Pulmonary pharmacology & therapeutics最新文献

{"title":"Treatment of respiratory viral infections through inhalation therapeutics: Challenges and opportunities","authors":"Nidhi Nainwal","doi":"10.1016/j.pupt.2022.102170","DOIUrl":"10.1016/j.pupt.2022.102170","url":null,"abstract":"<div><p>Respiratory viral infections are the leading cause of death worldwide. The current pandemic of coronavirus infection (COVID-19) challenged human beings for the treatment and prevention of this respiratory viral infection since its outbreak in 2019. Despite advancements in the medical field, scientists were helpless to give timely treatment and protection against this viral infection. Several drugs, whether antiviral or not, were given to the patients to reduce mortality and morbidity rate. Vaccines from various pharmaceutical manufacturers are now available to give immunization against covid-19. Still, coronavirus is continuously affecting people in the form of variants after mutation. Each new variant increases the infection risk and forces scientists to develop some innovative and effective treatments for this infection. The virus uses the host's cell machinery to grow and multiply in numbers. Therefore, scientists are facing challenges to develop antivirals that stop the virus without damaging the host cells too. The production of suitable antivirals or vaccines for the new virus would take several months, allowing the strain to cause severe damage to life. Inhalable formulation facilitates the delivery of medicinal products directly to the respiratory system without causing unwanted side effects associated with systemic absorption. Scientists are focusing on developing an inhaled version of the existing antivirals for the treatment of respiratory infections. This review focused on the inhalable formulations of antiviral agents in various respiratory viral infections including the ongoing covid-19 pandemic and important findings of the clinical studies. We also reviewed repurposed drugs that have been given through inhalation in covid-19 infection.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102170"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10388907","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":"Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics","authors":"Beth E. Davis,&nbsp;Donald W. Cockcroft","doi":"10.1016/j.pupt.2022.102174","DOIUrl":"10.1016/j.pupt.2022.102174","url":null,"abstract":"<div><h3>Introduction</h3><p>Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta₂<span><span><span><span>-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist </span>ipratropium bromide have reported no tolerance after regular use against inhaled </span>methacholine<span>. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on </span></span>methacholine induced bronchoconstriction in a population of mild asthmatics.</span></p></div><div><h3>Methods</h3><p>We performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge.</p></div><div><h3>Results</h3><p><span>The average doubling dose increase in methacholine PD</span>₂₀ following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD₂₀ was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p &lt; 0.001).</p></div><div><h3>Conclusion</h3><p><span>LAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta</span>₂<span>-agonist bronchodilators.</span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102174"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10710762","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":"Scoping review: The state of research on cryptogenic organizing pneumonia therapeutics","authors":"Christopher Lau ,&nbsp;Brannen Liang ,&nbsp;Ourfa Hovsepyan ,&nbsp;Tom Shreves ,&nbsp;Kenneth Wei","doi":"10.1016/j.pupt.2022.102175","DOIUrl":"10.1016/j.pupt.2022.102175","url":null,"abstract":"<div><p>Cryptogenic organizing pneumonia<span><span><span> is a diffuse interstitial lung disease<span> that starts in the alveolar wall and subsequently expands to the alveolar ducts and respiratory bronchioles. </span></span>Randomized controlled trials<span> are lacking to guide the treatment of cryptogenic </span></span>organizing pneumonia<span>, so treatment decisions and practice guidelines are often based upon observations from case series or expert clinical opinions. The backbone<span> of treatment involves immunosuppression<span> via corticosteroids. In refractory cases, cytotoxic therapy is considered. The evidence that supports the use of these regimens are limited. The goal of this scoping review is to conduct a systematic search of the literature to determine what regimens have been utilized to treat steroid refractory organizing pneumonia and to characterize the evidence supporting their use.