week, multicentre, randomised, double-blind, double-dummy, placebo and salmeterol controlled parallel group study. Doses ranging across three twice-daily doses and three once-daily doses were assessed in moderate and severe chronic obstructive pulmonary disease (COPD) patients. Trough forced expiratory volume in 1 s (FEV1) at day 29 was the primary end-point. At days 1 and 28, 12-h FEV1 spirometry was performed in all patients. A subset of patients underwent complete 24-h spirometry at day 28. The study recruited 436 patients. GSK961081 showed statistically and clinically significant differences from placebo in all doses and regimens for trough FEV1 on day 29 (155-277 mL). The optimal total daily dose was 400 μg, either as 400 μg once daily or as 200 μg twice daily, with an improvement in day 29 trough FEV1 of 215 mL and 249 mL, respectively. Other efficacy end-points also showed improvement. No effects were observed on glucose, potassium, heart rate, blood pressure and no dose-response effect was seen on corrected QT elongation. This study showed that GSK961081 is an effective bronchodilator in COPD and appeared to be safe and well tolerated.
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Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility.
Siedlinski, M, Tingley, D, Lipman, PJ, Cho, MH, Litonjua, AA, Sparrow, D, Bakke, P, Gulsvik, A, Lomas, DA, Anderson, W, et al
Human genetics. 2013;(4):431-41
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Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30% of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r (2) = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42%) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.
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The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility.
Castaldi, PJ, Cho, MH, Litonjua, AA, Bakke, P, Gulsvik, A, Lomas, DA, Anderson, W, Beaty, TH, Hokanson, JE, Crapo, JD, et al
American journal of respiratory cell and molecular biology. 2011;(6):1147-53
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Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.
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Supplementation of soy protein with branched-chain amino acids alters protein metabolism in healthy elderly and even more in patients with chronic obstructive pulmonary disease.
Engelen, MP, Rutten, EP, De Castro, CL, Wouters, EF, Schols, AM, Deutz, NE
The American journal of clinical nutrition. 2007;(2):431-9
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BACKGROUND It is often suggested that chronic wasting diseases [eg, chronic obstructive pulmonary disease (COPD)] may benefit from branched-chain amino acid (BCAA) administration via improved protein metabolism. OBJECTIVE The aim was to examine whether adding BCAAs to a soy protein meal would enhance protein anabolism in COPD patients and in healthy elderly persons. DESIGN Eight normal-weight COPD patients and 8 healthy control subjects were examined on 2 test days. Simultaneous continuous intravenous infusion of l-[ring-(2)H(5)]phenylalanine (Phe) and l-[ring-(2)H(2)]tyrosine tracers was done postabsorptively and at 2 h of ingestion of a maltodextrin soy or maltodextrin soy + BCAA protein meal (rate of ingestion: 0.02 g protein.kg body weight(-1).20 min(-1)) in a crossover design. Together with the meal, oral ingestion of 1-[(13)C]Phe was performed to measure first-pass Phe splanchnic extraction (SPE(Phe)). The endogenous rate of Phe appearance [reflecting whole-body protein breakdown (WbPB)], whole-body protein synthesis (WbPS), and net WbPS (WbPS - WbPB) were calculated. Arterialized venous blood was sampled for amino acid enrichment and concentration analyses. RESULTS Soy feeding induced a reduction in WbPB and an increase in WbPS. BCAA supplementation of soy protein resulted in a significantly higher (P < 0.05) increase in WbPS than did soy protein alone in COPD patients but not in the healthy elderly. BCAA supplementation did not significantly alter the change in WbPB or net WbPS. Furthermore, BCAA supplementation decreased (absolute) SPE(Phe) (P < 0.05) but did not change the percentage Phe hydroxylation in the splanchnic area, which indicates a BCAA-related reduction in splanchnic protein synthesis. CONCLUSION BCAA supplementation to soy protein enhances WbPS in patients with COPD and alters interorgan protein metabolism in favor of the peripheral (muscle) compartment in healthy elderly and even more in COPD patients.