Fundamental & Clinical Pharmacology最新文献

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148092151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148090012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148062057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148065432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual Targeting of Akt and MAPK Pathways With Capivasertib and B-Raf Inhibitors Synergistically Suppresses Tumor Growth in B-Raf-Mutated Melanoma Models.","authors":"Jun Tang, Lingling Zhao, Yuanyuan Zhu, Baoxue Duan","doi":"10.1111/fcp.70088","DOIUrl":"10.1111/fcp.70088","url":null,"abstract":"<p><p>Resistance to B-Raf inhibitors in melanoma poses a significant challenge to effective treatment. This study investigates the synergistic effects of capivasertib, an Akt pathway inhibitor, in combination with B-Raf inhibitors (vemurafenib and encorafenib) in B-Raf-mutated melanoma models. Combination index analysis demonstrated strong synergy between capivasertib and B-Raf inhibitors in melanoma cells. In contrast, combinations of capivasertib with standard chemotherapeutics were antagonistic, underscoring the specificity of the interaction. Mechanistic studies revealed that capivasertib effectively suppressed Akt signaling. Synergism was abolished in Akt-overexpressing cells, confirming Akt's role in the observed combination effects. The combination treatments significantly reduced tumor growth, with tumor volumes in the capivasertib-vemurafenib and capivasertib-encorafenib groups reduced by ~70% relative to control. Notably, this inhibition was sustained for at least 8 weeks, with tumors in the combination groups remaining minimal, while those in the control group reached maximal size by Week 4. Systemic toxicity analyses revealed no significant changes in body weight or serum markers of pancreatic, kidney, or liver function. These findings establish capivasertib and B-Raf inhibitor combinations as a safe and effective strategy for overcoming resistance B-Raf-mutated melanoma, providing new insights into the potential of dual pathway targeting.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":"e70088"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iohexol Clearance and Kidney Transplantation: Determinants of Its Variation in Living Kidney Donors One Year After Donation and Impact on Glomerular Filtration Rate Gain in Kidney Recipients.","authors":"Capucine Arrivé, Nathan Baran, Julia Tonini, Thomas Jouve, Françoise Stanke-Labesque","doi":"10.1111/fcp.70087","DOIUrl":"10.1111/fcp.70087","url":null,"abstract":"<p><strong>Background: </strong>Iohexol clearance (mGFR_ioh) is a marker of choice for measuring glomerular filtration rate (GFR) in potential living kidney donors.</p><p><strong>Objectives: </strong>We studied (1) the determinants of mGFR_ioh variation among kidney donors before and 1 year after donation and (2) the impact of donor mGFR_ioh change on the gain in estimated GFR 3 months after transplantation in kidney transplant recipients.</p><p><strong>Methods: </strong>We performed a retrospective, monocentric study in couples of living kidney donors/transplant recipients. In donors, mGFR_ioh was measured before and 1 year after donation and calculated using the slope-intercept method and the Bröchner-Mortensen correction. In recipients, eGFR was calculated by the CKD-EPI formula before and 3 months after transplantation. Determinants of mGFR_ioh change in donors and eGFR change in recipients were studied using univariate and multivariate general linear models.</p><p><strong>Results: </strong>Sixty-nine kidney donors (41 women), with a median age of 56 years, were included. The median (10th-90th percentiles) decrease in mGFR_ioh at 1 year post-donation was 29.7% (13.9-43.0). Determinants of a greater mGFR_ioh decline (estimate; standard deviation) included female sex (-9.8; 3.3), older age (-0.43; 0.14), and high pre-donation mGFR_ioh value (-0.24; 0.07). Smoking status and body mass index were not associated with mGFR_ioh decrease. In kidney recipients, the gain in eGFR_CKD-EPI at 3 months post-transplantation was not correlated to mGFR_ioh variation (before vs. 1 year post-donation) of donors.</p><p><strong>Conclusions: </strong>Our data identified female sex and age as key determinants of mGFR_ioh at 1 year post-donation. Donor mGFR_ioh pre-donation or mGFR_ioh change 1 year after donation had no impact on early recipient kidney graft function.