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Efficacy and safety of transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor in the treatment of advanced hepatocellular carcinoma: A meta-analysis 经动脉化疗栓塞联合来伐替尼和PD-1抑制剂治疗晚期肝细胞癌的有效性和安全性:一项荟萃分析。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-03-16 DOI: 10.1016/j.pharmthera.2024.108634
Lei Wang , Li Lin , Wei Zhou

The study aims to evaluate the benefits and potential adverse effects of transarterial chemoembolization (TACE) combined with lenvatinib and programmed cell death 1 (PD-1) protein inhibitors in the treatment of advanced hepatocellular carcinoma (HCC). A systematic literature search of several databases for relevant studies, published from inception up to May 2023, was performed. Clinical trials investigating TACE combined with lenvatinib and PD-1 inhibitors compared with other treatment regimens for advanced HCC were included. Data were pooled using fixed- or random-effects models and expressed as hazard ratios (HRs) or risk ratios (RRs) with corresponding 95% confidence interval (CI). Trial sequential analysis was used to determine whether the study results were sufficiently conclusive. Totally thirteen cohort studies comprising 1279 patients were included. The combined use of TACE, lenvatinib, and PD-1 inhibitors significantly improved overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) compared with other treatment regimens. The incidences of all-grade or grade ≥ 3 adverse events were comparable and did not differ significantly between the two groups. Prognostic factor analysis identified treatment options, portal vein tumor thrombus, extrahepatic metastasis, and Barcelona Clinic Liver Cancer (BCLC) stage as independent prognostic factors for OS. Extrahepatic metastasis, Child–Pugh score, and hepatic vein invasion emerged as independent prognostic factors for PFS. TSA suggested that the available data were adequate for drawing numerical conclusions regarding ORR and DCR. An approach combining TACE, lenvatinib, and PD-1 inhibitors appeared to offer significant improvements in OS, PFS, ORR, and DCR in patients with advanced HCC without significantly increasing the risk for all-grade adverse events.

本研究旨在评估经动脉化疗栓塞术(TACE)联合来伐替尼和程序性细胞死亡1(PD-1)蛋白抑制剂治疗晚期肝细胞癌(HCC)的益处和潜在不良反应。我们在多个数据库中系统检索了从开始到2023年5月发表的相关研究文献。纳入了研究TACE联合来伐替尼和PD-1抑制剂与其他晚期HCC治疗方案比较的临床试验。采用固定效应或随机效应模型对数据进行汇总,并以危险比(HRs)或风险比(RRs)及相应的95%置信区间(CI)表示。试验序列分析用于确定研究结果是否具有足够的结论性。共纳入了 13 项队列研究,包括 1279 名患者。与其他治疗方案相比,联合使用TACE、来伐替尼和PD-1抑制剂可显著提高总生存期(OS)、无进展生存期(PFS)、客观反应率(ORR)和疾病控制率(DCR)。所有级别或≥3级不良事件的发生率相当,两组之间无明显差异。预后因素分析表明,治疗方案、门静脉瘤栓、肝外转移和巴塞罗那临床肝癌(BCLC)分期是影响OS的独立预后因素。肝外转移、Child-Pugh评分和肝静脉侵犯则是影响PFS的独立预后因素。TSA认为,现有数据足以得出ORR和DCR的数字结论。结合TACE、来伐替尼和PD-1抑制剂的方法似乎能显著改善晚期HCC患者的OS、PFS、ORR和DCR,而不会明显增加所有级别不良事件的风险。
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引用次数: 0
Orthotopic and metastatic tumour models in preclinical cancer research 临床前癌症研究中的正位和转移性肿瘤模型。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-03-11 DOI: 10.1016/j.pharmthera.2024.108631
Stephen M. Stribbling , Callum Beach , Anderson J. Ryan

Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug discovery, but there is growing recognition of the importance of the more complex orthotopic and metastatic tumour models for understanding both target biology in the correct tissue context, and the impact of the tumour microenvironment and the immune system in responses to treatment. The aim of this review is to highlight the value that orthotopic and metastatic models bring to the study of tumour biology and drug development while pointing out those models that are most likely to be encountered in the literature. Important developments in orthotopic models, such as the increasing use of early passage patient material (PDXs, organoids) and humanised mouse models are discussed, as these approaches have the potential to increase the predictive value of preclinical studies, and ultimately improve the success rate of anticancer drugs in clinical trials.

