{"title":"Targeted inhibition of IDO1 by Kushenol A enhances radiosensitivity in non-small cell lung cancer","authors":"Yingwei Zhu , Yunqian Chu , Hanjue Dai , Enci Lu , Qian Geng , Qingying Xian , Hua Jiang , Wenyu Zhu","doi":"10.1016/j.pupt.2025.102362","DOIUrl":"10.1016/j.pupt.2025.102362","url":null,"abstract":"<div><div>Kushenol, a monomeric compound, was extracted from the roots of the medicinal plant Sophora flavescens. To explore the activity of Kushenol A in non-small cell lung cancer (NSCLC), CCK-8 assay, flow cytometry, and Western blot were performed. A xenograft mouse model was established. Our results demonstrated that Kushenol A treatment significantly enhanced the killing effect of radiation on NSCLC cells. Co-treatment with radiation and Kushenol A markedly reduced cell viability, increased intracellular ROS levels, and elevated the proportion of apoptotic cells compared to NSCLC cells treated with radiation alone. Animal experiments further confirmed that radiation therapy with simultaneous Kushenol A administration suppressed tumor growth and improved radiotherapy sensitivity compared to mice treated with radiation alone. Furthermore, Kushenol A did not produce significant toxic damage to the major organs of mice. Mechanistically, radiation therapy combined with Kushenol A treatment significantly upregulated protein levels of cleaved Caspase-3 and cleaved Caspase-9, leading to Bax translocation from the cytoplasm to mitochondria. Concurrently, Kushenol A treatment reduced NRF2 levels in the cytoplasm, thereby promoting an increase in ROS levels. Notably, Kushenol A enhanced tumor radiosensitivity by targeted inhibition of Indoleamine 2,3-dioxygenase 1 (IDO1). Taken together, our findings suggested that cotreatment with Kushenol A and radiation promoted the entry of Bax into mitochondria and activated the mitochondrial apoptotic pathway. Kushenol A exhibited targeted inhibition of IDO1, enhancing the sensitivity of non-small cell lung cancer to radiotherapy.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102362"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226489","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}
Michela Salvadori , Dave Singh , Kusum Mathews , Luca Girardello , Mauro Cortellini , Aida Emirova , Ilaria Pacchetti , Martina Foti , Veronica Puviani , Gianluigi Poli , François Rony
{"title":"The low global warming potential propellant HFA-152a does not induce bronchoconstriction or impair mucociliary clearance","authors":"Michela Salvadori , Dave Singh , Kusum Mathews , Luca Girardello , Mauro Cortellini , Aida Emirova , Ilaria Pacchetti , Martina Foti , Veronica Puviani , Gianluigi Poli , François Rony","doi":"10.1016/j.pupt.2025.102358","DOIUrl":"10.1016/j.pupt.2025.102358","url":null,"abstract":"<div><h3>Introduction</h3><div>Use of propellants with high global warming potential (e.g., HFA-134a) for pressurised metered-dose inhalers is being phased down. An alternative is reformulation using propellants with low global warming potential (e.g., HFA-152a), which requires evaluation of the propellant's safety, in particular whether it induces bronchoconstriction or impairs mucociliary clearance (MCC). In this manuscript, we describe two studies, the first comparing the bronchoconstriction potential of HFA-152a vs HFA-134a, the second comparing their effect on MCC.</div></div><div><h3>Methods</h3><div>The bronchoconstriction study was single-dose, randomised, double-blind, controlled, crossover, in adults with asthma. The primary endpoint was relative change from baseline in forced expiratory volume in 1 s (FEV<sub>1</sub>) at 15 min post-dose.</div><div>The MCC study was multiple-dose (8 days), randomised, open-label, controlled, crossover, in healthy volunteers. The primary endpoint was percent particle retention in the right whole lung at 2 and 4 h after inhalation of radiolabelled particles (PPR<sub>2</sub> and PPR<sub>4</sub>).</div></div><div><h3>Results</h3><div>For the bronchoconstriction study (N = 25), the 95 % CI of the adjusted mean FEV<sub>1</sub> difference between HFA-152a vs HFA-134a at 15 min post-dose was within the −10 % to +10 % equivalence limit (1.86 % [95 % CI –0.48 %, 4.20 %]; p = 0.113). Treatment-emergent adverse events were reported by 4.0 % (HFA-152a) and 12.0 % (HFA-134a) patients, all mild or moderate in intensity, and none serious.</div><div>For the MCC study (N = 20), the 95 % CIs for the adjusted mean differences between HFA-152a vs HFA-134a at Day 8 contained 0 for both PPR<sub>2</sub> (1.36 [–2.28, 4.99]%; p = 0.442) and PPR<sub>4</sub> (0.70 [–1.73, 3.12]%; p = 0.553). A similar proportion of subjects had treatment-emergent adverse events (25.0 % vs 35.0 %), all mild in intensity, and none serious.</div></div><div><h3>Conclusions</h3><div>These two studies suggest a switch in propellant from HFA-134a to HFA-152a is unlikely to induce post-dose bronchoconstriction in asthma or impact lung MCC, and is not accompanied by any safety concerns.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"89 ","pages":"Article 102358"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804106","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}
