Pub Date : 2025-06-11DOI: 10.1016/j.pupt.2025.102374
Daniel Connelly , Jessica Delahanty , Shyam Patel , Kimberly A. Ackerbauer , Nicholas A. Bosch , Elizabeth S. Klings , Justin K. Lui
Inhaled epoprostenol has remained an attractive and viable option for the delivery of prostacyclin to offset abnormalities in ventilation and perfusion mismatch while minimizing the typical adverse effects associated with systemic administration. There is a need to better understand pharmacologic properties of inhaled epoprostenol and its application to diseases affecting the cardiopulmonary system. The goal of this review is to provide an overview of inhaled epoprostenol and outline its use specifically in the medical management of acute hypoxemic respiratory failure and pulmonary vascular disease. Among patients with acute respiratory distress syndrome who ultimately required invasive ventilation, inhaled epoprostenol has not improved ventilator-free days, intensive care unit length of stay, or mortality. However, it may be beneficial in certain select patient populations. In the management of pulmonary hypertension, inhaled epoprostenol has allowed for continued maintenance of chronic pulmonary arterial hypertension-specific therapy and for possibly improving right ventricular function as an attractive option in the critical care management of pulmonary hypertension.
{"title":"Inhaled epoprostenol for management of acute respiratory failure and pulmonary vascular disease","authors":"Daniel Connelly , Jessica Delahanty , Shyam Patel , Kimberly A. Ackerbauer , Nicholas A. Bosch , Elizabeth S. Klings , Justin K. Lui","doi":"10.1016/j.pupt.2025.102374","DOIUrl":"10.1016/j.pupt.2025.102374","url":null,"abstract":"<div><div>Inhaled epoprostenol has remained an attractive and viable option for the delivery of prostacyclin to offset abnormalities in ventilation and perfusion mismatch while minimizing the typical adverse effects associated with systemic administration. There is a need to better understand pharmacologic properties of inhaled epoprostenol and its application to diseases affecting the cardiopulmonary system. The goal of this review is to provide an overview of inhaled epoprostenol and outline its use specifically in the medical management of acute hypoxemic respiratory failure and pulmonary vascular disease. Among patients with acute respiratory distress syndrome who ultimately required invasive ventilation, inhaled epoprostenol has not improved ventilator-free days, intensive care unit length of stay, or mortality. However, it may be beneficial in certain select patient populations. In the management of pulmonary hypertension, inhaled epoprostenol has allowed for continued maintenance of chronic pulmonary arterial hypertension-specific therapy and for possibly improving right ventricular function as an attractive option in the critical care management of pulmonary hypertension.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102374"},"PeriodicalIF":3.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272530","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}
Pub Date : 2025-06-03DOI: 10.1016/j.pupt.2025.102364
Jennifer Ann Kricker , Virginia Norris , Clive Page , Michael John Parnham
Macrolide antibiotics have been shown to reduce exacerbations of respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. This effect is believed to be due to the immunomodulatory properties of macrolides rather than their antimicrobial activity. However, prolonged use of macrolide antibiotics can result in the development of antimicrobial resistance, which prompted us to develop EP395, a compound with similar pharmacological actions to macrolides, but without antimicrobial activity. We investigated EP395 in several established models of neutrophilic airway inflammation in male BALB/c mice. Oral pretreatment with EP395 for 2 weeks had significant anti-inflammatory effects, reducing cytokines and neutrophil infiltration into bronchoalveolar lavage fluid (BAL) induced by either lipopolysaccharide (LPS), tobacco smoke or respiratory syncytial virus (RSV). EP395 had comparable inhibitory effects to azithromycin in all three models. The PDE4 inhibitor, roflumilast, was also included as a positive control in the LPS model, with comparable effects on neutrophil numbers. In vitro assays on neutrophil function revealed both stimulatory and inhibitory effects of treatment with EP395. These data demonstrate the beneficial pharmacological activity of EP395, a macrolide with negligible antimicrobial activity, in models of acute neutrophilic inflammation and on neutrophil activity and supported its progression into clinical development as a potential treatment for COPD.