小鼠疾病模型在癌症药物开发的各个阶段都起着举足轻重的作用。细胞系衍生的皮下肿瘤模型在早期药物发现中占主导地位,但越来越多的人认识到更复杂的原位和转移肿瘤模型对于了解正确组织背景下的靶点生物学以及肿瘤微环境和免疫系统对治疗反应的影响的重要性。本综述旨在强调原位和转移瘤模型对肿瘤生物学研究和药物开发的价值,同时指出文献中最有可能出现的模型。本文讨论了正位模型的重要发展,如越来越多地使用早期病人材料(PDXs、organoids)和人源化小鼠模型,因为这些方法有可能提高临床前研究的预测价值,并最终提高抗癌药物在临床试验中的成功率。
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引用次数: 0
Immunotherapy for depression: Recent insights and future targets 抑郁症的免疫疗法:最新见解和未来目标
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-03-03 DOI: 10.1016/j.pharmthera.2024.108624
Ying Bai , Yang Cai , Di Chang , Daxing Li , Xinchen Huo , Tianhao Zhu

Depression stands as a prominent contributor to global disability, entailing an elevated risk of suicide. Substantial evidence supports the notion that immune dysregulation may play a role in the development of depression and impede responses to antidepressant treatments. Immune dysregulation may cause depression in susceptible individuals through raising inflammatory responses. Differences in immune cell types and the release of pro-inflammatory mediators are observed in the blood and cerebrospinal fluid of patients with major depressive disorder, which is associated with neuroimmune dysfunction. Therefore, the interaction of peripheral and central immune targets in depression needs to be understood. Urgent attention is required for the development of innovative therapeutics directed at modulating immune responses for the treatment of depression. This review delineates the immune mechanisms involved in the pathogenesis of depression, assesses the therapeutic potential of immune system targeting for depression treatment, and deliberates on the merits and constraints of employing immunotherapy in the management of depression.

抑郁症是导致全球残疾的一个重要因素,同时也增加了自杀的风险。大量证据表明,免疫失调可能在抑郁症的发病过程中起作用,并阻碍对抗抑郁治疗的反应。免疫失调可能会通过提高炎症反应导致易感人群患上抑郁症。在重度抑郁症患者的血液和脑脊液中可以观察到免疫细胞类型的差异和促炎介质的释放,这与神经免疫功能紊乱有关。因此,需要了解抑郁症中外周和中枢免疫靶点的相互作用。开发旨在调节免疫反应的创新疗法以治疗抑郁症刻不容缓。本综述阐述了抑郁症发病机制中涉及的免疫机制,评估了以免疫系统为靶点治疗抑郁症的潜力,并探讨了在抑郁症治疗中采用免疫疗法的优点和限制因素。
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引用次数: 0
Chemical inhibitors targeting histone methylation readers 针对组蛋白甲基化阅读器的化学抑制剂
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-22 DOI: 10.1016/j.pharmthera.2024.108614
Xiaolei Huang, Yichang Chen, Qin Xiao, Xinci Shang, Yanli Liu

Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and potential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.

