Pharmaceuticals最新文献

{"title":"Bioactive Compounds, Antioxidant, Cytotoxic, and Genotoxic Investigation of the Standardized Liquid Extract from <i>Eugenia involucrata</i> DC. Leaves.","authors":"Monatha Nayara Guimarães Teófilo, Leonardo Gomes Costa, Jamira Dias Rocha, Fernando Gomes Barbosa, Anielly Monteiro de Melo, Grazzielle Guimarães de Matos, Cristiane Maria Ascari Morgado, Amanda Silva Fernandes, Lucas Barbosa Ribeiro de Carvalho, Clayson Moura Gomes, Milton Adriano Pelli de Oliveira, Joelma Abadia Marciano de Paula, Elisa Flávia Luiz Cardoso Bailão, Leonardo Luiz Borges","doi":"10.3390/ph18050764","DOIUrl":"10.3390/ph18050764","url":null,"abstract":"<p><p><b>Background:</b><i>Eugenia involucrata</i> DC., a Cerrado native plant, is recognized for its medicinal properties. However, its bioactive compounds remain inadequately explored. <b>Objectives</b>: This study investigated bioactive compounds from a standardized liquid extract from <i>E. involucrata</i> leaves that can act with antioxidant, cytogenotoxic, cytoprotective, and genoprotective effects. <b>Methods:</b> The phenolic compounds in the standardized liquid extract from <i>E. involucrata</i> leaves were screened by HPLC-DAD. The capture of the free radicals DPPH, ABTS⁺, and the metal reduction power FRAP determined the antioxidant potential. Cytotoxicity was evaluated in RAW 264.7 macrophages (MTT assay), and (anti)cytotoxic and (anti)genotoxic effects were assessed in human lymphocytes using the Trypan blue exclusion method and comet assay, respectively. <b>Results:</b> The extracts present key phenolic compounds, such as ellagic acid, myricitrin, and epicatechin gallate. The standardized extract demonstrated antioxidant capacity, evidenced by its ability to reduce iron and scavenge free radicals. The liquid extract from <i>E. involucrata</i> leaves exhibited cytotoxic effects on RAW 264.7 macrophages at higher concentrations, while demonstrating (anti)cytotoxic activity on human lymphocytes from all tested concentrations. The highest concentration tested of the standardized liquid extract from <i>E. involucrata</i> leaves (250 µg/mL) showed genotoxicity against human lymphocytes compared to the negative control. In contrast, the lowest concentration (62.5 µg/mL) exhibited an antigenotoxic effect on human lymphocytes, reducing the genotoxicity of doxorubicin by approximately 27%. <b>Conclusions:</b> The bioactive compounds in the standardized liquid extract from <i>E. involucrata</i> leaves exhibited antioxidant and antigenotoxic properties, suggesting potential value for nutraceutical and pharmaceutical applications, particularly those related to oxidative stress associated withaging and disease progression.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161294","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":"Targeting Hyperuricemia and NLRP3 Inflammasome in Gouty Arthritis: A Preclinical Evaluation of Allopurinol and Disulfiram Combination Therapy.","authors":"Yahya I Asiri, Manimekalai Pichaivel, Selva Prasanthi Parameshwaran, Krishnaraju Venkatesan, Saud Alqahtani, Taha Alqahtani, Rehab Ahmed, Hassabelrasoul Elfadil, Mahmoud Elodemi, Shaimaa Genena, Durgaramani Sivadasan, Premalatha Paulsamy","doi":"10.3390/ph18050762","DOIUrl":"10.3390/ph18050762","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Gouty arthritis (GA) is a chronic inflammatory condition characterized by hyperuricemia and NLRP3 inflammasome activation, leading to joint damage and systemic inflammation. Although allopurinol (ALP), a xanthine oxidase inhibitor, effectively lowers serum urate levels, it has limited anti-inflammatory effects. This study investigated whether combining disulfiram (DSF), a known NLRP3 inflammasome inhibitor, with ALP enhances therapeutic outcomes in a rat model of gout. <b>Methods:</b> Thirty male Albino Wistar rats (150-200 g) were randomly assigned to five groups (<i>n</i> = 6): control, disease control, ALP-treated, DSF-treated, and ALP + DSF combination. Hyperuricemia was induced using potassium oxonate, followed by MSU crystal injection to trigger acute gout. Treatment lasted 30 days. Efficacy was assessed through clinical scoring, paw swelling, serum uric acid levels, ELISA-based cytokine profiling (IL-1β, TNF-α, IL-6), renal function tests, radiography, and histopathology. <b>Results:</b> Combination therapy with ALP + DSF significantly reduced paw swelling (<i>p</i> < 0.05), inflammation index (<i>p</i> < 0.001), serum uric acid (<i>p</i> < 0.001), and pro-inflammatory cytokines compared to monotherapy. Histopathology revealed preserved synovial architecture and reduced inflammatory infiltration. Radiographic imaging showed attenuated soft tissue swelling and joint erosion. Renal function markers were also improved in the combination group. <b>Conclusions:</b> The combination of ALP and DSF provided superior anti-inflammatory and urate-lowering effects compared to individual treatments. These findings support the potential of disulfiram as an adjunct to conventional ULTs in gout management through dual modulation of urate metabolism and inflammasome-driven inflammation.