Alina Chykharivska, Leonid Kagan, Mary Wagner, Luigi Brunetti
Background
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.
Methods
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).
Results
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.
Conclusion
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.
背景左乙拉西坦（LEV）是一种抗癫痫药物（AED），用于治疗成人和儿童人群的各种癫痫发作。由于其良好的药代动力学（PK）和药效学特征以及与其他AED缺乏相互作用，它是一种理想的AED。方法本回顾性队列研究旨在确定影响LEV清除率和分布体积的协变量，并建立种群PK模型。在住院期间有癫痫发作史且至少有一种血清LEV浓度可用的成人纳入研究。使用MONOLIX Suite 2020R1 （Lixoft, France）进行种群PK建模和协变量检验。结果143例患者共采集162项血清浓度。评估年龄、性别、体重描述符、血清肌酐、肌酐清除率（CrCL）、血清白蛋白、肝酶和总胆红素。体表面积（BSA）是表观分布体积（V/F）的显著协变量。排除BSA作为V/F的协变量增加了目标函数值（OFV） 5.6。CrCL是表观血浆清除率（CL/F）的显著协变量。排除CrCL后，OFV增加了18.16%，参数的受试者间变异的根方误差（RSE） %显著增加。结论LEV清除率是血药浓度的有效预测因子。CrCL是影响LEV清除率的显著协变量，BSA影响分布体积。需要进一步的研究来确定体重描述符对LEV清除率和最终结果的影响。
{"title":"Real-world interpatient variability in the pharmacokinetics of levetiracetam","authors":"Alina Chykharivska, Leonid Kagan, Mary Wagner, 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}
Laïyna Lilo Aouichi, Elise Pape, Jean-Yves Jouzeau, Valérie Gibaja, Eyrian Aubin-Beale, Allan Kolodziej, Catherine Feliu, Elodie Marchand, Nicolas Gambier, Julien Scala-Bertola
Background and Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Detection of ketamine in the oral fluid of drivers in northeastern France during the years 2020–2023","authors":"Laïyna Lilo Aouichi, Elise Pape, Jean-Yves Jouzeau, Valérie Gibaja, Eyrian Aubin-Beale, Allan Kolodziej, Catherine Feliu, Elodie Marchand, Nicolas Gambier, 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}
Marwa M. Khalaf, Marina N. Malak, Tariq G. Alsahli, Musaad Althobaiti, Mohamed A. Hamzawy, Maha M. Abdel-Fattah
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.
{"title":"Repurposing bosentan as an anticancer agent: EGFR/ERK/c-Jun modulation inhibits NSCLC tumor growth","authors":"Marwa M. Khalaf, Marina N. Malak, Tariq G. Alsahli, Musaad Althobaiti, Mohamed A. Hamzawy, 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}
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.
Objectives
We aimed to investigate the mechanisms of the novel circMap2k1/miR-135b-5p/Pidd1 axis in the treatment of IS progression with fluoxetine.
Methods
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.
Results
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.
Conclusions
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.
{"title":"Fluoxetine-induced downregulation of circMap2k1 signaling cascade to improve neurological function after ischemic stroke","authors":"Langtao He, Hui Zhang, Jian Deng, Yibo He, Zhili Cai, 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}
Jean Escal, Marion Poudret, Sophie Hodin, Tiphany Neel, Irina Coman, Hervé Locrelle, Adamah Amouzougan, Thierry Thomas, Xavier Delavenne, Hubert Marotte
Background
Methotrexate (MTX) is the first-line treatment for Rheumatoid Arthritis (RA), yet 30%–50% of RA patients develop resistance to MTX, which can manifest several years after treatment initiation.
Objective
This study investigates the relationship between erythrocyte methotrexate polyglutamates (MTX-PGs) subtype concentrations and clinical disease activity in RA patients undergoing long-term MTX treatment.
