Current Opinion in Pharmacology最新文献

英文中文

Pharmacological silence: Revisiting the clinical and molecular impact of inactive metabolites. 药理学沉默：重新审视非活性代谢物的临床和分子影响。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2026-01-20 DOI: 10.1016/j.coph.2026.102609

Ahmed M Abd-Eldayem

The conventional binary classification of drug metabolites as either pharmacologically active or inert has created a persistent blind spot in drug development and toxicology. By disproportionately emphasizing parent compounds, this paradigm relegates so-called 'inactive' derivatives to the margins of mechanistic inquiry, thereby obscuring the true complexity of drug action. Therefore, this review challenges the reductionist framework, consolidating compelling evidence that these ostensibly silent metabolites function as contextual modulators with biologically significant consequences. Emerging data implicate them in time-dependent inhibition (TDI) of cytochrome P450 enzymes, amplification of oxidative stress cascades through chemically reactive intermediates, and subtle modulation of neuroimmune and apoptotic thresholds. Moreover, their cumulative impact is magnified under conditions of chronic dosing, polypharmacy, or impaired metabolic clearance, where low-affinity interactions with secondary receptors and signaling pathways can reshape pharmacodynamic and pharmacokinetic outcomes. We propose reframing 'inactive' metabolites not as inert byproducts but as mechanistic amplifiers and modulators whose influence contributes to unforeseen toxicological profiles, idiosyncratic adverse reactions, and drug-drug interactions. Recognizing this overlooked dimension of metabolite biology is essential for advancing molecular screening, refining therapeutic drug monitoring, and improving the safety and efficacy profiles of both established and novel chemical entities.

传统的药物代谢产物的二元分类要么药理活性或惰性已经造成了一个持续的盲点在药物开发和毒理学。通过过分强调母体化合物，这种范式将所谓的“非活性”衍生物置于机械研究的边缘，从而模糊了药物作用的真正复杂性。因此，这篇综述挑战了还原论的框架，巩固了令人信服的证据，证明这些表面上沉默的代谢物作为具有生物学意义的环境调节剂起作用。新出现的数据表明，它们与细胞色素P450酶的时间依赖性抑制（TDI）、通过化学反应性中间体放大氧化应激级联以及神经免疫和凋亡阈值的微妙调节有关。此外，在慢性给药、多药或代谢清除受损的情况下，它们的累积影响会被放大，在这种情况下，与次级受体和信号通路的低亲和力相互作用会重塑药效学和药代动力学结果。我们建议重新定义“非活性”代谢物，而不是惰性副产物，而是机械放大器和调节剂，其影响有助于不可预见的毒理学特征，特殊不良反应和药物-药物相互作用。认识到代谢物生物学这一被忽视的维度，对于推进分子筛选、完善治疗药物监测、提高已建立和新化学实体的安全性和有效性至关重要。

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引用次数: 0

Guiding contributions to Current Opinion in Pharmacology 对药理学当前观点的指导性贡献。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.coph.2026.102610

Sheng-Tao Hou

引用次数: 0

Transcutaneous electrical nerve stimulation and opioid analgesia: Exploring a potential synergistic relationship. 经皮神经电刺激和阿片镇痛：探讨潜在的协同关系。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.coph.2026.102606

Chaoran Li, Ruocheng Xu, Yunjing Qiu, Weibo Sun, Tiansong Yang

Clinical analgesia requires balancing effective pain relief against opioid-related risks. Transcutaneous electrical nerve stimulation (TENS), a nonpharmacological and noninvasive modality, demonstrates synergistic potential with opioids, which may enhance analgesia, reduce opioid consumption, and minimize adverse effects. This review synthesizes evidence on TENS-opioid synergy, categorizes TENS modalities and parameters, and examines their interactive mechanisms. We discuss optimization strategies, including early TENS application, parameter individualization, and a "TENS + low-dose opioid" regimen. This combination represents a promising multimodal approach integrating pharmacological and nonpharmacological therapies, potentially improving outcomes while reducing opioid-related harms. Future work should prioritize rigorous pharmacological studies to confirm synergy, alongside multicenter trials, parameter optimization, development of intelligent personalized systems, and further mechanistic research to advance precision pain medicine.

