Pulmonary pharmacology & therapeutics最新文献

{"title":"May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide?","authors":"Ralph Brattsand ,&nbsp;Olof Selroos","doi":"10.1016/j.pupt.2022.102167","DOIUrl":"10.1016/j.pupt.2022.102167","url":null,"abstract":"<div><p>The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile.</p><p>In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon.</p><p>Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as “maintenance plus reliever therapy” (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles.</p><p>We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as “anti-inflammatory reliever”.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102167"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S109455392200058X/pdfft?md5=f7938a46167cf44d9cae838602820799&pid=1-s2.0-S109455392200058X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10360053","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":"Statins’ still controversial role in pulmonary fibrosis: What does the evidence show?","authors":"Dimitrios Andreikos ,&nbsp;Theodoros Karampitsakos ,&nbsp;Argyrios Tzouvelekis ,&nbsp;Grigoris Stratakos","doi":"10.1016/j.pupt.2022.102168","DOIUrl":"10.1016/j.pupt.2022.102168","url":null,"abstract":"<div><p>Pulmonary fibrosis<span> (PF) represents the end stage of a broad range of interstitial lung diseases<span> (ILDs). Statins are among the compounds which have been implicated in drug-induced ILD development. However, recent studies (both in vitro and in vivo) have provided evidence that statins may exert anti-inflammatory and anti-fibrotic effects potentially offering benefits to patients with PF.</span></span></p><p><span><span>Several protective molecular mechanisms including the suppression of mevalonic acid<span> pathway, the inhibition of NADPH oxidase activation in macrophages and the inhibition of several profibrotic mediators have been proposed to explain the observed in vivo decrease of the </span></span>oxidative stress in the lung and the preservation of lung function </span>in patients.</p><p>Earlier clinical studies relating statins with drug-induced ILD development are contradicted by increasing new data showing the beneficial effects of statins in clinical outcomes in ILD patients who receive statins for concomitant cardiovascular indications.</p><p>Future research may further elucidate the wide spectrum of pathways of IPF pathogenesis, and genetic heterogeneity<span>, identifying clinically applicable biomarkers and specific endotypes thus recognizing in which patients statins could confer benefit and in which they might cause detrimental effects.</span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102168"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10360316","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":"Pyrroloquinoline quinone (PQQ) improves pulmonary hypertension by regulating mitochondrial and metabolic functions","authors":"Mohammad Shafiq ,&nbsp;Zahid Rasool Lone ,&nbsp;Pragya Bharati ,&nbsp;Satyapriya Mahapatra ,&nbsp;Prashant Rai ,&nbsp;Nilesh Khandelwal ,&nbsp;Anil Nilkanth Gaikwad ,&nbsp;Kumaravelu Jagavelu ,&nbsp;Kashif Hanif","doi":"10.1016/j.pupt.2022.102156","DOIUrl":"10.1016/j.pupt.2022.102156","url":null,"abstract":"<div><p><span><span>Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and </span>endothelial cells<span> (PAECs), inflammation, as well as mitochondrial and metabolic dysregulation, contributes to the development of pulmonary hypertension (PH). </span></span>Pyrroloquinoline quinone<span> (PQQ), a potent natural antioxidant<span><span> with anti-diabetic, neuroprotective<span><span>, and cardioprotective properties, is known to promote mitochondrial biogenesis. However, its effect on </span>cellular proliferation, </span></span>apoptosis<span> resistance, mitochondrial and metabolic alterations associated with PH remains unexplored. The current study was designed to investigate the effect of PQQ in the treatment<span><span> of PH. Human pulmonary artery smooth muscle cells (HPASMCs), endothelial cells (PAECs), and primary cultured cardiomyocytes were subjected to </span>hypoxia<span><span><span> to induce PH-like phenotype. Furthermore, Sprague Dawley (SD) rats injected with monocrotaline (MCT) (60 mg/kg, SC, once) progressively developed pulmonary hypertension. PQQ treatment (2 mg/kg, PO, for 35 days) attenuated cellular proliferation and promoted apoptosis via a mitochondrial-dependent pathway. Furthermore, PQQ treatment in HPASMCs prevented mitochondrial and metabolic dysfunctions, improved mitochondrial bioenergetics while preserving respiratory complexes, and reduced insulin resistance. In addition, PQQ treatment (preventive and curative) significantly attenuated the increase in </span>right ventricle pressure and hypertrophy as well as reduced </span>endothelial dysfunction<span> and pulmonary artery remodeling in MCT-treated rats. PQQ also prevented cardiac fibrosis and improved cardiac functions as well as reduced inflammation in MCT-treated rats. Altogether, the above findings demonstrate that PQQ can attenuate mitochondrial as well as metabolic abnormalities in PASMCs and also prevent the development of PH in MCT treated rats; hence PQQ may act as a potential therapeutic agent for the treatment of PH.