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1.
JCI Insight ; 5(3)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-31895696

RESUMO

BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.

3.
Bioorg Med Chem ; 28(1): 115213, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31810890

RESUMO

Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.

4.
Antimicrob Agents Chemother ; 64(2)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31712198

RESUMO

The diarylquinoline F1FO-ATP synthase inhibitor bedaquiline (BDQ) displays protonophore activity. Thus, uncoupling electron transport from ATP synthesis appears to be a second mechanism of action of this antimycobacterial drug. Here, we show that the new BDQ analogue TBAJ-876 did not retain the parental drug's protonophore activity. Comparative time-kill analyses revealed that both compounds exert the same bactericidal activity. These results suggest that the uncoupler activity is not required for the bactericidal activity of diarylquinolines.

5.
JAMA Intern Med ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31816012

RESUMO

Importance: Few studies have investigated the association of long-term ambient ozone exposures with respiratory morbidity among individuals with a heavy smoking history. Objective: To investigate the association of historical ozone exposure with risk of chronic obstructive pulmonary disease (COPD), computed tomography (CT) scan measures of respiratory disease, patient-reported outcomes, disease severity, and exacerbations in smokers with or at risk for COPD. Design, Setting, and Participants: This multicenter cross-sectional study, conducted from November 1, 2010, to July 31, 2018, obtained data from the Air Pollution Study, an ancillary study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). Data analyzed were from participants enrolled at 7 (New York City, New York; Baltimore, Maryland; Los Angeles, California; Ann Arbor, Michigan; San Francisco, California; Salt Lake City, Utah; and Winston-Salem, North Carolina) of the 12 SPIROMICS clinical sites. Included participants had historical ozone exposure data (n = 1874), were either current or former smokers (≥20 pack-years), were with or without COPD, and were aged 40 to 80 years at baseline. Healthy persons with a smoking history of 1 or more pack-years were excluded from the present analysis. Exposures: The 10-year mean historical ambient ozone concentration at participants' residences estimated by cohort-specific spatiotemporal modeling. Main Outcomes and Measures: Spirometry-confirmed COPD, chronic bronchitis diagnosis, CT scan measures (emphysema, air trapping, and airway wall thickness), 6-minute walk test, modified Medical Research Council (mMRC) Dyspnea Scale, COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), postbronchodilator forced expiratory volume in the first second of expiration (FEV1) % predicted, and self-report of exacerbations in the 12 months before SPIROMICS enrollment, adjusted for demographics, smoking, and job exposure. Results: A total of 1874 SPIROMICS participants were analyzed (mean [SD] age, 64.5 [8.8] years; 1479 [78.9%] white; and 1013 [54.1%] male). In adjusted analysis, a 5-ppb (parts per billion) increase in ozone concentration was associated with a greater percentage of emphysema (ß = 0.94; 95% CI, 0.25-1.64; P = .007) and percentage of air trapping (ß = 1.60; 95% CI, 0.16-3.04; P = .03); worse scores for the mMRC Dyspnea Scale (ß = 0.10; 95% CI, 0.03-0.17; P = .008), CAT (ß = 0.65; 95% CI, 0.05-1.26; P = .04), and SGRQ (ß = 1.47; 95% CI, 0.01-2.93; P = .048); lower FEV1% predicted value (ß = -2.50; 95% CI, -4.42 to -0.59; P = .01); and higher odds of any exacerbation (odds ratio [OR], 1.37; 95% CI, 1.12-1.66; P = .002) and severe exacerbation (OR, 1.37; 95% CI, 1.07-1.76; P = .01). No association was found between historical ozone exposure and chronic bronchitis, COPD, airway wall thickness, or 6-minute walk test result. Conclusions and Relevance: This study found that long-term historical ozone exposure was associated with reduced lung function, greater emphysema and air trapping on CT scan, worse patient-reported outcomes, and increased respiratory exacerbations for individuals with a history of heavy smoking. The association between ozone exposure and adverse respiratory outcomes suggests the need for continued reevaluation of ambient pollution standards that are designed to protect the most vulnerable members of the US population.