</span></span></span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102175"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10352810","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":"Comparative clinical pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate","authors":"Peter T. Daley-Yates ,&nbsp;Amanda Deans ,&nbsp;Rashmi Mehta ,&nbsp;Ana R. Sousa","doi":"10.1016/j.pupt.2022.102171","DOIUrl":"10.1016/j.pupt.2022.102171","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Aims&lt;/h3&gt;&lt;p&gt;&lt;span&gt;&lt;span&gt;To investigate the pharmacokinetics and effects on the hypothalamic-pituitary-adrenal (HPA) axis of &lt;/span&gt;mometasone furoate (MF), &lt;/span&gt;fluticasone propionate&lt;span&gt; (FP) and fluticasone furoate (FF).&lt;/span&gt;&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;&lt;em&gt;&lt;strong&gt;Study 1&lt;/strong&gt;&lt;/em&gt;: Fourteen healthy participants received inhaled and intravenous MF (inhaled dose via Twisthaler) and FP (inhaled dose via Diskus), both given at 400 μg, using a randomised, single-dose, four-way crossover design. &lt;em&gt;&lt;strong&gt;Study 2:&lt;/strong&gt;&lt;/em&gt;&lt;span&gt; Twenty-seven participants with mild to moderate asthma, who discontinued their corticosteroid medication for 5 days to obtain a baseline 24 h serum cortisol, received inhaled MF Twisthaler and FP Diskus, both given at 400 μg twice daily (BID), using a randomised, 14-day repeat dose, two-way crossover design. &lt;/span&gt;&lt;strong&gt;&lt;em&gt;Study 3:&lt;/em&gt;&lt;/strong&gt;&lt;span&gt; Forty-four healthy participants were randomised to a double-blind, placebo-controlled, five-period crossover study where the following treatments were administered via the inhaled route for 7 days: FP Diskus (250, 500, 1000 μg BID), FF Diskus (100, 200, 400, 800, 1600 μg once daily [QD]) or placebo Diskus. In each study, 24-h serial blood samples were collected and assayed to assess concentrations of MF, 6β-hydroxy mometasone, mometasone, FP, FF and cortisol. Pharmacokinetic and serum cortisol parameters were estimated as geometric means and 95% confidence intervals (CI).&lt;/span&gt;&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;&lt;em&gt;&lt;strong&gt;Study 1&lt;/strong&gt;&lt;/em&gt;&lt;span&gt;&lt;span&gt;: For intravenous MF and FP, respectively: absolute bioavailability was 11.4% (95% CI: 7.5, 17.6) and 7.8% (6.3, 9.6); plasma clearance&lt;span&gt; was 47 L/h (41, 52) and 60 L/h (52, 69); half-life was 7.4 h (6.9, 8.0) and 7.2 h (6.5, 8.0); and volume of distribution was 499 L (439, 567) and 623 L (557, 698). Inhalation of single dose MF or FP did not significantly affect serum cortisol (&lt;10% reduction from baseline), whereas &lt;/span&gt;&lt;/span&gt;intravenous administration of MF or FP each changed serum cortisol by approximately −50% from baseline. &lt;/span&gt;&lt;strong&gt;&lt;em&gt;Study 2&lt;/em&gt;&lt;/strong&gt;: For MF and FP, respectively: area under the curve up to the last measurable concentration on Day 1 was 421 pg h/mL (270, 659) and 248 pg h/mL (154, 400), and on Day 14 was 1092 pg h/mL (939, 1269) and 591 pg h/mL (501, 696); absolute bioavailability was 12.8% (11.2, 14.2) and 8.9% (7.7, 10.2). On Day 14, 24-h serum cortisol change from baseline was −35% (−44%, −26%) and −18% (−28%, −5%) for MF and FP, respectively; the reduction was significantly greater for MF than FP (ratio for geometric adjusted mean serum cortisol concentration: 1.28 [1.04, 1.56]). Low plasma concentrations of 6β-hydroxy mometasone were detected after intravenous dosing (&lt;strong&gt;Study 1&lt;/strong&gt;) and after multiple inhaled dosing (&lt;strong&gt;Study 2&lt;/strong&gt;); mometasone was not detected in any samples. &lt;strong&gt;&lt;em&gt;Study 3&lt;/em&gt;&lt;/strong&gt;: Inhaled F","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102171"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10359116","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":"A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells.","authors":"Shu-Ian Ma, Kuan Yang, Zhihong Li, L. Li, Yue Feng, Xiaowei