Fundamental & Clinical Pharmacology最新文献

英文中文

Psilocybin as Transformative Fast-Acting Antidepressant: Pharmacological Properties and Molecular Mechanisms 裸盖菇素作为变革性速效抗抑郁药：药理学性质和分子机制

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-07-16 DOI: 10.1111/fcp.70038

Makiath Adebo, Mathilda Bonnet, Ons Laouej, Celine Defaix, Josephine C. McGowan, Florence Butlen-Ducuing, Denis J. David, Erwan Poupon, Laurent Tritschler, Alain M. Gardier

In the 1950s–60s, serotonergic psychedelic drugs were studied as potential adjuvants to psychotherapy to treat addiction and alcoholism. However, starting in the 70s, preclinical and clinical studies on psychedelics stopped for decades because legislation controlled its recreational use, citing their hallucinogenic and psychotomimetic effects, as well as their abuse potential. Amazingly, we are witnessing an impressive return of these drugs due to recent clinical trials suggesting a therapeutic potential of psychedelics, among them psilocybin, for treating patients with depression resistant to conventional antidepressant drugs. Yet, their underlying mechanisms of action remain incompletely elucidated. This review provides an update on seminal clinical trials using psilocybin, as well as preclinical work uncovering the pharmacological properties and experimental pharmacology of psilocybin and its active metabolite psilocin. These drugs are primarily serotonin 5-HT_2A receptor (5-HT2AR) agonists. Although there is a consensus that 5-HT2AR activation mediates its psychedelic effects in human and rodent models of anxiety/depression, its role in psilocin's antidepressant effects remains controversial. This review also provides an overview of neurotransmitter systems, neuroplasticity, and neural circuits activated by psilocin. Further research in developing effective antidepressants for depression is prescient now more than ever, as according to the World Health Organization (WHO), depression will be the main cause of disability in 2030. Understanding the mechanisms through which psilocybin/psilocin would be an effective antidepressant is crucial to ultimately validate its therapeutic potential when combined with SSRIs/SNRIs in mood disorders.

在20世纪50年代至60年代，5 -羟色胺类迷幻药被研究作为治疗成瘾和酒精中毒的心理治疗的潜在辅助剂。然而，从20世纪70年代开始，对致幻剂的临床前和临床研究停止了几十年，因为立法限制了其娱乐用途，理由是它们的致幻和拟精神作用，以及它们的滥用潜力。令人惊讶的是，由于最近的临床试验表明致幻剂（其中包括裸盖菇素）在治疗对传统抗抑郁药物产生抗药性的抑郁症患者方面具有治疗潜力，我们正在见证这些药物的令人印象深刻的回归。然而，它们的潜在作用机制仍未完全阐明。本文综述了裸盖菇素的开创性临床试验的最新进展，以及裸盖菇素及其活性代谢物裸盖菇素的药理学性质和实验药理学的临床前工作。这些药物主要是5-羟色胺5-HT2A受体（5-HT2AR）激动剂。尽管人们一致认为5-HT2AR激活介导了人类和啮齿动物焦虑/抑郁模型的迷幻作用，但其在裸草素抗抑郁作用中的作用仍存在争议。这篇综述也提供了神经递质系统，神经可塑性和神经回路激活的psilocin的概述。现在比以往任何时候都更有先见之明，因为根据世界卫生组织（世卫组织）的数据，到2030年，抑郁症将成为导致残疾的主要原因。了解裸盖菇素/裸盖菇素成为有效抗抑郁药的机制对于最终验证其与SSRIs/SNRIs联合治疗情绪障碍的治疗潜力至关重要。

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引用次数: 0

Safety of Proton Pump Inhibitor in Paediatrics: A Study Based on EudraVigilance Data 质子泵抑制剂在儿科的安全性：基于EudraVigilance数据的研究

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-07-07 DOI: 10.1111/fcp.70036

Greta Santi Laurini, Victoria Nikitina, Nicola Montanaro, Domenico Motola

Background and Objectives

Despite limited paediatric approvals, the use of proton pump inhibitors (PPIs) among children has increased in recent years, and concerns have arisen about their safety, including the risk of allergies. To provide additional evidence on the paediatric safety of PPIs, we performed a study on suspected adverse drug reactions (ADRs) in clinical practice.

Methods

We retrieved from EudraVigilance reports of suspected ADRs for PPIs in the age class 0–11 years in the period 2003–2022. Most reported ADRs and allergic conditions were evaluated by descriptive analysis. A case-non-case analysis was performed using reporting odds ratio (ROR) with a 95% confidence interval (CI). Chi-square or Fisher's exact tests were used to detect differences in reporting rates.