Katharine B. Strickland , Jaclyn M. Hawn , Shawn Leverett , Carolyn Magee Bell
{"title":"A retrospective review of concurrent versus sequential administration of intrapleural tissue plasminogen activator and dornase alfa for empyemas","authors":"Katharine B. Strickland , Jaclyn M. Hawn , Shawn Leverett , Carolyn Magee Bell","doi":"10.1016/j.pupt.2025.102359","DOIUrl":"10.1016/j.pupt.2025.102359","url":null,"abstract":"<div><h3>Background</h3><div>Intrapleural tissue plasminogen activator (tPA) and dornase alfa (DNase) administered sequentially, separated by a one to 2 h interval, is a mainstay of pleural infection treatment. Recent literature supports similar efficacy and safety of concurrent therapy (administered immediately after one another). Insufficient evidence are available to utilize concurrent therapy routinely.</div></div><div><h3>Objective</h3><div>The primary objective of this study was to assess the safety and effectiveness of concurrent versus sequential intrapleural tPA and DNase in pleural infections.</div></div><div><h3>Methods</h3><div>This was a single-center, retrospective study of patients ≥18 years old admitted to the inpatient setting who received either concurrent or sequential intrapleural tPA or DNase between July 1, 2014, and January 1, 2023. The primary outcome was treatment failure, a composite of 30-day mortality and requirement for a video-assisted thoracoscopic surgery (VATS). Secondary outcomes included cumulative pleural fluid drainage, bleeding adverse events, and pain requiring analgesia dose escalation.</div></div><div><h3>Results</h3><div>A total of 184 patients were included: 158 patients in the concurrent group and 26 patients in the sequential group. Treatment failure was similar between groups (18.4 % vs 19.2 %, P > 0.99). Increased pleural fluid drainage occurred in the concurrent versus sequential therapy group (1453 mL vs 836 mL, P = 0.05) with no differences in bleeding (23.4 % vs 19.2 %, P = 0.64) or analgesia dose escalation between groups (41.1 % vs 23.1 %, P = 0.09).</div></div><div><h3>Conclusion and Relevance</h3><div>Concurrent intrapleural fibrinolytics have similar effectiveness and safety compared to sequential administration however, further investigation into the compatibility and stability of the medications is warranted to optimize future pleural infection management.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"89 ","pages":"Article 102359"},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781033","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}
François Rony , Maria Gloria Pittelli , Cristina Contursi , Ilaria Pacchetti , Emanuele Rocco Calabrò , Luca Vittorio Viganò , Kusum S. Mathews , Gianluigi Poli , Katrin Van Leuven , Matteo Martini
{"title":"Impact on beclometasone dipropionate pharmacokinetics when switching to a low global warming potential propellant in a pressurised metered-dose inhaler","authors":"François Rony , Maria Gloria Pittelli , Cristina Contursi , Ilaria Pacchetti , Emanuele Rocco Calabrò , Luca Vittorio Viganò , Kusum S. Mathews , Gianluigi Poli , Katrin Van Leuven , Matteo Martini","doi":"10.1016/j.pupt.2025.102356","DOIUrl":"10.1016/j.pupt.2025.102356","url":null,"abstract":"<div><h3>Introduction</h3><div>Use of high global warming potential propellants (e.g., HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Beclometasone dipropionate (BDP) is approved for the treatment of asthma in several countries via an HFA-134a propellant pMDI. This is being reformulated using the low global warming potential propellant HFA-152a. Two studies compared BDP pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.</div></div><div><h3>Methods</h3><div>Both studies (N = 71/study) were single-dose (four inhalations of BDP), randomised, double-blind, crossover (Study 1, four-way; Study 2, two-way), in healthy volunteers. In Study 1, subjects inhaled BDP via HFA-134a pMDI in two periods (200 μg/actuation in one period, 100 μg/actuation in the other) and HFA-152a pMDI in the other two (200 or 100 μg/actuation). In Study 2, subjects inhaled BDP 200 μg/actuation via HFA-134a or HFA-152a pMDI using a spacer device.</div><div>pMDIs containing HFA-152a and HFA-134a were compared in terms of lung availability (BDP comparisons) and total systemic exposure (beclometasone-17-monopropionate comparisons [B17MP; active metabolite of BDP]), with bioequivalence concluded if the 90 % confidence intervals (CIs) of the geometric mean ratios of maximum plasma concentration (C<sub>max</sub>) and area under the plasma concentration–time curve between time zero and the last quantifiable timepoint (AUC<sub>0–t</sub>) were between 80 and 125 %.