Wang, Jiahui Wang, Zhengdan Zhu, Zhiyong Wang, Juan Wang, Yizhun Zhu, Li Liu","doi":"10.2139/ssrn.4157323","DOIUrl":"https://doi.org/10.2139/ssrn.4157323","url":null,"abstract":"Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography-tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 μg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-β-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"78 1","pages":"102185"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42349688","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":"Assessment of extrafine beclomethasone/formoterol for the treatment of chronic obstructive pulmonary disease: A non-interventional study in a Bulgarian population","authors":"Vladimir A. Hodzhev ,&nbsp;Andrey N. Kenderov ,&nbsp;Yavor Y. Ivanov ,&nbsp;Diana P. Gospodinova-Vulkova ,&nbsp;Krasimir Kalinov","doi":"10.1016/j.pupt.2022.102169","DOIUrl":"10.1016/j.pupt.2022.102169","url":null,"abstract":"<div><h3>Background</h3><p>The beneficial effects of application of a fixed dose beclomethasone dipropionate (BDP) and formoterol fumarate (F) for the treatment of severe chronic obstructive disease (COPD) has been amply proven in well controlled clinical trials. Whether this also holds for real-world conditions and in such a heterogeneous patient population as is encountered in Bulgaria remained to be investigated.</p></div><div><h3>Methods</h3><p>In an observational, non-interventional study, 441 Bulgarian patients with severe COPD who were enrolled at 36 sites across the country received extrafine BDP/FF-combination therapy using the NEXThaler® DPI or the Foster® pMDI over a period of 16 weeks. At visits at the beginning, after 4 weeks and at the end of the study, alterations in lung function parameters FEV₁ and FVC, disease symptoms, changes in CAT score, and patient distribution in GOLD 2017 categories A through D were assessed.</p></div><div><h3>Results</h3><p>A large share of the Bulgarian patients with severe COPD suffered from serious comorbidities, received additional medication, and about 2/3 were former or current smokers. Extrafine BDP/FF caused an increase in mean FEV₁, FVC, a decrease of health impact as assessed by the CAT score, and a considerable shift of the share of category C and D patients towards A and B. In addition, the percentage of patients that were free of symptoms impacting everyday life such as fatigue and shortness of breath at rest increased throughout the study. A comparison of both application devices indicated that the NEXThaler® was superior in terms of lung functional aspects, as these parameters displayed a constant improvement over the observation period, whereas they plateaued at week 4 when using the pMDI.</p></div><div><h3>Conclusions</h3><p>The therapeutic benefits of extrafine BDP/FF known from clinical trials could also be observed in a real-world setting, even in such a heterogenous patient population as the Bulgarian. The NEXThaler® appeared to be highly efficient in this setting, opening a new choice for the lung specialist and the patient to select the one device considered most suitable and practical.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"77 ","pages":"Article 102169"},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553922000608/pdfft?md5=8a3a9a12308aad893fdd17871bb2061f&pid=1-s2.0-S1094553922000608-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10710715","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":"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":"Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials","authors":"Zhen Tan ,&nbsp;Pan-yun Wu ,&nbsp;Teng-teng Zhu,&nbsp;Wen Su,&nbsp;Zhen-fei Fang","doi":"10.1016/j.pupt.2022.102144","DOIUrl":"10.1016/j.pupt.2022.102144","url":null,"abstract":"<div><h3>Background</h3><p>Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies.</p></div><div><h3>Methods</h3><p>PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity.</p></div><div><h3>Results</h3><p>17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain.</p></div><div><h3>Conclusions</h3><p>For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"76 ","pages":"Article 102144"},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553922000359/pdfft?md5=f43bfa0987f95b4f26c56249d3c82169&pid=1-s2.0-S1094553922000359-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40595068","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}