临床镇痛需要平衡有效的疼痛缓解与阿片类药物相关的风险。经皮神经电刺激（TENS）是一种非药物和非侵入性的方式，具有与阿片类药物协同作用的潜力，可以增强镇痛作用，减少阿片类药物的消耗，并最大限度地减少不良反应。本文综合了关于TENS-阿片协同作用的证据，对TENS的模式和参数进行了分类，并探讨了它们的相互作用机制。我们讨论了优化策略，包括早期应用TENS、参数个性化和“TENS +低剂量阿片类药物”方案。这种结合代表了一种有前途的多模式方法，将药物和非药物治疗结合起来，可能改善结果，同时减少阿片类药物相关的危害。未来的工作应优先考虑严格的药理学研究，以确认协同作用，以及多中心试验，参数优化，智能个性化系统的开发，以及进一步的机制研究，以推进精准疼痛医学。

引用次数: 0

CPX-351: From preclinical studies to future directions CPX-351：从临床前研究到未来发展方向

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.coph.2026.102605

A. Sperotto , G. Ciotti , M. Basso , M. Gottardi

For decades, the standard induction treatment for patients with acute myeloid leukemia (AML) has been the 7 + 3 regimen (cytarabine plus daunorubicin). The US-Food and Drug Administration (FDA) approved, in August 2017, the use CPX-351 for adults with newly diagnosed secondary AML. CPX-351 (also known as VYXEOS) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin in a synergistic 5:1 M ratio, and CombiPlex was utilized, a combination drug technology platform. In this review, we analyze the path from preclinical studies to drug registration. Recent research highlights intestinal and heart toxicity of the drug, as well as current and potential future uses for CPX-351.

几十年来，急性髓性白血病（AML）患者的标准诱导治疗一直是7 + 3方案（阿糖胞苷加柔红霉素）。2017年8月，美国食品和药物管理局（FDA）批准将CPX-351用于新诊断的成人继发性AML。CPX-351（又称VYXEOS）是阿糖胞苷和柔红霉素的双药脂质体包封，协同比例为5:1 M，采用复合药物技术平台CombiPlex。在本文中，我们分析了从临床前研究到药物注册的路径。最近的研究强调了该药物的肠道和心脏毒性，以及CPX-351目前和未来的潜在用途。

引用次数: 0

Advancements in targeted therapies for acute myeloid leukemia 急性髓系白血病靶向治疗的进展

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.coph.2025.102604

Matthew P. Connor, Adam Barsouk, Omar Elghawy, Catherine Lai

For decades, the only therapeutic option for acute myeloid leukemia (AML) had been intensive combination chemotherapy. In recent years, understanding of the molecular mechanisms underlying myeloid oncogenesis has grown immensely and has led to the development of multiple effective small molecule inhibitors of aberrant cellular signaling. This review highlights the major AML mutational pathways currently being targeted with precision therapies: the receptor tyrosine kinase FLT3, the citric acid cycle enzymes IDH1 and IDH2, and the transcription-regulating KMT2A and NPM1 genes. We review the major clinical trials evaluating the safety and efficacy of agents targeting these pathways, as well as ongoing and upcoming studies of novel and combination therapies for these molecular subsets of AML.

几十年来，急性髓性白血病（AML）的唯一治疗选择是强化联合化疗。近年来，对髓系肿瘤发生的分子机制的理解得到了极大的发展，并导致了多种有效的小分子异常细胞信号抑制剂的开发。这篇综述强调了目前精确治疗的主要AML突变途径：受体酪氨酸激酶FLT3，柠檬酸循环酶IDH1和IDH2，以及转录调节基因KMT2A和NPM1。我们回顾了评估靶向这些途径的药物的安全性和有效性的主要临床试验，以及正在进行和即将进行的针对这些AML分子亚群的新型和联合治疗的研究。

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TMEM16A regulates MUC5AC production in airway diseases: A comprehensive review TMEM16A调控MUC5AC在气道疾病中的产生：一项全面的综述

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-12-22 DOI: 10.1016/j.coph.2025.102603

