Fundamental & Clinical Pharmacology最新文献

{"title":"Use and misuse of domperidone in patients living with Parkinson disease in France","authors":"Edouard Januel,&nbsp;Jean Christophe Corvol,&nbsp;Philippe Remy,&nbsp;Wassilios G. Meissner,&nbsp;Claire Thiriez,&nbsp;Aymeric Lanore,&nbsp;Cecilia Bonnet,&nbsp;Jean-Philippe Azulay,&nbsp;Caroline Giordana,&nbsp;David Maltete,&nbsp;Solene Frismand,&nbsp;Christine Tranchant,&nbsp;Francois Sellal,&nbsp;Alain Jager,&nbsp;Matthieu Béreau,&nbsp;Giovanni Castelnovo,&nbsp;Anne Evelyne Vallet,&nbsp;Maryse Lapeyre-Mestre,&nbsp;Jean-Denis Turc,&nbsp;Olivier Rascol,&nbsp;Florence Tubach,&nbsp;DUMP study group","doi":"10.1111/fcp.70002","DOIUrl":"https://doi.org/10.1111/fcp.70002","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Context</h3>\u0000 \u0000 <p>After observing increased sudden death risk associated with domperidone use, the European Medicines Agency (EMA) imposed usage restrictions in 2014, limiting age (≤60 years), daily dose (≤30 mg/day), and duration (≤7 days). Nausea commonly occurs as an adverse effect of dopaminergic drugs in Parkinson's disease (PD) patients, with few alternative anti-emetic options. This study aimed to assess domperidone prescription patterns in French PD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this multicenter study, all consecutive PD patients from participating expert centers, hospitals, and private neurologists were included. We documented demographics, clinical data, comorbidities, domperidone use (indication, dose, and duration), and concurrent medications (related to PD or not). Domperidone misuse was assessed based on EMA guidelines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Between January and October 2021, 1579 patients from 16 centers (12 French PD expert centers, two general hospitals, and two private practice neurologists) were included. Among them, 109 (7%) received domperidone: 32 (29%) for nausea during apomorphine infusion, 71 (65%) for nausea during other dopaminergic therapies, and three (3%) for orthostatic hypotension. Domperidone misuse was found in 103 patients (95%): treatment duration &gt;7 days (84%), age &gt;60 years (79%), contraindicated drug interactions (6%), and contraindications due to cardiac comorbidity (5%). Only one patient exceeded the recommended dose (30 mg/day).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Domperidone is still prescribed in France for PD patients with dopaminergic-induced nausea, mostly disregarding EMA guidelines due to patient age (&gt;60 years) and prolonged treatment (&gt;7 days). Our study underscores the unmet need for managing gastrointestinal symptoms in PD, highlighting the inadequacy of EMA guidelines in this population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582026","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":"Adrenaline enhances nociceptive and motor blockades by intrathecal carteolol and oxprenolol in rats","authors":"Chong-Chi Chiu,&nbsp;Kuo-Sheng Liu,&nbsp;Chieh-Yu Liu,&nbsp;Ching-Hsia Hung,&nbsp;Yu-Wen Chen,&nbsp;Jhi-Joung Wang","doi":"10.1111/fcp.70003","DOIUrl":"https://doi.org/10.1111/fcp.70003","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study examined the effects of beta-blockers and the combination of carteolol/oxprenolol with epinephrine on spinal nociceptive and motor blockades and compared them with propranolol.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Nociceptive and motor blockades were assessed in rats after intrathecal injection of carteolol, oxprenolol, metoprolol, acebutolol, and sotalol. Carteolol and oxprenolol were used in combination with epinephrine for spinal nociceptive and motor blockades. Propranolol was used as a control.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the same dose of 0.6 μmol, carteolol and oxprenolol are more potent than propranolol, and the duration of action of carteolol and oxprenolol is longer than or the same as that of propranolol. At ED₅₀ (50% effective dose), the potency rankings of drugs are carteolol &gt; oxprenolol &gt; propranolol (<i>P</i> &gt; 0.01). At ED₂₅, ED₅₀, and ED₇₅, the time to full recovery induced by carteolol was longer than that induced by oxprenolol or propranolol. When 1:40,000 epinephrine was added to beta-blocker (carteolol, oxprenolol, and propranolol) at ED₅₀, spinal blockades and duration of action were increased compared to beta-blockers alone (<i>P</i> &gt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Carteolol and oxprenolol are more effective than propranolol on spinal blockades, while other beta-blockers are relatively ineffective. Compared to propranolol, the duration of action of carteolol and oxprenolol is longer or the same. Epinephrine enhances spinal blockades of carteolol, oxprenolol, and propranolol, suggesting that alpha-adrenergic receptors may play an important role in enhancing the anti-nociceptive effects of