</span></span></span></span></span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"76 ","pages":"Article 102156"},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40645688","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-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients","authors":"Dorine Fournier ,&nbsp;Stéphane Jouneau ,&nbsp;Guillaume Bouzillé ,&nbsp;Elisabeth Polard ,&nbsp;Marie-Noëlle Osmont ,&nbsp;Lucie-Marie Scailteux","doi":"10.1016/j.pupt.2022.102149","DOIUrl":"10.1016/j.pupt.2022.102149","url":null,"abstract":"<div><h3>Introduction</h3><p><span><span><span>While pirfenidone and </span>nintedanib have greatly influenced the </span>treatment of </span>idiopathic pulmonary fibrosis<span> (IPF), both drugs<span> have significant early adverse drug reactions<span> (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals.</span></span></span></p></div><div><h3>Methods</h3><p>We analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January 2011 and January 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems.</p></div><div><h3>Results</h3><p>The 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients.</p></div><div><h3>Discussion</h3><p>Most ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"76 ","pages":"Article 102149"},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40595069","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":"Dexmedetomidine reduces IL-4 and IgE expression through downregulation of theTLR4/NF-κB signaling pathway to alleviate airway hyperresponsiveness in OVA mice","authors":"Juan Zhi ,&nbsp;Qirui Duan ,&nbsp;Qian yu Wang ,&nbsp;Xiyu Du ,&nbsp;Dong Yang","doi":"10.1016/j.pupt.2022.102147","DOIUrl":"10.1016/j.pupt.2022.102147","url":null,"abstract":"<div><h3>Background</h3><p><span><span><span><span>Airway hyperresponsiveness (AHR) is a clinical manifestation of airflow limitation due to abnormal tracheal and bronchial sensitivity and is the main basis for the diagnosis of asthma. Patients with AHR are at high risk of perioperative tracheal and </span>bronchospasm, which can lead to </span>hypoxaemia and </span>haemodynamic instability and, in severe cases, to a life-threatening ‘silent lung’. It is therefore important to reduce the incidence or intensity of AHR episodes in the </span>perioperative period. The inflammatory response is key to the development and progression of AHR.</p></div><div><h3>Hypothesis/purpose</h3><p><span>Based on the modulatory role of dexmedetomidine<span> (DEX) in the inflammatory response, we hypothesised that dexmedetomidine (DEX) attenuates inflammatory properties by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor (NF-κB) signalling pathway and can reduce the respiratory parameters of </span></span>mechanical ventilation in ovalbumin-induced allergic airway hyperresponsiveness.</p></div><div><h3>Study design</h3><p>BABL/C mice were divided into control and OVA groups (ovalbumin-induced allergy. Ten mice in all OVA models were randomly selected for in vivo invasive lung function monitoring to analyse airway resistance<span><span> parameters and demonstrate successful model establishment. The remaining OVA mice were treated with dexmedetomidine 25 μg/kg for 5 days (OVA + DEX group) or dexmedetomidine 25 μg/kg + yohimbine 1 mg/kg for 5 days (OVA + DEX + yohimbine). After </span>treatment<span>, bronchoalveolar lavage fluid<span> (BAL) and peripheral blood (ELISA) and lung tissue (H&amp;E and PAS) were collected for analysis of inflammatory factors, and lung tissue was verified by PCR for genes and proteins that do correlate with inflammatory mediators.</span></span></span></p></div><div><h3>Results</h3><p>All airway resistance parameters were increased in OVA mice by invasive lung function monitoring. Proximal airway resistance (parameter Rn) and total respiratory resistance (parameter Rrs) were attenuated after dexmedetomidine intervention treatment. Dexmedetomidine reduced total inflammatory cell<span> count and inflammatory infiltration of lung tissue in BALF and down-regulated IL-4 and IgE levels in BALF and peripheral blood, as shown by Giemsa, H&amp;E, PAS staining and ELISA; this mechanism of action was found to be related to the TLR4/NFκB pathway, but not to TLR4/NFκB, as measured by PCR.