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Apathy and Motivation: Biological Basis and Drug Treatment. 冷漠与动机:生物基础与药物治疗
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-022423-014645
Harry Costello, Masud Husain, Jonathan P Roiser

Apathy is a disabling syndrome associated with poor functional outcomes that is common across a broad range of neurological and psychiatric conditions. Currently, there are no established therapies specifically for the condition, and safe and effective treatments are urgently needed. Advances in the understanding of motivation and goal-directed behavior in humans and animals have shed light on the cognitive and neurobiological mechanisms contributing to apathy, providing an important foundation for the development of new treatments. Here, we review the cognitive components, neural circuitry, and pharmacology of apathy and motivation, highlighting converging evidence of shared transdiagnostic mechanisms. Though no pharmacological treatments have yet been licensed, we summarize trials of existing and novel compounds to date, identifying several promising candidates for clinical use and avenues of future drug development.

淡漠是一种致残性综合征,与功能障碍相关,常见于多种神经和精神疾病。目前,还没有专门针对这种病症的成熟疗法,迫切需要安全有效的治疗方法。人们对人类和动物的动机和目标导向行为的认识不断进步,揭示了导致冷漠的认知和神经生物学机制,为开发新的治疗方法奠定了重要基础。在此,我们回顾了冷漠和动机的认知成分、神经回路和药理学,强调了共同的跨诊断机制的趋同证据。虽然目前还没有药物治疗方法获得许可,但我们总结了迄今为止对现有和新型化合物的试验,确定了几种有希望用于临床的候选药物以及未来药物开发的途径。
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引用次数: 0
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation. 从沙利度胺到靶向蛋白质降解的合理分子胶设计
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-08-16 DOI: 10.1146/annurev-pharmtox-022123-104147
Vladas Oleinikovas, Pablo Gainza, Thomas Ryckmans, Bernhard Fasching, Nicolas H Thomä

Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas.

沙利度胺及其衍生物是强大的癌症治疗药物,也是人们最了解的分子胶降解剂(MGDs)之一。这些药物可选择性地重新编程 E3 泛素连接酶 cereblon (CRBN),将目标蛋白质交由泛素蛋白酶体系统降解。MGDs 可在 E3 连接酶表面创建新的识别界面,从而与新基质发生诱导的蛋白质-蛋白质相互作用。对其作用机制的分子洞察为通过特定的识别图案(G-环)与大量靶标相互作用提供了令人兴奋的机会。我们的分析表明,目前基于 CRBN 的 MGD 原则上可以识别人类蛋白质组中 2500 多种含有 G 环的蛋白质。我们回顾了最近在调整 CRBN 与其 MGD 诱导的新底物之间的特异性方面取得的进展,并推导出了一套管理这些相互作用的简单规则。我们的结论是,合理的 MGD 设计工作将使更多的蛋白质得到选择性降解,从而将这种治疗方式扩展到更多的疾病领域。
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引用次数: 0
Oral Anticoagulants Beyond Warfarin. 华法林之外的口服抗凝剂。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-09-27 DOI: 10.1146/annurev-pharmtox-032823-122811
Renske H Olie, Kristien Winckers, Bianca Rocca, Hugo Ten Cate

Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide.

直接口服抗凝剂(DOAC)在很大程度上取代了维生素K拮抗剂,主要是华法林,成为口服抗凝剂、预防和治疗静脉血栓栓塞以及预防心房颤动栓塞性中风的主要适应症。虽然DOAC为许多患者提供实用的固定剂量抗凝治疗,但可能存在特定的限制或禁忌症。DOAC在高血栓风险条件下(如抗磷脂综合征和机械心脏瓣膜)效果不佳。癌症相关血栓形成患者可能受益于DOAC,但出血风险,尤其是胃肠道或泌尿生殖道肿瘤患者,必须仔细权衡。对于虚弱、体重超标和/或中重度慢性肾脏疾病的患者,必须谨慎使用DOAC,并可能需要实验室监测。逆转剂已被开发并批准用于危及生命的出血。此外,对潜在更安全的抗凝药物(如因子XI(a)抑制剂)进行临床测试对于在全球日益老龄化和虚弱的人群中进一步优化抗凝治疗至关重要。《药理学与毒理学年度评论》第64卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Artificial Intelligence for Drug Discovery: Are We There Yet? 用于药物发现的人工智能:我们已经实现了吗?
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-09-22 DOI: 10.1146/annurev-pharmtox-040323-040828
Catrin Hasselgren, Tudor I Oprea