</div></div><div><h3>Results</h3><div>BDP C<sub>max</sub> and AUC<sub>0-t</sub> were equivalent for the two BDP 200 μg formulations, without (Study 1) and with spacer (Study 2). BDP 100 μg AUC<sub>0-t</sub> met the bioequivalence criteria, but the C<sub>max</sub> lower 90 % CI was marginally below the bioequivalence limit (79.46 %). B17MP C<sub>max</sub> and AUC<sub>0-t</sub> were bioequivalent with both propellants in all three comparisons.</div></div><div><h3>Conclusions</h3><div>Overall, bioequivalence was confirmed of HFA-152a and HFA-134a for BDP 200 μg/actuation, with and without a spacer. Although bioequivalence of the two formulations cannot be formally concluded for BDP 100 μg, the minimal difference suggests the two formulations can be considered therapeutically equivalent.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"89 ","pages":"Article 102356"},"PeriodicalIF":3.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639799","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":"Drug repurposing tactics in the USA: Known active pharmaceutical ingredients in new indications","authors":"Thomas P. Dooley","doi":"10.1016/j.pupt.2025.102348","DOIUrl":"10.1016/j.pupt.2025.102348","url":null,"abstract":"","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"89 ","pages":"Article 102348"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543223","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}
Elena Pistocchini , Alicia Maria Carrillo Heredero , Melissa Mazan , Laurent Couetil , Simone Bertini , Luigino Calzetta
{"title":"Corrigendum to “Clinical efficacy of inhaled corticosteroids in equine asthma: A meta-analysis and number needed to treat” [Pulm. Pharmacol. Therapeut. (88), March 2025, 102342]","authors":"Elena Pistocchini , Alicia Maria Carrillo Heredero , Melissa Mazan , Laurent Couetil , Simone Bertini , Luigino Calzetta","doi":"10.1016/j.pupt.2024.102343","DOIUrl":"10.1016/j.pupt.2024.102343","url":null,"abstract":"","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"88 ","pages":"Article 102343"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872803","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}
Chirag Ketan Gala , Sandeep , Abhay H. Pande , Shyam Sunder Sharma
{"title":"Bispecific domain antibody attenuates airway hyperresponsiveness and pulmonary inflammation in ovalbumin-lipopolysaccharide induced asthma model by inhibiting IL-23 and TNF-α","authors":"Chirag Ketan Gala , Sandeep , Abhay H. Pande , Shyam Sunder Sharma","doi":"10.1016/j.pupt.2025.102347","DOIUrl":"10.1016/j.pupt.2025.102347","url":null,"abstract":"<div><div>Asthma, a chronic multi-factorial pulmonary inflammatory condition with a high morbidity rate, is characterized by airway hyperresponsiveness and persistent pulmonary inflammation. There is a need to develop more effective treatment(s) for the management of asthma. In this study, we have investigated the therapeutic potential of BiSpekDAb (an engineered bispecific antibody comprising an anti-IL-23 domain antibody and an anti-TNF-α domain antibody fused together via flexible linkers to a half-life extension partner) in asthma. Asthma was established by sensitization and challenge of female Wistar rats with the combination of ovalbumin and lipopolysaccharide and the efficacy of BiSpekDAb was investigated by its subcutaneous administration for 11 days on each alternative day (6 doses) during the challenge phase. Significant deterioration of pulmonary functions, enhanced airway hyperresponsiveness, increase in the number of immune cells such as lymphocytes, eosinophils, neutrophils in blood circulation as well as in lungs, enhanced production of inflammatory cytokines (IL-23, TNF-α, IL-1β, IL-6, IL-22), allergic IgE antibodies, oxidative stress markers, and histopathological changes (thickening of epithelial lining, infiltration of immune cells, mast cell degranulation, and overproduction of mucus) were observed in asthma animals, and administration of BiSpekDAb attenuated airway hyperresponsiveness (AHR), pulmonary inflammation and other pathological changes. BiSpekDAb significantly inhibited IL-23 and TNF-α levels in the lungs of asthmatic rats. Our results suggest that targeting IL-23 and TNF-α simultaneously opens a new therapeutic window for biologics development aimed at mitigating pulmonary inflammation such as asthma.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"88 ","pages":"Article 102347"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510243","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}
Qin Wan , Dongdong Li , Shu Shang , Haifeng Wu , Faxiu Chen , Qiugen Li