6.
Sci Rep ; 9(1): 11367, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388056

RESUMO

Metabolomics is an emerging science that can inform pathogenic mechanisms behind clinical phenotypes in COPD. We aimed to understand disturbances in the serum metabolome associated with respiratory outcomes in ever-smokers from the SPIROMICS cohort. We measured 27 serum metabolites, mostly amino acids, by 1H-nuclear magnetic resonance spectroscopy in 157 white ever-smokers with and without COPD. We tested the association between log-transformed metabolite concentrations and one-year incidence of respiratory exacerbations after adjusting for age, sex, current smoking, body mass index, diabetes, inhaled or oral corticosteroid use, study site and clinical predictors of exacerbations, including FEV1% predicted and history of exacerbations. The mean age of participants was 53.7 years and 58% had COPD. Lower concentrations of serum amino acids were independently associated with 1-year incidence of respiratory exacerbations, including tryptophan (ß = -4.1, 95% CI [-7.0; -1.1], p = 0.007) and the branched-chain amino acids (leucine: ß = -6.0, 95% CI [-9.5; -2.4], p = 0.001; isoleucine: ß = -5.2, 95% CI [-8.6; -1.8], p = 0.003; valine: ß = -4.1, 95% CI [-6.9; -1.4], p = 0.003). Tryptophan concentration was inversely associated with the blood neutrophil-to-lymphocyte ratio (p = 0.03) and the BODE index (p = 0.03). Reduced serum amino acid concentrations in ever-smokers with and without COPD are associated with an increased incidence of respiratory exacerbations.

7.
Respir Med ; 156: 58-68, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31437649

RESUMO

Spirometry is the current gold standard for diagnosing and monitoring the progression of Chronic Obstructive Pulmonary Disease (COPD). However, many current and former smokers who do not meet established spirometric criteria for the diagnosis of this disease have symptoms and clinical courses similar to those with diagnosed COPD. Large longitudinal observational studies following individuals at risk of developing COPD offer us additional insight into spirometric patterns of disease development and progression. Analysis of forced expiratory maneuver changes over time may allow us to better understand early changes predictive of progressive disease. This review discusses the theoretical ability of spirometry to capture fine pathophysiologic changes in early airway disease, highlights the shortcomings of current diagnostic criteria, and reviews existing evidence for spirometric measures which may be used to better detect early airflow impairment.

8.
Eur Respir J ; 54(4)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31439683

RESUMO

The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio, CT-measured residual volume (RVCT) to total lung capacity (TLCCT) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RVCT/TLCCT had a greater differential rate of decline in FEV1/FVC; those in the upper RVCT/TLCCT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RVCT/TLCCT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RVCT/TLCCT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RVCT/TLCCT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.

9.
Korean J Radiol ; 20(7): 1236-1245, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31270987

RESUMO

OBJECTIVE: Considering the different prevalence rates of diseases such as asthma and chronic obstructive pulmonary disease in Asians relative to other races, Koreans may have unique airway structure and lung function. This study aimed to investigate unique features of airway structure and lung function based on quantitative computed tomography (QCT)-imaging metrics in the Korean Asian population (Koreans) as compared with the White American population (Whites). MATERIALS AND METHODS: QCT data of healthy non-smokers (223 Koreans vs. 70 Whites) were collected, including QCT structural variables of wall thickness (WT) and hydraulic diameter (Dh) and functional variables of air volume, total air volume change in the lung (ΔVair), percent emphysema-like lung (Emph%), and percent functional small airway disease-like lung (fSAD%). Mann-Whitney U tests were performed to compare the two groups. RESULTS: As compared with Whites, Koreans had smaller volume at inspiration, ΔVair between inspiration and expiration (p < 0.001), and Emph% at inspiration (p < 0.001). Especially, Korean females had a decrease of ΔVair in the lower lobes (p < 0.001), associated with fSAD% at the lower lobes (p < 0.05). In addition, Koreans had smaller Dh and WT of the trachea (both, p < 0.05), correlated with the forced expiratory volume in 1 second (R = 0.49, 0.39; all p < 0.001) and forced vital capacity (R = 0.55, 0.45; all p < 0.001). CONCLUSION: Koreans had unique features of airway structure and lung function as compared with Whites, and the difference was clearer in female individuals. Discriminating structural and functional features between Koreans and Whites enables exploration of inter-racial differences of pulmonary disease in terms of severity, distribution, and phenotype.

10.
Respir Res ; 20(1): 153, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307479

RESUMO

BACKGROUND: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. METHODS: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. RESULTS: We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. CONCLUSIONS: QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.