Jintao Gan , Xiaochun Huang , Danli Zhu , Jing Jia

Abnormal secretion of the airway mucin MUC5AC is a key pathological feature in the pathologic process of airway diseases, overproduction of MUC5AC leads to airway mucus accumulation and airway obstruction, which further triggers respiratory dysfunction and seriously threatens the health of patients. In recent years, studies have begun to focus on the role of transmembrane protein 16A (TMEM16A) in regulating the secretion of mucin MUC5AC in airway epithelial cells. Studies have shown that TMEM16A may play an important role in regulating MUC5AC secretion, and its precise regulation of MUC5AC profoundly affects the process of airway mucus secretion and inflammatory response, and plays a key role in the occurrence and development of airway diseases. In this paper, we mainly review the latest research progress of TMEM16A's effect on the production of mucus protein MUC5AC in airway diseases in recent years, aiming to provide new ideas and directions for the follow-up research in this field as well as for the optimization of clinical therapeutic strategies.

气道黏液蛋白MUC5AC的异常分泌是气道疾病病理过程中的一个关键病理特征，MUC5AC的过量分泌导致气道黏液积聚，气道阻塞，进而引发呼吸功能障碍，严重威胁患者的健康。近年来，跨膜蛋白16A （TMEM16A）在气道上皮细胞中调节粘蛋白MUC5AC分泌中的作用开始受到关注。研究表明，TMEM16A可能在调节MUC5AC分泌中发挥重要作用，其对MUC5AC的精准调控深刻影响气道粘液分泌和炎症反应过程，在气道疾病的发生发展中发挥关键作用。本文主要综述近年来TMEM16A对气道疾病中粘液蛋白MUC5AC产生影响的最新研究进展，旨在为该领域的后续研究以及临床治疗策略的优化提供新的思路和方向。

引用次数: 0

Targeting strategies and immune regulatory mechanisms of CAR-macrophages in the treatment of osteosarcoma car -巨噬细胞治疗骨肉瘤的靶向策略和免疫调节机制

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-12-22 DOI: 10.1016/j.coph.2025.102602

Rongrong Chai

Osteosarcoma (OS), the most common primary malignant bone tumor, poses significant clinical challenges owing to its high metastatic potential and resistance to chemotherapy. Although Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) has made significant progress in treating hematologic malignancies, its efficacy remains limited in solid tumors, such as OS. Chimeric antigen receptor macrophages (CAR-MΦ) represent an emerging cell therapy. It possesses potent phagocytic killing capabilities and inherent immune–modulatory properties. It has the unique potential to reshape the immunosuppressive microenvironment of OS. This review systematically outlines the target selection of CAR-MΦ in OS, its dual mechanisms of direct killing and indirect immune modulation, and thoroughly explores strategies to overcome tumor heterogeneity and immune suppression using CAR-MΦ approaches. Finally, it highlights the current challenges and future development directions. This emphasizes that CAR-MΦ therapy holds promise as a key breakthrough in overcoming the treatment bottleneck for OS. It is a key driver of the shift in the therapeutic paradigm from targeting cell toxicity to reshaping the immune microenvironment.

骨肉瘤（Osteosarcoma， OS）是最常见的原发性骨恶性肿瘤，由于其高转移潜力和对化疗的耐药性，给临床带来了重大挑战。尽管嵌合抗原受体t细胞免疫疗法（CAR-T）在治疗血液系统恶性肿瘤方面取得了重大进展，但其在实体肿瘤（如OS）中的疗效仍然有限。嵌合抗原受体巨噬细胞（CAR-MΦ）是一种新兴的细胞疗法。它具有强大的吞噬杀伤能力和固有的免疫调节特性。它具有重塑OS免疫抑制微环境的独特潜力。本文系统概述了CAR-MΦ在OS中的靶点选择，其直接杀伤和间接免疫调节的双重机制，并深入探讨了利用CAR-MΦ方法克服肿瘤异质性和免疫抑制的策略。最后，强调了当前面临的挑战和未来的发展方向。这强调CAR-MΦ疗法有望成为克服OS治疗瓶颈的关键突破。它是治疗范式从靶向细胞毒性到重塑免疫微环境转变的关键驱动因素。

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Modulating neuroimmune function: The key in taVNS therapy for neurological and psychiatric disorders 调节神经免疫功能：taVNS治疗神经和精神疾病的关键。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-12-13 DOI: 10.1016/j.coph.2025.102601