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161500","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":"Method-Driven Physicochemical Profiling of <i>Aconitum pendulum</i> Bush Polysaccharides and Optimization of Extraction Protocols.","authors":"Mingkun Meng, Linlin Zhao, Chunqiao Shi, Yuying Song, Qingya Yu, Mengjia Li, Xing Yang, Yue Liu, Tong Xu, Yi Zhang","doi":"10.3390/ph18050760","DOIUrl":"10.3390/ph18050760","url":null,"abstract":"<p><p><b>Background/Objectives</b>: This study aimed to characterize the physicochemical properties and antioxidant activities of polysaccharides from Aconitum pendulum Bush processed through different methods (the polysaccharide from A. pendulum (DT), the polysaccharide from A. pendulum processed with zanba (Z-DT), the polysaccharide from A. pendulum processed with highland barley wine (Q-DT), and the polysaccharide from A. pendulum processed with hezi (H-DT)). Additionally, the research focused on optimizing the hot water extraction process for DT using response surface methodology (RSM) to enhance extraction efficiency and establish a scientific basis for pharmaceutical applications. <b>Methods</b>: The physicochemical properties and antioxidant activities of the four polysaccharides were systematically evaluated. RSM with a 17-run Box-Behnken design was employed to investigate the extraction process, examining three factors: extraction runs, liquid-solid ratio, and extraction time. <b>Results</b>: The physicochemical properties and antioxidant assays demonstrated that the DT exhibited significantly higher properties. The factors influencing the extraction process were ranked as extraction runs > liquid-solid ratio > extraction time. The optimal conditions for DT were a liquid-solid ratio of 25 mL/g, extraction time of 2.5 h, and four extraction runs, yielding a sugar content of 63.4%. Under these conditions, the extraction rate of DT was significantly higher than before optimization. <b>Conclusions</b>: The study demonstrated distinct structural features among the four polysaccharides, providing a scientific framework for their potential pharmaceutical applications. What's more, the optimized hot water extraction protocol for DT was validated for high extraction rate and reproducibility.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161513","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":"Unveiling Therapeutic Powers of Indigenous Flora: Antimicrobial, Antioxidant, and Anticancer Properties of <i>Horwoodia dicksoniae</i>.","authors":"Khadijah A Altammar","doi":"10.3390/ph18050765","DOIUrl":"10.3390/ph18050765","url":null,"abstract":"<p><p><b>Background:</b><i>Horwoodia dicksoniae</i> Turrill. (Brassicaceae) and <i>Stipa capensis</i> Thunb. (Poaceae) are commonly grown in the eastern region of Saudi Arabia. <b>Methods</b>: This study evaluated the antibacterial and antifungal potential of these plants. <i>H. dicksoniae</i> extract was further subjected to antioxidant, anticancer, GC-MS, LC-MS/MS, and in silico analyses. <b>Results</b>: <i>H. dicksoniae</i> extract presented a higher antimicrobial efficiency than <i>S. capensis</i> extract by effectively inhibiting the growth of <i>Staphylococcus aureus</i>, <i>Escherichia coli</i>, <i>Proteus vulgaris</i>, <i>Bacillus subtilis</i>, and <i>Candida albicans</i>. <i>H. dicksoniae</i> ethanolic extract also demonstrated promising antioxidant and anticancer properties against the human colon cancer cell line HCT-116. GC-MS analysis revealed the presence of 12 natural compounds in the <i>H. dicksoniae</i> extract, whereas LC-MS/MS analysis revealed 19 different compounds in negative ion mode and 25 in positive ion mode. Furthermore, the presence of bioactive compounds in the <i>H. dicksoniae</i> extract, such as flavonoids (acacetin and hesperetin) and caffeic acid, confirmed the observed antibacterial, antifungal, antioxidant, and anticancer activities. Molecular docking revealed promising interactions between various bioactive compounds and target proteins associated with antimicrobial, antioxidant, and anticancer activities. <b>Conclusions</b>: This study is the first to report GC-MS and LC-MS/MS analyses of <i>H. dicksoniae</i> ethanolic extract. The findings provide valuable