Fundamental & Clinical Pharmacology最新文献

{"title":"Association of Acute Kidney Injury and Chronic Kidney Disease With Concentration-To-Dose Ratios of Midazolam and Its Main Metabolites in Critically Ill Adults","authors":"Kimberly Shudofsky,&nbsp;Johanna Abma,&nbsp;Johanna Driessen,&nbsp;Marielle Slikkerveer,&nbsp;Floris Vanmolkot,&nbsp;Paddy Janssen,&nbsp;Jos le Noble","doi":"10.1111/fcp.70108","DOIUrl":"https://doi.org/10.1111/fcp.70108","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Midazolam (MDZ) is used for sedation in critically ill patients. Although previous studies have examined MDZ pharmacokinetics in ICU patients, the differential effects of acute kidney injury (AKI) and chronic kidney disease (CKD), particularly in cohorts including COVID-19 and non-COVID-19 patients, remain insufficiently characterised.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To investigate whether AKI and CKD are associated with dose-normalised exposure of MDZ, 1-hydroxy-midazolam (1-OH-MDZ) and 1-hydroxy-midazolam glucuronide (1-OH-MDZ-G) in critically ill adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this retrospective observational study, ICU patients receiving continuous intravenous MDZ were included. Plasma concentrations of MDZ, 1-OH-MDZ and 1-OH-MDZ-G were converted to concentration-to-dose (C/D) ratios. Cross-sectional analysis used the first sample per patient; longitudinal analysis included all samples in GEE models. Analyses were adjusted for age, sex, BMI, COVID-19 status, CYP3A4 inhibitor use, APACHE IV score, time since MDZ initiation and CRP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Forty-seven patients contributed 137 samples. In the cross-sectional analysis, C/D ratios of MDZ and 1-OH-MDZ did not differ between patients with and without AKI, whereas 1-OH-MDZ-G C/D ratios were higher in AKI (median [IQR] 14.54 [6.14–26.20] vs. 4.53 [2.52–6.00]; <i>p</i> &lt; 0.01). Longitudinal analysis showed that AKI (<i>β</i> = 0.87), AKI Stage 1 (<i>β</i> = 0.81), AKI Stages 2–3 (<i>β</i> = 0.97) and CKD (<i>β</i> = 0.72) were all significantly associated with higher 1-OH-MDZ-G C/D ratios (all <i>p</i> ≤ 0.03). No significant associations were observed for MDZ or 1-OH-MDZ.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>AKI and CKD are associated with accumulation of 1-OH-MDZ-G in critically ill patients. Monitoring 1-OH-MDZ-G may help identify patients at risk of prolonged sedation and adverse outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467506","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":"The Effect of Chronic Angiotensin (1–7) Treatment on Functional Responses of Isolated Resistance Arteries in Streptozotocin-Induced Diabetic Rats","authors":"Esra Akcabag,&nbsp;Ikbal Ozen Kucukcetin,&nbsp;Gul Ozbey,&nbsp;Sebahat Ozdem,&nbsp;Sadi S. Ozdem","doi":"10.1111/fcp.70107","DOIUrl":"10.1111/fcp.70107","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Cardiovascular complications of diabetes mellitus (DM) are responsible for morbidity and mortality in DM patients. Recent evidence highlights the pathophysiological role of the renin-angiotensin-aldosterone system in DM. This study determined whether chronic angiotensin (1–7) (Ang (1–7); 576 μg/kg, s.c., 4 weeks) treatment improves vascular reactivity in mesenteric small resistance arteries of streptozotocin-induced diabetic rats using a wire myograph system and to investigate the underlying mechanisms. Increased sensitivity to vasoconstrictors and decreased responses to endothelium-dependent vasodilators in diabetic rats compared to control rats were partially reversed by Ang (1–7) treatment. Nω-nitro-L-arginine methyl ester (L-NAME, 10⁻⁴ M) incubation significantly decreased vasorelaxant responses to acetylcholine (ACH, 10⁻¹⁰–10⁻⁵ M) in all groups except the diabetic group. Superoxide dismutase (SOD, 50 U/mL) incubation produced significant increases in vasorelaxant responses to ACH only in the diabetic groups. Glibenclamide (10⁻⁵ M), 4-aminopyridine (4-AP, 5 mM), indomethacin (INDO, 10⁻⁵ M), or catalase (CAT, 200 U/mL) incubations did not alter ACH responses in any experimental groups, whereas charybdotoxin (ChTX, 10⁻⁷ M) or apamin (APA, 10⁻⁷ M) produced significant decreases in ACH-induced vasorelaxation, similar in extent in the control and diabetic rats. Following co-incubation with L-NAME and INDO, ACH-induced vasorelaxation in 30 mM KCl pre-contracted arterial rings did not differ significantly between the groups. These findings indicate that improved nitric oxide bioavailability and reduced superoxide activity contribute to the beneficial vascular effects of Ang (1–7) in diabetic rat resistance arteries. Further in vivo studies are warranted to clarify its therapeutic relevance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Summary</h3>\u0000 \u0000 <div>\u0000 \u0000 <ul>\u0000 \u0000 \u0000 <li>Ang (1–7) improves vascular function in diabetic rat resistance arteries.