Pulmonary pharmacology & therapeutics最新文献

{"title":"Ferroptosis mediates airway epithelial E-cadherin dysfunction in LPS-induced acute lung injury","authors":"Zemin Chen ,&nbsp;Haixiong Tang ,&nbsp;Sudan Gan ,&nbsp;Changyun Yang ,&nbsp;Shiyue Li ,&nbsp;Jing Li ,&nbsp;Lihong Yao","doi":"10.1016/j.pupt.2023.102284","DOIUrl":"10.1016/j.pupt.2023.102284","url":null,"abstract":"<div><h3>Background</h3><p>Loss of E-cadherin in the airway epithelial cells is a critical contributor to the development of ALI/ARDS. Yet the underlying mechanisms are largely unknown. Increasing evidences have revealed the significance of ferroptosis in the pathophysiological process of ALI/ARDS. The aim of this study was to investigate the role of ferroptosis in dysregulation of airway epithelial E-cadherin in ALI/ARDS.</p></div><div><h3>Methods</h3><p><span>BALB/c mice were subjected to intratracheal instillation of </span>lipopolysaccharide<span><span> (LPS) to establish an ALI model. Two inhibitors of ferroptosis, liproxstatin-1 (Lip-1, at the dose of 10 mg/kg and 30 mg/kg) and ferrostatin-1 (Fer-1, at the dose of 1 mg/kg and 5 mg/kg), were respectively given to the mice through </span>intraperitoneal injection after LPS challenge. The expression of ferroptotic markers, full-length E-cadherin and soluble E-cadherin (sE-cadherin) were both detected.</span></p></div><div><h3>Results</h3><p>LPS exposure dramatically down-regulated pulmonary expression of E-cadherin in mice, with profound loss of membrane E-cadherin in the airway epithelial cells and increased secretion of sE-cadherin in the airway lumen. At the same time, we found that the mitochondrial of airway epithelial cells in LPS-exposed mice exhibited significant morphological alterations that are hallmark features of ferroptosis, with smaller volume and increased membrane density. Other makers of ferroptosis were also detected, including increased cytoplasmic levels of iron and lipid peroxidates (MDA), as well as decreased GPX4 expression. 30 mg/kg of Lip-1 not only showed potent protective effects against the LPS-induced injury, inflammation, edema of the lung in those mice, but also rescued airway epithelial E-cadherin expression and decreased the release of sE-cadherin through inhibiting ferroptosis. While no noticeable changes induced by LPS were observed in mice treated with Lip-1 at 10 mg/kg nor Fer-1 at 1 mg/kg or 5 mg/kg.</p></div><div><h3>Conclusions</h3><p>Taken together, these data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in LPS-induced ALI.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"84 ","pages":"Article 102284"},"PeriodicalIF":3.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139058621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tolerability and efficacy of antifibrotic therapy in patients with idiopathic pulmonary fibrosis: Results from a real-world study","authors":"Ruiming Zhao ,&nbsp;Bingbing Xie ,&nbsp;Xin Wang ,&nbsp;Xinran Zhang ,&nbsp;Yanhong Ren ,&nbsp;Chen Wang ,&nbsp;Huaping Dai","doi":"10.1016/j.pupt.2024.102287","DOIUrl":"10.1016/j.pupt.2024.102287","url":null,"abstract":"<div><h3>Background</h3><p>Idiopathic pulmonary fibrosis<span><span><span> is a progressive and fatal lung disease lacking effective therapeutics. </span>Treatment<span><span> with pirfenidone or </span>nintedanib is recommended for patients to delay the progression of their disease. Adverse reactions caused by anti-fibrosis </span></span>drugs can sometimes interrupt treatment and even change the progression of the disease.</span></p></div><div><h3>Objective</h3><p><span>This study aimed to investigate the clinical use, adverse reactions, tolerability of pirfenidone and nintedanib </span>in patients<span> with idiopathic pulmonary fibrosis and the efficacy of antifibrotic therapy in a real world.</span></p></div><div><h3>Methods</h3><p>We recruited patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib at China-Japan Friendship Hospital from February 2017 to February 2022. We investigated the medication situation, adverse reactions, tolerability and survival of patients taking medications.