Drug discovery is adapting to novel technologies such as data science, informatics, and artificial intelligence (AI) to accelerate effective treatment development while reducing costs and animal experiments. AI is transforming drug discovery, as indicated by increasing interest from investors, industrial and academic scientists, and legislators. Successful drug discovery requires optimizing properties related to pharmacodynamics, pharmacokinetics, and clinical outcomes. This review discusses the use of AI in the three pillars of drug discovery: diseases, targets, and therapeutic modalities, with a focus on small-molecule drugs. AI technologies, such as generative chemistry, machine learning, and multiproperty optimization, have enabled several compounds to enter clinical trials. The scientific community must carefully vet known information to address the reproducibility crisis. The full potential of AI in drug discovery can only be realized with sufficient ground truth and appropriate human intervention at later pipeline stages.

药物发现正在适应数据科学、信息学和人工智能(AI)等新技术,以加快有效治疗的开发,同时降低成本和动物实验。正如投资者、工业和学术科学家以及立法者越来越感兴趣所表明的那样,人工智能正在改变药物发现。成功的药物发现需要优化与药效学、药代动力学和临床结果相关的特性。这篇综述讨论了人工智能在药物发现的三大支柱中的应用:疾病、靶点和治疗模式,重点是小分子药物。人工智能技术,如生成化学、机器学习和多属性优化,已经使几种化合物进入临床试验。科学界必须仔细审查已知信息,以解决再现性危机。人工智能在药物发现方面的全部潜力只有在后期阶段有足够的基本事实和适当的人类干预才能实现。《药理学与毒理学年度评论》第64卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Hear and Now: Ongoing Clinical Trials to Prevent Drug-Induced Hearing Loss. 现在就听:预防药物性听力损失的现行临床试验。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-08-10 DOI: 10.1146/annurev-pharmtox-033123-114106
John Lee, Katharine Fernandez, Lisa L Cunningham

Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results.

每年有 50 多万人因使用具有耳毒性副作用的治疗药物而导致永久性听力损失。目前,临床上急需一种既能防止听力损失,又不会降低这些救命药物疗效的疗法。目前至少有 17 项临床试验正在进行中,评估了 10 种旨在预防氨基糖苷类和/或顺铂诱导的耳毒性的疗法。本综述介绍了每种方法的临床前和临床开发,提供了正在进行的试验的最新情况,并强调了适当的结果测量在试验设计中的重要性以及报告标准在结果传播中的价值。
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引用次数: 0
LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics. LP(a):结构、遗传学、相关心血管风险和新兴疗法。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-031023-100609
Erfan Tasdighi, Rishav Adhikari, Omar Almaadawy, Thorsten M Leucker, Michael J Blaha

Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.