组蛋白甲基化阅读域是一种蛋白质模块,可识别特定的组蛋白甲基化标记,如组蛋白上甲基化或未甲基化的赖氨酸或精氨酸残基。这些阅读器蛋白在基因表达、染色质结构和 DNA 损伤修复的表观遗传调控中发挥着至关重要的作用。这些蛋白的失调与癌症、神经退行性疾病和发育障碍等多种疾病有关。因此,以这些蛋白为靶点的化学抑制剂已成为一种极具吸引力的治疗干预方法,该领域也取得了重大进展。在本综述中,我们将总结针对组蛋白甲基化阅读器(包括 MBT 结构域、染色质结构域、Tudor 结构域、PWWP 结构域、PHD 手指和 WD40 重复结构域)的抑制剂的开发情况。对于每个结构域,我们将简要讨论其识别和生物/生化功能,然后重点讨论针对该结构域的抑制剂的发现,总结大多数抑制剂的特性和潜在应用。我们还将讨论这些抑制剂的效力和选择性的结构基础,这将有助于进一步产生和优化先导物。最后,我们还将讨论开发这些抑制剂所面临的挑战和策略。在这些数据的帮助下,将有助于合理设计和开发新型化学支架以及组蛋白甲基化阅读域的新靶向策略。
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引用次数: 0
Nanotechnology and nano-sized tools: Newer approaches to circumvent oncolytic adenovirus limitations 纳米技术和纳米级工具:规避溶瘤腺病毒限制的新方法
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-20 DOI: 10.1016/j.pharmthera.2024.108611
Maryam Mashhadi Abolghasem Shirazi , Tayebeh Azam Saedi , Zahra Samadi Moghaddam , Mahnaz Nemati , Reza Shiri , Babak Negahdari , Nasser Hashemi Goradel

Oncolytic adenoviruses (OAds), engineered Ads preferentially infect and lyse tumor cells, have attracted remarkable attention as immunotherapy weapons for the treatment of various malignancies. Despite hopeful successes in preclinical investigations and translation into clinical phases, they face some challenges that thwart their therapeutic effectiveness, including low infectivity of cancer cells, liver sequestration, pre-existing neutralizing antibodies, physical barriers to the spread of Ads, and immunosuppressive TME. Nanotechnology and nano-sized tools provide several advantages to overcome these limitations of OAds. Nano-sized tools could improve the therapeutic efficacy of OAds by enhancing infectivity and cellular uptake, targeting and protecting from pre-existing immune responses, masking and preventing liver tropism, and co-delivery with other therapeutic agents. Herein, we reviewed the constructs of various OAds and their application in clinical trials, as well as the limitations they have faced. Furthermore, we emphasized the potential applications of nanotechnology to solve the constraints of OAds to improve their anti-tumor activities.

作为治疗各种恶性肿瘤的免疫疗法武器,肿瘤溶解性腺病毒(OAds)已引起广泛关注。尽管在临床前研究和转化为临床阶段取得了令人鼓舞的成功,但它们仍面临着一些挑战,包括癌细胞感染率低、肝脏螯合、预先存在的中和抗体、Ads 传播的物理障碍以及免疫抑制性 TME 等,这些挑战阻碍了它们的治疗效果。纳米技术和纳米级工具具有多种优势,可以克服 OAds 的这些局限性。纳米工具可以通过增强感染性和细胞摄取、靶向性和保护免受已有免疫反应的影响、掩蔽和防止肝脏滋养以及与其他治疗剂联合递送等方式提高 OAds 的疗效。在此,我们回顾了各种 OAds 的构建及其在临床试验中的应用,以及它们所面临的局限性。此外,我们还强调了应用纳米技术解决 OAds 限制因素以提高其抗肿瘤活性的潜力。
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引用次数: 0
Uric acid in health and disease: From physiological functions to pathogenic mechanisms 健康与疾病中的尿酸:从生理功能到致病机制
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-19 DOI: 10.1016/j.pharmthera.2024.108615
Shijie Wen, Hiroshi Arakawa, Ikumi Tamai

Owing to renal reabsorption and the loss of uricase activity, uric acid (UA) is strictly maintained at a higher physiological level in humans than in other mammals, which provides a survival advantage during evolution but increases susceptibility to certain diseases such as gout. Although monosodium urate (MSU) crystal precipitation has been detected in different tissues of patients as a trigger for disease, the pathological role of soluble UA remains controversial due to the lack of causality in the clinical setting. Abnormal elevation or reduction of UA levels has been linked to some of pathological status, also known as U-shaped association, implying that the physiological levels of UA regulated by multiple enzymes and transporters are crucial for the maintenance of health. In addition, the protective potential of UA has also been proposed in aging and some diseases. Therefore, the role of UA as a double-edged sword in humans is determined by its physiological or non-physiological levels. In this review, we summarize biosynthesis, membrane transport, and physiological functions of UA. Then, we discuss the pathological involvement of hyperuricemia and hypouricemia as well as the underlying mechanisms by which UA at abnormal levels regulates the onset and progression of diseases. Finally, pharmacological strategies for urate-lowering therapy (ULT) are introduced, and current challenges in UA study and future perspectives are also described.

