Pilot evaluation of ivacaftor for chronic bronchitis.
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ABSTRACT:
SUBMITTER: Solomon GM
PROVIDER: S-EPMC4916910 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Pilot evaluation of ivacaftor for chronic bronchitis.
Solomon George M GM Hathorne Heather H Liu Bo B Raju S Vamsee SV Reeves Ginger G Acosta Edward P EP Dransfield Mark T MT Rowe Steven M SM
The Lancet. Respiratory medicine 20160516 6
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Project description:BackgroundChronic bronchitis (CB) is associated with poor outcomes in patients with chronic obstructive pulmonary disease. The aim of this study was to identify the characteristics that distinguish chronic bronchitis (CB) from non-CB. In addition, the features of mild CB versus severe CB were compared and a cut-off level was defined according to CAT1 and CAT2 scores.MethodsThis study was based on the Korea COPD Subgroup Study (KOCOSS) database, constructed in a multicenter COPD cohort study that recruited patients from 54 centers. CB was defined as CAT1 and CAT2 scores ≥ 3; severe CB was defined as CAT1 and CAT2 scores ≥ 4, while mild CB was defined as either a CAT1 or a CAT2 score < 4. Baseline characteristics, 1-year exacerbation rate, and 3-year FEV1 decline were compared in non-CB versus CB patients and in patients with mild CB versus severe CB.ResultsAmong the 2162 patients enrolled in this study, 497 (23%) had CB. These patients were more likely than non-CB patients to be current smokers; they also had higher symptom and depression/anxiety scores. Lung function tests showed lower FEV1, FEV1/FVC, and DLco values in CB patients. Among CB patients, 67.6% had mild disease. Symptom and depression/anxiety scores were worse in patients with severe CB than in patients with mild CB. There were no significant differences in the lung function tests of the two groups. Analysis of 1-year exacerbation rates in CB patients and non-CB patients revealed that patients with CB more frequently had moderate-to-severe exacerbations (OR = 1.46, p < 0.01). More severe exacerbation was also present in patients with severe CB than in patients with mild CB (OR = 2.52, p = 0.01). The difference in annual FEV1 decline rate did not significantly differ either between CB patients and non-CB patients or between patients with severe CB and patients with mild CB.ConclusionsCB patients had worse symptoms and lung function than non-CB patients; CB patients also had more frequent moderate-to-severe exacerbation. Patients with severe CB had higher symptom scores and more frequent severe exacerbation than did patients with mild CB.
| S-EPMC8858532 | biostudies-literature
Project description:Chronic bronchitis (CB) is a common clinical chronic respiratory disease, which has a high incidence in the middle aged and elderly population. With the development of the disease, the number of acute attacks becomes more and more frequent, which leads to the continuous decrease of lung function. If not treated in time, it will lead to a variety of complications and seriously affect the quality of life of patients. Traditional Chinese medicine (TCM) or TCM combined with western medicine is highly effective in the treatment of CB disease. In recent years, there are many systematic reviews on the use of TCM therapy in the treatment of CB, and the efficacy and safety of TCM in the treatment of CB diseases are evaluated. The aim of this study was to re-evaluate the Meta analysis/Systematic reviews (MAs/SRs) of TCM for the treatment of CB, aiming to provide a clinical basis for the treatment of CB by TCM. Retrieval among Chinese and English databases such as China National Knowledge Infrastructure, Wanfang database, China Scientific Journals Database, SinoMed, PubMed, Web of Science, The Cochrane Library and EMbase, etc. were conducted within the duration from database establish Tion date to March 2023.The included research was independently conducted by 2 researchers for literature screening, data extraction, and quality evaluation. The AMSTAR 2 scale was used to evaluate the quality of the report, the PRISMA 2020 statement evaluated the quality of the report, the ROBIS tool evaluated the risk of bias, and the GRADE quality evaluation tool evaluated the quality of the evidence. Fifteen MAs/SRs were included, for a total of 224 studies involving 20,710 patients with CB. The 15 studies included in AMSTAR 2 are of very low quality. The ROBIS evaluation results showed that 8 MAs/SRs were considered to have high risk and 7 with low risk. The PRISMA 2020 report quality showed evaluation results of the included studies scores between 24 and 30, among them 13 with high quality and 2 with low quality. The GRADE system results showed that, within 70 outcome indicators, only 14 of them have moderate quality for evidence, with 31 for low quality, 25 for very low quality, and none for high quality. The MAs/SRs methodological quality of using TCM for treatment CB is generally poor, the quality of reports as well as evidence are generally low, and the risk of bias is high, therefore we should treat these results with caution.
