Pulmonary pharmacology & therapeutics最新文献

{"title":"Interaction between fluticasone furoate and umeclidinium in passively sensitized isolated human airways","authors":"","doi":"10.1016/j.pupt.2024.102331","DOIUrl":"10.1016/j.pupt.2024.102331","url":null,"abstract":"<div><div>Asthma management often includes inhaled corticosteroids (ICSs), with additional controllers like long-acting muscarinic antagonists (LAMAs) for severe cases. The primary goal of this study was to investigate the pharmacological interaction between various concentrations of fluticasone furoate (FF) and umeclidinium (UME) in isolated human airways to determine the nature of their interaction, whether synergistic or additive. Medium bronchi and small airways obtained from patients undergoing lobectomy were passively sensitized to mimic asthmatic conditions. The effects of FF and UME, alone and in combination, on airway relaxation were evaluated using histamine-induced contraction and electrical field stimulation. Pharmacological interactions were analyzed using the Bliss Independence theory. Results indicated that FF induced a partial, concentration-dependent relaxation of sensitized airways, while UME induced a larger relaxation in medium bronchi but a weaker effect in small airways. The combination of FF and UME resulted in significantly greater relaxation than either drug alone, demonstrating synergism at high concentrations in medium bronchi but only additive effects in small airways. This study suggests that higher doses of FF might be necessary in a fixed dose combination to achieve optimal synergistic bronchodilation with UME. Future research should focus on clinical trials to confirm these findings and explore the molecular mechanisms underlying these interactions, potentially improving personalized asthma therapy.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406808","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":"Hyperbaric oxygen therapy as an immunomodulatory intervention in COVID-19-induced ARDS: Exploring clinical outcomes and transcriptomic signatures in a randomised controlled trial","authors":"","doi":"10.1016/j.pupt.2024.102330","DOIUrl":"10.1016/j.pupt.2024.102330","url":null,"abstract":"<div><div>Immunomodulatory agents with the potential to reverse critical COVID-19, targeting host-virus immune response are needed.</div><div>In this exploratory sub study of a randomised controlled clinical trial, critical COVID-19 patients with moderate acute respiratory distress syndrome at one Swedish university hospital were randomly assigned (1:1) to hyperbaric oxygen therapy (HBOT) group plus best practice, or best practice (Control). Follow-up was 30 days. HBOT was administered with five treatments at 2.4 atm absolute (ATA), lasting 80 min, within the first seven days. Clinical outcome, inflammatory markers, and bulk RNA sequencing (RNAseq) on peripheral blood mononuclear cells were analysed.</div><div>Between December 3rd, 2020, and May 17th, 2021, 23 patients were randomised, and 17 were analysed. RNA-sequencing revealed 791 differentially expressed genes in the HBOT group compared to 46 in the control group at Day 7 vs. baseline. Gene set enrichment analysis revealed a unique transcriptomic signature associated with endoplasmic reticulum stress (ERS) in the HBOT group. Patients in the HBOT group recovered faster and had a shorter mean hospital length of stay (HLoS), 16 vs. 26 days (95.99 % CI -16-0), p = 0.045. National early warning score (NEWS) was lower in the HBOT group (ANOVA, F [8, 120] = 3.817, p &lt; 0.001) and PaO₂/FiO₂ was higher in the HBOT group (Mixed effects model, F [8, 94] = 2.900, p &lt; 0.01).</div><div>We showed a unique transcriptomic signature related to viral-induced ERS in critically ill COVID-19 patients treated with HBOT. The finding was associated with a positive clinical outcome; the HBOT patients recovered faster and had a reduced HLoS compared with controls.</div></div><div><h3>Trial registration</h3><div>NCT04327505 (March 31, 2020) and EudraCT 2020-001349-37 (April 24, 2020).</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406807","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":"Chest CT assess the impact of omalizumab treatment on airway remodeling in refractory asthma","authors":"","doi":"10.1016/j.pupt.2024.102329","DOIUrl":"10.1016/j.pupt.2024.102329","url":null,"abstract":"<div><h3>Background</h3><div>To evaluate the benefits of omalizumab treatment in patients through real-world follow-up and assess the impact of omalizumab treatment on airway remodeling using chest CT.