由于肾脏的重吸收作用和尿酸酶活性的丧失,人类体内的尿酸(UA)严格维持在比其他哺乳动物更高的生理水平,这在进化过程中提供了生存优势,但却增加了对痛风等某些疾病的易感性。虽然已在患者的不同组织中检测到单钠尿酸盐(MSU)晶体沉淀是疾病的诱发因素,但由于在临床环境中缺乏因果关系,可溶性尿酸盐的病理作用仍存在争议。尿酸水平的异常升高或降低与某些病理状态有关,也被称为 U 型关联,这意味着由多种酶和转运体调节的尿酸生理水平对维持健康至关重要。此外,人们还提出了尿酸在衰老和某些疾病中的保护潜力。因此,作为一把双刃剑,尿酸在人体中的作用取决于其生理或非生理水平。在这篇综述中,我们总结了 UA 的生物合成、膜运输和生理功能。然后,我们讨论了高尿酸血症和高尿酸血症的病理参与,以及尿酸水平异常调节疾病发生和发展的潜在机制。最后,介绍了降尿酸治疗(ULT)的药物策略,并阐述了当前尿酸研究面临的挑战和未来展望。
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引用次数: 0
Immunotherapy in melanoma: Can we predict response to treatment with circulating biomarkers? 黑色素瘤的免疫疗法:我们能否利用循环生物标志物预测治疗反应?
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-16 DOI: 10.1016/j.pharmthera.2024.108613
Elena Splendiani , Zein Mersini Besharat , Alessia Covre , Michele Maio , Anna Maria Di Giacomo , Elisabetta Ferretti

Melanoma is the most aggressive form of skin cancer, representing approximately 4% of all cutaneous neoplasms and accounting for up to 80% of deaths. Advanced stages of melanoma involve metastatic processes and are associated with high mortality and morbidity, mainly due to the rapid dissemination and heterogeneous responses to current therapies, including immunotherapy. Immune checkpoint inhibitors (ICIs) are currently used in the treatment of metastatic melanoma (MM) and despite being linked to an increase in patient survival, a high percentage of them still do not benefit from it. Accordingly, the number of therapeutic regimens for MM patients using ICIs either alone or in combination with other therapies has increased, together with the need for reliable biomarkers that can both predict and monitor response to ICIs.

In this context, circulating biomarkers, such as DNA, RNA, proteins, and cells, have emerged due to their ability to reflect disease status. Moreover, blood tests are minimally invasive and provide an attractive option to detect biomarkers, avoiding stressful medical procedures.

This systematic review aims to evaluate the possibility of a non-invasive biomarker signature that can guide therapeutic decisions. The studies reported here offer valuable insight into how circulating biomarkers can have a role in personalized treatments for melanoma patients receiving ICIs therapy, emphasizing the need for rigorous clinical trials to confirm findings and establish standardized procedures.