Results

A total of 1389 reports and 4157 suspected ADRs were analysed. Most reports involved omeprazole (46.9%) and esomeprazole (27.3%), and 75.8% concerned serious outcomes. Gastrointestinal disorders were among the most common suspected ADRs, with vomiting being the most frequently reported (2.3%). Among allergic conditions, there were six cases of toxic epidermal necrolysis, five of Stevens–Johnson syndrome and four of drug reaction with eosinophilia and systemic symptoms. Statistically significant reactions for omeprazole were choking (ROR 5.54; 95% CI, 1.04–29.56) and pneumonia (3.61; 1.41–9.20), while for esomeprazole gastrointestinal disorder (7.57; 1.18–48.60) and constipation (4.74; 2.25–9.98).

Conclusions

Most common suspected ADRs reported with paediatric PPI use in Europe were gastrointestinal disorders, consistent with the safety profile in the product license. However, a high proportion of serious ADRs and few cases of severe cutaneous adverse reactions were reported.

背景和目的尽管儿科批准有限，但近年来质子泵抑制剂（PPIs）在儿童中的使用有所增加，人们对其安全性（包括过敏风险）的担忧也有所增加。为了提供关于PPIs的儿科安全性的额外证据，我们在临床实践中对疑似药物不良反应（adr）进行了研究。方法我们从2003-2022年0-11岁年龄段的PPIs疑似不良反应的EudraVigilance报告中检索。大多数报告的不良反应和过敏情况通过描述性分析进行评估。采用报告优势比（ROR）进行病例-非病例分析，置信区间为95%。使用卡方检验或费雪精确检验来检测报告率的差异。结果共分析报告1389份，疑似不良反应4157份。大多数报告涉及奥美拉唑（46.9%）和埃索美拉唑（27.3%），75.8%涉及严重后果。胃肠道疾病是最常见的疑似不良反应，呕吐是最常见的报告（2.3%）。其中，中毒性表皮坏死松解6例，Stevens-Johnson综合征5例，药物反应伴嗜酸性粒细胞增多及全身症状4例。奥美拉唑有统计学意义的反应是窒息(ROR 5.54；95% CI, 1.04-29.56)和肺炎(3.61；1.41-9.20)，埃索美拉唑胃肠道疾病(7.57；1.18-48.60)和便秘(4.74；2.25 - -9.98)。结论：欧洲报告的儿科PPI最常见的疑似不良反应是胃肠道疾病，这与产品许可中的安全性相符。然而，严重不良反应的比例很高，严重皮肤不良反应的病例很少报道。

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引用次数: 0

DPD Ultra-Rapid Metabolizer Status and Efficacy of 5-Fluorouracil Treatment: A Real-World Study 5-氟尿嘧啶治疗DPD超快速代谢状态和疗效：一项现实世界研究

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-07-07 DOI: 10.1111/fcp.70035

Govind Kallee, Gérard Milano, Florence Duffaud, Laetitia Dahan, Joseph Ciccolini

Background

Anticancer drug 5FU is extensively metabolized by dihydropyrimidine dehydrogenase (DPD), an enzyme with high interindividual variability. Poor metabolizer (PM, i.e., DPD deficient) patients are at risk of life-threatening toxicities. Whether ultra-rapid metabolizer (UM) status could conversely compromise 5FU efficacy remains to be investigated.

Methods

In this real-world study, 352 adult patients treated with a 5FU-containing regimen were screened. Patients were classified as normal (extensive metabolizer, EM), PM, or UM on DPD function based upon baseline plasma uracil monitoring. The impact of DPD status on efficacy and safety endpoints was investigated.

Results

Patients were categorized on DPD as UM (11.9%), EM (75.9%), and PM (12.2%). The response rate was 54.5%, with median PFS and OS of 13.9 and 19 months, respectively. PM patients were treated with an average 13% lower 5FU starting dose. There was no statistical difference in efficacy between UM and other patients. Severe toxicities were observed in less than 5% of patients, an incidence significantly lower than commonly reported with 5FU-containing regimen and was comparable between UM, EM, and PM patients. Our observations suggest that UM status is not associated with the lack of efficacy of 5FU. In addition, upfront DPD testing with adaptive dosing helps to reduce the incidence of severe toxicities, as PM patients on reduced doses did not have more severe toxicities than other patients treated with standard doses, while exhibiting similar efficacy in terms of response rate and survival.

Conclusion

When upfront DPD screening with adaptive dosing is performed, no difference is observed between UM, EM, and PM patients in terms of efficacy and safety.

