Pharmacology Research & Perspectives最新文献_第5页

In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting. 在体外筛选UGT2B10的计算机优先考虑了儿童造血干细胞移植中使用的药物的推定配体。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-12-01 DOI: 10.1002/prp2.70011

Yahia Bennani, Khalil Ben Hassine, Muhammed Gencaslan, Mary Boudal-Khoshbeen, Caroline Samer, Marc Ansari, Youssef Daali, Chakradhara Rao Satyanarayana Uppugunduri

{"title":"In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting.","authors":"Yahia Bennani, Khalil Ben Hassine, Muhammed Gencaslan, Mary Boudal-Khoshbeen, Caroline Samer, Marc Ansari, Youssef Daali, Chakradhara Rao Satyanarayana Uppugunduri","doi":"10.1002/prp2.70011","DOIUrl":"10.1002/prp2.70011","url":null,"abstract":"UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N-oxide (VCZ N-oxide) for in vitro investigations. In this report, we present in vitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10. Enzyme kinetics experiments included recombinant UGT2B10 and analytical methods based on ultra high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). To determine potential substrates, candidates were incubated at various therapeutically observed concentrations with recombinant UGT2B10 to identify the corresponding glucuronide metabolite. Inhibition capacity was tested using the selective probe cotinine for its glucuronidation to cotinine N-ß-d-glucuronide. IC50 was determined for compounds exhibiting inhibition. Among the tested compounds, LOR (IC50 = 0.01 μM, R2 = 0.9257) and MPA (IC50 = 0.38 mM, R2 = 0.9212) exhibited inhibition potential for UGT2B10. None of the other tested compounds featured inhibition potential and none of the compounds tested exhibited metabolism through UGT2B10. Further exploration on the clinical relevance of this inhibition using modeling strategies, overlapping nature with other UGT isoforms, and screening other molecules for their inhibition potential on UGT2B10 is warranted.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 6","pages":"e70011"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of vitamin D supplementation on clinical outcomes in adult patients with COVID-19: A GRADE-assessed systematic review and meta-analysis of randomized controlled trials. 补充维生素 D 对 COVID-19 成年患者临床疗效的影响：对随机对照试验进行GRADE评估的系统综述和荟萃分析。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70013

Zohreh-Al-Sadat Ghoreshi, Javad Charostad, Nasir Arefinia, Mohsen Nakhaie, Mohammad Rezaei Zadeh Rukerd, Faranak Salajegheh

{"title":"Effect of vitamin D supplementation on clinical outcomes in adult patients with COVID-19: A GRADE-assessed systematic review and meta-analysis of randomized controlled trials.","authors":"Zohreh-Al-Sadat Ghoreshi, Javad Charostad, Nasir Arefinia, Mohsen Nakhaie, Mohammad Rezaei Zadeh Rukerd, Faranak Salajegheh","doi":"10.1002/prp2.70013","DOIUrl":"10.1002/prp2.70013","url":null,"abstract":"The COVID-19 pandemic has emerged as a major global health crisis. Vitamin D, a crucial fat-soluble vitamin, has been recommended for COVID-19 patients, though evidence of its effectiveness is inconsistent. This systematic literature review and meta-analysis aimed to evaluate the impact of vitamin D supplementation on COVID-19-related outcomes. A comprehensive search was conducted across PubMed, Scopus, Web of Science, Embase, and Cochrane databases. Primary outcomes included mortality and hospital length of stay, while secondary outcomes encompassed C-reactive protein (CRP), ferritin, D-dimer, hemoglobin (Hb) concentrations, and lymphocyte, neutrophil, and platelet counts. Data analysis was performed using Stata™ Version 14. A total of 16 trials were analyzed. The meta-analysis revealed that vitamin D supplementation significantly reduced hospital length of stay (mean difference = -1.16; 95% confidence interval [CI]: -2.23, -0.09; p = .033) with significant heterogeneity (I2 = 69.2%, p = .002). Subgroup analysis showed a more pronounced reduction in studies with vitamin D dosages ≤10 000 international units (IU) (mean difference = -1.27; 95% CI: -1.96, -0.57; p < .001) and in patients over 60 years old (mean difference = -1.84; 95% CI: -2.53, -1.14; p < .001). Additionally, vitamin D significantly reduced CRP concentrations in older adults (>60 years) (mean difference = -1.13; 95% CI: -2.07, -0.18; p = .019). No significant changes were found in ferritin, D-dimer, Hb concentrations, or in lymphocyte, neutrophil, and platelet counts (p > .05). In conclusion, while vitamin D supplementation did not significantly affect most COVID-19-related biomarkers, however, it reduces the length of hospital stay.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70013"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes. 产气荚膜梭菌的epsilon毒素刺激钙激活的氯离子通道，在爪蟾卵母细胞中产生细胞外囊泡。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70005

