Chronic inflammation is involved in various mechanisms of memory impairment (MI). Although Janus kinase inhibitors (JAKi), which inhibit cytokine-induced JAK–STAT pathway, could theoretically protect against MI, we faced an unexpected case of MI in a non-elderly patient treated with JAKi.
Objective
Our study aims to investigate the association between JAKi and MI.
Methods
We searched VigiBase, the global pharmacovigilance database, for MI cases reported with JAKi from January 2011 to December 2023 and reviewed the literature for additional cases. The potential association was further explored through disproportionality analyses by calculating Reporting Odds Ratios (ROR), with statistical significance defined as a ROR and its 95% confidence interval exceeding 1.
Results
A total of 3788 MI cases associated with JAKi were included, 36.3% of which were serious. Over half involved non-elderly patients, and co-reported confounding drugs were rare. According to disproportionality analyses, MI was reported nearly three times more frequently with JAKi than with all other drugs (ROR 2.92; 95% CI: 2.83–3.01). To illustrate, a 54-year-old woman with rheumatoid arthritis treated with tofacitinib for 6 months experienced MI with word-finding difficulties (e.g., reduced categorical fluency: 25 animals named in 2 min; norm 30–47) and short-term memory loss, fully resolved 6 weeks post-discontinuation.
Conclusion
Our data support the positive association between MI and JAKi, potentially mediated through hippocampal JAK/STAT pathway inhibition, impairing cholinergic neurotransmission and synaptic plasticity. While further investigations are warranted to confirm or refute this pharmacovigilance signal, clinicians should remain vigilant given this potentially serious adverse effect.
{"title":"JAK Inhibitors and Memory Impairment: Disproportionality Analyses in the WHO Global Pharmacovigilance Database, VigiBase","authors":"Marilou Duboëlle, Adriano Lercara, Yves-Marie Pers, Céline Michel, Marion Lepelley, Marie-Blanche Valnet-Rabier, Jean-Luc Faillie, Virginie Bres, Pascale Palassin","doi":"10.1111/fcp.70072","DOIUrl":"10.1111/fcp.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic inflammation is involved in various mechanisms of memory impairment (MI). Although Janus kinase inhibitors (JAKi), which inhibit cytokine-induced JAK–STAT pathway, could theoretically protect against MI, we faced an unexpected case of MI in a non-elderly patient treated with JAKi.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Our study aims to investigate the association between JAKi and MI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched VigiBase, the global pharmacovigilance database, for MI cases reported with JAKi from January 2011 to December 2023 and reviewed the literature for additional cases. The potential association was further explored through disproportionality analyses by calculating Reporting Odds Ratios (ROR), with statistical significance defined as a ROR and its 95% confidence interval exceeding 1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 3788 MI cases associated with JAKi were included, 36.3% of which were serious. Over half involved non-elderly patients, and co-reported confounding drugs were rare. According to disproportionality analyses, MI was reported nearly three times more frequently with JAKi than with all other drugs (ROR 2.92; 95% CI: 2.83–3.01). To illustrate, a 54-year-old woman with rheumatoid arthritis treated with tofacitinib for 6 months experienced MI with word-finding difficulties (e.g., reduced categorical fluency: 25 animals named in 2 min; norm 30–47) and short-term memory loss, fully resolved 6 weeks post-discontinuation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data support the positive association between MI and JAKi, potentially mediated through hippocampal JAK/STAT pathway inhibition, impairing cholinergic neurotransmission and synaptic plasticity. While further investigations are warranted to confirm or refute this pharmacovigilance signal, clinicians should remain vigilant given this potentially serious adverse effect.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12819935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010054","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}
Demirpolat, et al., Topical Probiotic Therapy Reduces Chemotherapy-Induced Oral Mucositis: Preclinical Evaluation in a Rat Model, Fundamental & Clinical Pharmacology2025, 39(6): e70050, https://doi.org/10.1111/fcp.70050.
Initially, Eren Demirpolat was mistakenly placed as the second author, although he should have been listed first according to contributorship. The author list has been revised as follows:
Eren Demirpolat1, Buse Kose Demirezen2, Arzu Yay3, Ozge Cengiz Mat4, Mustafa Ermis5
We apologize for this error.