</p></div><div><h3>Results</h3><p>A total of 303 patients with idiopathic pulmonary fibrosis were enrolled in the study. Treatment was divided between 205 patients receiving pirfenidone and 98 patients receiving nintedanib. Baseline data between the two groups were not significantly different. Patients treated with nintedanib had a higher overall discontinuation rate than those treated with pirfenidone (61.22 vs. 32.68 %, <em>p</em> &lt; 0.001). Across all patient groups, the most common reason for discontinuing treatment was medication-related adverse effects. Compared to pirfenidone, nintedanib had a significantly higher discontinuation rate due to adverse events (48.98 % vs 27.80 %, <em>p</em> &lt; 0.001). The most common side effect of both drugs was diarrhea. Pirfenidone was associated with a higher rate of extra-digestive adverse effects than nintedanib. Survival was not significantly different between the two drugs and using pirfenidone above 1200 mg/day did not confer significant survival benefits. The survival rate of patients who adhere to anti-fibrosis therapy for more than 6 months can be significantly improved (HR = 0.323, <em>p</em> = 0.0015).</p></div><div><h3>Conclusion</h3><p>Gastrointestinal adverse effects were the most common adverse effects and the main reason of discontinuation of antifibrotic therapy, especially nintedanib. Consistent adherence to antifibrotic therapy may make the patients benefit from adjusting their antifibrotic medications, dosage, and active management of side effects.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"84 ","pages":"Article 102287"},"PeriodicalIF":3.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139495753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cefepime pharmacokinetics in adult extracorporeal membrane oxygenation patients","authors":"Lily Zheng ,&nbsp;Mohammad H. Alshaer ,&nbsp;Charles Peloquin ,&nbsp;Veena Venugopalan ,&nbsp;Hassan M. Alnuaimat ,&nbsp;Maureen Converse","doi":"10.1016/j.pupt.2023.102271","DOIUrl":"10.1016/j.pupt.2023.102271","url":null,"abstract":"<div><h3>Background</h3><p>The impact of extracorporeal membrane oxygenation<span><span> (ECMO) on the pharmacokinetics/dynamics (PK/PD) of beta-lactam antibiotics have not been well studied in general, but cefepime specifically has the least amount of data. We aimed to investigate whether ECMO alters the PK of cefepime in adult </span>intensive care unit (ICU) patients.</span></p></div><div><h3>Methods</h3><p>This single-center, retrospective case-control study evaluated cefepime therapeutic drug<span><span><span> monitoring (TDM) results from ECMO patients that were matched 1:1 with TDM results in non-ECMO patients for drug regimen and renal function. The primary outcome was the difference in PK/PD of cefepime in ECMO compared with non-ECMO ICU patients. Secondary outcomes included hospital length of stay, treatment failure, </span>superinfection, </span>bacterial resistance, and survival to discharge.</span></p></div><div><h3>Results</h3><p><span>Eighty-two patients were included with 44 matched cefepime concentrations in each group. ECMO patients had higher free maximum concentrations (fCmax) (p = 0.003), lower free minimum concentration (fCmin)/1x minimum inhibitory concentration (MIC) ratios (</span><em>p</em> = 0.040), and lower attainment of free Cmin/4x MIC (<em>p</em><span> = 0.010). There were no differences between the groups for free Cmin, time above 1xMIC or 4x MIC, and pharmacokinetic parameters (ke, half-life, and Vd). Of those who survived to discharge, hospital length of stay was longer in the ECMO group (</span><em>p</em> &lt; 0.001). Patients on ECMO were more likely to experience treatment failure (<em>p</em> = 0.036). The incidence of bacterial resistance, superinfection, or survival were similar among the groups.</p></div><div><h3>Conclusion</h3><p>These data suggest that more aggressive empiric dosing may be warranted in patients on ECMO. Therapeutic drug monitoring and future prospective studies would provide more evidence to guide decision making regarding dose adjustments.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"84 ","pages":"Article 102271"},"PeriodicalIF":3.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138441167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study","authors":"L. Jayaram, P.T. King, J. Hunt, M. Lim, C. Park, E. Hu, L. Dousha, P. Ha, J.B. Bartlett, Southcott Am, S. Muruganandan, S. Vogrin, M.A. Rees, O.M. Dean, C.A. Wong","doi":"10.1016/j.pupt.2023.102283","DOIUrl":"https://doi.org/10.1016/j.pupt.2023.102283","url":null,"abstract":"<h3>Background</h3><p>High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis.</p><h3>Aims</h3><p>Primary outcome: to assess the efficacy of NAC 2400 mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects.</p><h3>Methods</h3><p>Participants were randomised to receive 2400 mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed.</p><h3>Results</h3><p>The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n = 9) vs placebo (n = 8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV₁1.56 L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p = 0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups.</p><h3>Conclusion</h3><p>High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.</p>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"88 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139022393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyvaso DPI: Drug-device characteristics and patient clinical considerations","authors":"Colleen McEvoy ,&nbsp;Rahul Argula ,&nbsp;Sandeep Sahay ,&nbsp;Shelley Shapiro ,&nbsp;Christina Eagan ,&nbsp;Anthony J. Hickey ,&nbsp;Chad Smutney ,&nbsp;Chris Dillon ,&nbsp;Thomas Winkler ,&nbsp;Brittany N. Davis ,&nbsp;Meredith Broderick ,&nbsp;Charles Burger","doi":"10.1016/j.pupt.2023.102266","DOIUrl":"10.1016/j.pupt.2023.102266","url":null,"abstract":"<div><p>Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry treprostinil into the airways, with a high fraction of the particles in the respirable range. In a clinical study in patients with pulmonary arterial hypertension, Tyvaso DPI had similar exposure and pharmacokinetics, low incidence of adverse events, and high patient satisfaction compared with nebulized treprostinil solution. Tyvaso DPI may be considered as a first prostacyclin agent or for those that do not tolerate other prostacyclin formulations, patients with pulmonary comorbidities, patients with mixed Group 1 and Group 3 pulmonary hypertension, or those that prefer an active lifestyle and need a portable, non-invasive treatment. Tyvaso DPI is a patient-preferred, maintenance-free, safe delivery option that may improve patient compliance and adherence.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102266"},"PeriodicalIF":3.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553923000780/pdfft?md5=a2533bc287439f9ecc193b026c7bf7fd&pid=1-s2.0-S1094553923000780-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134649629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"m6A-modified miR-143-3p inhibits epithelial mesenchymal transition in bronchial epithelial cells and extracellular matrix production in lung fibroblasts by targeting Smad3","authors":"Jing Wang ,&nbsp;Qiang Jian ,&nbsp;Kun Yan ,&nbsp;Jiao Yang ,&nbsp;Liping Yan ,&nbsp;Wei Cheng","doi":"10.1016/j.pupt.2023.102251","DOIUrl":"https://doi.org/10.1016/j.pupt.2023.102251","url":null,"abstract":"<div><h3>Background</h3><p><span><span>Airway epithelial cells epithelial mesenchymal transition (EMT) and </span>lung fibroblasts </span>extracellular matrix<span><span> (ECM) production are the key steps in airway remodeling. Our previous study demonstrated that miR-143-3p has the ability to impede airway smooth muscle </span>cell proliferation and ECM deposition. However, the function of miR-143-3p in airway epithelial cells and lung fibroblasts remains unclear.</span></p></div><div><h3>Methods</h3><p><span><span>Cell viability was determined using MTT method, while cell migration was evaluated through scratch assay. EMT and </span>ECM proteins<span> were detected by western blot<span>, RT-qPCR, and ELISA. To determine the level of miR-143-3p m</span></span></span>⁶<span><span>A methylation, we employed the meRIP-qPCR assay. Additionally, the binding of miR-143-3p with Smad3 were projected by bioinformatics and validated by dual </span>luciferase reporter assays.</span></p></div><div><h3>Results</h3><p>It was discovered that the expression of miR-143-3p were lower in both asthma patients and TGF-β1-treated human bronchial epithelial 16HBE cells and human lung fibroblast HPF cells. Upregulation of miR-143-3p restrained 16HBE cell migration, and decreased EMT mesenchymal markers and increased epithelial markers. And upregulation of miR-143-3p impaired cell viability and ECM protein production in HPF cells. Mechanistically, interfering with METTL3 resulted in decreased m⁶A modification of miR-143-3p and led to lower levels of miR-143-3p. Moreover, miR-143-3p were verified to directly target and downregulate Smad3. Upregulation of Smad3 attenuated the effects of miR-143-3p on cell EMT and ECM production.</p></div><div><h3>Conclusion</h3><p>MiR-143-3p inhibits airway epithelial cell EMT as well as lung fibroblast ECM production by downregulating Smad3. Therefore, miR-143-3p may be a promising target to reduce airway remodeling in asthma.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102251"},"PeriodicalIF":3.