| S-EPMC10713115 | biostudies-literature
Project description:Mutations in the unique ATP-binding cassette anion channel, the cystic fibrosis conductance regulator (CFTR), lead to the inherited fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel gating of CFTR by stabilizing its open state and has been approved as monotherapy for CF patients with CFTR gating mutations (e.g., G551D) and as part of combination therapy with lumacaftor for CFTR folding mutations (e.g., ΔF508). However, in the latter context, ivacaftor may destabilize folding-rescued ΔF508-CFTR and membrane-associated proteins and attenuate lumacaftor pharmacotherapy. Here, we tested the hypothesis that the high lipophilicity of ivacaftor may contribute to this effect. We describe the synthesis of three glutamic acid ivacaftor derivatives with reduced lipophilicity that bear different charges at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel activity at comparable or better levels than ivacaftor. Furthermore, unlike ivacaftor, compound 3 did not attenuate levels of folding-rescued ΔF508 at the cell surface. Molecular modeling predicts that the increased polarity of compound 3 allows engagement with polar amino acids present in the binding pocket with hydrogen bonding and ionic interactions, which are collectively higher in strength as compared to hydrophobic interactions that stabilize ivacaftor. Overall, the data suggests that reduced lipophilicity may improve the efficacy of this class of CFTR potentiators when used for folding-rescued ΔF508-CFTR.
| S-EPMC10702196 | biostudies-literature
Project description:Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR?=?1.93, P?=?4.99?×?10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR?=?1.88, P?=?4.99?×?10-7).We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.ClinicalTrials.gov NCT00608764, NCT00292552.
| S-EPMC4190389 | biostudies-literature
Project description:Research on the association between chronic bronchitis and chronic obstructive pulmonary disease (COPD) exacerbations has led to discordant results. Furthermore, the impact of chronic bronchitis on mortality in COPD subjects is unclear.Within the Rotterdam Study, a population-based cohort study of subjects aged ?45?years, chronic bronchitis was defined as having a productive cough for ?3?months per year for two consecutive years. Linear, logistic regression and Cox proportional hazard models were adjusted for age, sex and pack-years.Out of 972 included COPD subjects, 752 had no chronic phlegm production (CB-) and 220 had chronic phlegm production, of whom 172 met the definition of chronic bronchitis (CB+). CB+ subjects were older, more frequently current smokers and had more pack-years than CB- subjects. During a median 6.5?years of follow-up, CB+ subjects had greater decline in lung function (-38?mL·year-1, 95% CI -61.7--14.6; p=0.024). CB+ subjects had an increased risk of frequent exacerbations (OR 4.0, 95% CI 2.7-5.9; p<0.001). In females, survival was significantly worse in CB+ subjects compared to CB- subjects. Regarding cause-specific mortality, CB+ subjects had an increased risk of respiratory mortality (hazard ratio 2.16, 95% CI 1.12-4.17; p=0.002).COPD subjects with chronic bronchitis have an increased risk of exacerbations and respiratory mortality compared to COPD subjects without chronic phlegm production.
| S-EPMC5593375 | biostudies-literature
Project description:A man in his early 70s with a long-standing history of chronic bronchitis presented to our department 3 years ago with debilitating chronic cough and excessive sputum production. He had no previous diagnosis of chronic obstructive pulmonary disease and without evidence of severe respiratory tract infections. Due to his symptom burden and impairments in daily activities, the patient was considered to be an appropriate candidate for bronchial rheoplasty, a novel endoscopic treatment for patients with chronic bronchitis. The patient responded well to bilateral treatment but then experienced symptom recurrence roughly 14 months after completing the initial treatment. In the absence of an alternative explanation for the return of these symptoms, he then underwent uneventful retreatment. The patient, again, reported significant symptom improvement and no adverse effects since retreatment. While further studies are necessary to assess the safety and efficacy of retreatment, the findings from this case are encouraging.
| S-EPMC10875532 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US. The majority of COPD patients have symptoms of chronic bronchitis, which lacks specific therapies. A major impediment to therapeutic development has been the absence of animal models that recapitulate key clinical and pathologic features of human disease. Ferrets are well suited for the investigation of the significance of respiratory diseases, given prior data indicating similarities to human airway physiology and submucosal gland distribution. Here, we exposed ferrets to chronic cigarette smoke and found them to approximate complex clinical features of human COPD. Unlike mice, which develop solely emphysema, smoke-exposed ferrets exhibited markedly higher numbers of early-morning spontaneous coughs and sporadic infectious exacerbations as well as a higher level of airway obstruction accompanied by goblet cell metaplasia/hyperplasia and increased mucus expression in small airways, indicative of chronic bronchitis and bronchiolitis. Overall, we demonstrate the first COPD animal model exhibiting clinical and pathologic features of chronic bronchitis to our knowledge, providing a key advance that will greatly facilitate the preclinical development of novel treatments for this disease.