</li>\u0000 \u0000 \u0000 <li>Treatment increases NO bioavailability and reduces oxidative stress.</li>\u0000 \u0000 \u0000 <li>Vasoconstrictor sensitivity is decreased, improving endothelium-dependent vasorelaxation.</li>\u0000 \u0000 \u0000 <li>Ang (1–7) restores vascular responses to endogenous vasoactive agents.</li>\u0000 \u0000 \u0000 <li>Findings suggest Ang (1–7) as a potential target for diabetes-related vascular issues.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436331","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":"The Challenges of Scientific Publishing: An Editor-In-Chief's Perspective","authors":"Luc Zimmer,&nbsp;Pascal Bousquet","doi":"10.1111/fcp.70105","DOIUrl":"10.1111/fcp.70105","url":null,"abstract":"<p>The current and former editors-in-chief of the Fundamental &amp; Clinical Pharmacology journal share their experience and perspectives regarding the present landscape of scientific publishing and the challenges and threats it faces. Several challenges are identified, three of which are of particular significance. The first is how to manage the growing number of submissions. This is a global trend: The number of indexed articles has increased by 50% in less than 10 years, and the challenge of finding efficient and motivated reviewers is particularly acute. The second challenge is how the impact factor has come to be the sole quality criterion for a scientific journal, and by extension for evaluating researchers: Might there not be alternatives? The third challenge is publication fraud, where the editor-in-chief is invariably exposed to endless attempts at manipulation. However, there are fortunately now tools to help combat this. Of course, the editor-in-chief's ultimate weapon is the power to retract a suspicious article, but this is not so simple and is not without consequences.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390471","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":"A Semi-Isolation Housing Paradigm Affects Anxiety, Ethanol Intake, and the Gut Microbiota in Adult Male C57BL/6JRj Mice.","authors":"Anish Nusrat, Bienvenue Koffi, Yann Pelloux, Morgane Benardeau, Solène Jouvanceau, Nicolas Trainel, Caroline Sevoz-Couche, Gabriel Perlemuter, Emmanuelle Corruble, Denis J David, Anne-Marie Cassard, Dragos M Ciocan, Sofia Cussotto","doi":"10.1111/fcp.70093","DOIUrl":"10.1111/fcp.70093","url":null,"abstract":"<p><strong>Background: </strong>There is a complex link between environmental factors, anxiety levels, and ethanol consumption. Social conditions such as loneliness, peer influence, and housing environment shape drinking behaviors and mental health outcomes. The gut microbiota, in the context of the gut-brain axis, may act as a biomarker.</p><p><strong>Objectives: </strong>This study investigates how different housing conditions impact anxiety-like behavior, ethanol consumption, and gut microbiota in adult male mice.</p><p><strong>Methods: </strong>Adult male C57BL/6JRj mice were housed under isolated, semi-isolated, or group-housed conditions. Anxiety-like behavior was assessed using the open field (OF), elevated plus maze (EPM), and novelty-suppressed feeding (NSF) tests. Ethanol intake was evaluated using a 4-week intermittent two-bottle choice paradigm. Fecal samples were collected and analyzed by 16S rRNA sequencing to characterize gut microbiota. Behavioral, drinking, and microbiota data were analyzed using ANOVA-based statistics and QIIME2 pipelines.</p><p><strong>Results: </strong>Semi-isolated mice displayed anxiety-like behavior only in the NSF test. Gut microbiota analysis revealed no significant changes in global diversity. Semi-isolated mice exhibited a specific reduction in the Prevotellaceae, particularly Prevotella UCG_001. Housing conditions also influenced ethanol intake: isolated mice exhibited a low initial preference that increased over time, whereas semi-isolated mice showed a high initial preference followed by avoidance.</p><p><strong>Conclusion: </strong>Housing conditions strongly shape voluntary ethanol consumption. Semi-isolation was associated with elevated initial alcohol preference and anxiety-like behavior only in the NSF test, while isolation led to a gradual escalation of ethanol intake. These findings highlight the importance of housing environment and anxiety-related factors in alcohol-related preclinical research.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":"e70093"},"PeriodicalIF":2.