deirpolat，等，局部益生菌治疗减少化疗诱导的口腔黏膜炎：大鼠模型的临床前评估，基础与临床药理，2015,39(6):e70050, https://doi.org/10.1111/fcp.70050。最初，即使Demirpolat也被错误地列为第二作者，尽管根据贡献，他应该被列为第一。作者名单修改如下：even Demirpolat 1， Buse Kose Demirezen 2, Arzu Yay 3, Ozge Cengiz Mat 4, Mustafa Ermis 5。我们为这个错误道歉。
{"title":"Correction to “Topical Probiotic Therapy Reduces Chemotherapy-Induced Oral Mucositis: Preclinical Evaluation in a Rat Model”","authors":"","doi":"10.1111/fcp.70071","DOIUrl":"10.1111/fcp.70071","url":null,"abstract":"<p>\u0000 <span>Demirpolat, </span> et al., <span>Topical Probiotic Therapy Reduces Chemotherapy-Induced Oral Mucositis: Preclinical Evaluation in a Rat Model</span>, <i>Fundamental & Clinical Pharmacology</i> <span>2025</span>, <span>39</span>(<span>6</span>): e70050, https://doi.org/10.1111/fcp.70050.\u0000 </p><p>Initially, Eren Demirpolat was mistakenly placed as the second author, although he should have been listed first according to contributorship. The author list has been revised as follows:</p><p>\u0000 <b>Eren Demirpolat</b>\u0000 <sup>\u0000 <b>1</b>\u0000 </sup>\u0000 <b>, Buse Kose Demirezen</b>\u0000 <sup>\u0000 <b>2</b>\u0000 </sup>\u0000 <b>, Arzu Yay</b>\u0000 <sup>\u0000 <b>3</b>\u0000 </sup>\u0000 <b>, Ozge Cengiz Mat</b>\u0000 <sup>\u0000 <b>4</b>\u0000 </sup>\u0000 <b>, Mustafa Ermis</b>\u0000 <sup>\u0000 <b>5</b>\u0000 </sup>\u0000 </p><p>We apologize for this error.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932782","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}
Nicolas Picard, Estelle Ayme-Dietrich, Sylvie Quaranta, Tiphaine Adam-De-Beaumais, Abd El Kader Ait Tayeb, Hugo Alarcan, Dorra Amor, David Barthelemy, Mouna Ben Sassi, Séverine Cunat, Mouna Daldoul, Hervé Delacour, Marie-Christine Etienne-Grimaldi, Xavier Fonrose, Benjamin Hennart, Louis Lebreton, Stephanie Malard, Céline Narjoz, Asma Omezzine, Nicolas Pallet, Léa Payen, Jeanne Petit, Fabienne Thomas, Sameh Trabelsi, Camille Tron, Céline Verstuyft, Paul Vilquin, Jean-Christophe Boyer, Vincent Haufroid, French-Speaking Network of Pharmacogenetics (RNPGx)
Background
The implementation of pharmacogenetics in clinical practice increasingly relies on multigene panels.
Objectives
The objective of this study is to develop harmonized recommendations for the design and analytical implementation of multigene pharmacogenetic panels, defining clinically relevant genes and associated regions of interest (ROIs) based on evidence strength, therapeutic applicability, and compatibility with genotyping or sequencing technologies.
Methods
The French-Speaking Network of Pharmacogenetics (RNPGx) evaluated 81 candidate genes across five therapeutic domains (i.e., oncology and supportive care, anesthesia and pain management, cardiology, neurology and psychiatry and immunology and infectious diseases) using a structured, evidence-based scoring system. Each gene was evaluated using a 25-point scoring system integrating pharmacogenetic importance, regulatory and professional society recommendations, and expert consensus. For the genes ultimately selected for the core panel, clinically relevant regions of interest were defined and assigned to one of three analytical classes. Class 1 includes variants with established clinical actionability; Class 2 adds optional variants suitable for extended testing in specialized settings; and Class 3 covers broader genomic regions mainly intended for rare variant or structural analyses.
Results
A 28-gene core panel was retained. Class 1 included 76 prioritized variants (including CYP2D6 CNV variants), and Class 2 comprised 62 additional variants (with extended analysis for CYP2D6). Class 3 eligibility was retained for 18 genes.
Conclusion
The RNPGx recommendations offer a harmonized and flexible framework for pharmacogenetic panel design and for the extraction and interpretation of pharmacogenetic data from whole-exome or whole-genome sequencing.