黑色素瘤是最具侵袭性的皮肤癌,约占所有皮肤肿瘤的 4%,其致死率高达 80%。黑色素瘤晚期涉及转移过程,死亡率和发病率都很高,这主要是由于黑色素瘤扩散迅速,而且对包括免疫疗法在内的现有疗法反应不一。事实上,免疫检查点抑制剂(ICIs),无论是单独使用还是与其他疗法联合使用,目前都被用于转移性黑色素瘤(MM)的治疗,并提高了患者的生存率。值得注意的是,使用 ICIs 对 MM 患者进行治疗的方案越来越多,这突出表明越来越需要可靠的生物标志物来预测和监测对 ICIs 的反应。在这种情况下,DNA、RNA、蛋白质和细胞等循环生物标志物因其检测疾病状态的能力而应运而生。此外,血液检测具有微创性,为检测生物标志物提供了一个有吸引力的选择,避免了紧张的医疗过程。这篇系统综述总结了评估非侵入性生物标志物特征的可能性,以指导治疗决策。本文报告的研究为循环生物标志物如何在接受 ICIs 治疗的黑色素瘤患者的个性化治疗中发挥作用提供了有价值的见解,同时强调了进行严格临床试验以确认研究结果和建立标准化程序的必要性。
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引用次数: 0
Pathological and pharmacological functions of the metabolites of polyunsaturated fatty acids mediated by cyclooxygenases, lipoxygenases, and cytochrome P450s in cancers 由环氧酶、脂氧酶和细胞色素 P450s 介导的多不饱和脂肪酸代谢物在癌症中的病理和药理功能。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-16 DOI: 10.1016/j.pharmthera.2024.108612
Yi-Wen Meng , Jun-Yan Liu

Oxylipins have garnered increasing attention because they were consistently shown to play pathological and/or pharmacological roles in the development of multiple cancers. Oxylipins are the metabolites of polyunsaturated fatty acids via both enzymatic and nonenzymatic pathways. The enzymes mediating the metabolism of PUFAs include but not limited to lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P450s (CYPs) pathways, as well as the down-stream enzymes. Here, we systematically summarized the pleiotropic effects of oxylipins in different cancers through pathological and pharmacological aspects, with specific reference to the enzyme-mediated oxylipins. We discussed the specific roles of oxylipins on cancer onset, growth, invasion, and metastasis, as well as the expression changes in the associated metabolic enzymes and the associated underlying mechanisms. In addition, we also discussed the clinical application and potential of oxylipins and related metabolic enzymes as the targets for cancer prevention and treatment. We found the specific function of most oxylipins in cancers, especially the underlying mechanisms and clinic applications, deserves and needs further investigation. We believe that research on oxylipins will provide not only more therapeutic targets for various cancers but also dietary guidance for both cancer patients and healthy humans.

由于在多种癌症的发病过程中,氧脂素一直被证明起着病理和/或药理作用,因此受到越来越多的关注。氧脂素是多不饱和脂肪酸通过酶和非酶途径产生的代谢产物。介导多不饱和脂肪酸代谢的酶包括但不限于脂氧合酶 (LOX)、环氧化酶 (COX)、细胞色素 P450s (CYPs) 途径以及下游酶。在此,我们从病理学和药理学方面系统地总结了氧化脂素在不同癌症中的多效应,并特别提到了酶介导的氧化脂素。我们讨论了氧脂对癌症发病、生长、侵袭和转移的具体作用,以及相关代谢酶的表达变化和相关的内在机制。此外,我们还讨论了作为癌症预防和治疗靶点的氧脂素及相关代谢酶的临床应用和潜力。我们发现,大多数氧脂素在癌症中的特定功能,尤其是其潜在机制和临床应用,值得并需要进一步研究。我们相信,对氧脂素的研究不仅能为各种癌症提供更多的治疗靶点,还能为癌症患者和健康人提供饮食指导。
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引用次数: 0
Harnessing and delivering microbial metabolites as therapeutics via advanced pharmaceutical approaches 通过先进的制药方法利用和提供微生物代谢物作为治疗药物。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-16 DOI: 10.1016/j.pharmthera.2024.108605
Lindsey M. Williams, Shijie Cao

Microbial metabolites have emerged as key players in the interplay between diet, the gut microbiome, and host health. Two major classes, short-chain fatty acids (SCFAs) and tryptophan (Trp) metabolites, are recognized to regulate inflammatory, immune, and metabolic responses within the host. Given that many human diseases are associated with dysbiosis of the gut microbiome and consequent reductions in microbial metabolite production, the administration of these metabolites represents a direct, multi-targeted treatment. While a multitude of preclinical studies showcase the therapeutic potential of both SCFAs and Trp metabolites, they often rely on high doses and frequent dosing regimens to achieve systemic effects, thereby constraining their clinical applicability. To address these limitations, a variety of pharmaceutical formulations approaches that enable targeted, delayed, and/or sustained microbial metabolite delivery have been developed. These approaches, including enteric encapsulations, esterification to dietary fiber, prodrugs, and nanoformulations, pave the way for the next generation of microbial metabolite-based therapeutics.