</div></div><div><h3>Methods</h3><div>This is a single-center prospective, observational study included Chinese patients with refractory asthma who received omalizumab treatment from May 2021 to December 2022. We collected real-world clinical data, including their hospitalization information, pulmonary function, FENO, laboratory assessment, ACT scores, chest CT at baseline and every follow-up month. A comparison was made between the pre-treatment and post-treatment laboratory indicators, pulmonary function, airway parameters, and mucous plug scores under chest CT.</div></div><div><h3>Results</h3><div>This study included a total of 61 patients with refractory asthma treated with omalizumab. The study found that: ①regardless of whether the treatment lasted for a full four months or not, it significantly improved patient asthma control scores and reduced hospitalization costs and length of stay (p &lt; 0.05). ②After four months of treatment, pulmonary ventilation function examination revealed significant improvements (p &lt; 0.05) in MEF75, MEF50, MEF75/25, PEF, and FEV1/FVC. ③After four months of omalizumab treatment, the ratio of wall thickness and outer radius (T/D) and wall area percentage (WA%) of the bronchial wall decreased significantly (p &lt; 0.05). ④After medication, the expression of airway mucous plugs decreased.</div></div><div><h3>Conclusions</h3><div>Omalizumab treatment can reduce airway wall thickness, decrease the percentage of airway wall area, and the expression of airway mucous plugs, thereby improving airflow limitation. Utilizing chest CT provides a novel and intuitive assessment of the efficacy of omalizumab treatment.</div></div><div><h3>Trial registration</h3><div>This study was registered in Chinese Clinical Trial Registry, the number is ChiCTR2100046343.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378215","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":"Elexacaftor/tezacaftor/ivacaftor, a game-changer in cystic fibrosis: The Portuguese experience","authors":"","doi":"10.1016/j.pupt.2024.102328","DOIUrl":"10.1016/j.pupt.2024.102328","url":null,"abstract":"<div><h3>Background</h3><p>Phase 3 trials of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) combination treatment in people with cystic fibrosis (CF) with ≥1 <em>F508del-CFTR</em> allele showed profound short-term effects on lung function, weight, and pulmonary exacerbations (PEx). The authors conducted a 12-month study to add evidence on the real-world long-term effectiveness and safety of CFTR modulator therapy with ELX/TEZ/IVA in Portuguese CF adult population.</p></div><div><h3>Methods</h3><p>Ambispective, multicentre, observational, real-life study involving all the Portuguese CF Reference Centres. Adult patients on treatment with ELX/TEZ/IVA combination outside clinical trials were included. Demographics, efficacy, and safety variables on the first 12 months of treatment were compared with the pre-treatment year.</p></div><div><h3>Results</h3><p>132 adult people with CF were included, of which 119 completed 12 months treatment (mean duration of treatment 21.5 months). Mean age was 31.7 ± 11.0 years, 53 % patients were homozygous for the <em>F508del</em> variant, baseline sweat chloride was 86.7 ± 25.9 mmol/L and pre-treatment percent-predicted FEV₁ was 77.9 ± 19.7 %. At 1 year, mean absolute change from baseline in FEV₁ was +0.46L (95 % CI: 0.37, 0.55; p &lt; 0.001) and +13.9 percentage points (95 % CI: 11.5, 16.2; p &lt; 0.001). PEx episodes decreased by 78 % (p &lt; 0.001) and hospitalizations for PEx decreased by 91.4 % (p &lt; 0.001). Body mass index (BMI) increased 1.2 kg/m² (95 % CI: 0.9, 1.5; p &lt; 0.001). Mean sweat chloride variation was −44.5 mmol/L (95 % CI: −49.8, −39.2; p &lt; 0.001). No correlation was found between sweat chloride and lung function (r = −0.116, p = 0.335). There were no major safety concerns. Of note, headache was reported in 7.6 % and neuropsychiatric manifestations occurred in 12.6 % treated patients, being anxiety and depressive disorders the most common.</p></div><div><h3>Conclusions</h3><p>ELX/TEZ/IVA treatment in Portuguese adults with CF was associated with significant improvement in lung function, a drop in PEx and PEx-related hospitalizations and increase in BMI at 12 months and was well tolerated. These results add knowledge to our understanding of clinical benefits and tolerability of ELX/TEZ/IVA. Careful evaluation of adverse effects of ELX/TEZ/IVA therapy and its determinants, mainly concerning mental health, are a research priority.