{"title":"French-Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Gene Panel Analysis Through Genotyping or Sequencing in Pharmacogenetics","authors":"Nicolas Picard, Estelle Ayme-Dietrich, Sylvie Quaranta, Tiphaine Adam-De-Beaumais, Abd El Kader Ait Tayeb, Hugo Alarcan, Dorra Amor, David Barthelemy, Mouna Ben Sassi, Séverine Cunat, Mouna Daldoul, Hervé Delacour, Marie-Christine Etienne-Grimaldi, Xavier Fonrose, Benjamin Hennart, Louis Lebreton, Stephanie Malard, Céline Narjoz, Asma Omezzine, Nicolas Pallet, Léa Payen, Jeanne Petit, Fabienne Thomas, Sameh Trabelsi, Camille Tron, Céline Verstuyft, Paul Vilquin, Jean-Christophe Boyer, Vincent Haufroid, French-Speaking Network of Pharmacogenetics (RNPGx)","doi":"10.1111/fcp.70068","DOIUrl":"10.1111/fcp.70068","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The implementation of pharmacogenetics in clinical practice increasingly relies on multigene panels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The objective of this study is to develop harmonized recommendations for the design and analytical implementation of multigene pharmacogenetic panels, defining clinically relevant genes and associated regions of interest (ROIs) based on evidence strength, therapeutic applicability, and compatibility with genotyping or sequencing technologies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The French-Speaking Network of Pharmacogenetics (RNPGx) evaluated 81 candidate genes across five therapeutic domains (i.e., oncology and supportive care, anesthesia and pain management, cardiology, neurology and psychiatry and immunology and infectious diseases) using a structured, evidence-based scoring system. Each gene was evaluated using a 25-point scoring system integrating pharmacogenetic importance, regulatory and professional society recommendations, and expert consensus. For the genes ultimately selected for the core panel, clinically relevant regions of interest were defined and assigned to one of three analytical classes. Class 1 includes variants with established clinical actionability; Class 2 adds optional variants suitable for extended testing in specialized settings; and Class 3 covers broader genomic regions mainly intended for rare variant or structural analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 28-gene core panel was retained. Class 1 included 76 prioritized variants (including CYP2D6 CNV variants), and Class 2 comprised 62 additional variants (with extended analysis for CYP2D6). Class 3 eligibility was retained for 18 genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The RNPGx recommendations offer a harmonized and flexible framework for pharmacogenetic panel design and for the extraction and interpretation of pharmacogenetic data from whole-exome or whole-genome sequencing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905981","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}
Receptor occupancy is an important indicator of drug efficacy. Pulsed drug delivery is aimed at accurately determining the dosing time on the basis of the onset rhythm.
Objective
Seeking analytical expressions to describe steady-state receptor occupancy and providing the essential principles that must be met when designing pulsed drug delivery.
Methods
We use a simplified model that integrates pharmacokinetics and binding kinetics to obtain analytical results.
Results
It was found that a Hill–Langmuir equation can integrate pharmacokinetics and pharmacodynamics and describe receptor occupancy under multiple-dose regimens and pulsed drug delivery without rapid equilibrium assumption. In this equation, the effective dissociation constant is the product of the elimination rate constant, the dosing interval, and the dissociation constant. Thus, the regulation of receptor occupancy by these three parameters has a mutual compensatory function. Regardless of the dosing regimen, the association rate constant mainly controls the rising rate and maximum receptor occupancy, whereas the dissociation rate constant determines the decline rate and maximum receptor occupancy and thus controls the stability of the binding kinetics. The regulation of receptor occupancy by the association and dissociation rate constants is consistent with the classical definition of binding affinity. These results may be useful for drug discovery.
Conclusion
When designing pulsed drug delivery, the elimination rate constant must be greater than the dose frequency. The association rate constant produces a fast effect, whereas the dissociation rate constant produces a slow but sustained effect.
{"title":"The Hill–Langmuir Equation Governs Drug–Target Binding Kinetics for Pulsed Drug Delivery","authors":"Xiaomin Shi","doi":"10.1111/fcp.70069","DOIUrl":"10.1111/fcp.70069","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Receptor occupancy is an important indicator of drug efficacy. Pulsed drug delivery is aimed at accurately determining the dosing time on the basis of the onset rhythm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Seeking analytical expressions to describe steady-state receptor occupancy and providing the essential principles that must be met when designing pulsed drug delivery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We use a simplified model that integrates pharmacokinetics and binding kinetics to obtain analytical results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>It was found that a Hill–Langmuir equation can integrate pharmacokinetics and pharmacodynamics and describe receptor occupancy under multiple-dose regimens and pulsed drug delivery without rapid equilibrium assumption. In this equation, the effective dissociation constant is the product of the elimination rate constant, the dosing interval, and the dissociation constant. Thus, the regulation of receptor occupancy by these three parameters has a mutual compensatory function. Regardless of the dosing regimen, the association rate constant mainly controls the rising rate and maximum receptor occupancy, whereas the dissociation rate constant determines the decline rate and maximum receptor occupancy and thus controls the stability of the binding kinetics. The regulation of receptor occupancy by the association and dissociation rate constants is consistent with the classical definition of binding affinity. These results may be useful for drug discovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>When designing pulsed drug delivery, the elimination rate constant must be greater than the dose frequency. The association rate constant produces a fast effect, whereas the dissociation rate constant produces a slow but sustained effect.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843550","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}
Zeinab Abbas, Clémence Lacroix, Elisabeth Jouve, Céline Eiden, Joelle Micallef, Hélène Peyrière, and the French Addictovigilance network
Background
The objective of this study was to assess the prevalence of dependence and abuse of psychoactive substances (PAS) among prison inmates, using data from the OPPIDUM program between 2013 and 2022.