{"title":"Effects of EP395, a novel macrolide, on acute neutrophilic airway inflammation","authors":"Jennifer Ann Kricker , Virginia Norris , Clive Page , Michael John Parnham","doi":"10.1016/j.pupt.2025.102364","DOIUrl":"10.1016/j.pupt.2025.102364","url":null,"abstract":"<div><div>Macrolide antibiotics have been shown to reduce exacerbations of respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. This effect is believed to be due to the immunomodulatory properties of macrolides rather than their antimicrobial activity. However, prolonged use of macrolide antibiotics can result in the development of antimicrobial resistance, which prompted us to develop EP395, a compound with similar pharmacological actions to macrolides, but without antimicrobial activity. We investigated EP395 in several established models of neutrophilic airway inflammation in male BALB/c mice. Oral pretreatment with EP395 for 2 weeks had significant anti-inflammatory effects, reducing cytokines and neutrophil infiltration into bronchoalveolar lavage fluid (BAL) induced by either lipopolysaccharide (LPS), tobacco smoke or respiratory syncytial virus (RSV). EP395 had comparable inhibitory effects to azithromycin in all three models. The PDE4 inhibitor, roflumilast, was also included as a positive control in the LPS model, with comparable effects on neutrophil numbers. In vitro assays on neutrophil function revealed both stimulatory and inhibitory effects of treatment with EP395. These data demonstrate the beneficial pharmacological activity of EP395, a macrolide with negligible antimicrobial activity, in models of acute neutrophilic inflammation and on neutrophil activity and supported its progression into clinical development as a potential treatment for COPD.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102364"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221986","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}
Lung cancer remains one of the leading causes of cancer-related deaths, with current chemotherapy limited by poor drug delivery, toxicity, and resistance. To overcome these challenges, we developed a dry powder inhaler (DPI) system incorporating a PLGA-PEG-LHRH (PPL) nanoconjugate (NC) for enhanced delivery. Curcumin (CUR), with known anticancer and P-gp inhibition properties, was co-loaded with bcl2 siRNA (bclsR) to target bcl2 protein and combat resistance mechanisms.
The CUR and bclsR-loaded PLGA NC (172.12 ± 24.23 nm) were prepared using double emulsion solvent evaporation (DESE) method and converted into DPI using a carbohydrate carrier, showing a mass mean aerodynamic diameter of 4.62 μm and fine particle fraction of 65.39 ± 0.19 %, ideal for lung delivery. Animal studies showed that DPI delivered via tracheal administration in lung cancer models exhibited superior anticancer effects compared to free CUR, particularly in terms of pathological improvements and upregulation of cancer markers like P53 and TNF-α.
In vivo biodistribution studies in tumor-bearing mice revealed higher CUR concentrations in plasma (326.85 ± 6.17 μg) and lungs (207.03 ± 4.11 μg), with enhanced systemic exposure as indicated by higher AUC and Cmax values. These findings suggest that CUR-siRNA loaded DPI could provide an effective therapeutic approach for lung cancer.
{"title":"Development of Dry Powder Inhaler formulation for site specific delivery of nanoconjugates loaded with Curcumin and BCL2 siRNA in Lung Cancer","authors":"Madhuchandra Lahan , Trideep Saikia , Rinku Baishya , Alakesh Bharali , Sunayana Baruah , Shatabdi Ghose , Nikhil Biswas , Damiki Laloo , Subhash Medhi , Bhanu P Sahu","doi":"10.1016/j.pupt.2025.102361","DOIUrl":"10.1016/j.pupt.2025.102361","url":null,"abstract":"<div><div>Lung cancer remains one of the leading causes of cancer-related deaths, with current chemotherapy limited by poor drug delivery, toxicity, and resistance. To overcome these challenges, we developed a dry powder inhaler (DPI) system incorporating a PLGA-PEG-LHRH (PPL) nanoconjugate (NC) for enhanced delivery. Curcumin (CUR), with known anticancer and P-gp inhibition properties, was co-loaded with bcl2 siRNA (bclsR) to target bcl2 protein and combat resistance mechanisms.</div><div>The CUR and bclsR-loaded PLGA NC (172.12 ± 24.23 nm) were prepared using double emulsion solvent evaporation (DESE) method and converted into DPI using a carbohydrate carrier, showing a mass mean aerodynamic diameter of 4.62 μm and fine particle fraction of 65.39 ± 0.19 %, ideal for lung delivery. Animal studies showed that DPI delivered via tracheal administration in lung cancer models exhibited superior anticancer effects compared to free CUR, particularly in terms of pathological improvements and upregulation of cancer markers like P53 and TNF-α.</div><div><em>In vivo</em> biodistribution studies in tumor-bearing mice revealed higher CUR concentrations in plasma (326.85 ± 6.17 μg) and lungs (207.03 ± 4.11 μg), with enhanced systemic exposure as indicated by higher AUC and Cmax values. These findings suggest that CUR-siRNA loaded DPI could provide an effective therapeutic approach for lung cancer.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102361"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221985","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}
Pub Date : 2025-06-03DOI: 10.1016/j.pupt.2025.102365
Jens M. Hohlfeld , Philipp Badorrek , Olof Breuer , Kate Hanrott , Jennifer Kricker , Michael J. Parnham , Virginia Norris
EP395, a macrolide with negligible antimicrobial activity but with anti-inflammatory effects in murine lipopolysaccharide (LPS) challenge model, is being developed as a potential treatment to reduce COPD exacerbations. This double-blind, placebo-controlled clinical study evaluated the pharmacodynamics of EP395 in response to inhaled LPS, an established clinical model for assessing anti-inflammatory effects of potential new treatments.