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272570","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":"Lipid nanoparticles for pulmonary fibrosis: A comprehensive review","authors":"","doi":"10.1016/j.pupt.2024.102319","DOIUrl":"10.1016/j.pupt.2024.102319","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a fatal progressive and irreversible ailment associated with the proliferation of fibroblast and accumulation of extracellular matrix (ECM) with gradual scarring of lung tissue. Despite several research studies, the treatments available are not efficient enough for the reversal of the disease and are constantly in progress. No drugs other than Pirfenidone and Nintedanib have been approved for the treatment of IPF, necessitating the exploration of novel therapeutic strategies. Recently, lipid-based nanoparticles (LNPs) have drawn more attention because of their potential to enhance the solubility of drugs, cross biological barriers of the lungs and specifically target lung fibrotic tissues, overcoming various challenges in treating IPF. LNPs offer a versatile platform to encapsulate a wide range of drugs, both hydrophilic and lipophilic, improving their bioavailability, allowing sustained release and reducing toxicity, which radiates their significant role in addressing the complexities of IPF. This review summarizes the pathogenesis and conventional treatment of idiopathic pulmonary fibrosis, along with their drawbacks. The review focuses on different types of lipid-based nanoparticles that have been tested in the treatment of idiopathic pulmonary fibrosis, including nanoemulsions, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, niosomes and lipid-polymer hybrid nanoparticles. The review also highlights the future prospects that can offer a potential approach for developing novel strategies to treat idiopathic pulmonary fibrosis.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142111375","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":"Ensifentrine approval: A milestone in the treatment of COPD","authors":"","doi":"10.1016/j.pupt.2024.102318","DOIUrl":"10.1016/j.pupt.2024.102318","url":null,"abstract":"","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018427","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":"FTO promotes gefitinib-resistance by enhancing PELI3 expression and autophagy in non-small cell lung cancer","authors":"","doi":"10.1016/j.pupt.2024.102317","DOIUrl":"10.1016/j.pupt.2024.102317","url":null,"abstract":"<div><p>The established recognition of N6-methyladenosine (m6A) modification as an indispensable regulatory agent in human cancer is widely accepted. However, the understanding of m6A's role and the mechanisms underlying its contribution to gefitinib resistance is notably limited. Herein, using RT-qPCR, Western blot, Cell proliferation and apoptosis, as well as RNA m6A modification assays, we substantiated that heightened FTO (Fat Mass and Obesity-associated protein) expression substantially underpins the emergence of gefitinib resistance in NSCLC cells. This FTO-driven gefitinib resistance is hinged upon the co-occurrence of PELI3 (Pellino E3 Ubiquitin Protein Ligase Family Member 3) expression and concurrent autophagy activation. Manipulation of PELI3 expression and autophagy activation, including its attenuation, was efficacious in both inducing and overcoming gefitinib resistance within NSCLC cells, as validated <em>in vitro</em> and <em>in vivo</em>. In summary, this study has successfully elucidated the intricate interplay involving FTO-mediated m6A modification, its consequential downstream effect on PELI3, and the concurrent involvement of autophagy in fostering the emergence of gefitinib resistance within the therapeutic context of NSCLC.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000600","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":"Applicability of mouse models for induction of severe acute lung injury","authors":"","doi":"10.1016/j.pupt.2024.102316","DOIUrl":"10.1016/j.pupt.2024.102316","url":null,"abstract":"<div><p>Acute lung injury (ALI) is a significant clinical challenge associated with high morbidity and mortality. Worldwide, it affects approximately 200.000 individuals annually, with a staggering 40 % mortality rate in hospitalized cases and persistent complications in out-of-hospital cases. This review focuses on the key immunological pathways underlying bacterial ALI and the exploration of mouse models as tools for its induction. These models serve as indispensable platforms for unraveling the inflammatory cascades and biological responses inherent to ALI, while also facilitating the evaluation of novel therapeutic agents. However, their utility is not without challenges, mainly due to the stringent biosafety protocols required by the diverse bacterial virulence profiles. Simple and reproducible models of pulmonary bacterial infection are currently available, including intratracheal, intranasal, pleural and, intraperitoneal approaches. These models use endotoxins such as commercially available lipopolysaccharide (LPS) or live pathogens such as <em>Pseudomonas aeruginosa</em>, <em>Mycobacterium tuberculosis</em>, and <em>Streptococcus pneumoniae</em>, all of which are implicated in the pathogenesis of ALI. Combining murine models of bacterial lung infection with in-depth studies of the underlying immunological mechanisms is a cornerstone in advancing the therapeutic landscape for acute bacterial lung injury.