Methods
OPPIDUM is an annual, cross-sectional national program, conducted among users consulting in specialised addiction centres. Prison inmates were questioned about their PAS use during the week preceding their incarceration. Two groups of participants were compared: prison inmates who reported simple use of PAS and those with abuse/dependence problems.
Results
A total of 2626 individuals responded to the program (men, 91.6%; mean age, 34.4 ± 9.30 years), reporting 5352 PAS. The main PAS consumed were cannabis (52.8%), cocaine/crack (28.6%), benzodiazepines (23.1%) and heroin (14.8%). Opioid substitution treatment (OST) was reported by 54.9% of participants. Several variables were associated with a significantly increased odds of abuse/dependence: intravenous use (OR, 4.608; 95% CI, 1.44–14.69; p = 0.01), PAS illegal acquisition (OR, 3.79; 95% CI, 2.19–6.58; p < 0.0001), heroin/speedball use (OR, 4.24; 95% CI, 1.16–15.48; p = 0.029) and cocaine/crack use (OR, 3.3; 95% CI, 1.47–7.39; p = 0.004). Conversely, being on OST protocol was associated with a lower odds of abuse/dependence (OR, 0.511; 95% CI, 0.28–0.93; p = 0.028).
Limitations and Conclusion
The main limitations of the study include self-reported PAS use without objective diagnoses, sometimes incomplete data on PAS use and incarceration and a sample biased toward inmates linked to substance abuse services, which likely overestimates the prevalence of PAS use. However, these results highlight the importance of assessing factors associated with substance abuse and dependence for appropriate prevention and management among prison inmates.
本研究的目的是利用2013年至2022年OPPIDUM项目的数据，评估监狱囚犯对精神活性物质（PAS）的依赖和滥用程度。方法OPPIDUM是一个年度、横断面的国家项目，在专门的成瘾中心对使用者进行咨询。监狱囚犯被询问了他们在被监禁前一周使用PAS的情况。研究人员对两组参与者进行了比较：报告单纯使用PAS的囚犯和有滥用/依赖问题的囚犯。结果共有2626人对该计划有反应（男性，91.6%，平均年龄34.4±9.30岁），报告5352 PAS。吸食大麻（52.8%）、可卡因/快克（28.6%）、苯二氮卓类药物（23.1%）和海洛因（14.8%）。54.9%的参与者报告了阿片替代治疗（OST）。有几个变量与滥用/依赖的几率显著增加有关：静脉注射（OR, 4.608; 95% CI, 1.44-14.69; p = 0.01），非法获取PAS (OR, 3.79; 95% CI, 2.19-6.58; p < 0.0001)，海洛因/速效球使用（OR, 4.24; 95% CI, 1.16-15.48; p = 0.029）和可卡因/快克使用（OR, 3.3; 95% CI, 1.47-7.39; p = 0.004）。相反，使用OST方案与较低的滥用/依赖几率相关（OR, 0.511; 95% CI, 0.28-0.93; p = 0.028）。该研究的主要局限性包括自我报告PAS使用情况而没有客观诊断，有时关于PAS使用和监禁的数据不完整，以及偏向于与药物滥用服务有关的囚犯的样本，这可能高估了PAS使用的普遍程度。然而，这些结果强调了评估与药物滥用和依赖有关的因素对监狱囚犯进行适当预防和管理的重要性。
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Humbert de Freminville, Laura Lucatelli, Marc Chanelière, Guillaume Grenet, Sabine Mainbourg, Rémy Boussageon
Neuropathic pain remains a complex condition to manage. While current literature provides best practice guidelines for the use of gabapentinoids in this indication, these recommendations are primarily based on randomised clinical trials (RCTs) and meta-analyses of varying methodological quality. To support evidence-based prescribing, we conducted an evaluation of the overall confidence in meta-analytic findings on the efficacy of gabapentinoid in adults. A systematic review of the meta-analyses of RCTs retrieved from the MEDLINE (PubMed) database was performed. The methodological quality of these meta-analyses was assessed using the AMSTAR 2 tool (A MeaSurement Tool to Assess systematic Reviews) and compared when available with the quality of evidence determined by the GRADE approach. Among the 16 included meta-analyses, 14 were rated as having ‘critically low’ quality, one as ‘low’ and one as ‘moderate’ according to AMSTAR 2. GRADE and AMSTAR 2 assessments were both available for six meta-analyses, but only one yielded a concordant result. According to AMSTAR 2, the highest-quality meta-analysis was the one published in the Cochrane Database of Systematic Reviews and concluded that more participants had substantial benefit (at least 50% pain relief or patient global impression change very much improved) with gabapentin at 1200 mg daily or greater than with placebo (in postherpetic neuralgia: RR = 1.8 [95% CI 1.5 to 2.1] and in painful diabetic neuropathy: RR = 1.9 [95% CI 1.5 to 2.3]). One limitation of this work is the inconsistent use of the term neuropathic pain, which may be defined differently across studies.