Trial Registration

#PADSA3GKW7

抗癌药物5FU被二氢嘧啶脱氢酶（DPD）广泛代谢，这是一种具有高度个体差异的酶。代谢不良（PM，即DPD缺乏）的患者有发生危及生命的毒性的危险。超快速代谢（UM）状态是否会反过来影响5FU的疗效仍有待研究。方法在这项现实世界的研究中，筛选了352名接受含5fu方案治疗的成年患者。根据基线血浆尿嘧啶监测，将患者分为DPD功能正常（广泛代谢物，EM）、PM或UM。研究了DPD状态对疗效和安全性终点的影响。结果DPD患者分为UM（11.9%）、EM（75.9%）和PM（12.2%）。有效率为54.5%，中位PFS和OS分别为13.9个月和19个月。PM患者的5FU起始剂量平均降低13%。UM与其他患者的疗效无统计学差异。在不到5%的患者中观察到严重毒性，发生率显著低于通常报道的含5fu方案，并且在UM， EM和PM患者之间具有可比性。我们的观察表明，UM状态与5FU疗效的缺乏无关。此外，采用适应性剂量的前期DPD测试有助于减少严重毒性的发生率，因为减少剂量的PM患者没有比其他接受标准剂量治疗的患者更严重的毒性，而在缓解率和生存方面表现出相似的疗效。结论采用适应性给药的前期DPD筛查，UM、EM和PM患者在疗效和安全性方面均无差异。试验注册#PADSA3GKW7

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引用次数: 0

Effects of FECH Gene Polymorphisms and Serum Ferrochelatase Levels on Antituberculosis Drug-Induced Liver Injury in China FECH基因多态性和血清铁螯合酶水平对中国抗结核药物性肝损伤的影响

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-29 DOI: 10.1111/fcp.70034

Jingru Cheng, Nannan Wang, Ruina Chen, Hongqiu Pan, Lihuan Lu, Meiling Zhang, Xiaomin He, Honggang Yi, Shaowen Tang

Objectives

The pathogenic mechanism of antituberculosis drug-induced liver injury (ATLI) has not been elucidated. This study aimed to investigate the effects of FECH genetic polymorphisms and serum ferrochelatase levels on ATLI in the Chinese population.

Methods

One case–control study was conducted to investigate the association between four SNPs in FECH gene and ATLI, while another was used to analyze the association of serum ferrochelatase levels at three different times with ATLI. Multivariate logistic regression model was used to screen potential risk factors for ATLI, and the results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the performance for distinguishing ATLI cases from controls.

Results

Serum ferrochelatase levels were lower in ATLI cases than in controls at the time of baseline test, the first test and the second test after initial treatment. A multivariate logistic regression model showed that SNP rs536560 in the FECH gene (OR = 2.063, 95%CI: 1.112–3.892, p = 0.023), baseline serum ferrochelatase level (OR = 3.162, 95%CI: 1.605–6.234, p = 0.001), and liver disease history (OR = 2.915, 95%CI: 1.301–6.461, p = 0.008) were the risk factors for ATLI. The ROC curves demonstrated that the model including the above three factors has strong discriminating ability (AUC = 0.709, 95%CI: 0.639–0.779, p < 0.0001).

Conclusions

This study is the first to explore the relationships between SNPs in the FECH gene, serum ferrochelatase levels, and ATLI in China, and SNP rs536560 in the FECH gene, baseline ferrochelatase level, and liver disease history may be associated with susceptibility to ATLI.

目的尚不清楚抗结核药物性肝损伤（ATLI）的发病机制。本研究旨在探讨中国人群FECH基因多态性和血清铁螯合酶水平对ATLI的影响。方法采用1例病例对照研究FECH基因4个snp与ATLI的关系，1例病例对照研究3个不同时间血清铁螯合酶水平与ATLI的关系。采用多因素logistic回归模型筛选ATLI的潜在危险因素，结果以95%置信区间（ci）的比值比（ORs）表示。计算受试者工作特征曲线下面积（AUC），以估计区分ATLI病例与对照组的性能。结果ATLI患者血清铁螯合酶水平在基线试验、第一次试验和初次治疗后第二次试验时均低于对照组。多因素logistic回归模型显示，FECH基因SNP rs536560 （OR = 2.063, 95%CI: 1.112 ~ 3.892, p = 0.023）、血清铁螯合酶基线水平（OR = 3.162, 95%CI: 1.605 ~ 6.234, p = 0.001）和肝脏疾病史（OR = 2.915, 95%CI: 1.301 ~ 6.461, p = 0.008）是ATLI的危险因素。ROC曲线显示，包含上述三个因素的模型具有较强的判别能力（AUC = 0.709, 95%CI: 0.639 ~ 0.779, p < 0.0001）。结论本研究首次探讨了中国人FECH基因SNP、血清铁螯合酶水平和ATLI之间的关系，以及FECH基因SNP rs536560、铁螯合酶基线水平和肝脏疾病史可能与ATLI易感性相关。