</span></p></div><div><h3>Conclusion</h3><p>Dexmedetomidine reduces hyperresponsiveness and airway inflammatory responses. This mechanism of action may be related to the TLR4/NFκB signalling pathway. Overall conclusions are presented in.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"75 ","pages":"Article 102147"},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40527847","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":"Strongyloides venezuelensis-derived venestatin ameliorates asthma pathogenesis by suppressing receptor for advanced glycation end-products-mediated signaling","authors":"Daigo Tsubokawa ,&nbsp;Masashi Satoh","doi":"10.1016/j.pupt.2022.102148","DOIUrl":"10.1016/j.pupt.2022.102148","url":null,"abstract":"<div><h3>Introduction</h3><p>EF-hand Ca²⁺<span>-binding proteins such as S100 protein family members are recognized by the receptor for advanced glycation end-products (RAGE) and are involved in the pathogenesis of asthma/allergic airway inflammation (AAI). Venestatin, an EF-hand Ca</span>²⁺<span>-binding protein, which is secreted by the parasitic helminth </span><span><em>Strongyloides</em><em> venezuelensis</em></span><span><span>, binds with RAGE and suppresses RAGE-mediated inflammatory responses after parasite invasion. In this study, we evaluated the effect of venestatin on pathogenesis in a </span>house dust mite (HDM) murine model of asthma/AAI.</span></p></div><div><h3>Methods</h3><p><span>Mice were intranasally treated with HDM, HDM with recombinant venestatin, or HDM with synthetic peptides, which were designed based on the EF-hand Ca</span>²⁺-binding domain of venestatin. Pro-inflammatory responses in the lungs of mice were assessed.</p></div><div><h3>Results</h3><p><span>HDM treatment induced inflammatory </span>cell infiltration, phosphorylation of the mitogen-activated protein kinase and inhibitor κB, and production of the cytokines tumor necrosis factor-α and interleukin-5 in the lungs. Co-administration of recombinant venestatin with HDM suppressed these pro-inflammatory responses. Treatment with synthetic peptides reduced inflammatory cell infiltration in a RAGE-dependent manner.</p></div><div><h3>Conclusion</h3><p>The EF-hand domain of venestatin may have potential therapeutic benefits in asthma.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"75 ","pages":"Article 102148"},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10401079","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":"Reduction in asthma exacerbation rate after mepolizumab treatment initiation in patients with severe asthma: A real-world database study in Japan","authors":"Hiroyuki Nagase ,&nbsp;Jun Tamaoki ,&nbsp;Takeo Suzuki ,&nbsp;Yasuko Nezu ,&nbsp;Shoko Akiyama ,&nbsp;Ashley L. Cole ,&nbsp;Shibing Yang ,&nbsp;George Mu ,&nbsp;Masayuki Katsumata ,&nbsp;Masaki Komatsubara ,&nbsp;Rafael Alfonso-Cristancho","doi":"10.1016/j.pupt.2022.102130","DOIUrl":"10.1016/j.pupt.2022.102130","url":null,"abstract":"<div><h3>Objective</h3><p>To investigate the changes in asthma exacerbation, as well as in oral corticosteroid (OCS) use, exacerbation-related healthcare resource utilization (HRU), and healthcare costs before and after mepolizumab treatment initiation in patients with severe asthma who started treatment with mepolizumab in a real-world clinical setting in Japan.</p></div><div><h3>Methods</h3><p>A retrospective, observational, self-controlled study was conducted in Japan using a hospital-based administrative claims database. Patients who were diagnosed with asthma and who were new users of mepolizumab were included in the study. The primary outcome was the incidence rate of any asthma exacerbation/patient-year during the 12-month period before (baseline period) and after (follow-up period) the first mepolizumab prescription. Secondary outcome measures included the proportion of patients with ≥1 any asthma exacerbation, patients with exacerbation requiring hospitalization, the incidence rate of exacerbations requiring hospitalization/patient-year, the median daily OCS dose (OCS sparing effect), exacerbation-related HRU (hospitalization length, the proportion of patients with emergency visits, and the number of emergency/outpatient visits), and associated costs.