beta-blockers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513849","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":"Severe fluoropyrimidine toxicity in older adults with cancer with DPYD wild type","authors":"Edwin Brokaar,&nbsp;Jonathan Knikman,&nbsp;Loes Visser,&nbsp;Frederiek van den Bos,&nbsp;Linda Henricks,&nbsp;Carin Lunenburg,&nbsp;Femke de Man,&nbsp;Hans Gelderblom,&nbsp;Jan Schellens,&nbsp;Ron Mathijssen,&nbsp;Henk-Jan Guchelaar,&nbsp;Johanneke Portielje,&nbsp;Annemieke Cats,&nbsp;Wout Postmus,&nbsp;Nienke de Glas","doi":"10.1111/fcp.70000","DOIUrl":"https://doi.org/10.1111/fcp.70000","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Despite the implementation of <i>DPYD</i> genotype-guided dosing, approximately 1 in 3 patients receiving fluoropyrimidine-containing chemotherapy continues to experience severe toxicity. While clinical studies have demonstrated a favorable tolerance among highly selected fit older adults, real-world studies have shown an increased risk of toxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To identify predictors of severe toxicity or treatment deintensification in older <i>DPYD</i> wild-type adults receiving fluoropyrimidine-containing chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Patients wild type for four tested <i>DPYD</i> variants, aged ≥65 years, who participated in a prospective clinical trial investigating genotype-guided individualized fluoropyrimidine dosing, were eligible for the study. The association between tumor-, treatment-, and patient-related characteristics and the occurrence of severe toxicity (grade ≥3, CTCAE v5.0) was analyzed in univariate and multivariate logistic regression analyses. The same analyses were performed for a composite endpoint of severe toxicity or treatment deintensification (including dose reduction, cycle delay, or discontinuation).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 311 patients were included. Median age was 71.2 years and 58.8% were male. Grade ≥3 toxicity occurred in 23.2% of patients. In multivariate analysis, none of the characteristics studied were significantly associated with the occurrence of grade ≥3 toxicity. The composite endpoint occurred in 41.2% of patients and was associated with the use of full dose monotherapy in multivariate analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Despite <i>DPYD</i> genotype-based dosing, grade ≥3 toxicity and treatment deintensification frequently occur in older patients treated with fluoropyrimidine chemotherapy. No patient-related variables were found to be associated with grade ≥3 toxicity, but treatment with dose-reduced monotherapy resulted in fewer treatment deintensification or severe toxicity events.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438949","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":"Population pharmacokinetics of sivelestat in Chinese patients with severe pneumonia","authors":"Xiaolin Zhang,&nbsp;Huiliang Hu,&nbsp;Ziran Li,&nbsp;Peng Zhang,&nbsp;Lei Pan,&nbsp;Lei Wang,&nbsp;Jingqin Mao,&nbsp;Feng Li,&nbsp;Lijun Zhang","doi":"10.1111/fcp.70001","DOIUrl":"https://doi.org/10.1111/fcp.70001","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sivelestat sodium, an inhibitor of neutrophil elastase, was broadly used in the treatment of severe pneumonia. However, the pharmacokinetic (PK) characteristics of sivelestat in patients with severe pneumonia were still unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To understand the PK characteristics of sivelestat for optimizing the dose in Chinese patients with severe pneumonia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we enrolled 15 participants who received sivelestat 300–500 mg every 24 h with an infusion duration of 5 to 14 days. Blood samples of 48 were collected and separated for plasma drug concentration detection by an ultra-high-performance liquid chromatography/tandem mass spectrometry. A population pharmacokinetic (PPK) analysis of sivelestat was performed using a monolix2024R1 software. A Monte Carlo simulation was conducted to assess various dosing schedules and varying covariate levels within the desired therapeutic drug-monitoring concentration range (C_min,ss 8–12 mg/L).