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引用次数: 0

Differential Effects of Prenatal Poly I:C Exposure and Antipsychotics on NMDA/GABA Receptors and GSK3β-Mediated Signaling in the Dorsal Raphe Nucleus of Female Rats 产前Poly I:C暴露和抗精神病药物对雌性大鼠中缝背核NMDA/GABA受体和gsk3 β介导的信号传导的差异影响

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-25 DOI: 10.1111/fcp.70033

Shiyan Chen, Jiamei Lian, Yueqing Su, Chao Deng

Background

The dorsal raphe nucleus (DRN) is the origin of the 5-HT neurotransmission pathways. The 5-HT, dopamine D2, GABA, and NMDA receptors, as well as the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and G protein-independent protein kinase B (PKB/Akt)-glycogen synthase kinase 3β (GSK3β) signaling, are involved in the pathophysiology of schizophrenia and are modulated by antipsychotics. However, their pathological changes and antipsychotic modulations in the DRN are not well understood in schizophrenia.

Objectives

This study explored effects of antipsychotics on NMDA and GABA_A receptors, as well as PKA, AKT-GSK3β, cAMP-responsive element-binding protein 1 (CREB1), and disheveled (Dvl)-β-catenin signaling in the DRN using a maternal immune activation rat model.

Methods

Prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure was delivered at gestational Day 15. Female rats were treated with risperidone, olanzapine, or vehicle from postnatal day 70 for 35 days.

Results

Prenatal Poly I:C exposure increased mRNA expression of NMDA receptor Grin2a/2b subunits, the GABA_A receptor β3 subunit, glutamic acid decarboxylase 1 (GAD1), AKT1/3, and GSK3β in the DRN. Antipsychotics significantly increased the mRNA expression of PKA, CREB1, β-catenin, GSK3β, and Grin2d subunits in the DRN of Poly I:C rats. Prenatal Poly I:C exposure led to decreased expression of GAD2, which was partially reversed antipsychotics.

Conclusion

This study suggests that prenatal Poly I:C exposure and antipsychotics differentially modulate NMDA and GABA_A receptors, as well as AKT-GSK3β, PKA-CREB1, and Dvl-β-catenin signaling in the DRN of rats. Poly I:C mainly influenced the AKT-GSK3β signaling, while antipsychotics modulated the AKT-GSK3β, PKA-CREB1, and Dvl-GSK3β-β-catenin signaling pathways in the DRN.

中缝背核（DRN）是5-HT神经传递通路的起源。5-HT、多巴胺D2、GABA和NMDA受体以及环腺苷单磷酸(cAMP)-蛋白激酶A （PKA）和G蛋白独立蛋白激酶B (PKB/Akt)-糖原合成酶激酶3β (GSK3β)信号通路参与了精神分裂症的病理生理，并受到抗精神病药物的调节。然而，它们在精神分裂症中的病理改变和DRN的抗精神病调节作用尚不清楚。目的利用母体免疫激活大鼠模型，探讨抗精神病药物对DRN中NMDA和GABAA受体以及PKA、AKT-GSK3β、cAMP-responsive element-binding protein 1 （CREB1）和disheveled (Dvl)-β-catenin信号的影响。方法在妊娠第15天给予产前多核糖素-多核糖素（Poly I:C）暴露。雌性大鼠从出生后第70天开始分别给予利培酮、奥氮平或对照物治疗，持续35天。结果产前Poly I:C暴露增加了DRN中NMDA受体Grin2a/2b亚基、GABAA受体β3亚基、谷氨酸脱羧酶1 （GAD1）、AKT1/3和GSK3β mRNA的表达。抗精神病药物显著增加Poly I:C大鼠DRN中PKA、CREB1、β-catenin、GSK3β和Grin2d亚基的mRNA表达。产前Poly I:C暴露导致GAD2表达降低，部分逆转抗精神病药物的作用。结论产前Poly I:C暴露和抗精神病药物对大鼠DRN中NMDA和GABAA受体以及AKT-GSK3β、PKA-CREB1和Dvl-β-catenin信号通路的影响存在差异。Poly I:C主要影响AKT-GSK3β信号通路，而抗精神病药物则调节DRN中AKT-GSK3β、PKA-CREB1和Dvl-GSK3β-β-catenin信号通路。

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引用次数: 0

Master 2 award 二级大师奖

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-23 DOI: 10.1111/fcp.70019

引用次数: 0

Discussed poster abstracts—PM2 讨论海报摘要- pm2

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-23 DOI: 10.1111/fcp.70022

引用次数: 0

Drug news and therapeutic news 药物新闻和治疗新闻

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-23 DOI: 10.1111/fcp.70017

引用次数: 0

Oral communication abstracts 口头交流摘要

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-23 DOI: 10.1111/fcp.70018

引用次数: 0

Thesis awards 论文奖

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-06-23 DOI: 10.1111/fcp.70020

引用次数: 0

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