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49856435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of body weight–based dosing, alternative dosing regimens, and treatment interruptions for α1-proteinase inhibitors and implications on biochemical efficacy in patients with α1-antitrypsin deficiency","authors":"Zhaoyang Li ,&nbsp;Mitali Gaurav ,&nbsp;Leman Yel","doi":"10.1016/j.pupt.2023.102265","DOIUrl":"10.1016/j.pupt.2023.102265","url":null,"abstract":"<div><h3>Introduction</h3><p>The recommended standard dose for α₁-proteinase inhibitor (A1PI) augmentation therapy is 60 mg/kg once-weekly (QW) intravenous (IV) infusions that aim to maintain systemic A1PI levels &gt;11 μM, the biochemical efficacy threshold, in patients with α₁-antitrypsin deficiency (AATD). However, this standard dose may not be optimal for all patients. Body weight–based dosing, alternative dosing regimens, and treatment interruption periods were evaluated using population pharmacokinetic (PopPK) modeling and simulations.</p></div><div><h3>Methods</h3><p>A nonlinear mixed-effects PopPK model with covariate effects was developed using data from 3 clinical studies investigating 60 mg/kg QW IV A1PI infusions in patients with AATD (n = 65) to evaluate A1PI pharmacokinetic (PK) characteristics. Model-based simulations were conducted for predefined body weight categories, alternative dosing regimens (60–180 mg/kg QW or once every 2 weeks [Q2W]), and treatment interruption periods ranging from 3 to 14 days.</p></div><div><h3>Results</h3><p>A1PI PK characteristics were well described by a 2-compartment turnover model with zero-order input and linear elimination. Body weight was a statistically significant determinant of variability in central volume of distribution. Model-based simulations suggested that patients with a higher body weight may attain the 11 μM threshold quicker than patients with a lower body weight and that QW dosing was better at maintaining A1PI levels &gt;11 μM, even when higher Q2W doses were administered. Missing a dose for as few as 3 days could result in A1PI levels &lt;11 μM.</p></div><div><h3>Discussion</h3><p>Findings suggest that doses higher than 60 mg/kg administered QW might be more clinically beneficial in some patients with AATD, and that body weight should be considered in dose optimization.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102265"},"PeriodicalIF":3.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71485360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of nintedanib and pirfenidone on lung function and survival in patients with idiopathic pulmonary fibrosis in real-life setting","authors":"Gabriela Santos ,&nbsp;André Fabiano ,&nbsp;Patrícia Caetano Mota ,&nbsp;Inês Rodrigues ,&nbsp;Diogo Carvalho ,&nbsp;Natália Melo ,&nbsp;Hélder Novais-Bastos ,&nbsp;André Terras Alexandre ,&nbsp;Conceição Souto Moura ,&nbsp;Susana Guimarães ,&nbsp;José Miguel Pereira ,&nbsp;André Carvalho ,&nbsp;António Morais","doi":"10.1016/j.pupt.2023.102261","DOIUrl":"10.1016/j.pupt.2023.102261","url":null,"abstract":"<div><h3>Background</h3><p><span>Idiopathic pulmonary fibrosis<span> (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2–5 years was reported previously to the advent of antifibrotics. According to </span></span>clinical trials<span>, nintedanib<span> and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival.</span></span></p></div><div><h3>Methods</h3><p><span><span><span>A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of </span>treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with </span>immunosuppressive drugs and/or N- </span>acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®.</p></div><div><h3>Results</h3><p>A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC<span> and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was −40.95 ± 438.26 mL and −0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p &lt; 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656).</span></p></div><div><h3>Conclusions</h3><p>In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102261"},"PeriodicalIF":3.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials","authors":"Alaa Ramadan ,&nbsp;Mohamed El-Samahy ,&nbsp;Amr Elrosasy ,&nbsp;Mohammed Al-Tawil ,&nbsp;Ahmed Abdelaziz ,&nbsp;Mostafa A Soliman ,&nbsp;Mohamed Abouzid","doi":"10.1016/j.pupt.2023.102252","DOIUrl":"10.1016/j.pupt.2023.102252","url":null,"abstract":"<div><h3>Background and objectives</h3><p><span>Chronic refractory cough is a challenging condition that requires a thorough evaluation and management approach. P2X3 receptors<span> that are ATP-dependent play an important part in nerve fiber sensitization and pathological pain pathways. We conducted this </span></span>systematic review<span> and meta-analysis to determine the long-term safety and efficacy of P2X3 receptor antagonist drugs<span> in chronic cough.