{"title":"Novel synergistic therapeutic approach in idiopathic pulmonary fibrosis: Combining the antifibrotic nintedanib with the anti-inflammatory baricitinib","authors":"Qin Wan , Dongdong Li , Shu Shang , Haifeng Wu , Faxiu Chen , Qiugen Li","doi":"10.1016/j.pupt.2025.102346","DOIUrl":"10.1016/j.pupt.2025.102346","url":null,"abstract":"<div><h3>Background</h3><div>Baricitinib and nintedanib can target inflammation and fibrosis respectively, which are the two most important processes in idiopathic pulmonary fibrosis (IPF). However, it is still unknown whether targeting these two processes simultaneously can synergistically improve the therapeutic effect of IPF. Therefore, it is necessary to predict the possible translational potential through preclinical studies.</div></div><div><h3>Methods</h3><div>We evaluated both the <em>in vitro</em> and <em>in vivo</em> efficacy of a drug combination, nintedanib with baricitinb, a JAK1/JAK2 inhibitor. We first examined the fibroblast proliferation and myofibroblast differentiation of single agents or combinations by the MTT assay. Then we determined the migration of the fibroblasts by a wound healing assay. Meanwhile, we quantified the protein level of related growth factor or cytokines in the cell supernatant by ELISA. Finally, we investigated the therapeutic potential and mechanism in a bleomycin-induced mouse model.</div></div><div><h3>Results</h3><div>Our results showed that the combination of nintedanib and baricitinib was more effective in suppressing fibroblast proliferation, myofibroblast transformation and fibroblast migration compared to either agent alone. In a bleomycin-induced IPF mouse model, the combination therapy resulted in a higher survival rate, increased body weight, and a lower lung/body weight ratio compared to the individual drugs. Moreover, both drugs improved lung functions in mice, but their combined administration led to superior outcomes. Histopathological analysis also revealed that the combination therapy mitigated pulmonary inflammation and fibrosis to a greater extent than the individual compounds. Mechanistically, baricitinib appears to orchestrate the effects of nintedanib in IPF by modulating the expression of genes such as <em>il-6</em>, <em>tgf-β</em>, <em>col1α1</em> and <em>fibronectin</em>.</div></div><div><h3>Conclusion</h3><div>The synergistic targeting of inflammation by baricitinib and fibrosis by nintedanib preclinically improves IPF outcomes, thus suggesting their potential as a novel combination therapy for this condition.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"89 ","pages":"Article 102346"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516522","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":"Real-life impact of genotype and severity of lung disease on efficacy of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis","authors":"Shahid Sheikh , Melissa Holtzlander , Mariah Eisner , Courtney Gushue , Sabrina Palacios , Kavitha Kotha , Sehyr Imran , Karen S. McCoy","doi":"10.1016/j.pupt.2025.102345","DOIUrl":"10.1016/j.pupt.2025.102345","url":null,"abstract":"<div><h3>Background</h3><div>Elexacaftor-tezacaftor-ivacaftor (ETI) therapy has shown improvement in lung function, BMI and reduction in pulmonary exacerbations but the impact of genotype and severity of lung disease on heterogeneity of ETI efficacy in real life is not known.</div></div><div><h3>Methods</h3><div>This is a prospective observational study. Clinical data at baseline and at one-year of therapy were compared for the total cohort and for two subgroups; genotype [homozygous vs. heterozygous for F508del], and severity of lung disease at ETI initiation (ppFEV<sub>1</sub> <80 % vs. ≥80 %).</div></div><div><h3>Results</h3><div>Among the total cohort of 115 pwCF, median age of 23 (17, 32) years, 66 (58 %) were homozygous, 76 (66 %) had ppFEV<sub>1</sub> <80 %. Significant increases in mean ppFEV<sub>1</sub> and mean BMI and decrease in MRSA and Pa culture positivity on sputum/throat swab were observed at one year of ETI therapy in the total cohort, and in groups based on either genotype or disease severity (p < 0.05 in all). Comparing one-year prior to one-year on ETI therapy, significant improvements were noted in pulmonary exacerbations, hospital admissions, antibiotic courses, number of pwCF receiving daily chest therapy, dornase alfa and hypertonic saline in the total cohort and in all four subgroups (p < 0.05 for all). Though improvements were not dependent on genotype, we noted larger mean differences in ppFEV<sub>1</sub>, BMI, pulmonary exacerbations and antibiotic use in the group with more severe lung disease (ppFEV<sub>1</sub> <80 %) after one year of ETI therapy.</div></div><div><h3>Conclusion</h3><div>ETI therapy improved clinical outcomes in pwCF which were impacted by severity of underlying lung disease.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"88 ","pages":"Article 102345"},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446136","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}