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148014833","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":"TAAR1-Associated Trace Amines for Cutaneous Nociceptive Blockade in Rats","authors":"Chong-Chi Chiu,&nbsp;Li-Kai Wang,&nbsp;Yu-Wen Chen,&nbsp;Ching-Hsia Hung,&nbsp;Jhi-Joung Wang","doi":"10.1111/fcp.70094","DOIUrl":"10.1111/fcp.70094","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to evaluate whether TAAR1 (trace amine–associated receptor 1)–associated trace amines (β-phenylethylamine, tryptamine, octopamine, tyramine, and <i>N</i>-methyltyramine) produced cutaneous nociceptive blockade compared to lidocaine. Cutaneous nociceptive blockade was assessed by inhibition of the cutaneous trunci muscle reflex in response to local noxious stimuli. After subcutaneous injection in rats, the nociceptive blockade produced by β-phenylethylamine, tryptamine, octopamine, tyramine, and <i>N</i>-methyltyramine was compared. We demonstrated that, at a dose of 255.3 μmol/kg, β-phenylethylamine, tryptamine, octopamine, tyramine, and <i>N</i>-methyltyramine produced cutaneous nociceptive blockade. At the ED₅₀ (50% effective dose), the relative potency of β-phenylethylamine (85.5 [87.5–93.2] μmol/kg) was lower than that of lidocaine (17.7 [14.6–2.15] μmol/kg; <i>p</i> &lt; 0.01). On an equianesthetic basis (ED₂₅, ED₅₀, and ED₇₅), β-phenylethylamine exhibited a duration of action similar to that of lidocaine. The addition of clonidine or epinephrine did not prolong the duration of action of β-phenylethylamine, whereas the addition of clonidine or epinephrine prolonged the duration of action of lidocaine. Among these five TAAR1-associated trace amines, β-phenylethylamine was the most potent for producing cutaneous nociceptive blockade, tryptamine and octopamine were moderately potent, and tyramine and <i>N</i>-methyltyramine were the least potent. Although β-phenylethylamine was less potent than lidocaine, it exhibited a similar duration of action. Clonidine and epinephrine did not prolong the duration of action of β-phenylethylamine.</p>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360037","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":"Glucagon-Like Peptide-1 Receptor Agonists in Cocaine Use Disorder: Clinical Observations and Underlying Mechanisms","authors":"Céline Eiden,&nbsp;Ghjulia Chautard,&nbsp;Anne Batisse,&nbsp;Aurélie Aquizerate,&nbsp;Amandine Luquiens,&nbsp;Hélène Donnadieu,&nbsp;Jean-Luc Faillie,&nbsp;Hélène Peyriere","doi":"10.1111/fcp.70103","DOIUrl":"10.1111/fcp.70103","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cocaine use disorder (CUD) remains a major public health concern, characterized by high relapse rates and the absence of approved pharmacological treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RA), widely prescribed for metabolic disorders, modulate mesolimbic reward pathways and have been proposed as potential modulators of addictive behaviors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To describe clinical observations of GLP-1RA exposure in individuals with CUD identified through the French national vigilance system and to contextualize these findings through a structured narrative review of preclinical and clinical evidence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cases involving GLP-1RA exposure in individuals with ongoing cocaine use were identified through the French national vigilance system and described. A structured literature search (MEDLINE, Embase, Google Scholar) identified original preclinical and clinical studies examining the effects of GLP-1 receptor activation on cocaine-related behavioral and neurobiological outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two cases involving patient-initiated off-label GLP-1RA use motivated by perceived anti-craving effects were identified through the vigilance system. The literature synthesis included 22 original publications (17 preclinical and 5 human studies). Across experimental models, GLP-1 receptor activation reduced cocaine self-administration, conditioned reward, and relapse-like behaviors. These effects were associated with the attenuation of mesolimbic dopamine signaling, including reduced cocaine-evoked dopamine release and modulation of dopamine transporter function. Human evidence remains limited and heterogeneous.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>GLP-1 receptor signaling represents a biologically plausible target in CUD. However, current clinical evidence remains preliminary. Patient-driven observations underscore the need for controlled clinical trials and continued vigilance monitoring</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360084","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":"Synergistic Cardioprotection of Colchicine and Hyperbaric Oxygen Therapy in a Rat Model of Remote Ischemia-Reperfusion Injury","authors":"Şahhan Kılıç,&nbsp;Süha Asal,&nbsp;Mert Babaoğlu,&nbsp;Cumaali Demirtaş,&nbsp;Samet Yavuz,&nbsp;Eray Metin Güler,&nbsp;Hakan Beyaztaş,&nbsp;Yavuz Aslan,&nbsp;Cansu Türker Sarıçoban,&nbsp;Özge Bengisu Uysal,&nbsp;Mehmet Yıldırım,&nbsp;Mert İlker Hayıroğlu,&nbsp;Tufan