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The patients had a mean age of 65 years (range, 35–87), with 2 females and 13 males. These data were best described by a one-compartment model with proportional residual error. The apparent distribution volume and apparent clearance (CL) of sivelestat were 20.88 L and 1.79 L/h, respectively. The clearance of sivelestat is influenced by the covariate total bilirubin (TBIL), prompting a recommendation for a reduced dose in patients with elevated TBIL levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, our findings suggest that the CL/F in patients with severe pneumonia is similar to that in healthy individuals. TBIL can affect CL/F of sivelestat; therefore, TBIL-based dosing regimens provide a practical strategy for achieving sivelestat therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379903","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":"Real-world interpatient variability in the pharmacokinetics of levetiracetam","authors":"Alina Chykharivska,&nbsp;Leonid Kagan,&nbsp;Mary Wagner,&nbsp;Luigi Brunetti","doi":"10.1111/fcp.13059","DOIUrl":"https://doi.org/10.1111/fcp.13059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Levetiracetam (LEV) is an antiepileptic drug (AED) used to treat a variety of seizures in adult and pediatric populations. It is an ideal AED due to its favorable pharmacokinetic (PK) and pharmacodynamic profile and lack of interactions with other AEDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective cohort study was designed to identify covariates that affect LEV clearance and volume of distribution and to generate a population PK model. Adults with a seizure history receiving LEV during hospital admission with a minimum of one serum LEV concentration available were included in the study. Population PK modeling and covariate testing was performed with MONOLIX Suite 2020R1 (Lixoft, France).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 162 serum concentrations were collected from 143 patients. Age, sex, body weight descriptors, serum creatinine, creatinine clearance (CrCL), serum albumin, liver enzymes, and total bilirubin were evaluated. Body surface area (BSA) was a significant covariate for the apparent volume of distribution (V/F). The exclusion of BSA as a covariate of V/F increased the objective function value (OFV) 5.6. CrCL was a significant covariate of apparent plasma clearance (CL/F). The exclusion of CrCL increased the OFV by 18.16 and significantly increased the root square error (RSE) % of the between-subject variabilities of the parameters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>LEV clearance is an effective predictor of serum concentration. CrCL was a significant covariate influencing LEV clearance, and BSA was found to influence the volume of distribution. Further studies are needed to determine the effect of body weight descriptors on LEV clearance and, ultimately, outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.13059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248512","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":"Detection of ketamine in the oral fluid of drivers in northeastern France during the years 2020–2023","authors":"Laïyna Lilo Aouichi,&nbsp;Elise Pape,&nbsp;Jean-Yves Jouzeau,&nbsp;Valérie Gibaja,&nbsp;Eyrian Aubin-Beale,&nbsp;Allan Kolodziej,&nbsp;Catherine Feliu,&nbsp;Elodie Marchand,&nbsp;Nicolas Gambier,&nbsp;Julien Scala-Bertola","doi":"10.1111/fcp.13060","DOIUrl":"https://doi.org/10.1111/fcp.13060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Objectives</h3>\u0000 \u0000 <p>Ketamine is a psychoactive substance used for its stimulant and hallucinogenic properties. As the use of ketamine may lead to impaired driving, we aimed to assess the occurrence of ketamine in the driving population tested positive for narcotics in roadside checks using oral fluid analysis. Oral fluid concentrations of ketamine and norketamine were examined to determine the percentage of drivers susceptible to ketamine impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective descriptive study was conducted over a 32-month period in 2020–2023 on drivers who tested positive to the DrugWipe®5S saliva test in our region of northeastern France. Mass spectrometry was used to confirm the DrugWipe®5S result and to determine oral fluid concentrations of ketamine and norketamine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During the entire study period, 3364 drivers were tested positive at the roadside using the DrugWipe®5S rapid test. After mass spectrometry, 3043 drivers were finally confirmed as true positives. Ketamine was detected in 88 drivers who were 80.7% male, 95.4% polydrug users and were 27.5 ± 7.1 years old, representing 2.6% of the total driver population. Ketamine concentrations were 821 ± 2264 and 7.8 ± 12.3 ng/mL in the presence and absence of norketamine, respectively. Finally, 26.1% of the ketamine-positive drivers had a ketamine oral fluid concentration potentially associated with impaired driving.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ketamine and norketamine should be added to the list of drugs to be tested in oral fluid for driving under the influence of drugs. Besides blood or urine, oral fluid could be an interesting alternative biological matrix for addiction medicine.