insights into the potential mechanisms and therapeutic applications of the identified bioactive compounds. Thus, the present work can serve as a platform for the isolation of natural compounds from <i>H. dicksoniae</i> extract, which may play a significant role in the discovery and design of new drugs for the treatment of human diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161655","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":"Protective Effect of Obeticholic Acid on Sepsis-Induced Liver Dysfunction via Regulating Bile Acid Homeostasis.","authors":"Jiahui Wang, Li Ma, Yuan An, Yan Ge, Dan Xu, Enqiang Mao","doi":"10.3390/ph18050763","DOIUrl":"10.3390/ph18050763","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR agonist obeticholic acid (OCA) on liver dysfunction when sepsis occurs. <b>Methods:</b> A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 24 h. Systematic inflammation, tissue injury, hepatic FXR, and BA transporter expression were investigated in the CLP rats and sham-operated control rats with and without OCA pre-treatment (10 mg/kg, gavage) at 2 h before operation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was performed to access BA composition in the rats' serum and livers. The injury and inflammatory effects of the elevated unconjugated BAs found in the CLP rats was further verified in a hepatic cell line BRL-3A in vitro. <b>Results:</b> Hepatic FXR was repressed in CLP rats, whereas OCA upregulated liver FXR and hepatic BA transporter expression, reduced total serum BA concentration, ameliorated the elevation of serum levels of IL-1β and IL-6, and improved liver and ileal tissue injuries. OCA administration reduced the elevated unconjugated BAs in both serum and liver, and effectively inhibited increases in cholic acid (CA), deoxycholic acid (DCA), and 7-ketoDCA concentrations in CLP rat livers. These BA fractions promoted the release of aspartate aminotransferase (AST) from BRL-3A cells and increased IL-6, CXCL2, and monocyte chemoattractant protein-1 (MCP-1) expression in the cells, along with enhanced transcription factor nuclear factor-κB activation. <b>Conclusions:</b> Liver inflammation and dysfunction during sepsis is attributable to significant changes in bile acid composition in the blood and liver. FXR activation reduces systemic inflammation and liver dysfunction by regulating bile acid homeostasis, especially inflammatory unconjugated bile acid components.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161560","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":"Design, Synthesis, and Evaluation of Antinociceptive Properties of Novel CBD-Based Terpene-Cinnamoyl-Acyl-Hydrazone Analogues.","authors":"Mikaela Lucinda de Souza, João Pedro Barros de Paiva, Graziella Dos Reis Rosa Franco, Vanessa Silva Gontijo, Marina Amaral Alves, Hygor Marcos Ribeiro de Souza, Anna Carolina Pereira Lontra, Eduardo Araújo de Oliveira, Thaís Biondino Sardella Giorno, Isabella Alvim Guedes, Laurent Emmanuel Dardenne, Patrícia Dias Fernandes, Claudio Viegas","doi":"10.3390/ph18050755","DOIUrl":"10.3390/ph18050755","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and synthesis of a novel series of CBD-based structural analogues, and the in vivo evaluation of their potential antinociceptive activity. <b>Methods</b>: Using a two-step synthetic route, 26 new terpene-cinnamoyl acyl-hydrazone analogues were obtained and were submitted to in vivo screening in the classical formalin-induced paw edema and hot plate assays. <b>Results</b>: The compounds PQM-292, PQM-293, PQM-295, PQM-307, PQM-308, and PQM-309 exhibited the best results in the neurogenic phase (first phase) of the formalin-induced licking response, showing comparable results to morphine. Notably, in the inflammatory phase (second phase), compound PQM-292 exhibited the best anti-inflammatory activity. Interestingly, in the hot plate model, six other compounds (PQM-274, PQM-291, PQM-294, PQM-304, PQM-305, and PQM-378) showed the best antinociceptive activity in comparison to morphine, especially PQM-274, which exhibited an antinociceptive effect almost equivalent to the reference drug. Interestingly, these findings suggested that these bioactive compounds, despite their structural similarity, act through different mechanisms, which were investigated by molecular docking with CB1, CB2, and TRPV1 receptors. In silico results indicated that the most active compounds should act through different mechanisms, probably involving interactions with TRPA1. <b>Conclusions</b>: Therefore, due to the promising antinociceptive activity observed for these highlighted compounds, particularly for PQM-292 and PQM-274, without apparent toxicity and psychoactive effects, and the possible involvement of diverse mechanisms of action, these compounds could be considered as promising starting points to the development of new drug candidate prototypes of clinical interest.