Assuntos
Imagem Tridimensional/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-31358589

RESUMO

The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α3:ß3 headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. However, the drug is highly lipophilic, displays a long terminal half-life, and has a cardiotoxicity liability by causing QT interval prolongation. Recent medicinal chemistry campaigns have resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ that are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, which is a new developmental compound of this series, shows attractive antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 and selected analogues of the compound retain BDQ's mechanism of action. Biochemical assays showed that TBAJ-876 is a potent inhibitor of mycobacterial F-ATP synthase. Selection of spontaneous TBAJ-876-resistant mutants identified missense mutations at BDQ's binding site on the c subunit, suggesting that TBAJ-876 retains BDQ's targeting of the c ring. Susceptibility testing against a strain overexpressing the ε subunit and a strain harboring an engineered mutation in BDQ's ε subunit binding site suggest that TBAJ-876 retains BDQ's activity on the ε subunit. Nuclear magnetic resonance (NMR) titration studies confirmed that TBAJ-876 binds to the ε subunit at BDQ's binding site. We show that TBAJ-876 retains BDQ's antimycobacterial mode of action. The developmental compound inhibits the mycobacterial F-ATP synthase via a dual-subunit mechanism of interfering with the functions of both the enzyme's c and ε subunits.

12.
Sports Med Int Open ; 3(2): E48-E57, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31312715

RESUMO

Behavioral modification (BM) is a strategy designed to sustain or restore well-being through effects such as enhanced relaxation, reduced stress, and improved sleep. Few studies have explored the role of BM delivered in the context of fitness programs for healthy adults. Thus, the purpose of this investigation was to examine whether BM combined with aerobic and resistance training programs would improve health and fitness measures more than the exercise training alone. Thirty-two healthy fitness club members (19 men) were randomized to receive a BM program (n=15) or an equal-attention (EA) control (n=17). BM consisted of twelve, 10-min education sessions between a trained fitness professional and the participant, coupled with weekly, individualized relaxation, stress reduction, and sleep improvement assignments. All participants engaged in 1 h of coached resistance training and remotely guided aerobic exercise thrice weekly for 12 weeks. Fitness measures (aerobic performance, body composition, muscle strength and endurance, lower-body power), sleep characteristics, and heart rate variability (HRV) were obtained at baseline and after the 12-week program. BM resulted in greater improvements in aerobic performance (increased maximum oxygen uptake, metabolic (lactate) threshold, and percent of maximum oxygen uptake at which metabolic threshold occurred), peak and average lower-body power, and body composition (decreased body fat percentage and fat mass) compared to EA. BM also positively influenced parasympathetic tone through increased High-frequency HRV. BM resulted in greater improvements in fitness measures, body composition, and heart rate variability compared with EA. These findings have intriguing implications regarding the role of BM in augmenting health and physical performance.

13.
Lung India ; 36(3): 207-211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031340

RESUMO

Background: There are limited data on home mechanical ventilation (HMV) in developing countries. This study aimed to describe the patient characteristics, feasibility, and outcomes of an HMV program at a university hospital in Thailand. Materials and Methods: Data were collected on all patients who were discharged with HMV between October 2014 and August 2015 at Thammasat University Hospital. Results: Twelve patients (eight men and four women) underwent HMV. They were aged 71.5 ± 17.6 years; mean ± standard deviation. Indications for HMV were 6 neurologic diseases (4 amyotrophic lateral sclerosis, 1 multiple system atrophy, and 1 stroke), 2 chronic obstructive pulmonary disease (COPD), 1 tracheomalacia, and 3 combined neurologic diseases and respiratory diseases (2 stroke and COPD, 1 stroke and tracheomalacia). The duration of follow-up was 799.5 ± 780.5 days. The ratio of family income to cost of HMV usage was 77.2:1 ± 5.5:1. All patients had tracheostomies. Modes of HMV were biphasic positive airway pressure (66.7%), pressure-controlled ventilation (16.7%), pressure-support ventilation (8.3%), and volume-controlled ventilation (8.3%). Complications occurred in ten patients (83.3%), including tracheobronchitis (20 events) and ventilator-associated pneumonia (12 events). Overall mortality was 41.7% (5/12 patients), including two patients who died due to ventilator-associated pneumonia. There were no instances of ventilator malfunction. Conclusions: HMV is feasible for patients with neurological diseases and COPD in a developing country. The relatively high rate of complications indicates the need for more comprehensive clinical services for chronic ventilator-dependent patients in this setting.

