自 1961 年出版的《药理学和毒理学年度评论》涵盖了药理学和毒理学领域的重大发展，包括受体、转运蛋白、酶和化学试剂；药物开发科学；免疫系统、中枢和自主神经系统、胃肠系统、心血管系统、内分泌系统和肺系统等系统；和专题。

The Annual Review of Pharmacology and Toxicology, published since 1961, covers significant developments in the fields of pharmacology and toxicology, including research on receptors, transport proteins, enzymes, and chemical agents; the science of drug development; and topics related to various systems such as the immune system, central and autonomic nervous systems, gastrointestinal system, cardiovascular system, endocrine system, and pulmonary system.

《Annual Review of Pharmacology and Toxicology》自1961年出版，涵盖了药理学和毒理学领域的重要进展，包括受体、转运蛋白、酶和化学试剂的研究；药物开发的科学；以及免疫系统、中枢神经系统、自主神经系统、胃肠系统、心血管系统、内分泌系统和肺系统等多个系统的相关内容。

Annual Review of Pharmacology and Toxicology

Tinnitus is a highly prevalent condition that is associated with hearing loss in most cases. In the absence of external stimuli, phantom perceptions of sounds emerge from alterations in neuronal activity within central auditory and nonauditory structures. Pioneering studies using lidocaine revealed that tinnitus is susceptible to pharmacological interventions. However, lidocaine is not effective in all patients, and no other drug has been identified with clear efficacy for the long-term treatment of tinnitus. In this review, we present recent advances in tinnitus research, including more detailed knowledge of its pathophysiology and involved neurotransmitter systems. Moreover, we summarize results from animal and clinical treatment studies as well as from studies that identified tinnitus as a side effect of pharmacological treatments. Finally, we focus on challenges in the development of pharmacological compounds for the treatment of tinnitus, namely the limitations of available animal models and of standardized clinical research methodologies.

Berthold Langguth

Ana Belen Elgoyhen

Christopher R. Cederroth

The Annual Review of Pharmacology and Toxicology

Annu. Rev. Pharmacol. Toxicol.

Therapeutic Approaches to the Treatment of Tinnitus

耳鸣治疗的疗法

Lysosomes play fundamental roles in material digestion, cellular clearance, recycling, exocytosis, wound repair, Ca2+ signaling, nutrient signaling, and gene expression regulation. The organelle also serves as a hub for important signaling networks involving the mTOR and AKT kinases. Electrophysiological recording and molecular and structural studies in the past decade have uncovered several unique lysosomal ion channels and transporters, including TPCs, TMEM175, TRPMLs, CLN7, and CLC-7. They underlie the organelle's permeability to major ions, including K+, Na+, H+, Ca2+, and Cl-. The channels are regulated by numerous cellular factors, ranging from H+ in the lumen and voltage across the lysosomal membrane to ATP in the cytosol to growth factors outside the cell. Genetic variations in the channel/transporter genes are associated with diseases that include lysosomal storage diseases and neurodegenerative diseases. Recent studies with human genetics and channel activators suggest that lysosomal channels may be attractive targets for the development of therapeutics for the prevention of and intervention in human diseases.

Erika Riederer

Chunlei Cang

Dejian Ren

Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?

溶酶体离子通道：它们有什么用处，是否可作为药物靶点？

The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.

Colleen M. Niswender

P. Jeffrey Conn

Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease

代谢型谷氨酸受体：生理学、药理学与疾病

Designed ankyrin repeat proteins (DARPins) can recognize targets with specificities and affinities that equal or surpass those of antibodies, but because of their robustness and extreme stability, they allow a multitude of more advanced formats and applications. This review highlights recent advances in DARPin design, illustrates their properties, and gives some examples of their use. In research, they have been established as intracellular, real-time sensors of protein conformations and as crystallization chaperones. For future therapies, DARPins have been developed by advanced, structure-based protein engineering to selectively induce apoptosis in tumors by uncoupling surface receptors from their signaling cascades. They have also been used successfully for retargeting viruses. In ongoing clinical trials, DARPins have shown good safety and efficacy in macular degeneration diseases. These developments all ultimately exploit the high stability, solubility, and aggregation resistance of these molecules, permitting a wide range of conjugates and fusions to be produced and purified.