Mercè Cases, Jonatan Dorca-Arévalo, Marta Blanch, Sergi Rodil, Beatrice Terni, Mireia Martín-Satué, Artur Llobet, Juan Blasi, Carles Solsona

{"title":"The epsilon toxin from Clostridium perfringens stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes.","authors":"Mercè Cases, Jonatan Dorca-Arévalo, Marta Blanch, Sergi Rodil, Beatrice Terni, Mireia Martín-Satué, Artur Llobet, Juan Blasi, Carles Solsona","doi":"10.1002/prp2.70005","DOIUrl":"https://doi.org/10.1002/prp2.70005","url":null,"abstract":"The epsilon toxin (Etx) from Clostridium perfringens has been identified as a potential trigger of multiple sclerosis, functioning as a pore-forming toxin that selectively targets cells expressing the plasma membrane (PM) myelin and lymphocyte protein (MAL). Previously, we observed that Etx induces the release of intracellular ATP in sensitive cell lines. Here, we aimed to re-examine the mechanism of action of the toxin and investigate the connection between pore formation and ATP release. We examined the impact of Etx on Xenopus laevis oocytes expressing human MAL. Extracellular ATP was assessed using the luciferin-luciferase reaction. Activation of calcium-activated chloride channels (CaCCs) and a decrease in the PM surface were recorded using the two-electrode voltage-clamp technique. To evaluate intracellular Ca2+ levels and scramblase activity, fluorescent dyes were employed. Extracellular vesicles were imaged using light and electron microscopy, while toxin oligomers were identified through western blots. Etx triggered intracellular Ca2+ mobilization in the Xenopus oocytes expressing hMAL, leading to the activation of CaCCs, ATP release, and a reduction in PM capacitance. The toxin induced the activation of scramblase and, thus, translocated phospholipids from the inner to the outer leaflet of the PM, exposing phosphatidylserine outside in Xenopus oocytes and in an Etx-sensitive cell line. Moreover, Etx caused the formation of extracellular vesicles, not derived from apoptotic bodies, through PM fission. These vesicles carried toxin heptamers and doughnut-like structures in the nanometer size range. In conclusion, ATP release was not directly attributed to the formation of pores in the PM, but to scramblase activity and the formation of extracellular vesicles.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70005"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies. 食欲、饱腹感、食物摄入量和进食行为中的肠脑轴：动物模型和人体研究的启示

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70027

Georgia S Clarke, Amanda J Page, Sally Eldeghaidy

{"title":"The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies.","authors":"Georgia S Clarke, Amanda J Page, Sally Eldeghaidy","doi":"10.1002/prp2.70027","DOIUrl":"https://doi.org/10.1002/prp2.70027","url":null,"abstract":"The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70027"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11483575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of cyclosporin A on respiratory viral replication in fully differentiated ex vivo human airway epithelia. 环孢素 A 对完全分化的体外人体气道上皮细胞呼吸道病毒复制的影响

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.1242

Louise Bondeelle, Song Huang, Samuel Constant, Sophie Clément, Maud Salmona, Jérôme Le Goff, Anne Bergeron, Caroline Tapparel