</span></span></p></div><div><h3>Methods</h3><p>We systematically searched PubMed, Scopus, Web of Science, and Embase to identify all relevant published studies through January 15, 2023 that assessed P2X3 antagonists in chronic cough. The protocol was registered in the PROSPERO database with ID: CRD42023422408. Efficacy outcomes were awake (daytime) cough frequency, night cough frequency, 24-h cough frequency, Cough Severity Diary, and total Leicester Cough Questionnaire score. We used the random-effect model to pool the data using RStudio and CMA software.</p></div><div><h3>Results</h3><p><span>A total of 11 randomized controlled trials comprising 1350 patients receiving a p2x3 antagonist compared to the placebo group were included in this meta-analysis. A significant decrease in 24-h cough frequency (MD = −4.99, 95% CI [−7.15 to −2.82], P &lt; 0.01), awake (daytime) cough frequency (MD = −7.18, 95% CI [−9.98 to 4.37], P &lt; 0.01), and total Leicester Cough Questionnaire score (MD = 1.74, 95% CI [1.02 to 2.46], P &lt; 0.01) exhibited between the P2X3 antagonist and placebo groups. The frequency of the night cough showed an insignificant difference between the two groups. According to the safety, drug-related adverse events, </span>dysgeusia<span><span>, hypogeusia, and </span>ageusia significantly increased between the P2X3 antagonist and placebo groups.</span></p></div><div><h3>Conclusion</h3><p>P2X3 receptor antagonists are promising drugs for treating chronic cough by significantly reducing the frequency, severity, and quality. Some potential side effects may include drug-related adverse events such as hypogeusia, ageusia, and dysgeusia.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102252"},"PeriodicalIF":3.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10569480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SIRT3 activator ganoderic acid D regulates airway mucin MUC5AC expression via the NRF2/GPX4 pathway","authors":"Jiancheng Wang ,&nbsp;Jiayao Li ,&nbsp;Yingying He ,&nbsp;Xiaochun Huang ,&nbsp;Jianguo Feng ,&nbsp;Li Liu ,&nbsp;Yulin Liu ,&nbsp;Xian Jiang ,&nbsp;Jing Jia","doi":"10.1016/j.pupt.2023.102262","DOIUrl":"10.1016/j.pupt.2023.102262","url":null,"abstract":"<div><h3>Purpose</h3><p><span><span>The expression of MUC5AC, a highly prevalent </span>airway mucin, is regulated by stimulatory factors such as </span>oxidative stress<span><span>. Ganoderic acid D (GAD) activates mitochondrial deacetylase SIRT3. SIRT3 regulates mitochondrial function through deacetylation of </span>mitochondrial proteins, thereby playing a significant role in alleviating oxidative stress-related diseases. Therefore, this study aimed to investigate the mechanisms and rationale underlying the regulation of MUC5AC expression by GAD.</span></p></div><div><h3>Methods</h3><p><span>Human airway epithelial cells (NCI–H292) were exposed to pyocyanin (PCN) to establish an </span><em>in vitro</em><span> cell model of airway mucus hypersecretion. The expression of SIRT3, MUC5AC, and NRF2 pathway proteins in cells was assessed. Cellular mitochondrial morphology and oxidative stress markers were analyzed. C57BL/6 mice were induced with </span><span><em>Pseudomonas aeruginosa</em></span> (PA) to establish an <em>in vivo</em><span> mouse model of airway mucus hypersecretion. The expression of SIRT3 and MUC5AC in the airways was examined. In addition, the differential expression of target genes in the airway epithelial tissues of patients with chronic obstructive pulmonary disease (COPD) was analyzed using publicly available databases.</span></p></div><div><h3>Results</h3><p>The results revealed a significant upregulation of MUC5AC expression and a significant downregulation of SIRT3 expression in relation to airway mucus hypersecretion. GAD inhibited the overexpression of MUC5AC in PCN-induced NCI-H292 cells and PA-induced mouse airways by upregulating SIRT3. GAD activated the NRF2/GPX4 pathway and inhibited PCN-induced oxidative stress and mitochondrial morphological changes in NCI-H292 cells. However, ML385 inhibited the regulatory effects of GAD on MUC5AC expression.</p></div><div><h3>Conclusion</h3><p>The SIRT3 activator GAD downregulated MUC5AC expression, potentially through activation of the NRF2/GPX4 pathway. Accordingly, GAD may be a potential treatment approach for airway mucus hypersecretions.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102262"},"PeriodicalIF":3.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50162573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}