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248514","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":"RETRACTION: Mineralocorticoid receptor antagonist-mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF-H2S-Nrf2 signaling","authors":"","doi":"10.1111/fcp.13051","DOIUrl":"10.1111/fcp.13051","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023238","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":"Repurposing bosentan as an anticancer agent: EGFR/ERK/c-Jun modulation inhibits NSCLC tumor growth","authors":"Marwa M. Khalaf,&nbsp;Marina N. Malak,&nbsp;Tariq G. Alsahli,&nbsp;Musaad Althobaiti,&nbsp;Mohamed A. Hamzawy,&nbsp;Maha M. Abdel-Fattah","doi":"10.1111/fcp.13052","DOIUrl":"10.1111/fcp.13052","url":null,"abstract":"<p>Drug repurposing of well-established drugs to be targeted against lung cancer has been a promising strategy. Bosentan is an endothelin 1 (ET-1) blocker widely used in pulmonary hypertension. The current experiment intends to inspect the anticancer and antiangiogenic mechanism of bosentan targeting epidermal growth factor receptor (EGFR) /extra-cellular Signal Regulated Kinase (ERK) /c-Jun/vascular endothelial growth factor (VEGF) carcinogenic pathway. BALB/c mice were randomized into four groups, the first received the vehicle, the second received 100 mg/kg oral bosentan alone, the third has non-small cell lung cancer (NSCLC) induced by two doses of 1.5 g/kg urethane i.p. and finally the fourth has NSCLC received bosentan. To determine the anti-proliferative impact of bosentan, cytokeratin 19 fragments (CYFRA 21-1) level was assessed, and Ki-67 positive cells were counted by immunohistochemical (IHC). Molecular expression of EGFR via IHC, relative expression of p-ERK1/2 and p-c-Jun via western blotting and caspase 3, Bcl-2 Associated X-protein (BAX)/B-cell lymphoma 2 (Bcl-2) ratio and VEGF via ELISA were quantified. Bosentan showed pronounced improvement in lung index and histopathological examinations. Bosentan exerted a noticeable arrest of lung cancer growth indicated by the attenuation of CYFRA 21-1 and Ki-67 positive cell counts besides the boost of BAX/Bcl-2 ratio and caspase 3. Bosentan induced a remarkable decline of EGFR, T-ERK1/2/p-ERK1/2, T-c-Jun/p-c-Jun, and VEGF. Bosentan induced cytotoxic and anti-angiogenic impact through regulation of EGFR/ERK/c-Jun/VEGF axis suggesting its potential therapeutic impact against lung cancer.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970445","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":"Fluoxetine-induced downregulation of circMap2k1 signaling cascade to improve neurological function after ischemic stroke","authors":"Langtao He,&nbsp;Hui Zhang,&nbsp;Jian Deng,&nbsp;Yibo He,&nbsp;Zhili Cai,&nbsp;Yitao He","doi":"10.1111/fcp.13048","DOIUrl":"10.1111/fcp.13048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ischemic stroke (IS) is known for its high incidence, disability, and mortality, and there is an urgent need to investigate the pathophysiological mechanisms and develop novel treatment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to investigate the mechanisms of the novel circMap2k1/miR-135b-5p/Pidd1 axis in the treatment of IS progression with fluoxetine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The middle cerebral artery occlusion (MCAO) model was done in adult male Sprague–Dawley (SD) rats and followed by fluoxetine treatment and the injection of adeno-associated virus (AAV)-sh-ctr and AAV-sh-circMap2k1 into the bilateral hippocampal tissues of rats. Dual-luciferase reporter gene assay was employed to confirm the binding between miR-135b-5p and Pidd1. Enzyme-linked immunosorbent assay was performed to measure the concentrations of the inflammatory factors TNF-α, IL-6, and IL-1β in the plasma. The role of circMap2k1 in cells was tested by overexpression of circMap2k1. Cell viability was assessed using Cell Counting Kit-8 assay, while apoptosis was measured by flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Knockdown of circMap2k1 enhanced the therapeutic and protective effect of fluoxetine on IS injury in rats. Dual-luciferase reporter gene assay confirmed the targeting of miR-135b-5p to Pidd1. Additionally, fluoxetine deactivated the adsorption of miR-135b-5p by downregulating circMap2k1, and miR-135b-5p further exerted its inhibitory effect on Pidd1 and finally attenuated the inflammatory response caused by microglial polarization after IS. Cell experiments revealed that overexpression of circMap2k1 repressed cell viability and promoted cell apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Fluoxetine downregulated of circMap2k1 was associated ameliorate neurological injury and inflammatory responses induced by microglial polarization after IS. The manuscript is available as a preprint at this link: doi.org/10.21203/rs.3.rs-3209057/v1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946909","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":"Fundamental and Clinical Pharmacology of drug repositioning","authors":"Lars Petter Jordheim","doi":"10.1111/fcp.13046","DOIUrl":"10.1111/fcp.13046","url":null,"abstract":"","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947256","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}