{"title":"Effect of cyclosporin A on respiratory viral replication in fully differentiated ex vivo human airway epithelia.","authors":"Louise Bondeelle, Song Huang, Samuel Constant, Sophie Clément, Maud Salmona, Jérôme Le Goff, Anne Bergeron, Caroline Tapparel","doi":"10.1002/prp2.1242","DOIUrl":"10.1002/prp2.1242","url":null,"abstract":"Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID-19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS-CoV-2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose-dependent antiviral effect against the SARS-CoV-2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS-CoV-2 Omicron or HPIV3, indicating a virus-specific effect. At high concentrations, CsA was associated with an increase of IL-8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug-virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e1242"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The endocannabinoid system in appetite regulation and treatment of obesity. 内源性大麻素系统在食欲调节和肥胖症治疗中的作用。

IF 2.6 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70009

Marija Kurtov,Igor Rubinić,Robert Likić

引用次数: 0

Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model. 色甘酸钠和马西替尼复方制剂可抑制成纤维细胞-肌成纤维细胞转化，并对博莱霉素诱导的体外纤维化模型产生细胞保护和抗氧化作用。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70018

Azize Yasemin Göksu, Hulya Dirol, Fatma Gonca Kocanci

{"title":"Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced in vitro fibrosis model.","authors":"Azize Yasemin Göksu, Hulya Dirol, Fatma Gonca Kocanci","doi":"10.1002/prp2.70018","DOIUrl":"10.1002/prp2.70018","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70018"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. 一项关于脓毒症重症患者使用 STC3141 的安全性、耐受性和药代动力学的剂量调整、开放标签试验研究。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70015

Rinaldo Bellomo, John Patava, Ruth Van Lancker, Nathalie Layios, Marijke Peetermans, Mark Plummer, Rachid Attou, Robert McNamara, Andrew Udy, Bradley Wibrow, Adam Deane, Edward Litton, Marcel Tanudji, Fuhong Su, Zhang Zhong, Linda Shi, Li Ning

{"title":"A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.","authors":"Rinaldo Bellomo, John Patava, Ruth Van Lancker, Nathalie Layios, Marijke Peetermans, Mark Plummer, Rachid Attou, Robert McNamara, Andrew Udy, Bradley Wibrow, Adam Deane, Edward Litton, Marcel Tanudji, Fuhong Su, Zhang Zhong, Linda Shi, Li Ning","doi":"10.1002/prp2.70015","DOIUrl":"https://doi.org/10.1002/prp2.70015","url":null,"abstract":"Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70015"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants. 口服新型 5-脂氧合酶激活蛋白抑制剂 Atuliflapon 在健康参与者体内的分布情况。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70029

Xue-Qing Li, Bo Lindmark, Carl Amilon, Kristin Samuelsson, Lars Weidolf, Karin Nelander, Jane Knöchel, Maria Heijer, Ryan A Bragg, Malin Gränfors, Eva-Lotte Lindstedt, Sharan Sidhu, Pavlo Garkaviy, Hans Ericsson

{"title":"Disposition of orally administered atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor in healthy participants.","authors":"Xue-Qing Li, Bo Lindmark, Carl Amilon, Kristin Samuelsson, Lars Weidolf, Karin Nelander, Jane Knöchel, Maria Heijer, Ryan A Bragg, Malin Gränfors, Eva-Lotte Lindstedt, Sharan Sidhu, Pavlo Garkaviy, Hans Ericsson","doi":"10.1002/prp2.70029","DOIUrl":"https://doi.org/10.1002/prp2.70029","url":null,"abstract":"In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70029"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses. 基于蛋白质组分析的紫锥菊苷防治缺氧性肺动脉高压的机制研究

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI: 10.1002/prp2.70025

Xiangyun Gai, Qingqing Xia, Hongmai Wang, Hongtao Bi, Jinyu Wang, Yuefu Zhao

{"title":"Study on the mechanism of echinacoside in preventing and treating hypoxic pulmonary hypertension based on proteomic analyses.","authors":"Xiangyun Gai, Qingqing Xia, Hongmai Wang, Hongtao Bi, Jinyu Wang, Yuefu Zhao","doi":"10.1002/prp2.70025","DOIUrl":"https://doi.org/10.1002/prp2.70025","url":null,"abstract":"Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 5","pages":"e70025"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0