Xinjiang Zhang , Qi Zou , Jinling Zhang , Peijing Rong , Yu Wang

Numerous lines of evidence indicate that the inflammatory state of neural tissue plays a significant role in the pathogenesis of neurological and psychiatric disorders, with neuroinflammation contributing to the dysregulation of cellular immunity and heightened susceptibility to such disorders. Previous research has demonstrated that vagus nerve stimulation (VNS) can attenuate inflammatory responses in both central and peripheral tissues, thereby ameliorating certain neurological disorders and enhancing cognitive function in the brain. Transcutaneous auricular vagal nerve stimulation (taVNS) has been validated in both clinical and preclinical studies as a noninvasive, straightforward, and cost-effective VNS technique. Nevertheless, the mechanisms by which taVNS modulates immunopathological responses within brain tissue remain incompletely understood. Currently, there is a growing body of research investigating the modulation of neuroimmune function as a therapeutic approach for neurological and psychiatric disorders. Several studies have elucidated the molecular mechanisms through which taVNS alleviates depression and cognitive dysfunction by inhibiting central immune inflammation from various perspectives. This review initially delineates the immunoregulatory role of VNS technology and its therapeutic relevance within the central nervous system (CNS). Within the framework of neuroimmune regulation, it offers an exhaustive analysis of pertinent research concerning the application of taVNS in the treatment of neurological and psychiatric disorders, emphasizing the modulation of immunoinflammatory pathways. Furthermore, this review constructs a theoretical framework to elucidate the pathogenic mechanisms of neurological and psychiatric disorders. The investigation into the interaction between VNS and neuroimmune regulatory networks facilitates the identification and development of novel therapeutic targets and pathways.

许多证据表明，神经组织的炎症状态在神经和精神疾病的发病机制中起着重要作用，神经炎症导致细胞免疫失调，并增加对这类疾病的易感性。先前的研究表明，迷走神经刺激（VNS）可以减轻中枢和外周组织的炎症反应，从而改善某些神经系统疾病，增强大脑的认知功能。经皮耳迷走神经刺激（taVNS）在临床和临床前研究中都被证实是一种无创、直接、经济的VNS技术。然而，taVNS调节脑组织内免疫病理反应的机制仍不完全清楚。目前，越来越多的研究将神经免疫功能的调节作为神经和精神疾病的治疗方法。多项研究从多个角度阐明了taVNS通过抑制中枢免疫炎症减轻抑郁和认知功能障碍的分子机制。本文综述了VNS技术的免疫调节作用及其在中枢神经系统（CNS）中的治疗意义。在神经免疫调节的框架内，对taVNS在神经和精神疾病治疗中的应用的相关研究进行了详尽的分析，强调了免疫炎症途径的调节。此外，本文将构建一个理论框架来阐明神经和精神疾病的致病机制。研究VNS与神经免疫调节网络之间的相互作用有助于识别和开发新的治疗靶点和途径。

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引用次数: 0

Lipidomics-driven insights into acupuncture mechanisms: From dynamic signaling networks to multi-dimensional regulations 脂质组学对针灸机制的洞察：从动态信号网络到多维调节。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-12-11 DOI: 10.1016/j.coph.2025.102600

Xi Ruan , Junqi Zhou , Lizhexiong Song , Changfeng Hu , Xuanming Hu

This review summarizes lipidomics as a key approach to dissect the multi-dimensional regulatory mechanisms of acupuncture, and reveals the role of lipid networks serve as critical ‘molecular transducers’ in the conversion of mechanical stimulation to biochemical signals. It systematically illustrates how lipid molecules mediate acupuncture's integrative regulation of the ‘metabolic-immune-neurological’ system through five-dimensional networks, including metabolic reprogramming, transmembrane signaling transduction, immune microenvironment regulation, cell death regulation, and neuroepigenetic communication. By integrating advanced lipidomics technologies (including high-resolution mass spectrometry, spatial analysis, and single-cell platforms) with multi-omics approaches and artificial intelligence (AI)-driven predictive modeling, a precise three-dimensional map of ‘acupuncture point-lipid targets–effector pathways’ is constructed. Overcoming the technical challenges in lipid isomer detection and in vivo lipid imaging is crucial. This advancement will facilitate a paradigm shift in medicine by enabling precise, personalized acupuncture and moxibustion treatments guided by lipid biomarkers. It also highlights the scientific value of integrating systems biology with traditional medicine.