脂蛋白(a)[Lp(a)]是一种与载脂蛋白(a)结合的分子,与低密度脂蛋白胆固醇(LDL-C)有些相似,已被发现是心血管疾病(CVD)的危险因素。脂蛋白(a)似乎能诱发炎症、动脉粥样硬化和血栓形成。全球约有 20% 的人脂蛋白(a)水平升高,这主要是由遗传因素决定的。目前临床上治疗血脂异常的方法无法有效降低脂蛋白(a)水平。不断发展的基于 RNA 的疗法,如反义寡核苷酸 pelacarsen 和小干扰 RNA olpasiran,在降低脂蛋白(a)水平方面取得了可喜的成果。Lp(a)HORIZON 和 OCEAN(a)]正在进行第三期关键心血管结果试验,以评估它们在 Lp(a) 升高患者主要心血管事件二级预防方面的疗效。降低心血管残余风险的未来可能会过渡到一种个性化方法,即在高强度他汀类药物治疗后,根据每位患者的个体风险状况和偏好选择进一步降低低密度脂蛋白胆固醇、甘油三酯或脂蛋白(a)。
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引用次数: 0
Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease. 催产素受体拮抗剂:使老年和疾病患者的睡眠结构正常化
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-09-14 DOI: 10.1146/annurev-pharmtox-040323-031929
Jarrah O-Z J Kron, Ryan J Keenan, Daniel Hoyer, Laura H Jacobson

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

睡眠对人类的健康至关重要,但随着年龄的增长,睡眠的质量和数量都会下降。老年人(年龄大于 65 岁)更容易因睡眠不足而患上和/或加重各种疾病。此外,有证据表明,睡眠中断与阿尔茨海默病(AD)或相关痴呆症之间存在双向关系。奥曲肽/甲状腺素神经肽能稳定觉醒,有几种奥曲肽受体拮抗剂(ORAs)已被批准用于治疗成人失眠症。老龄化和注意力缺失症会导致奥曲肽系统失调,因此奥曲肽受体拮抗剂对这些人群具有优势。事实上,多项临床研究表明,奥拉西坦对老年人和痴呆症患者是有效的催眠药,而且与成人一样,一般都能很好地耐受。在睡眠/觉醒失调的早期使用催眠药,以重建良好的睡眠/觉醒相关行为,减少痴呆症相关蛋白病理底物的积累,可能会更有效。改善老龄化和痴呆症患者的睡眠是造福患者、护理人员和医疗系统的巨大机遇。
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引用次数: 0
High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions. 推进体外毒理学的高通量筛选:成就、挑战和未来方向》。
IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-112122-104310
Caitlin Lynch, Srilatha Sakamuru, Masato Ooka, Ruili Huang, Carleen Klumpp-Thomas, Paul Shinn, David Gerhold, Anna Rossoshek, Sam Michael, Warren Casey, Michael F Santillo, Suzanne Fitzpatrick, Russell S Thomas, Anton Simeonov, Menghang Xia

Traditionally, chemical toxicity is determined by in vivo animal studies, which are low throughput, expensive, and sometimes fail to predict compound toxicity in humans. Due to the increasing number of chemicals in use and the high rate of drug candidate failure due to toxicity, it is imperative to develop in vitro, high-throughput screening methods to determine toxicity. The Tox21 program, a unique research consortium of federal public health agencies, was established to address and identify toxicity concerns in a high-throughput, concentration-responsive manner using a battery of in vitro assays. In this article, we review the advancements in high-throughput robotic screening methodology and informatics processes to enable the generation of toxicological data, and their impact on the field; further, we discuss the future of assessing environmental toxicity utilizing efficient and scalable methods that better represent the corresponding biological and toxicodynamic processes in humans.

传统上,化学物质的毒性是通过体内动物实验来确定的,这种实验通量低、成本高,有时还无法预测化合物对人体的毒性。由于正在使用的化学品数量不断增加,而候选药物因毒性而失败的比例很高,因此开发体外高通量筛选方法来确定毒性势在必行。Tox21 计划是一个由联邦公共卫生机构组成的独特研究联盟,其成立的目的是利用一系列体外检测方法,以高通量、浓度响应的方式解决和确定毒性问题。在这篇文章中,我们回顾了高通量机器人筛选方法和信息学流程在生成毒理学数据方面取得的进步及其对该领域的影响;此外,我们还讨论了利用高效、可扩展的方法评估环境毒性的未来,这些方法能更好地代表人类相应的生物和毒效学过程。
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引用次数: 0
Pharmacogenomics Beyond Single Common Genetic Variants: The Way Forward. 药物基因组学超越单一常见基因变异:前进之路。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-07-28 DOI: 10.1146/annurev-pharmtox-051921-091209
Volker M Lauschke, Yitian Zhou, Magnus Ingelman-Sundberg

Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response to drugs with regard to efficacy and safety. Enabled by both technological and conceptual advances, the field of pharmacogenomics is developing rapidly. Major progress in omics profiling methods has enabled novel genotypic and phenotypic characterization of patients and biobanks. These developments are paralleled by advances in machine learning, which have allowed us to parse the immense wealth of data and establish novel genetic markers and polygenic models for drug selection and dosing. Pharmacogenomics has recently become more widespread in clinical practice to personalize treatment and to develop new drugs tailored to specific patient populations. In this review, we provide an overview of the latest developments in the field and discuss the way forward, including how to address the missing heritability, develop novel polygenic models, and further improve the clinical implementation of pharmacogenomics.

编码药物代谢酶、转运体、受体和人类白细胞抗原的基因的个体间变异对患者在疗效和安全性方面对药物的反应有重大影响。在技术和概念进步的推动下,药物基因组学领域正在迅速发展。全息分析方法的重大进展使得对患者和生物库进行新的基因型和表型特征描述成为可能。与此同时,机器学习也取得了进展,使我们能够解析大量数据,并建立新的遗传标记和多基因模型,用于药物选择和剂量。最近,药物基因组学在临床实践中越来越广泛地应用于个性化治疗和开发针对特定患者群体的新药。在这篇综述中,我们概述了该领域的最新进展,并讨论了未来的发展方向,包括如何解决遗传率缺失问题、开发新型多基因模型以及进一步改善药物基因组学的临床应用。
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引用次数: 0
Antiepileptic Drugs as Potential Dementia Prophylactics Following Traumatic Brain Injury. 抗癫痫药物作为创伤性脑损伤后潜在的痴呆预防药物。
IF 12.5 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-23 Epub Date: 2023-10-03 DOI: 10.1146/annurev-pharmtox-051921-013930
Laszlo F Locskai, Hadeel Alyenbaawi, W Ted Allison

Seizures and other forms of neurovolatility are emerging as druggable prodromal mechanisms that link traumatic brain injury (TBI) to the progression of later dementias. TBI neurotrauma has both acute and long-term impacts on health, and TBI is a leading risk factor for dementias, including chronic traumatic encephalopathy and Alzheimer's disease. Treatment of TBI already considers acute management of posttraumatic seizures and epilepsy, and impressive efforts have optimized regimens of antiepileptic drugs (AEDs) toward that goal. Here we consider that expanding these management strategies could determine which AED regimens best prevent dementia progression in TBI patients. Challenges with this prophylactic strategy include the potential consequences of prolonged AED treatment and that a large subset of patients are refractory to available AEDs. Addressing these challenges is warranted because the management of seizure activity following TBI offers a rare opportunity to prevent the onset or progression of devastating dementias.

癫痫发作和其他形式的神经波动性正在成为将创伤性脑损伤(TBI)与后期痴呆进展联系起来的药物前驱机制。TBI神经损伤对健康有急性和长期影响,TBI是痴呆症的主要风险因素,包括慢性创伤性脑病和阿尔茨海默病。TBI的治疗已经考虑了创伤后癫痫发作和癫痫的急性治疗,并且令人印象深刻的努力已经优化了抗癫痫药物(AED)的方案来实现这一目标。在这里,我们认为扩大这些管理策略可以确定哪些AED方案最能预防TBI患者的痴呆进展。这种预防策略的挑战包括长期AED治疗的潜在后果,以及大量患者对可用的AED难以治疗。应对这些挑战是有必要的,因为TBI后癫痫发作活动的管理为预防毁灭性痴呆的发作或进展提供了难得的机会。《药理学与毒理学年度评论》第64卷预计最终在线出版日期为2024年1月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
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Annual review of pharmacology and toxicology
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