Çınar","doi":"10.1111/fcp.70102","DOIUrl":"https://doi.org/10.1111/fcp.70102","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Lower extremity ischemia-reperfusion injury (IRI) triggers systemic inflammation and oxidative stress, causing myocardial remote ischemia-reperfusion injury (MIRI). Current treatments are limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male Sprague-Dawley rats (<i>n</i> = 6 per group) were assigned to Sham, I/R, I/R + colchicine (C), I/R + HBOT, and I/R + HBOT + C. IRI was induced by 60-min infrarenal aortic clamping and 120-h reperfusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Treatment</h3>\u0000 \u0000 <p>Once daily colchicine (0.3 mg/kg) and HBOT (2.5 ATA, 100% O₂) twice daily were administered for 5 days post-reperfusion. Cardiac damage, oxidative stress, inflammation, and NRF-2/HO-1 signaling were measured, and electrocardiography (ECG) was performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>I/R caused severe MIRI (Hs-Troponin T: 568.54 pg/mL; heart OSI: 20.98; TNF-α: 582.89 pg/mL). Both monotherapies reduced damage, but HBOT + C was superior: Hs-Troponin T 342.07 pg/mL, OSI 2.26, TNF-α 278.82 pg/mL, and IL-6 12.25 pg/mL, with the upper end of the interquartile range for NRF-2 (41.03) and HO-1 (14.45) activation and restored redox balance (%DIS/NT: 26.31). No differences were observed between groups on the ECG.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Colchicine suppresses inflammation, relieving inhibition of antioxidant defenses, enabling HBOT to fully activate NRF-2/HO-1. This synergistic HBOT + C strategy effectively mitigates MIRI, offering a promising multimodal therapy for remote organ protection after major ischemia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324999","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":"Probucol Exerts Anticancer Effects on SW480 Human Colorectal Cancer Cells via Modulation of Apoptosis- and Angiogenesis-Related Proteins","authors":"Ecem Kaya-Sezginer,&nbsp;Filiz Bakar-Ates","doi":"10.1111/fcp.70104","DOIUrl":"https://doi.org/10.1111/fcp.70104","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the need for novel therapeutic agents with multitarget anticancer activity. Probucol is a phenolic compound with well-established antioxidant and anti-inflammatory properties; however, its effects on colorectal cancer cells have not been fully elucidated. The present study aimed to investigate the antitumor effects of probucol on SW480 human colorectal cancer cells and to explore the underlying molecular mechanisms focusing on cell cycle, apoptosis-, and angiogenesis-associated proteins. SW480 cells treated with probucol were subjected to MTT analysis. Cell cycle distribution and apoptosis were evaluated using cell cycle assay, Annexin V binding assay, and multicaspase activity assay. Apoptosis- and angiogenesis-related protein expression was analyzed by western blot, matrix metalloproteinase-9 (MMP-9) mRNA expression was quantified by real-time PCR. Probucol significantly reduced cell viability in a dose-dependent manner and induced cell cycle arrest at the G0/G1 phase. Treatment with probucol markedly increased early and late apoptotic cell populations and enhanced multicaspase activation. The upregulation of pro-apoptotic Bax protein was accompanied by downregulation of antiapoptotic Bcl-2. In addition, probucol significantly suppressed the expression of angiogenesis-associated proteins, including vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) and also decreased MMP-9 mRNA expression, indicating a potential antimetastatic effect. These findings demonstrate that probucol exerts significant anticancer effects on colorectal cancer cells by inhibiting cell proliferation, inducing apoptosis, and suppressing angiogenesis- and metastasis-related molecular markers. Probucol may represent a promising candidate for further investigation as a potential multitarget agent in colorectal cancer.</p>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324846","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":"Nebivolol Protects the Thoracic and Abdominal Aorta and Their Perivascular Adipose Tissue From the Differential Detrimental Effects of Obesity","authors":"Thales M. H. Dourado,&nbsp;Gustavo F. Pimenta,&nbsp;Leonardo P. Silva,&nbsp;Victor O. Assis,&nbsp;Alessandra O. Silva,&nbsp;Carlos R. Tirapelli","doi":"10.1111/fcp.70096","DOIUrl":"10.1111/fcp.70096","url":null,"abstract":"<p>The effects of obesity on the vasculature and perivascular adipose tissue (PVAT) function vary according to the vascular territory. Nebivolol is a third-generation β-blocker that exerts vasculoprotective effects in obesity. The thoracic and abdominal aorta show different responses under physiological conditions, and their PVATs have a distinctive composition and secretory profile. We