Forty-nine healthy, non-smoking participants were randomised to oral 375 mg EP395 or placebo, daily for 3 weeks. An inhaled LPS challenge (2 μg) was then given, followed 6 h later by bronchoscopy for bronchoalveolar lavage fluid (BALF) collection. Blood samples were collected pre, 6 and 24 h after LPS challenge.
BALF concentrations of IL-6, TNF-α, MIP-1α, MIP-1β and MCP-1 were lower with EP395 than placebo, while IL-33, IL-8, and IL-1β were higher with EP395 than placebo (not statistically significant). Neutrophil counts were unaffected, but neutrophil elastase and myeloperoxidase were higher with EP395 than placebo (not statistically significant). Serum concentrations of surfactant protein-D significantly increased in the EP395 group in response to LPS at both 6 and 24 h compared with pre-LPS (mean pre-LPS 148.8 ng/mL; mean 24 h post-LPS 183.0 ng/mL) but not in the placebo group (mean pre-LPS 142.4 ng/mL; mean 24 h post-LPS 142.4 ng/mL). The log2 transformed fold difference in the EP395 group, before and 24 h after LPS challenge was 0.33 (95 % CI 0.52, 0.14; p = 0.0007).
EP395 treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst reducing inflammatory site pro-inflammatory mediators.
EP395是一种大环内酯类药物，抗菌活性可忽略不计，但在小鼠脂多糖（LPS）挑战模型中具有抗炎作用，目前正被开发为一种减少COPD恶化的潜在治疗方法。这项双盲、安慰剂对照的临床研究评估了EP395对吸入LPS的药效学反应，这是一种评估潜在新疗法抗炎作用的临床模型。49名健康、不吸烟的参与者被随机分组，每天口服375毫克EP395或安慰剂，持续3周。然后给予吸入LPS (2 μg)， 6小时后进行支气管镜检查收集支气管肺泡灌洗液（BALF）。在LPS刺激前、6和24小时采集血样。EP395组IL-6、TNF-α、MIP-1α、MIP-1β、MCP-1的BALF浓度低于安慰剂组，IL-33、IL-8、IL-1β浓度高于安慰剂组（差异无统计学意义）。中性粒细胞计数未受影响，但EP395组中性粒细胞弹性酶和髓过氧化物酶高于安慰剂组（无统计学意义）。与LPS处理前相比，EP395组在LPS处理后6和24小时血清表面活性剂蛋白d浓度均显著升高(LPS处理前平均148.8 ng/mL；lps后平均24小时183.0 ng/mL)，但安慰剂组没有(lps前平均142.4 ng/mL；lps后平均24 h 142.4 ng/mL)。LPS刺激前和24小时后，EP395组的log2转化倍数差异为0.33 (95% CI 0.52, 0.14；p = 0.0007)。EP395处理增加了宿主对吸入LPS的防御反应，包括上皮反应，同时减少了炎症部位的促炎介质。
{"title":"Effect of EP395, a novel anti-inflammatory macrolide, in an inhaled lipopolysaccharide challenge model in healthy volunteers: a randomised controlled trial","authors":"Jens M. Hohlfeld , Philipp Badorrek , Olof Breuer , Kate Hanrott , Jennifer Kricker , Michael J. Parnham , Virginia Norris","doi":"10.1016/j.pupt.2025.102365","DOIUrl":"10.1016/j.pupt.2025.102365","url":null,"abstract":"<div><div>EP395, a macrolide with negligible antimicrobial activity but with anti-inflammatory effects in murine lipopolysaccharide (LPS) challenge model, is being developed as a potential treatment to reduce COPD exacerbations. This double-blind, placebo-controlled clinical study evaluated the pharmacodynamics of EP395 in response to inhaled LPS, an established clinical model for assessing anti-inflammatory effects of potential new treatments.</div><div>Forty-nine healthy, non-smoking participants were randomised to oral 375 mg EP395 or placebo, daily for 3 weeks. An inhaled LPS challenge (2 μg) was then given, followed 6 h later by bronchoscopy for bronchoalveolar lavage fluid (BALF) collection. Blood samples were collected pre, 6 and 24 h after LPS challenge.</div><div>BALF concentrations of IL-6, TNF-α, MIP-1α, MIP-1β and MCP-1 were lower with EP395 than placebo, while IL-33, IL-8, and IL-1β were higher with EP395 than placebo (not statistically significant). Neutrophil counts were unaffected, but neutrophil elastase and myeloperoxidase were higher with EP395 than placebo (not statistically significant). Serum concentrations of surfactant protein-D significantly increased in the EP395 group in response to LPS at both 6 and 24 h compared with pre-LPS (mean pre-LPS 148.8 ng/mL; mean 24 h post-LPS 183.0 ng/mL) but not in the placebo group (mean pre-LPS 142.4 ng/mL; mean 24 h post-LPS 142.4 ng/mL). The log<sub>2</sub> transformed fold difference in the EP395 group, before and 24 h after LPS challenge was 0.33 (95 % CI 0.52, 0.14; p = 0.0007).</div><div>EP395 treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst reducing inflammatory site pro-inflammatory mediators.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102365"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226488","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}
Pub Date : 2025-06-03DOI: 10.1016/j.pupt.2025.102363
Thorarinn Gudjonsson , Jon Petur Joelsson , Ari Jon Arason , Arni Asbjarnarson , Fridrik Runar Gardarsson , Fredrik Lehmann , Peter Teodorovic , Saevar Ingthorsson , Snaevar Sigurdsson , Bryndis Valdimarsdottir , Michael John Parnham , Clive Page , Jennifer Ann Kricker