神经性疼痛仍然是一种复杂的疾病。虽然目前的文献提供了加巴喷丁类药物用于该适应症的最佳实践指南，但这些建议主要基于随机临床试验（rct）和不同方法学质量的荟萃分析。为了支持循证处方，我们对加巴喷丁类药物对成人疗效的meta分析结果的总体置信度进行了评估。对从MEDLINE （PubMed）数据库中检索的随机对照试验的meta分析进行系统回顾。使用AMSTAR 2工具（评估系统评价的测量工具）评估这些荟萃分析的方法学质量，并在可用时与GRADE方法确定的证据质量进行比较。在纳入的16项荟萃分析中，根据AMSTAR 2, 14项被评为“极低”质量，1项被评为“低”质量，1项被评为“中等”质量。GRADE和AMSTAR 2评估均可用于6项荟萃分析，但只有一项得出了一致的结果。根据AMSTAR 2，质量最高的荟萃分析是发表在Cochrane系统评价数据库上的荟萃分析，得出的结论是，与安慰剂相比，每天1200mg或更大剂量的加巴喷丁有更多的参与者获得了实质性的益处（至少50%的疼痛缓解或患者整体印象改变非常改善）（疱疹后神经痛：RR = 1.8 [95% CI 1.5至2.1]，疼痛性糖尿病神经病变：RR = 1.9 [95% CI 1.5至2.3]）。这项工作的一个局限性是术语神经性疼痛的使用不一致，在不同的研究中可能有不同的定义。
{"title":"Gabapentinoids and Neuropathic Pain: Evaluation of the Quality of Randomised Controlled Trials: An Umbrella Review","authors":"Humbert de Freminville, Laura Lucatelli, Marc Chanelière, Guillaume Grenet, Sabine Mainbourg, Rémy Boussageon","doi":"10.1111/fcp.70052","DOIUrl":"https://doi.org/10.1111/fcp.70052","url":null,"abstract":"<div>\u0000 \u0000 <p>Neuropathic pain remains a complex condition to manage. While current literature provides best practice guidelines for the use of gabapentinoids in this indication, these recommendations are primarily based on randomised clinical trials (RCTs) and meta-analyses of varying methodological quality. To support evidence-based prescribing, we conducted an evaluation of the overall confidence in meta-analytic findings on the efficacy of gabapentinoid in adults. A systematic review of the meta-analyses of RCTs retrieved from the MEDLINE (PubMed) database was performed. The methodological quality of these meta-analyses was assessed using the AMSTAR 2 tool (A MeaSurement Tool to Assess systematic Reviews) and compared when available with the quality of evidence determined by the GRADE approach. Among the 16 included meta-analyses, 14 were rated as having ‘critically low’ quality, one as ‘low’ and one as ‘moderate’ according to AMSTAR 2. GRADE and AMSTAR 2 assessments were both available for six meta-analyses, but only one yielded a concordant result. According to AMSTAR 2, the highest-quality meta-analysis was the one published in the Cochrane Database of Systematic Reviews and concluded that more participants had substantial benefit (at least 50% pain relief or patient global impression change very much improved) with gabapentin at 1200 mg daily or greater than with placebo (in postherpetic neuralgia: RR = 1.8 [95% CI 1.5 to 2.1] and in painful diabetic neuropathy: RR = 1.9 [95% CI 1.5 to 2.3]). One limitation of this work is the inconsistent use of the term neuropathic pain, which may be defined differently across studies.</p>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145739879","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}
Marianne Leger, Michel Boulouard, Christophe Liet, Ben Grayson, Michael Harte, Joanna C. Neill, Marie-Laure Bocca, Véronique Lelong-Boulouard
Rational
Zolpidem, a hypnotic Z-drug commonly prescribed to promote sleep, is predominantly used over the age of 50. In this elderly population, adverse behavioral disturbances, impaired driving performance, and an increased risk of falls have been frequently reported. These concerns have raised questions about the residual adverse effects of zolpidem in older adults, particularly on cognitive processes such as executive and attentional functions.
Objectives
This study aimed to investigate the residual effects of zolpidem on attentional performance following either acute or subchronic administration in aged rats.
Methods
A zolpidem dose of 3 mg/kg and a 3-h postadministration time point were selected based on pharmacokinetic data from the literature and a dose–response analysis of its locomotor effects in the open-field test. Attentional performance was then assessed in aged female rats treated with either saline or zolpidem (acutely or for 7 days), using the 5-choice continuous performance task (5C-CPT).