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161419","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":"Metformin-Induced Apoptosis Is Mediated Through Mitochondrial VDAC1.","authors":"Anna Shteinfer-Kuzmine, Meital M Moyal, Aditya Karunanithi Nivedita, Sweta Trishna, Almog Nadir, Shubhandra Tripathi, Varda Shoshan-Barmatz","doi":"10.3390/ph18050757","DOIUrl":"10.3390/ph18050757","url":null,"abstract":"<p><p><b>Background:</b> Besides diabetes mellitus, metformin has been identified as a potential therapeutic agent for treating various other conditions that include various cancers, cardiovascular diseases, neurodegenerative diseases, and aging. In cancer, metformin increased apoptotic cell death, while inhibiting it in neurodegenerative diseases. Thus, different modes of metformin action at the molecular level have been proposed. <b>Methods:</b> In this study, we present the mitochondria and the VDAC1 (voltage-dependent anion channel) as a potential target of metformin. <b>Results:</b> Metformin induces VDAC1 overexpression, its oligomerization, and subsequent apoptosis. Metformin analogs phenformin and buformin at much lower concentrations also induce VDAC1 overexpression, oligomerization, and cell death. We demonstrate the interaction of metformin with purified VDAC1, which inhibited its channel conduction in a voltage-dependent manner. Metformin bound to the synthetic VDAC1-<i>N</i>-terminal peptide and binding to this domain was also found by its molecular docking with VDAC1. Moreover, we demonstrated metformin binding to purified hexokinases (HK-I) with a 400-fold lower metformin concentration than that required for cell death induction. In cells, metformin induced HK-I detachment from the mitochondrial VDAC1. Lastly, metformin increased the expression of NLRP3 and ASC and induced their co-localization, suggesting inflammasome activation. <b>Conclusions:</b> The results suggest that VDAC1 is a target for metformin and its analogs, and this is associated with metformin's adverse effects on many diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161407","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":"Pregabalin Safety in Pregnancy: A Disproportionality Analysis of VigiBase Spontaneous Reporting System.","authors":"Sarah Mondada, Francesca Bedussi, Jonathan L Richardson, Roberta Noseda, Alessandro Ceschi","doi":"10.3390/ph18050759","DOIUrl":"10.3390/ph18050759","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Some product information on pregabalin suggests a potential risk for congenital anomalies (CAs), although evidence remains inconsistent and lacks clear patterns. This study aimed to provide additional safety information on pregabalin use in pregnancy by analyzing VigiBase, the World Health Organization's global pharmacovigilance database of individual case safety reports (ICSRs). <b>Methods</b>: The analysis included de-duplicated ICSRs related to pregabalin exposure in pregnancy, collected up to 16 January 2024. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated for CA categories reported in at least 10 ICSRs, with a statistical threshold defined as a 95% CI lower bound > 1. <b>Results</b>: Among 410 ICSRs, the majority originated from Europe (64.8%) and North America (26.5%). Of these, 59 (14.4%) ICSRs documented only pregabalin exposure in pregnancy, while 351 (85.6%) also reported adverse events in pregnancy. CAs occurred in 82 ICSRs (23.3%), most commonly involving heart defects (30), nervous system anomalies (18), and limb anomalies (12). No signals of disproportionate reporting were identified for these categories compared to the full database (heart defects: ROR 0.587, 95% CI 0.410-0.839; nervous system anomalies: ROR 0.588, 95% CI 0.370-0.933; limb anomalies: ROR 0.671, 95% CI 0.381-1.183). <b>Conclusions</b>: Future disproportionality analyses, along with pharmacovigilance and pharmacoepidemiological studies using patient registries and large-scale collaborative projects, are essential for the ongoing monitoring of pregabalin safety in pregnancy.