| S-EPMC5033751 | biostudies-literature
Project description:ImportanceCystic fibrosis (CF) is a multiorgan genetic disease with progressive upper and lower airway involvement. The effects of CF transmembrane conductance regulator (CFTR) modifier therapies on CF-related upper airway disease, specifically chronic rhinosinusitis (CRS), are not characterized.ObjectiveTo determine the outcome of elexacaftor-tezacaftor-ivacaftor (ETI) on CRS as measured by changes in sinus computed tomography (CT) metrics and on clinical parameters in individuals with CF.Design, setting, and participantsThis prospective longitudinal cohort study was conducted at the CF center of a tertiary care hospital between October 1, 2019, and July 31, 2021. A total of 64 participants with CF were included in the analysis.InterventionSinus CT was obtained within 1 month of initiation of ETI therapy (baseline), and within 1 month of 1 year of ETI therapy. Images were independently analyzed by pulmonology, radiology, and otolaryngology physicians, using the Lund-Mackay and Sheikh-Lind scoring systems. Percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), and microbiologic data collected at initiation of ETI therapy and 3-month intervals for 1 year were also measured.Main outcomes and measuresThe study hypothesis was that ETI therapy will improve CRS as measured by changes in sinus CT at initiation and 1 year after ETI therapy and clinical parameters in individuals with CF.ResultsAmong the 64 participants (39 [60.9%] female; median age, 18.5 [IQR, 16.0-28.5] years; 64 [100%] White), improvement in CRS was noted by improvements in sinus CT scans using both sinus CT scoring systems after 1 year of ETI therapy. The reduction in the median total score using the Lund-Mackay sinus CT scoring system (from 5.8 [IQR, 5.0-7.0] to 3.3 [IQR, 2.6-4.2]) and the Sheikh-Lind scoring system (from 3.8 [IQR, 3.0-5.0] to 2.2 [IQR, 2.0-2.5]) was noted. Increases in ppFEV1 and BMI were also observed by 3 months of ETI therapy with persistent improvement through 1 year of treatment. Similarly, after 1 year of ETI therapy, participants with CF had reductions in positivity for Pseudomonas aeruginosa and Staphylococcus aureus in oropharyngeal cultures.Conclusion and relevanceThis cohort study found that use of ETI therapy was associated with improved CRS outcomes in participants with CF as quantified by improved sinus CT scans measured by 2 radiographic scoring systems and was also associated with improved clinical outcomes. Despite improvement in CT scan scores, most people with CF continue to have scores that indicate severe sinus disease.
| S-EPMC10485743 | biostudies-literature
Project description: Not available
| S-EPMC6527426 | biostudies-literature
Project description:BackgroundChronic bronchitis (CB) importantly affects outcomes in smokers with COPD, but the effects on smokers without COPD are less well known and less emphasized. The aim of our study was to investigate the possible effects of CB on clinical outcomes in smokers without COPD (noCOPD) and compare them with the effects in smokers with COPD (COPD).MethodsFor that purpose, we studied 511 smokers, 302 with and 209 without COPD, followed for 10 years in an academic COPD ambulatory setting. Chronic bronchitis was defined as the presence of cough and sputum production for at least 3 months in each of two consecutive years. All subjects underwent clinical and functional examination with spirometry, diffusion capacity (DLco), 6-min walking test (6MWT), mMRC Dyspnoea Scale, COPD Assessment Test (CAT), and recording of annual frequency of exacerbations. All-cause mortality during follow-up was recorded.Results27% of noCOPD and 45% of COPD had CB. noCOPD with CB had lower FEV1 and DLco, worse 6MWT, more dyspnoea, a higher number of exacerbations and lower survival than noCOPD without CB. CB did not affect FEV1 decline in noCOPD but it significantly did in COPD.ConclusionsThe presence of chronic bronchitis in smokers without COPD will significantly affect symptoms, quality of life, and survival, underlining the importance of recognizing the condition and managing it accordingly.
| S-EPMC9410001 | biostudies-literature