Epithelial barrier failure, a feature of several inflammatory lung diseases, contributes to exacerbations and disease progression. Acute exacerbations are often treated with macrolides, including azithromycin (AZM). In part, this is due to both primary antimicrobial and additional immunomodulatory actions, complemented by recently reported enhanced integrity of respiratory epithelial barriers. However, long-term “off label” use of macrolides is associated with increased bacterial resistance. We now introduce a new class of compounds, “Barriolides” that are analogues of AZM promoting airway epithelial barrier integrity in vitro, with negligible antibacterial activity. The lead compound is EP395 which does not affect cell viability up to 100 μM in VA10 bronchial epithelial cells. Treatment with EP395 for three weeks enhanced epithelial barrier integrity, measured by increased transepithelial electrical resistance, reduced paracellular flux in air-liquid interface culture and increased expression of tight junction proteins. EP395 also induced epidermal differentiation and formation of lamellar bodies, complemented by a relevant genetic footprint. In mice exposed to sulphur dioxide, pre-treatment with EP395 reduced extravasation of human serum albumin into the bronchoalveolar lavage fluid. These data demonstrate epithelial barrier-protecting effects of EP395, a promising candidate for treatment of chronic respiratory diseases without risk of bacterial resistance.
{"title":"A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial barrier","authors":"Thorarinn Gudjonsson , Jon Petur Joelsson , Ari Jon Arason , Arni Asbjarnarson , Fridrik Runar Gardarsson , Fredrik Lehmann , Peter Teodorovic , Saevar Ingthorsson , Snaevar Sigurdsson , Bryndis Valdimarsdottir , Michael John Parnham , Clive Page , Jennifer Ann Kricker","doi":"10.1016/j.pupt.2025.102363","DOIUrl":"10.1016/j.pupt.2025.102363","url":null,"abstract":"<div><div>Epithelial barrier failure, a feature of several inflammatory lung diseases, contributes to exacerbations and disease progression. Acute exacerbations are often treated with macrolides, including azithromycin (AZM). In part, this is due to both primary antimicrobial and additional immunomodulatory actions, complemented by recently reported enhanced integrity of respiratory epithelial barriers. However, long-term “off label” use of macrolides is associated with increased bacterial resistance. We now introduce a new class of compounds, “Barriolides” that are analogues of AZM promoting airway epithelial barrier integrity <em>in vitro</em>, with negligible antibacterial activity. The lead compound is EP395 which does not affect cell viability up to 100 μM in VA10 bronchial epithelial cells. Treatment with EP395 for three weeks enhanced epithelial barrier integrity, measured by increased transepithelial electrical resistance, reduced paracellular flux in air-liquid interface culture and increased expression of tight junction proteins. EP395 also induced epidermal differentiation and formation of lamellar bodies, complemented by a relevant genetic footprint. In mice exposed to sulphur dioxide, pre-treatment with EP395 reduced extravasation of human serum albumin into the bronchoalveolar lavage fluid. These data demonstrate epithelial barrier-protecting effects of EP395, a promising candidate for treatment of chronic respiratory diseases without risk of bacterial resistance.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102363"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230280","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}
Pub Date : 2025-06-03DOI: 10.1016/j.pupt.2025.102360
Luis J. Nannini
Current GOLD guidelines recommend initial dual therapy with a LABA and LAMA for COPD patients with a high risk of exacerbations (at least two moderate or one severe exacerbation in the previous 12 months), with Inhaled Corticosteroids (ICS) added for specific phenotypes or continued exacerbations. Systemic corticosteroids (SCS) are advised for severe exacerbations, but cumulative SCS exposure is linked to significant adverse outcomes such as endocrine disorders and pneumonia. Studies suggest that after limited exacerbations, COPD patients may exhaust their “SCS credit,” increasing their risk of severe comorbidities. Earlier initiation of triple therapy in high-risk, symptomatic patients shows substantial benefits, including improved quality of life, compared to standard care. Like asthma management, SCS exposure in COPD should be minimised, and precision medicine should guide early triple therapy to preserve SCS use for future exacerbations.