Results
Acute zolpidem administration significantly reduced the percentage of correct responses, increased correct response latency, and showed a trend toward more omissions, indicative of impaired attentional performance and psychomotor slowing. These effects were not further observed after subchronic treatment, suggesting a potential tolerance over time.
Conclusion
Our findings highlight a critical period of vulnerability following the initiation of zolpidem treatment, during which residual cognitive impairments may emerge. Such effects may compromise complex tasks requiring sustained attention and processing speed, such as driving, especially in older adults.
{"title":"Residual Effects of Acute and Subchronic Zolpidem Treatments on Attentional Processes in Aged Female Rats","authors":"Marianne Leger, Michel Boulouard, Christophe Liet, Ben Grayson, Michael Harte, Joanna C. Neill, Marie-Laure Bocca, Véronique Lelong-Boulouard","doi":"10.1111/fcp.70067","DOIUrl":"https://doi.org/10.1111/fcp.70067","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rational</h3>\u0000 \u0000 <p>Zolpidem, a hypnotic Z-drug commonly prescribed to promote sleep, is predominantly used over the age of 50. In this elderly population, adverse behavioral disturbances, impaired driving performance, and an increased risk of falls have been frequently reported. These concerns have raised questions about the residual adverse effects of zolpidem in older adults, particularly on cognitive processes such as executive and attentional functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to investigate the residual effects of zolpidem on attentional performance following either acute or subchronic administration in aged rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A zolpidem dose of 3 mg/kg and a 3-h postadministration time point were selected based on pharmacokinetic data from the literature and a dose–response analysis of its locomotor effects in the open-field test. Attentional performance was then assessed in aged female rats treated with either saline or zolpidem (acutely or for 7 days), using the 5-choice continuous performance task (5C-CPT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Acute zolpidem administration significantly reduced the percentage of correct responses, increased correct response latency, and showed a trend toward more omissions, indicative of impaired attentional performance and psychomotor slowing. These effects were not further observed after subchronic treatment, suggesting a potential tolerance over time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings highlight a critical period of vulnerability following the initiation of zolpidem treatment, during which residual cognitive impairments may emerge. Such effects may compromise complex tasks requiring sustained attention and processing speed, such as driving, especially in older adults.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719648","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}
Erwan Drezen, André Happe, Vincent Thevenet, Nicolas Penel, François Gouin, François Le Loarer, Gonzague Du Bouexic De Pinieux, Hugo Crochet, Claire Chemin Airiau, Françoise Ducimetiere, Simone Mathoulin Pelissier, Jean-Yves Blay, Emmanuel Oger
Background
DEEPSARC, one of the first projects running on the Health Data Hub, aimed to identify real-life treatment regimens that could improve overall survival. The project is based on matching the national database of the sarcoma reference network with the SNDS.
Objectives
We aimed to report a transparent description of the linking process and its results.
Methods
The sarcoma database encompasses 33 548 patients matching the selection criteria divided into three subsets: 13507 patients with a complete dataset gathering clinical and pathological data; 5844 patients with clinical data alone; and 14 197 patients with pathological data alone. As no ICD-10 code reliably identifies patients with sarcoma, the subpopulation extracted from the SNDS was extended to 3 million patients who underwent surgery for their cancer. An indirect record linkage process used a combination (called a signature) of so-called chaining variables to uniquely identify a pair of patients from each of the bases. Two metrics (signature robustness and overall quality) were calculated for ease of interpretation.
Results
The overall matching rate of 73.1% (24 539 pairs out of 33 548 observations), reaching 90.5% in the intersection of the sarcomas databases (with extended data, 12 225 pairs out of 13 507 observations).
Conclusion
An optimized and transparent process led to a moderate matching rate but enhanced the confidence in true matching. Representativeness is an issue related to the missing data pattern across the three NETSARC databases. For instance, an individual present only in the RREPS database has a greater probability of not being linked.