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":"e70087"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the Environmental Impact of Clinical Research: A Full Life Cycle Analysis of a French Academic Randomised Clinical Trial.","authors":"Claire Fougerou-Leurent, Louise Forteau, Maëlle Perrot-Loyer, Alain Renault, Margot Brion, Catherine Mouchel, Chloé Rousseau, Enora Marion, Sabrina Cochennec, Anne Ganivet, Marie-Laure Gervais, Loïc Fin, Bruno Laviolle","doi":"10.1111/fcp.70086","DOIUrl":"10.1111/fcp.70086","url":null,"abstract":"<p><p>Climate change poses the greatest threat to human health in the 21st century. The healthcare sector contributes approximately 5% of global greenhouse gas emissions and has a significant environmental impact. Although clinical trials are crucial for identifying effective and safe treatments and preventing disease, their environmental impact is poorly documented. Our study aimed to assess the environmental impact of a publicly funded, academic clinical trial by adapting life cycle assessment (LCA) methodology to clinical research. We performed a retrospective, simplified, full LCA using the EF 3.0 methodology on a prospective, double-blind, randomised controlled neurosurgery trial. The trial included 202 patients at 18 university hospitals throughout France. To identify hotspots of interest, 16 impact indicators and their combination into a single score were evaluated. The results showed that climate change (or greenhouse gas emissions) was the most important indicator, accounting for almost 30% of the single score. Greenhouse gas emissions were estimated at 31.6 t of carbon dioxide equivalent. The next most important were resource use of fossils (24%), resource use of minerals and metals (12%), and particulate matter emissions (8%). The main hotspots identified were patient transport and travel by clinical research assistants for source data verification. In conclusion, by using a full LCA approach, our study confirms that conducting a clinical trial has a substantial environmental impact, particularly with regard to greenhouse gas emissions. The main hotspots identified were related to patient transport and clinical research assistants' travel. Trial Registration: The SUCRE study (Treatment of Chronic Subdural Hematoma by Corticosteroids: A Prospective Randomised Study)-clinicaltrials.gov identifier: NCT02650609.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":"e70086"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13090804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716631","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}

{"title":"Repurposing Cimetidine as a Therapeutic Candidate for Irritable Bowel Syndrome in a Rat Model.","authors":"Tsukasa Nozu, Saori Miyagishi, Masatomo Ishioh, Kaoru Takakusaki, Toshikatsu Okumura","doi":"10.1111/fcp.70091","DOIUrl":"10.1111/fcp.70091","url":null,"abstract":"<p><strong>Background: </strong>Visceral hypersensitivity and impaired intestinal barrier function are hallmark features of irritable bowel syndrome (IBS), linked to activation of corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4), and proinflammatory cytokine pathways. Cimetidine, a classical H₂ blocker, has been shown to inhibit Na⁺/H⁺ exchangers (NHEs), thereby potentially suppressing proinflammatory cytokine release.</p><p><strong>Objectives: </strong>This study examined whether cimetidine alleviates visceral hypersensitivity and colonic hyperpermeability in rat models of IBS.</p><p><strong>Methods: </strong>Visceral pain threshold in response to colonic balloon distention was assessed by electromyographic detection of abdominal muscle contractions during colonic balloon distention, and colonic permeability was measured using Evans blue uptake in LPS- and CRF-induced IBS models in male Sprague-Dawley rats.</p><p><strong>Results: </strong>Intragastric cimetidine (20-100 mg/kg daily for 3 days) prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability dose-dependently and also attenuated CRF-induced changes. In contrast, famotidine, another H₂ blocker, did not replicate these effects. Amiloride, an NHE inhibitor, mimicked cimetidine's effects, both of which were abolished by intracisternal SB-334867, an orexin 1 receptor antagonist. Furthermore, atropine, sulpiride, and N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, but not scopolamine butylbromide, a peripheral muscarinic receptor antagonist, or domperidone, a peripheral dopamine D₂ receptor antagonist, blocked cimetidine's action.</p><p><strong>Conclusion: </strong>These findings suggest that cimetidine prevents visceral hypersensitivity and colonic hyperpermeability in IBS models through mechanisms involving central orexin signaling possibly triggered by NHE inhibition, NO, and central muscarinic and dopamine D₂ receptor pathways. These findings may provide a basis for future therapeutic approaches targeting IBS.