{"title":"Mitigating systemic corticosteroid risks in COPD: A call for earlier triple therapy initiation","authors":"Luis J. Nannini","doi":"10.1016/j.pupt.2025.102360","DOIUrl":"10.1016/j.pupt.2025.102360","url":null,"abstract":"<div><div>Current GOLD guidelines recommend initial dual therapy with a LABA and LAMA for COPD patients with a high risk of exacerbations (at least two moderate or one severe exacerbation in the previous 12 months), with Inhaled Corticosteroids (ICS) added for specific phenotypes or continued exacerbations. Systemic corticosteroids (SCS) are advised for severe exacerbations, but cumulative SCS exposure is linked to significant adverse outcomes such as endocrine disorders and pneumonia. Studies suggest that after limited exacerbations, COPD patients may exhaust their “SCS credit,” increasing their risk of severe comorbidities. Earlier initiation of triple therapy in high-risk, symptomatic patients shows substantial benefits, including improved quality of life, compared to standard care. Like asthma management, SCS exposure in COPD should be minimised, and precision medicine should guide early triple therapy to preserve SCS use for future exacerbations.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102360"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230281","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}
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.
{"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}
Pub Date : 2025-04-05DOI: 10.1016/j.pupt.2025.102358
Michela Salvadori , Dave Singh , Kusum Mathews , Luca Girardello , Mauro Cortellini , Aida Emirova , Ilaria Pacchetti , Martina Foti , Veronica Puviani , Gianluigi Poli , François Rony
Introduction
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.
Methods
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 (FEV1) at 15 min post-dose.
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 (PPR2 and PPR4).
Results
For the bronchoconstriction study (N = 25), the 95 % CI of the adjusted mean FEV1 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.
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 PPR2 (1.36 [–2.28, 4.99]%; p = 0.442) and PPR4 (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.
Conclusions
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.
{"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}
Pub Date : 2025-04-01DOI: 10.1016/j.pupt.2025.102359
Katharine B. Strickland , Jaclyn M. Hawn , Shawn Leverett , Carolyn Magee Bell
Background
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.
Objective
The primary objective of this study was to assess the safety and effectiveness of concurrent versus sequential intrapleural tPA and DNase in pleural infections.
Methods
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.
Results
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).
Conclusion and Relevance
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.
背景：胸膜组织纤溶酶原激活剂（tPA）和核糖核酸酶（DNase）按顺序给药，间隔1至2小时，是胸膜感染治疗的主要方法。最近的文献支持类似的疗效和安全性的同时治疗（立即给药后，另一个）。常规应用并行治疗的证据不足。目的：本研究的主要目的是评估并发与顺序胸膜内tPA和DNase治疗胸膜感染的安全性和有效性。方法：这是一项单中心、回顾性研究，纳入了2014年7月1日至2023年1月1日期间同时或顺序接受胸膜内tPA或DNase治疗的≥18岁住院患者。主要结局是治疗失败，综合30天死亡率和需要视频胸腔镜手术（VATS）。次要结局包括累积胸腔积液引流、出血不良事件和需要增加镇痛剂量的疼痛。结果：共纳入184例患者：同期组158例，序贯组26例。两组治疗失败率相似（18.4% vs 19.2%, P < 0.99）。同期治疗组与顺序治疗组相比，胸水引流增加（1453 mL vs 836 mL, P = 0.05），出血（23.4% vs 19.2%, P = 0.64）或镇痛剂量增加（41.1% vs 23.1%, P = 0.09）组间无差异。结论：与序次给药相比，同时使用胸膜内纤溶药物具有相似的有效性和安全性，然而，有必要进一步研究药物的相容性和稳定性，以优化未来胸膜感染的治疗。
{"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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号