{"title":"Linking the NETSARC+ National Sarcoma Database With the SNDS to Evaluate Adjuvant and/or Neoadjuvant Therapy: Report on the Linkage Process and Result (Health Data Hub's DEEPSARC Pilot Project)","authors":"Erwan Drezen, André Happe, Vincent Thevenet, Nicolas Penel, François Gouin, François Le Loarer, Gonzague Du Bouexic De Pinieux, Hugo Crochet, Claire Chemin Airiau, Françoise Ducimetiere, Simone Mathoulin Pelissier, Jean-Yves Blay, Emmanuel Oger","doi":"10.1111/fcp.70066","DOIUrl":"https://doi.org/10.1111/fcp.70066","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>DEEPSARC, one of the first projects running on the Health Data Hub, aimed to identify real-life treatment regimens that could improve overall survival. The project is based on matching the national database of the sarcoma reference network with the SNDS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to report a transparent description of the linking process and its results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The sarcoma database encompasses 33 548 patients matching the selection criteria divided into three subsets: 13507 patients with a complete dataset gathering clinical and pathological data; 5844 patients with clinical data alone; and 14 197 patients with pathological data alone. As no ICD-10 code reliably identifies patients with sarcoma, the subpopulation extracted from the SNDS was extended to 3 million patients who underwent surgery for their cancer. An indirect record linkage process used a combination (called a signature) of so-called chaining variables to uniquely identify a pair of patients from each of the bases. Two metrics (signature robustness and overall quality) were calculated for ease of interpretation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The overall matching rate of 73.1% (24 539 pairs out of 33 548 observations), reaching 90.5% in the intersection of the sarcomas databases (with extended data, 12 225 pairs out of 13 507 observations).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>An optimized and transparent process led to a moderate matching rate but enhanced the confidence in true matching. Representativeness is an issue related to the missing data pattern across the three NETSARC databases. For instance, an individual present only in the RREPS database has a greater probability of not being linked.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.70066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730468","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}
Tuğçe Nomenoğlu, İbrahim Mert Yüksel, Soner Mamuk, Eyüp Sabri Akarsu
Background
Pattern recognition receptors (PRR) are responsible for detecting pathogens and danger signals in organisms. Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and some danger-associated molecular patterns (DAMPs). Activation of this receptor initiates sickness behavior. Fever is a hallmark of this process.
Objectives
We hypothesized that TLR4 signal inhibitors may have antipyretic activity. We evaluated the effect of TLR4 signal inhibitors on LPS or carrageenan-induced fever in male Wistar rats.
Methods
Core body temperature was measured via telemetric implants. Fever was induced by injection of LPS (E. coli O111:B4, 250 μg/kg, sc) or carrageenan (50 mg/kg, sc). For TLR4 signal inhibition, LPS from Rhodobacter sphaeroides (LPS-RS), IAXO-102, or naltrexone was used. Intracardiac blood samples were collected for measurement of interleukin-6 (IL-6), an endogenous pyrogen cytokine in plasma, by ELISA during the initial phase of LPS-induced fever.
Results
LPS-RS pretreatment (25 or 100 μg/kg, sc) did not inhibit LPS-induced fever and plasma IL-6 elevation. Other alternative TLR4 signal inhibitors, such as IAXO-102 (3 mg/kg, sc) or naltrexone (10 mg/kg, sc), also failed to abolish LPS-induced fever. An intriguing finding is that LPS-RS or naltrexone inhibited the fever caused by carrageenan.
Conclusion
Data show that TLR4 signal inhibitors have differential antipyretic activity on fever suggesting that some alternative or complementary mechanisms might be operational for LPS-induced fever. Data also suggest that TLR4 signal inhibitors may be an alternative as a possible treatment option for DAMP-mediated clinical pathologies.
{"title":"Differential Antipyretic Effects of Toll-Like Receptor 4 Signal Inhibitors in Male Rats","authors":"Tuğçe Nomenoğlu, İbrahim Mert Yüksel, Soner Mamuk, Eyüp Sabri Akarsu","doi":"10.1111/fcp.70059","DOIUrl":"10.1111/fcp.70059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pattern recognition receptors (PRR) are responsible for detecting pathogens and danger signals in organisms. Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and some danger-associated molecular patterns (DAMPs). Activation of this receptor initiates sickness behavior. Fever is a hallmark of this process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We hypothesized that TLR4 signal inhibitors may have antipyretic activity. We evaluated the effect of TLR4 signal inhibitors on LPS or carrageenan-induced fever in male Wistar rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Core body temperature was measured via telemetric implants. Fever was induced by injection of LPS (<i>E. coli</i> O111:B4, 250 μg/kg, sc) or carrageenan (50 mg/kg, sc). For TLR4 signal inhibition, LPS from <i>Rhodobacter sphaeroides</i> (LPS-RS), IAXO-102, or naltrexone was used. Intracardiac blood samples were collected for measurement of interleukin-6 (IL-6), an endogenous pyrogen cytokine in plasma, by ELISA during the initial phase of LPS-induced fever.