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788934","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 efficacy and safety of inhaled antibiotics for pneumonia: A systematic review and meta-analysis","authors":"","doi":"10.1016/j.pupt.2024.102315","DOIUrl":"10.1016/j.pupt.2024.102315","url":null,"abstract":"<div><h3>Objectives</h3><p>The aim of this study was to evaluate the efficacy and safety of inhaled antibiotics for adults with pneumonia by meta-analysis.</p></div><div><h3>Methods</h3><p>Literature retrieval was completed through five databases (PubMed, Embase, Cochrane Library, Web of Science and Scopus) by the deadline of May 31, 2024. The process of study selection and data extraction were performed independently by two reviewers. The quality of observational studies and randomized controlled trial (RCT) studies were evaluated by Newcastle Ottawa scale and Jadad scale, respectively. The primary outcomes included mortality, clinical cure, and microbiological cure. Secondary outcomes were recurrence and renal impairment.</p></div><div><h3>Results</h3><p>There were 30 studies were analyzed, including 12 RCT studies and 18 observational studies. Inhaled antibiotics did not significantly reduce mortality in RCT studies (odds ratio (OR) = 1.06, 95 % confidence interval (CI): 0.80–1.41). Inhaled antibiotics were associated with higher rates of clinical cure (OR = 1.47 95%CI: 0.82–2.66 in RCT studies and OR = 2.09, 95%CI: 1.36–3.21 in observational studies) and microbiological cure (OR = 7.00 in RCT studies and OR = 2.20 in observational studies). Subgroup analysis showed patients received inhaled antibiotics combined with intravenous administration and inhaled amikacin had better improvements of mortality, clinical cure and microbiological cure. Inhaled antibiotics were not associated with recurrence. The pooled OR of renal impairment were 0.65 (95%CI: 0.27–1.13; I-squared = 43.5 %, P = 0.124) and 0.63(95%CI: 0.26–1.11; I-squared = 69.0 %, P = 0.110) in RCT studies and observational studies, respectively.</p></div><div><h3>Conclusions</h3><p>Inhaled antibiotics decreased risk of renal impairment and achieved significant improvements of clinical and microbiological cure in patients with pneumoniae.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553924000312/pdfft?md5=5f0cf7dddad61179a42ab1db817fec41&pid=1-s2.0-S1094553924000312-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620800","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":"Differential distribution of ivacaftor and its metabolites in plasma and human airway epithelia","authors":"","doi":"10.1016/j.pupt.2024.102314","DOIUrl":"10.1016/j.pupt.2024.102314","url":null,"abstract":"<div><p>Ivacaftor is the first clinically approved monotherapy potentiator to treat <em>CFTR</em> channel dysfunction in people with cystic fibrosis. Ivacaftor (Iva) is a critical component for all current modulator therapies, including highly effective modulator therapies. Clinical studies show that CF patients on ivacaftor-containing therapies present various clinical responses, off-target effects, and adverse reactions, which could be related to metabolites of the compound. In this study, we reported the concentrations of Iva and two of its major metabolites (M1-Iva and M6-Iva) in capillary plasma and estimated M1-Iva and M6-Iva metabolic activity via the metabolite parent ratio in capillary plasma over 12 h. We also used the ratio of capillary plasma versus human nasal epithelial cell concentrations to evaluate entry into epithelial cells <em>in vivo</em>. M6-Iva was rarely detected by LC-MS/MS in epithelial cells from participants taking ivacaftor, although it was detected in plasma. To further explore this discrepancy, we performed <em>in vitro</em> studies, which showed that M1-Iva, but not M6-Iva, readily crossed 16HBE cell membranes. Our studies also suggest that metabolism of these compounds is unlikely to occur in airway epithelia despite evidence of expression of metabolism enzymes. Overall, our data provide evidence that there are differences between capillary and cellular concentrations of these compounds that may inform future studies of clinical response and off-target effects.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535142","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}