Andreas Plückthun

Designed Ankyrin Repeat Proteins (DARPins): Binding Proteins for Research, Diagnostics, and Therapy

设计锚蛋白重复蛋白（DARPin）：用于研究、诊断和治疗的结合蛋白

We face an impending crisis in our ability to treat infectious disease brought about by the emergence of antibiotic-resistant pathogens and a decline in the development of new antibiotics. Urgent action is needed. This review focuses on a less well-understood aspect of antibiotic action: the complex metabolic events that occur subsequent to the interaction of antibiotics with their molecular targets and play roles in antibiotic lethality. Independent lines of evidence from studies of the action of bactericidal antibiotics on diverse bacteria collectively suggest that the initial interactions of drugs with their targets cannot fully account for the antibiotic lethality and that these interactions elicit the production of reactive oxidants including reactive oxygen species that contribute to bacterial cell death. Recent challenges to this concept are considered in the context of the broader literature of this emerging area of research. Possible ways that this new knowledge might be exploited to improve antibiotic therapy are also considered.

Daniel J. Dwyer

James J. Collins

Graham C. Walker

Unraveling the Physiological Complexities of Antibiotic Lethality

揭示抗生素致死性的生理复杂性

Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA-based therapeutics and the application of artificial intelligence.

Paul McGonigle

How Biologics Have Changed the Drug Discovery Landscape

生物制剂如何改变了药物发现领域

Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration–approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.

Tri Q. Do

Björn C. Knollmann

Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases

细胞内RyR2钙释放通道抑制剂作为心律失常性心脏疾病的疗法

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation—Ca2+-permeable or CP-AMPARs—mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.

Marina E. Wolf

Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics

靶向神经可塑性在物质使用障碍中的作用：对治疗的启示

Obesity is a global health concern. Progress in understanding the physiology of obesity and weight reduction has provided new drug targets. Development and testing of new antiobesity medications (AOMs) has the potential to quickly expand options for treatment. In this review, we briefly summarize the physiology of obesity and weight reduction, as well as medications currently approved for weight management. We highlight the increasing use of incretin and nutrient-stimulated hormone-based therapies. We conclude with an overview of AOMs progressing through the pipeline and discuss their implications for the rapidly evolving field of obesity management.

Ariana M. Chao

Simeon Taylor

Molly Moore

Anastassia Amaro

Thomas A. Wadden

Evolving Approaches for Pharmacological Therapy of Obesity

肥胖药物治疗的演变方法

Genetically driven clinical trial enrichment has been proposed to accelerate and reduce the cost of developing new therapeutics. Usage of this approach has not been comprehensively reviewed. We searched Ovid MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and WHO ICTRP for articles published between 2010 and 2023. Excluding absorption, distribution, metabolism, and elimination pharmacogenetic studies and anti-infectives, we found 95 completed, 4 terminated, and 22 ongoing prospective genetically enriched trials on 110 drugs for 48 nononcology, nonrare syndromic indications. Trial sizes ranged from 4 to 6,147 participants (median 72) and covered numerous disease areas, particularly neurology (30), metabolism (22), and psychiatry (17). Fifty-six completed studies (60%) met their primary end point. Overall, this scoping review demonstrates that genetically enriched trials are feasible and scalable across disease areas and provide critical information for further development, or attrition, of investigational drugs. Large, appropriately designed disease-, hospital-, or population-based biobanks will undoubtedly facilitate this type of precision drug development approach.

短名	Annu. Rev. Pharmacol. Toxicol.
Journal Impact	11.18
国际分区	TOXICOLOGY(Q1)
期刊索引	SCI Q1中科院 1 区

ISSN	0362-1642, 1545-4304
h-index	224
国内分区	医学(1区)医学药学(1区)医学毒理学(1区)

涉及主题	医学生物化学内科学生物化学遗传学药理学心理学内分泌学有机化学物理受体精神科基因细胞生物学神经科学核磁共振
出版信息	出版商: Annual Reviews Inc.，出版周期: Annual，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 1975，原创研究文献占比: 0.00%，自引率:0.00%， Gold OA占比: 33.66%
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