这篇综述总结了脂质组学作为剖析针灸多维调控机制的关键方法，并揭示了脂质网络在机械刺激转化为生化信号的过程中作为关键的“分子传感器”的作用。它系统地说明了脂质分子如何通过五维网络介导针灸对“代谢-免疫-神经”系统的综合调节，包括代谢重编程、跨膜信号转导、免疫微环境调节、细胞死亡调节和神经表观遗传通讯。通过将先进的脂质组学技术（包括高分辨率质谱、空间分析和单细胞平台）与多组学方法和人工智能（AI）驱动的预测建模相结合，构建了“穴位-脂质靶点-效应通路”的精确三维地图。克服脂质异构体检测和体内脂质成像的技术挑战是至关重要的。这一进步将促进医学范式的转变，通过脂质生物标志物的指导，实现精确、个性化的针灸治疗。它还突出了将系统生物学与传统医学相结合的科学价值。

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引用次数: 0

The underlying mechanisms of acupuncture for alleviating pain-induced negative emotions: Synergistic regulation of multiple brain regions 针刺减轻疼痛负性情绪的潜在机制：多脑区的协同调节

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology

Pub Date : 2025-12-08 DOI: 10.1016/j.coph.2025.102599

Zhen Liu , Chaoyang Zhang , Zelin Chen , Zhifang Xu , Tianyi Zhao

Brain regions associated with pain perception also subsume those involved in emotional regulation, which likely constitutes the physiological basis underlying the comorbidity of pain and negative emotions. Acupuncture has unique advantages compared with drugs. Studies have shown that acupuncture can achieve multi-targeted and bidirectional regulation, simultaneously improving pain and accompanying negative emotional symptoms without causing drug resistance or systemic toxicity. In the hippocampus, acupuncture may contribute to the regulation of painful emotional memory processing by inhibiting ventral hippocampal neuron apoptosis, promoting neurogenesis, and regulating synaptic plasticity. In the anterior cingulate cortex, acupuncture may partially reduce the perception and transmission of pain-related emotions by inhibiting the release of glutamate and the expression of its receptors, enhancing the inhibitory effect of GABAergic receptors. In the medial prefrontal cortex, acupuncture might alleviate inflammatory responses by inhibiting microglial activation and the release of pro-inflammatory cytokines, thereby preserving the integrity of the descending regulatory circuit for painful emotions. This protects the integrity of the descending pain-emotion regulatory circuit. In the amygdala, acupuncture may improve reward deficiency and fear-related abnormal synaptic plasticity by regulating the expression of dopamine receptors, thus avoiding the excessive amplification of pain emotions. This article reviews the mechanisms by which acupuncture improves the induced negative emotions, which is helpful to promote the integration of acupuncture as a complementary approach into the precision medical treatment system for chronic pain-induced anxiety, depression, or comorbidities, and provides a scientific basis for the application of non-pharmacological therapies in neuropsychiatric disorders.

与疼痛感知相关的大脑区域也包括那些参与情绪调节的区域，这可能构成了疼痛和负面情绪并存的生理基础。与药物相比，针灸具有独特的优势。研究表明，针灸可以实现多靶点、双向调节，同时改善疼痛和伴随的负面情绪症状，而不会产生耐药性和全身毒性。在海马体中，针刺可能通过抑制海马腹侧神经元凋亡、促进神经发生、调节突触可塑性来调节痛苦情绪记忆加工。在前扣带皮层，针刺可能通过抑制谷氨酸的释放及其受体的表达，增强gaba能受体的抑制作用，部分减少疼痛相关情绪的感知和传递。在内侧前额叶皮层，针灸可能通过抑制小胶质细胞的激活和促炎细胞因子的释放来减轻炎症反应，从而保持疼痛情绪下行调节回路的完整性。这保护了下行疼痛-情绪调节回路的完整性。在杏仁核中，针刺可能通过调节多巴胺受体的表达来改善奖励缺失和恐惧相关的突触异常可塑性，从而避免疼痛情绪的过度放大。本文综述了针刺改善负性情绪的机制，有助于促进针刺作为一种辅助手段融入慢性疼痛性焦虑、抑郁或合并症的精准医疗体系，并为非药物治疗在神经精神疾病中的应用提供科学依据。

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