</p></div><div><h3>Results</h3><p>Of the 377 patients included, 56.2% were ≥65 years of age. Following the first mepolizumab prescription, incidence rates for any asthma exacerbation were reduced by 40.6% (4.00/patient-year to 2.38/patient-year; the incidence rate ratio [95% confidence interval]: 0.60 [0.53–0.67]; p &lt; 0.0001) from the baseline to follow-up periods. The incidence rate of exacerbations requiring hospitalization was reduced by 55.8% (0.37/patient-year to 0.16/patient-year) from the baseline to follow-up periods. The proportion of patients experiencing any exacerbation decreased from 84.4% to 57.8% and those requiring hospitalization decreased from 23.9% to 10.3% both from the baseline to follow-up periods. The median daily OCS dose decreased by 44.6% (median [interquartile range]: 6.7 [4.7–9.9] mg/day to 3.3 [0.9–5.6] mg/day) from the last baseline quarter to the 4th quarter of the follow-up period. All exacerbation-related HRUs decreased from the baseline to follow-up periods. Inpatient cost reduced by &gt;50% (123,279 Japanese Yen [JPY]/patient-year vs. 57,283 JPY/patient-year), reducing the total cost by 80,716 JPY from the baseline to follow-up periods.</p></div><div><h3>Conclusion</h3><p>Mepolizumab was effective in treating patients with severe asthma by reducing the incidence rates of exacerbations and exacerbation requiring hospitalization, OCS dose, exacerbation-related HRU, and cost in routine clinical practice in Japan.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"75 ","pages":"Article 102130"},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553922000219/pdfft?md5=e5e87bc6d150ec24a23ff366b7852f63&pid=1-s2.0-S1094553922000219-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43550457","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":"Time-resolved proteome and transcriptome of paraquat-induced pulmonary fibrosis","authors":"Lu Fan ,&nbsp;Yuan Li ,&nbsp;Xiaomin Zhang ,&nbsp;Yuxuan Wu ,&nbsp;Yang Song ,&nbsp;Feng Zhang ,&nbsp;Jinsong Zhang ,&nbsp;Hao Sun","doi":"10.1016/j.pupt.2022.102145","DOIUrl":"10.1016/j.pupt.2022.102145","url":null,"abstract":"<div><h3>Backgrounds</h3><p>Pulmonary fibrosis (PF) is a pathological state presenting at the progressive stage of heterogeneous interstitial lung disease (ILD). The current understanding of the molecular mechanisms involved is incomplete. This clinical toxicology study focused on the pulmonary fibrosis induced by paraquat (PQ), a widely-used herbicide. Using proteo-transcriptome analysis, we identified differentially expressed proteins (DEPs) derived from the initial development of fibrosis to the dissolved stage and provided further functional analysis.</p></div><div><h3>Methods</h3><p>We established a mouse model of progressive lung fibrosis via intratracheal instillation of paraquat. To acquire a comprehensive and unbiased understanding of the onset of pulmonary fibrosis, we performed time-series proteomics profiling (iTRAQ) and RNA sequencing (RNA-Seq) on lung samples from paraquat-treated mice and saline control. The biological functions and pathways involved were evaluated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis. Correlation tests were conducted on comparable groups 7 days and 28 days post-exposure. Differentially expressed proteins and genes following the same trend on the protein and mRNA levels were selected for validation. The functions of the selected molecules were identified <em>in vitro</em>. The protein level was overexpressed by transfecting gene-containing plasmid or suppressed by transfecting specific siRNA in A549 cells. The levels of endothlial-mesenchymal transition (EMT) markers, including E-cadherin, vimentin, FN1, and α-SMA, were determined via western blot to evaluate the fibrotic process.</p></div><div><h3>Results</h3><p>We quantified 1358 DEPs on day 7 and 426 DEPs on day 28 post exposure (Fold change &gt;1.2; Q value &lt; 0.05). The top 5 pathways – drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, complement and coagulation cascades, chemical carcinogenesis, protein digestion and absorption — were involved on both day 7 and day 28. Several pathways, including tight junction, focal adhesion, platelet activation, and ECM-receptor interaction, were more enriched on day 28 than on day 7. Integrative analysis of the proteome and transcriptome revealed a moderate correlation of quantitative protein abundance ratios with RNA abundance ratios (Spearman R = 0.3950 and 0.2477 on days 7 and 28, respectively), indicating that post-transcriptional regulation plays an important role in lung injury and repair. Western blot identified that the protein expressions of FN1, S100A4, and RBM3 were significantly upregulated while that of CYP1A1, FMO3, and PGDH were significantly downregulated on day 7. All proteins generally recovered to baseline on day 28. qPCR showed the mRNA levels of <em>Fn1, S100a4, Rbm3, Cyp1a1, Fmo3,</em> and <em>Hpgd</em> changed following the same trend as the levels of their respective proteins. Further, <em>in vitro</em> experim","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"75 ","pages":"Article 102145"},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40493647","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":"Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation","authors":"Hubert Chen ,&nbsp;Rebecca Kunder ,&nbsp;Yixuan Zou ,&nbsp;Tracy Staton ,&nbsp;Rui Zhu ,&nbsp;Joshua Galanter ,&nbsp;Hallam Gugelmann ,&nbsp;Ryan Owen ,&nbsp;Michele A. Grimbaldeston ,&nbsp;Joanna K. Chang ,&nbsp;Matthew R. Durk ,&nbsp;Avi Eliahu ,&nbsp;Mark S. Wilson ,&nbsp;David F. Choy ,&nbsp;Maria Wilson ,&nbsp;Melissa Black ,&nbsp;Marjan Doppen ,&nbsp;Stacey Kung ,&nbsp;Karen Oldfield ,&nbsp;Jenny Sparks ,&nbsp;Irene Braithwaite","doi":"10.1016/j.pupt.2022.102133","DOIUrl":"10.1016/j.pupt.2022.102133","url":null,"abstract":"<div><h3>Background</h3><p><span>Janus Kinases<span> (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) </span></span>in patients with mild asthma, but required an excessive number of inhalations.