hypothesized that obesity would affect thoracic and abdominal aortic responsiveness, as well as their PVAT function, differently and that nebivolol would restore obesity-induced vascular and PVAT changes. To test this hypothesis, male Wistar Hannover rats were fed a hypercaloric diet for 14 weeks. Nebivolol (10 mg/kg/day) was administered via gavage during the last 4 weeks. Obesity increased superoxide (O₂•⁻) generation within the thoracic PVAT, but this response did not result in a loss of its anticontractile effect. Vascular hypercontractility was detected in thoracic aortas, which was mediated by the overproduction of NADPH oxidase-derived O₂•⁻ and reduced nitric oxide (NO) bioavailability. Conversely, obesity induced a pro-contractile phenotype in the PVAT of the abdominal aorta. This response occurred in an endothelium-dependent manner, was ameliorated by tiron, and was accompanied by increased O₂•⁻ levels. In all cases, nebivolol reversed the effects of obesity. In summary, obesity differentially affects the thoracic and abdominal aorta and their respective PVATs. Nebivolol exerts vasculoprotective effects through antioxidant mechanisms, leading to a reversal of obesity-induced vascular hypercontractility in both aortic segments. The beneficial effects of nebivolol described here could help mitigate cardiovascular complications associated with obesity. Obesity induces PVAT dysfunction. Extending this knowledge, we demonstrated that obesity differentially affects the thoracic and abdominal aorta along with their associated PVATs. This widespread impairment of PVAT function can drive various adverse vascular consequences, including arterial hypertension and aneurysm formation. Critically, peri-aortic PVAT is of particular clinical relevance due to its association with metabolic risk factors and vascular calcification. Nebivolol exerts vasculoprotective effects via antioxidant mechanisms within PVAT, ultimately reversing obesity-induced vascular hypercontractility in both aortic segments. Thus, investigating pharmacological agents that restore PVAT function, as demonstrated here with nebivolol, represents a promising therapeutic strategy to mitigate obesity-related cardiovascular complications.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257947","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":"Monitoring of Clinics That Use Direct-to-Consumer Advertising for Off-Label Ketamine in the New York Metropolitan Area: A Cross-Sectional Systematic Web Search","authors":"Nina Abukahok,&nbsp;Steven Lawrence,&nbsp;Samrachana Adhikari,&nbsp;Samuel T. Wilkinson,&nbsp;Joseph J. Palamar","doi":"10.1111/fcp.70095","DOIUrl":"10.1111/fcp.70095","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ketamine is increasingly prescribed in an off-label manner to treat psychiatric disorders, raising concerns about direct-to-consumer advertising and the proliferation of clinics offering ketamine for at-home use without direct medical supervision.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to identify and characterize clinics advertising ketamine for psychiatric conditions online in the New York metropolitan area (New York, New Jersey, and Connecticut), with attention to advertising suggesting ketamine is prescribed for at-home use.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In 2025, systematic web searches were conducted to identify clinics advertising prescription ketamine for psychiatric indications. Public-facing website content was reviewed to describe clinic characteristics: service delivery modality, clinician credentials, routes of administration, disorders treated, and advertising practices. A generalized linear model was used to delineate correlates of clinics advertising ketamine for at-home use.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>233 clinics were located; 36.5% prescribed ketamine for at-home use. 51.5% listed a medical doctor as part of their team and 42.9% advertised oral ketamine. Depression was the most commonly listed disorder treated (94.0%) and 21.9% advertised ketamine to treat substance use disorder. In the multivariable model, advertising ketamine for at-home use was more common among clinics advertising oral ketamine (aPR = 4.10, 95% CI: 2.20–7.60) and less common among clinics listing a medical doctor (aPR = 0.54, 95% CI: 0.30–0.99).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Over a third of clinics advertised ketamine for at-home use. A limitation is that we only focused on public-facing websites. Advertising practices and clinician representation suggest clinics may be advertising in a more consumer-oriented manner, underscoring the need for monitoring and clearer guidance to mitigate potential safety risks.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217189","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}