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161519","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":"Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study.","authors":"Klaus Francke, Sybille Baumann, Isabella Gashaw, Stefan Klein, Beate Rohde, Oliver Zolk, Oliver M Fischer, Christian Friedrich","doi":"10.3390/ph18050758","DOIUrl":"10.3390/ph18050758","url":null,"abstract":"<p><p><b>Background/Objectives:</b> P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects compared to the unselective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. This study assessed the tolerability, safety and PK of filapixant, the effect of food on PK and relative BA of a tablet vs. solution. <b>Methods</b>: This study (NCT03212586) followed a randomized, double-blind single-ascending-dose design. A total of 72 healthy male subjects received a solution (6-60 mg) or immediate-release tablets (120-1250 mg) of filapixant or corresponding placebo in fasted state. The subjects at 60 mg were re-dosed with 60 mg tablets in both fasted and fed states. The endpoints included PK parameters, dose proportionality, adverse events, and taste assessments (taste strips; dysgeusia questionnaire). <b>Results</b>: Filapixant showed dose-proportional PK with a half-life (about 10-15 h), supporting once-daily dosing. Food minimally affected PK and BA was comparable between tablet and solution. Filapixant was well tolerated; however, the number of taste side effects was unexpectedly high. Comparing the results observed across clinical filapixant studies, the threshold for such side effects seems to be well below the in vitro IC₅₀ for P2X2/3. <b>Conclusions</b>: Treatment with filapixant was safe and well tolerated. Filapixant showed dose-proportional PK, bioavailability similar to that of a solution and a tablet, and a minor effect of food on PK. The number of taste side effects was unexpectedly high considering the high in vitro P2X3 receptor selectivity. Factors other than selectivity are needed to explain taste profile differences between P2X3 antagonists.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161626","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":"Skimmianine Modulates Tumor Proliferation and Immune Dynamics in Breast Cancer by Targeting PCNA and TNF-α.","authors":"Tuğcan Korak, Hayat Ayaz, Fırat Aşır","doi":"10.3390/ph18050756","DOIUrl":"10.3390/ph18050756","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics analyses. <b>Methods</b>: Thirty-six female Wistar albino rats were divided into three groups: control, 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer, and DMBA + skimmianine (<i>n</i> = 12/group). Breast cancer was induced with a single oral dose of 50 mg/kg DMBA in sesame oil. After 16 weeks, skimmianine (40 mg/kg) was administered intraperitoneally for four weeks. Serum CA15-3 levels were measured via enzyme-linked immunosorbent assay (ELISA). Histopathological assessment was performed using hematoxylin and eosin (H&E) staining, and proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) were evaluated immunohistochemically. Pathway and hub gene analyses were performed using Cytoscape, functional annotation with Enrichr, and immune analyses via the Tumor and Immune System Interaction Database (TISIDB) and Sangerbox. <b>Results</b>: The tumor burden in the animals increased after DMBA induction compared to the control groups (0.00 ± 0.00% vs. 89.00 ± 6.60%, respectively, <i>p</i> < 0.001), while skimmianine treatment significantly reduced the tumor burden in the animals (49.00 ± 9.40%, vs. DMBA group, <i>p</i> = 0.191). Histopathological analysis showed DMBA-induced structural disorganization and malignant clustering, whereas skimmianine preserved ductal structures and mitigated the damage. Compared to the control group, DMBA administration markedly elevated serum CA15-3 levels (0.23 ± 0.06 ng/mL vs. 8.57 ± 1.01 ng/mL, respectively), along with PCNA (13.0 ± 3.0% vs. 25.0 ± 4.0%, respectively) and TNF-α (8.4 ± 1.7% vs. 34.0 ± 5.3%, respectively) expression, indicating active tumor progression. Skimmianine treatment significantly reduced CA15-3 (3.72 ± 0.58 ng/mL), PCNA (20.0 ± 4.1%), and TNF-α (25.0 ± 3.9%) levels (<i>p</i> < 0.001). In silico analyses indicated skimmianine's effects on PCNA influence cell cycle pathways, while TNF-α suppression impacts toll-like receptor (TLR) signaling (adjusted <i>p</i> < 0.05). PCNA- and TNF-α-related anticancer effects were especially notable in basal molecular and C2 immune subtypes (<i>p</i> < 0.05). Related hub proteins may regulate immune dynamics by reducing immunosuppression and tumor-promoting inflammation (<i>p</i> < 0.05). <b>Conclusions</b>: Skimmianine shows promise as a breast cancer therapy by simultaneously targeting tumor growth and immune regulation, with PCNA and TNF-α identified as potential key players.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 5","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12114961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161062","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}