</p></div><div><h3>Aim</h3><p>To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation.</p></div><div><h3>Methods</h3><p><span>This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18–65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV</span>₁<span><span><span>)&gt; 70% predicted, FeNO &gt;40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, </span>pharmacokinetics<span>, and pharmacodynamic biomarkers, including blood </span></span>eosinophils, serum CCL17, and serum CCL18, were also assessed.</span></p></div><div><h3>Results</h3><p><span>Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41–222) ppb. GDC-4379 treatment<span> led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: −6 (−43, 32) at 10 mg QD, −26 (−53, 2) at 30 mg QD, −55 (−78, −32) at 40 mg BID and −52 (−72, −32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma </span></span>drug<span> concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain<span>. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful.</span></span></p></div><div><h3>Conclusions</h3><p>In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.</p><p>Australian New Zealand Clinical Trials Registry: ACTRN12619000227190.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"75 ","pages":"Article 102133"},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10413646","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":"Pharmacokinetic profile of beclometasone dipropionate/formoterol fumarate administered through a novel dry-powder inhaler in Chinese healthy volunteers","authors":"Zhu Luo ,&nbsp;Germano Lucci ,&nbsp;Luigi Santoro ,&nbsp;Eva Topole ,&nbsp;Fabrizia Mariotti","doi":"10.1016/j.pupt.2022.102129","DOIUrl":"10.1016/j.pupt.2022.102129","url":null,"abstract":"<div><h3>Introduction</h3><p>An extrafine formulation of the inhaled corticosteroid beclometasone dipropionate (BDP) plus the long-acting β₂-agonist formoterol fumarate (FF) has been available for years via a pressurised metered-dose inhaler for the management of asthma and chronic obstructive pulmonary disease. More recently, the same extrafine BDP/FF formulation has become available in a multidose dry-powder inhaler (DPI) called the NEXThaler. The pharmacokinetics (PK) of BDP/FF via this DPI have previously been evaluated in a Caucasian population. The current study aimed to evaluate the PK profile of BDP/FF via DPI in healthy Chinese volunteers. The results were then compared to previous Caucasian data.</p></div><div><h3>Methods</h3><p>This open-label parallel group study randomised subjects to single-dose BDP/FF 200/12, 400/24, or 800/48 μg via DPI. Blood samples were taken up to 24 h post-dose for PK evaluation of BDP, beclometasone 17-monopropionate (B17MP, active metabolite of BDP) and formoterol. The primary objective of the study was to evaluate the PK of BDP/FF (BDP, B17MP and formoterol). The study is registered on the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900021899).</p></div><div><h3>Results</h3><p>Of 36 subjects randomised, all completed the study. Following inhalation of all three doses, plasma concentration of formoterol and BDP increased rapidly, with peak mean values at the first post-dose timepoint (5 min), then rapidly decreasing; B17MP reached peak concentration slightly later. Plasma exposure to formoterol, BDP and B17MP increased broadly in a dose-proportional manner to BDP/FF dose, with t_max values similar across the dose range. All BDP/FF doses were generally well tolerated.</p></div><div><h3>Conclusions</h3><p>Therapeutic and supra-therapeutic doses of BDP/FF administered via DPI resulted in approximately dose-proportional plasma exposure in healthy Chinese subjects, with PK profiles that were comparable to previous data from Caucasian subjects.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"73 ","pages":"Article 102129"},"PeriodicalIF":3.2,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553922000207/pdfft?md5=fee1920c173b40823cfecc203b5cd23b&pid=1-s2.0-S1094553922000207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43288210","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}