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":"e70091"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexamethasone-Mediated Regulation of CYP3A4 and UGTs in Human Hepatoma HuH-7 Cells.","authors":"Hana Yu, Song Hee Lee, Ji Hyeon Kim, Seung Jin Kim, Hee Eun Kang","doi":"10.1111/fcp.70089","DOIUrl":"10.1111/fcp.70089","url":null,"abstract":"<p><strong>Background: </strong>The application of human hepatic cell lines to early drug discovery and development instead of human primary hepatocytes (HPHs) has been limited because of the low level of drug-metabolizing enzymes (DMEs).</p><p><strong>Objective: </strong>The study aimed to evaluate the effects of dexamethasone (DEX) treatment on DME expression, activities, and regulation in HuH-7 hepatoma cells.</p><p><strong>Methods: </strong>Expression and transcriptional regulation of major CYPs and UGTs in HuH-7 cells was evaluated by immunoblotting, probe substrate assays, and treatments with nuclear receptor agonists, including DEX, and antagonists.</p><p><strong>Results: </strong>DEX increased the expression and activity of cytochrome P450 (CYP) 3A4, uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, and UGT2B7 but had minimal effects on CYP1A2, CYP2B6, or CYP2C9. These augmented activities of CYP3A4, UGT1A1, and UGT2B7 were concentration-dependently inhibited by their corresponding selective inhibitors. DEX-induced upregulation of CYP3A4 protein expression was abolished by co-treatment with the glucocorticoid receptor (GR) inhibitor, but not by co-treatment with the pregnane X receptor (PXR) inhibitor. However, treatment with PXR or constitutive androstane receptor (CAR) agonist did not lead to transcriptional activation of CYP3A4 and 2B6. Only CYP1A1 was transactivated by an aryl hydrocarbon receptor (AhR) ligand.</p><p><strong>Conclusion: </strong>Our results suggest that the activities of some major DMEs (CYP3A4, UGT1A1, and UGT2B7) in HuH-7 cells are promoted by DEX treatment possibly through GR activation. However, unlike HPHs, HuH-7 cells fail to show transcriptional regulation of DMEs by PXR or CAR, which limits their suitability for evaluating DME induction potential of investigational drugs.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":"e70089"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769422","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}

{"title":"Alogliptin Delays the Healing of Traumatic Oral Ulcers in the Buccal Mucosa of Wistar Rats.","authors":"Maria Imaculada de Queiroz Rodrigues, Joyce Ohana de Lima Martins, Debora de Souza Collares Maia Castelo-Branco, Paulo Goberlânio de Barros Silva, Fabrício Bitu Sousa, Mário Rogério Lima Mota, Ana Paula Negreiros Nunes Alves","doi":"10.1111/fcp.70090","DOIUrl":"10.1111/fcp.70090","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study is to evaluate the influence of alogliptin treatment on the healing process of traumatic oral ulcers.</p><p><strong>Methods: </strong>Four experimental groups were used: control group (GC) and three test groups treated with oral Alogliptin at 1 (GTA1), 3 (GTA3), and 9 mg/kg/day (GTA9). Ulcer diameter, body weight, glycemic index, colony-forming unit (CFU), and discomfort were analyzed. Histological slides were prepared for healing scores, inflammatory cell counts, collagen deposition analysis, and immunohistochemistry.</p><p><strong>Results: </strong>Alogliptin treatment increased ulcer area (GTA3-7D: 5.2 ± 1.2; GTA9-3D: 11.8 ± 0.8; GTA9-7D: 5.8 ± 1.3; p < 0.001), CFU counts (p = 0.049), and Grimace/discomfort scores (p = 0.02), while reducing body weight gain (p = 0.007) in GTA3 and GTA9 groups. Microscopic analysis revealed higher histopathological scores (p = 0.039), increased mononuclear cells (p = 0.006), reduced polymorphonuclear cells (p < 0.05), and decreased collagen deposition (18.2 ± 2.6; p = 0.031) in GTA9. Lower TLR4 (p = 0.001) and TGF-β (p < 0.001) expression, alongside increased CD31 immunostaining (p < 0.001), were observed in GTA3 and GTA9, as well as reduced TLR2 expression (p = 0.001) in GTA9.</p><p><strong>Conclusion: </strong>Alogliptin delays oral ulcer healing by sustaining inflammation, reducing TGF-β expression, and impairing collagen deposition, and may contribute via reduced TLR2/TLR4 expression, increased microbial burden, and decreased TGF-β.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 3","pages":"e70090"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769366","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}