Methods
In this cross-sectional study, patients on a stable dose of subcutaneous MTX for several years were included. The study protocol was registered in the European Medicines Agency's clinical trials register (n°2017-004348-39). Patients were classified as either in clinical remission (DAS28 <2.6) or having active disease (DAS28 >3.2). Erythrocyte MTX-PGs concentrations were measured using liquid chromatography coupled with mass spectrometry. Multivariate logistic regression analysis assessed the probability of remission status based on MTX-PG3 concentrations.
Results
The study included 34 patients with active RA and 25 in remission. The remission group had a median MTX treatment duration of 6.4 years compared to 2.6 years for the active group (p = 0.001). Patients in remission had a longer median disease duration (p = 0.02) and a lower Body Mass Index (BMI) (p = 0.03) than those with active RA. A positive correlation was found between remission status and high MTX-PG3 concentrations in patients with a BMI <25 kg/m2.
Conclusion
Erythrocyte MTX-PG3 concentrations may serve as a marker for RA activity after prolonged treatment. However, BMI could limit their utility as a biomarker.
{"title":"Long-term evaluation of rheumatoid arthritis activity with erythrocyte methotrexate-polyglutamate 3","authors":"Jean Escal, Marion Poudret, Sophie Hodin, Tiphany Neel, Irina Coman, Hervé Locrelle, Adamah Amouzougan, Thierry Thomas, Xavier Delavenne, Hubert Marotte","doi":"10.1111/fcp.13050","DOIUrl":"10.1111/fcp.13050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Methotrexate (MTX) is the first-line treatment for Rheumatoid Arthritis (RA), yet 30%–50% of RA patients develop resistance to MTX, which can manifest several years after treatment initiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigates the relationship between erythrocyte methotrexate polyglutamates (MTX-PGs) subtype concentrations and clinical disease activity in RA patients undergoing long-term MTX treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this cross-sectional study, patients on a stable dose of subcutaneous MTX for several years were included. The study protocol was registered in the European Medicines Agency's clinical trials register (n°2017-004348-39). Patients were classified as either in clinical remission (DAS28 <2.6) or having active disease (DAS28 >3.2). Erythrocyte MTX-PGs concentrations were measured using liquid chromatography coupled with mass spectrometry. Multivariate logistic regression analysis assessed the probability of remission status based on MTX-PG3 concentrations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 34 patients with active RA and 25 in remission. The remission group had a median MTX treatment duration of 6.4 years compared to 2.6 years for the active group (<i>p</i> = 0.001). Patients in remission had a longer median disease duration (<i>p</i> = 0.02) and a lower Body Mass Index (BMI) (<i>p</i> = 0.03) than those with active RA. A positive correlation was found between remission status and high MTX-PG3 concentrations in patients with a BMI <25 kg/m<sup>2</sup>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Erythrocyte MTX-PG3 concentrations may serve as a marker for RA activity after prolonged treatment. However, BMI could limit their utility as a biomarker.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921504","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}
Paul Maroselli, Raphaelle Fanciullino, Julien Colle, Laure Farnault, Pauline Roche, Geoffroy Venton, Régis Costello, Joseph Ciccolini
Background
Imatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure.
Objectives
We searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing.
Methods
We present data from 60 adult CML patients upon imatinib with therapeutic drug monitoring (TDM) and adaptive dosing.
Results
Mean trough levels after treatment initiation were 994.2 ± 560.6 ng/ml with 56% inter-patient variability). Only 29% of patients were in the therapeutic range. Body weight, height, body surface area, body mass index (BMI), and age were associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with imatinib trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI < 18.5 kg/m2, with exposure +61.5% higher than in patients with 18.5 < BMI ≤ 24.9 and +76.3% higher than in patients with BMI ≥ 25. After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg. No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing.
Conclusion
Our data suggest that low BMI has a significant impact on imatinib exposure but that pharmacokinetically-guided dosing limits its clinical impact in patients.