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LPS-RS pretreatment (25 or 100 μg/kg, sc) did not inhibit LPS-induced fever and plasma IL-6 elevation. Other alternative TLR4 signal inhibitors, such as IAXO-102 (3 mg/kg, sc) or naltrexone (10 mg/kg, sc), also failed to abolish LPS-induced fever. An intriguing finding is that LPS-RS or naltrexone inhibited the fever caused by carrageenan.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Data show that TLR4 signal inhibitors have differential antipyretic activity on fever suggesting that some alternative or complementary mechanisms might be operational for LPS-induced fever. Data also suggest that TLR4 signal inhibitors may be an alternative as a possible treatment option for DAMP-mediated clinical pathologies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714143","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}
An-Kuo Chou, Chong-Chi Chiu, Yu-Wen Chen, Ching-Hsia Hung, Jhi-Joung Wang
The aim of this study was to examine the effects of intrathecal lidocaine combined with guanfacine or dexmedetomidine on nociceptive and motor blockade, in comparison to clonidine. Using a rat model of intrathecal injection, we evaluated the effects of lidocaine combined with guanfacine, dexmedetomidine, or clonidine on nociceptive and motor blockade. The dose-dependent effects of guanfacine on spinal nociceptive and motor blockade were compared to those of lidocaine, a well-known local anesthetic. Guanfacine (0.46 μmol/kg, 3 mM), dexmedetomidine (0.02 μmol/kg, 0.1 mM), or clonidine (1.52 μmol/kg, 10 mM) alone produced no spinal nociceptive or motor blockade. Co-administration of guanfacine (0.46 μmol/kg) or dexmedetomidine (0.02 μmol/kg) with lidocaine (3.14 or 8.38 μmol/kg) prolonged the duration of spinal blockade, an effect attenuated by yohimbine (0.76 μmol/kg), which alone produced no spinal nociceptive or motor blockade. In contrast, the addition of clonidine (1.52 μmol/kg) did not enhance the duration of lidocaine-induced spinal blockade. Guanfacine produced a dose-dependent spinal blockade of both nociceptive and motor functions. The potency ranking (ED50, 50% effective dose) of spinal blockade showed that guanfacine and lidocaine were equal. Guanfacine resulted in a markedly longer spinal block duration than lidocaine at equivalent anesthetic doses (ED25, ED50, and ED75). In summary, co-administration of subeffective doses of guanfacine or dexmedetomidine with lidocaine prolonged the duration of spinal blockade, likely involving α2-adrenergic receptors, whereas subeffective doses of clonidine did not. Guanfacine produced dose-dependent spinal blockade and was equipotent to lidocaine. At equianesthetic doses, guanfacine produced a longer duration of blockade than lidocaine.
{"title":"Comparative Analysis of Intrathecal Lidocaine Combined With Guanfacine or Dexmedetomidine on Nociceptive and Motor Blockade in Rats","authors":"An-Kuo Chou, Chong-Chi Chiu, Yu-Wen Chen, Ching-Hsia Hung, Jhi-Joung Wang","doi":"10.1111/fcp.70057","DOIUrl":"10.1111/fcp.70057","url":null,"abstract":"<div>\u0000 \u0000 <p>The aim of this study was to examine the effects of intrathecal lidocaine combined with guanfacine or dexmedetomidine on nociceptive and motor blockade, in comparison to clonidine. Using a rat model of intrathecal injection, we evaluated the effects of lidocaine combined with guanfacine, dexmedetomidine, or clonidine on nociceptive and motor blockade. The dose-dependent effects of guanfacine on spinal nociceptive and motor blockade were compared to those of lidocaine, a well-known local anesthetic. Guanfacine (0.46 μmol/kg, 3 mM), dexmedetomidine (0.02 μmol/kg, 0.1 mM), or clonidine (1.52 μmol/kg, 10 mM) alone produced no spinal nociceptive or motor blockade. Co-administration of guanfacine (0.46 μmol/kg) or dexmedetomidine (0.02 μmol/kg) with lidocaine (3.14 or 8.38 μmol/kg) prolonged the duration of spinal blockade, an effect attenuated by yohimbine (0.76 μmol/kg), which alone produced no spinal nociceptive or motor blockade. In contrast, the addition of clonidine (1.52 μmol/kg) did not enhance the duration of lidocaine-induced spinal blockade. Guanfacine produced a dose-dependent spinal blockade of both nociceptive and motor functions. The potency ranking (ED<sub>50</sub>, 50% effective dose) of spinal blockade showed that guanfacine and lidocaine were equal. Guanfacine resulted in a markedly longer spinal block duration than lidocaine at equivalent anesthetic doses (ED<sub>25</sub>, ED<sub>50</sub>, and ED<sub>75</sub>). In summary, co-administration of subeffective doses of guanfacine or dexmedetomidine with lidocaine prolonged the duration of spinal blockade, likely involving α2-adrenergic receptors, whereas subeffective doses of clonidine did not. Guanfacine produced dose-dependent spinal blockade and was equipotent to lidocaine. At equianesthetic doses, guanfacine produced a longer duration of blockade than lidocaine.</p>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"39 6","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563538","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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