14.
Chem Rev ; 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013076

RESUMO

Dye-sensitized solar cells (DSCs) are a next-generation photovoltaic technology, whose natural transparency and good photovoltaic output under ambient light conditions afford them niche applications in solar-powered windows and interior design for energy-sustainable buildings. Their ability to be fabricated on flexible substrates, or as fibers, also makes them attractive as passive energy harvesters in wearable devices and textiles. Cosensitization has emerged as a method that affords efficiency gains in DSCs, being most celebrated via its role in nudging power conversion efficiencies of DSCs to reach world-record values; yet, cosensitization has a much wider potential for applications, as this review will show. Cosensitization is a chemical fabrication method that produces DSC working electrodes that contain two or more different dyes with complementary optical absorption characteristics. Dye combinations that collectively afford a panchromatic absorption spectrum emulating that of the solar emission spectrum are ideal, given that such combinations use all available sunlight. This review classifies existing cosensitization efforts into seven distinct ways that dyes have been combined in order to generate panchromatic DSCs. Seven cognate molecular-engineering strategies for cosensitization are thereby developed, which tailor optical absorption toward optimal DSC-device function.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31010860

RESUMO

Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated M. tuberculosis cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant M. tuberculosis, these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.

16.
Bioorg Med Chem ; 27(7): 1283-1291, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30792104

RESUMO

The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.


Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Piridinas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Diarilquinolinas/síntese química , Diarilquinolinas/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
17.
Sci Adv ; 5(2): eaat4600, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30801003

RESUMO

Tough, biological materials (e.g., collagen or titin) protect tissues from irreversible damage caused by external loads. Mimicking these protective properties is important in packaging and in emerging applications such as durable electronic skins and soft robotics. This paper reports the formation of tough, metamaterial-like core-shell fibers that maintain stress at the fracture strength of a metal throughout the strain of an elastomer. The shell experiences localized strain enhancements that cause the higher modulus core to fracture repeatedly, increasing the energy dissipated during extension. Normally, fractures are catastrophic. However, in this architecture, the fractures are localized to the core. In addition to dissipating energy, the metallic core provides electrical conductivity and enables repair of the fractured core for repeated use. The fibers are 2.5 times tougher than titin and hold more than 15,000 times their own weight for a period 100 times longer than a hollow elastomeric fiber.

18.
Bioorg Med Chem ; 27(7): 1292-1307, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30803745

RESUMO

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.


Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Piridinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Diarilquinolinas/síntese química , Diarilquinolinas/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
19.
Int J Exerc Sci ; 12(2): 144-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761193

RESUMO

Exercise intensity is a critical component of the exercise prescription model. However, current research employing various non-specific exercise intensity protocols have reported wide variability in maximum oxygen uptake (VO2max) improvement after training, suggesting a present lack of consensus regarding optimal heart rate (fC) training zones for maximal athletic performance. This study examined the relationship between percentage of time (%time) spent training between the metabolic (VO2θ) and ventilatory thresholds (VEθ), and the resultant change in markers of aerobic performance. Thirteen (6 males) collegiate club-level triathletes were recruited for eight weeks of remote fC monitoring during all running and cycling sessions. Participants donned a forearm-worn optical fC sensor paired to a smartphone that collected and stored fCs. Subjects were categorized into Low and High groups based on %time spent training between the VO2θ and VEθ. Significant increases were observed in relative VO2max (P = 0.007, g = 0.48), VO2θ (P = 0.018, g = 0.35), and VEθ (P = 0.030, g = 0.29) from baseline after eight weeks for both groups. A 95% bootstrapped confidence interval that did not include zero (-0.38, -0.03; g = 1.26) revealed a large and significantly greater change in VO2θ in the High group (0.37 ± 0.15 L/min) versus the Low group (0.17 ± 0.14 L/min). No significant differences were observed in other variables between groups. Increasing triathletes' %time spent exercising between VO2θ and VEθ may optimize increases in VO2θ after eight weeks of training.

20.
Chest ; 155(5): 908-917, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30684474

RESUMO

BACKGROUND: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. METHODS: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV1/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV1. RESULTS: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. CONCLUSIONS: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.


Assuntos
Biomarcadores , Inflamação , Doença Pulmonar Obstrutiva Crônica , Fumar , Espirometria/métodos , Asma/diagnóstico , Asma/imunologia , Asma/fisiopatologia , Biomarcadores/análise , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Feminino , Fibrinogênio/imunologia , Humanos , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Índice de Gravidade de Doença , Fumar/efeitos adversos , Fumar/imunologia , Avaliação de Sintomas/métodos , Estados Unidos/epidemiologia
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