{"title":"Body mass index affects imatinib exposure: Real-world evidence from TDM with adaptive dosing","authors":"Paul Maroselli, Raphaelle Fanciullino, Julien Colle, Laure Farnault, Pauline Roche, Geoffroy Venton, Régis Costello, Joseph Ciccolini","doi":"10.1111/fcp.13049","DOIUrl":"10.1111/fcp.13049","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Imatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We present data from 60 adult CML patients upon imatinib with therapeutic drug monitoring (TDM) and adaptive dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mean trough levels after treatment initiation were 994.2 ± 560.6 ng/ml with 56% inter-patient variability). Only 29% of patients were in the therapeutic range. Body weight, height, body surface area, body mass index (BMI), and age were associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with imatinib trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI < 18.5 kg/m<sup>2</sup>, with exposure +61.5% higher than in patients with 18.5 < BMI ≤ 24.9 and +76.3% higher than in patients with BMI ≥ 25. After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg. No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data suggest that low BMI has a significant impact on imatinib exposure but that pharmacokinetically-guided dosing limits its clinical impact in patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921495","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}
Amanda V. Jacques, Natália M. Stefanes, Laura O. Walter, Stephanie M. Syracuse, Alisson Bigolin, Louise D. Chiaradia-Delatorre, Luiz F. S. de Souza, Ana C. R. de Moraes, Ricardo J. Nunes, Maria C. Santos-Silva
Background
Chalcones have been described in the literature as promising antineoplastic compounds.
Objectives
Therefore, the objective of this study was to analyze the cytotoxic effect of 23 synthetic chalcones on human acute leukemia (AL) cell lines (Jurkat and K562).
Methods
Cytotoxicity assessment was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cell death was evaluated using fluorescence microscopy, the DNA fragmentation technique, and the assessment of proteins involved in apoptosis by flow cytometry.
Results
The most cytotoxic chalcone (R32) showed no cytotoxicity towards peripheral blood mononuclear cells (PBMC). It exhibited no hemolytic activity, did not alter platelet aggregation after adenosine diphosphate (ADP) and epinephrine stimulation, and did not affect blood coagulation as measured by prothrombin time (PT) and activated partial thromboplastin time (APTT). R32 demonstrated cytotoxic activity by inducing both intrinsic and extrinsic apoptosis, leading to caspase-3 activation and DNA fragmentation. In Jurkat and K562 cells, intrinsic apoptosis was associated with changes in mitochondrial membrane potential (MMP). There was a decreased expression of Bcl-2, increased expression of Bax, decreased expression of survivin, and increased expression of apoptosis-inducing factor (AIF). Extrinsic apoptosis involvement was also observed in both cell lines, characterized by increased expression of the Fas receptor. Additionally, Jurkat cells exhibited decreased expression of the KI-67 cell proliferation marker.
Conclusion
These findings suggest R32 as a potential compound for the development of novel drugs for the treatment of AL.