In this review, we first provide an overview of the roles of microbial metabolites in maintaining host homeostasis and outline how compromised metabolite production contributes to the pathogenesis of inflammatory, metabolic, autoimmune, allergic, infectious, and cancerous diseases. Additionally, we explore the therapeutic potential of metabolites in these disease contexts. Then, we provide a comprehensive and up-to-date review of the pharmaceutical strategies that have been employed to enhance the therapeutic efficacy of microbial metabolites, with a focus on SCFAs and Trp metabolites.

微生物代谢物已成为饮食、肠道微生物组和宿主健康之间相互作用的关键因素。短链脂肪酸(SCFAs)和色氨酸(Trp)代谢物这两大类代谢物被认为可以调节宿主体内的炎症、免疫和代谢反应。鉴于许多人类疾病都与肠道微生物群落失调以及随之而来的微生物代谢物生成减少有关,因此服用这些代谢物是一种直接、多靶点的治疗方法。虽然大量临床前研究展示了 SCFAs 和 Trp 代谢物的治疗潜力,但它们往往依赖于高剂量和频繁的给药方案来达到全身效果,从而限制了它们的临床适用性。为了解决这些局限性,人们开发了多种药物制剂方法,以实现定向、延迟和/或持续的微生物代谢物给药。这些方法包括肠道封装、膳食纤维酯化、原药和纳米制剂,为下一代基于微生物代谢物的疗法铺平了道路。在这篇综述中,我们首先概述了微生物代谢物在维持宿主体内平衡中的作用,并概述了代谢物的产生受到损害是如何导致炎症、代谢、自身免疫、过敏、感染和癌症等疾病的发病机制的。此外,我们还探讨了代谢物在这些疾病中的治疗潜力。然后,我们全面回顾了为提高微生物代谢物的疗效而采用的最新药物策略,重点是 SCFAs 和 Trp 代谢物。
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引用次数: 0
Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA) 脑外伤与γ-氨基丁酸(GABA)的机理和治疗关系。
IF 13.5 1区 医学 Q1 Medicine Pub Date : 2024-02-16 DOI: 10.1016/j.pharmthera.2024.108609
Jeffrey M. Witkin , Hana Shafique , Rok Cerne , Jodi L. Smith , Ann M. Marini , Robert H. Lipsky , Elizabeth Delery

Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.

创伤性脑损伤是一种发病率很高的疾病,目前还没有预防或治疗这种疾病的特效药物。其症状包括昏迷、头痛、癫痫发作、认知障碍、抑郁和焦虑。尽管人们多年来一直知道抑制性神经递质γ-氨基丁酸(GABA)与创伤性脑损伤有关,但基于这一机制的新型疗法尚未被引入临床实践。我们回顾了 GABA 神经传递与创伤性脑损伤之间的神经解剖学、神经生理学、神经化学和神经药理学关系,以期开发出基于 GABA 的潜在新药。长期以来,人们一直认为创伤性脑损伤会破坏兴奋和抑制(GABA 及其他)的平衡,这一观点得到了实验数据的支持,但却未能发明出恢复这种平衡的新方法。新疗法进展缓慢的原因在于创伤性脑损伤的复杂性,它包含多种动态相互作用的生物过程,包括血液动力学和新陈代谢系统、神经变性和神经再生、神经网络和轴突的严重破坏、脑损伤以及具有不同神经元和神经激素调节机制的多种症状。尽管目前和正在进行的临床研究包括 GABA 能药物,但尚未发现新型 GABA 化合物。有人认为,填补对特定 GABAA 受体配置在特定神经元回路中所起作用的认识空白,有助于确定新的治疗方法。进一步研究 GABA 调节剂的时间和空间传递也会有所帮助。除了 GABA 调节,还需要对 GABA 和非 GABA 治疗的排序进行研究。
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引用次数: 0
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Pharmacology & Therapeutics
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