{"title":"A novel naphthylchalcone ([E]-4-(3-[naphthalen-2-yl]-3-oxoprop-1-en-1-yl) induces intrinsic and extrinsic apoptosis in human acute leukemia cell lines","authors":"Amanda V. Jacques, Natália M. Stefanes, Laura O. Walter, Stephanie M. Syracuse, Alisson Bigolin, Louise D. Chiaradia-Delatorre, Luiz F. S. de Souza, Ana C. R. de Moraes, Ricardo J. Nunes, Maria C. Santos-Silva","doi":"10.1111/fcp.13047","DOIUrl":"10.1111/fcp.13047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chalcones have been described in the literature as promising antineoplastic compounds.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Therefore, the objective of this study was to analyze the cytotoxic effect of 23 synthetic chalcones on human acute leukemia (AL) cell lines (Jurkat and K562).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cytotoxicity assessment was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cell death was evaluated using fluorescence microscopy, the DNA fragmentation technique, and the assessment of proteins involved in apoptosis by flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The most cytotoxic chalcone (<b>R32</b>) showed no cytotoxicity towards peripheral blood mononuclear cells (PBMC). It exhibited no hemolytic activity, did not alter platelet aggregation after adenosine diphosphate (ADP) and epinephrine stimulation, and did not affect blood coagulation as measured by prothrombin time (PT) and activated partial thromboplastin time (APTT). <b>R32</b> demonstrated cytotoxic activity by inducing both intrinsic and extrinsic apoptosis, leading to caspase-3 activation and DNA fragmentation. In Jurkat and K562 cells, intrinsic apoptosis was associated with changes in mitochondrial membrane potential (MMP). There was a decreased expression of Bcl-2, increased expression of Bax, decreased expression of survivin, and increased expression of apoptosis-inducing factor (AIF). Extrinsic apoptosis involvement was also observed in both cell lines, characterized by increased expression of the Fas receptor. Additionally, Jurkat cells exhibited decreased expression of the KI-67 cell proliferation marker.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest <b>R32</b> as a potential compound for the development of novel drugs for the treatment of AL.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921493","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}
Youyi Wu, Tingting Chen, Songsong Wu, Yiwei Huang, Fuyao Li
Background
The development of resistance to oxaliplatin is a multifaceted process, often involving modifications in drug transport, DNA repair mechanisms, and the ability of cells to evade drug-induced apoptosis.
Objective
To evaluate whether knocking down RFC3 promotes the sensitivity of colorectal cancer (CRC) cells to oxaliplatin, potentially offering a new approach to combat drug resistance.
Methods
siRNA-mediated knockdown of RFC3 was employed in colorectal cancer cell lines to assess the impact on oxaliplatin responsiveness. Cell viability assays, clonogenic survival assays, and flow cytometry were conducted to evaluate the effects on cell growth and apoptosis. Additionally, immunoblot analysis was used to scrutinize modifications in the expression of pivotal protein expression in the Wnt/β-catenin/GPX4 axis.
Results
RFC3 is highly expressed in CRC tissues and associated with prognosis. Knocking down RFC3 enhances the sensitivity of CRC cells to oxaliplatin. Additionally, the reduction of RFC3 promotes the susceptibility of chemoresistant tumor cells to oxaliplatin by inducing ferroptosis. Furthermore, the knockdown of RFC3 disrupts the Wnt/β-catenin/GPX4 axis.
Conclusion
Depletion of RFC3 enhances the sensitivity of CRC cells to oxaliplatin via inducing ferroptosis.
{"title":"Knockdown of RFC3 enhances the sensitivity of colon cancer cells to oxaliplatin by inducing ferroptosis","authors":"Youyi Wu, Tingting Chen, Songsong Wu, Yiwei Huang, Fuyao Li","doi":"10.1111/fcp.13044","DOIUrl":"10.1111/fcp.13044","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The development of resistance to oxaliplatin is a multifaceted process, often involving modifications in drug transport, DNA repair mechanisms, and the ability of cells to evade drug-induced apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate whether knocking down RFC3 promotes the sensitivity of colorectal cancer (CRC) cells to oxaliplatin, potentially offering a new approach to combat drug resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>siRNA-mediated knockdown of RFC3 was employed in colorectal cancer cell lines to assess the impact on oxaliplatin responsiveness. Cell viability assays, clonogenic survival assays, and flow cytometry were conducted to evaluate the effects on cell growth and apoptosis. Additionally, immunoblot analysis was used to scrutinize modifications in the expression of pivotal protein expression in the Wnt/β-catenin/GPX4 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RFC3 is highly expressed in CRC tissues and associated with prognosis. Knocking down RFC3 enhances the sensitivity of CRC cells to oxaliplatin. Additionally, the reduction of RFC3 promotes the susceptibility of chemoresistant tumor cells to oxaliplatin by inducing ferroptosis. Furthermore, the knockdown of RFC3 disrupts the Wnt/β-catenin/GPX4 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Depletion of RFC3 enhances the sensitivity of CRC cells to oxaliplatin via inducing ferroptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921499","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}
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