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Environmental Epigenetic Transgenerational Inheritance and Generational Toxicology. 环境表观遗传跨代遗传与世代毒理学。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-13 DOI: 10.1146/annurev-pharmtox-060425-072130
Yasna Bahrainian, Eric E Nilsson, Michael K Skinner
{"title":"Environmental Epigenetic Transgenerational Inheritance and Generational Toxicology.","authors":"Yasna Bahrainian, Eric E Nilsson, Michael K Skinner","doi":"10.1146/annurev-pharmtox-060425-072130","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060425-072130","url":null,"abstract":"<p><p>Environmental chemicals and toxicants can promote phenotypic variation or disease not only in the individual exposed but also in individuals for multiple subsequent generations. This phenomenon is termed epigenetic transgenerational inheritance and generational toxicology. Most environmental factors and toxicants do not promote genetic mutations that alter the DNA sequence, but they can alter epigenetics and the epigenome. Epigenetic changes in the germline allow for epigenetic transgenerational inheritance and generational toxicology as a result of the previous generations' exposures. The toxicology and pharmacology of environmental chemicals and epigenetic transgenerational inheritance are discussed in the context of generational toxicology.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tobacco and Cannabis Use Disorders: Similarities, Differences and Therapeutic Approaches. 烟草和大麻使用障碍：相似性，差异和治疗方法。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-12 DOI: 10.1146/annurev-pharmtox-060325-101830
Paulina Antwi, Justin Matheson, Bernard Le Foll
{"title":"Tobacco and Cannabis Use Disorders: Similarities, Differences and Therapeutic Approaches.","authors":"Paulina Antwi, Justin Matheson, Bernard Le Foll","doi":"10.1146/annurev-pharmtox-060325-101830","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060325-101830","url":null,"abstract":"<p><p>Cannabis and tobacco are two of the most commonly used drugs worldwide. Both drugs can lead to a use disorder, characterized by compulsive use despite harm and mediated by neurobiological changes in reward and motivational circuitry. Co-use of cannabis and tobacco is common and influences disorder severity and outcomes. Both cannabis use disorder (CUD) and tobacco use disorder (TUD) share key features, such as dopaminergic reward system involvement, severity of withdrawal symptoms, and mental health comorbidities, yet they differ in neurobiological pathways, diagnostic profiles, and available pharmacotherapies. Diagnostic frameworks like the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and International Classification of Diseases 11 provide standardized criteria for assessment. Optimal management integrates pharmacological and psychosocial interventions, though approved medications exist for TUD and not yet for CUD. Understanding similarities, distinctions, and treatment strategies is critical for effective prevention and clinical care.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Circadian Rhythms in Drug Response: From Molecular Clocks to Precision Dosing. 药物反应中的昼夜节律：从分子钟到精确给药。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-12 DOI: 10.1146/annurev-pharmtox-060325-102258
Ronan Lordan, Christine Butler, Annie Curtis, Garret A FitzGerald
{"title":"Circadian Rhythms in Drug Response: From Molecular Clocks to Precision Dosing.","authors":"Ronan Lordan, Christine Butler, Annie Curtis, Garret A FitzGerald","doi":"10.1146/annurev-pharmtox-060325-102258","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060325-102258","url":null,"abstract":"<p><p>Circadian rhythms organize mammalian physiology across the 24-h day through molecular clocks coordinated by the central clock in the suprachiasmatic nucleus and distributed to peripheral oscillators. These clocks regulate processes central to pharmacology, including drug absorption, distribution, metabolism, elimination, and target responsiveness. Consequently, drug efficacy and toxicity can vary substantially depending on the time of administration. Despite decades of progress in pharmacogenomics and systems pharmacology, consideration of time of day remains largely absent from clinical drug development and prescription. In this review, we evaluate emerging research on circadian regulation of drug responses, considering both pharmacokinetics and pharmacodynamics. We review chronotherapeutic strategies to treat diseases, including cancer, cardiovascular disease, and bipolar disorder. We also discuss the use of wearable technologies to enable time-resolved drug evaluation. Finally, we discuss the challenges to clinical translation and the integration of circadian timing into precision medicine and optimized dosing strategies.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exercise as Medicine: The Potential of Exerkines as Therapeutics. 运动作为医学：运动作为治疗的潜力。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-12 DOI: 10.1146/annurev-pharmtox-060325-031237
David Jimenez-Morales, Vidal M Arroyo, Katryn I Ashley, Russ B Altman, Euan A Ashley
{"title":"Exercise as Medicine: The Potential of Exerkines as Therapeutics.","authors":"David Jimenez-Morales, Vidal M Arroyo, Katryn I Ashley, Russ B Altman, Euan A Ashley","doi":"10.1146/annurev-pharmtox-060325-031237","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060325-031237","url":null,"abstract":"<p><p>Exercise delivers a wide variety of health benefits through many mechanisms, including the release of exerkines, signaling molecules secreted by multiple tissues during physical activity. We evaluated 34 exerkines with therapeutic potential alongside IC7Fc (an engineered IL-6/CNTF derivative), classifying them based on (<i>a</i>) their translational readiness as therapeutics and (<i>b</i>) their primary clinical domains (cardiovascular, metabolic, neurological, musculoskeletal, anti-inflammatory, and oncology). Only four have clear clinical validation, and nine others have reached clinical testing or late preclinical development. Across these molecular entities, three challenges emerge: context-dependent effects, drug-delivery constraints, and network dynamics. We conclude with an assessment of opportunities and strategies for the creation of exerkine-based biomarkers and for using exerkines to facilitate therapeutic discovery. Finally, we present the Exerkine Atlas (<b>https://exerkineatlas.org/</b>), an open-access web resource integrating curated literature and clinical trial data for all 35 molecules.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endocannabinoid Signaling and Mood Regulation. 内源性大麻素信号和情绪调节。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-12 DOI: 10.1146/annurev-pharmtox-052825-085837
Aditya Rayasam, Cecilia J Hillard
{"title":"Endocannabinoid Signaling and Mood Regulation.","authors":"Aditya Rayasam, Cecilia J Hillard","doi":"10.1146/annurev-pharmtox-052825-085837","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-052825-085837","url":null,"abstract":"<p><p>The endocannabinoid (eCB) signaling system is a local regulator of synaptic activity across brain circuits involved in the regulation of emotional behaviors. Preclinical studies predominantly show that eCB signaling dampens acute stress responses, although notable exceptions exist. Various forms of chronic stress downregulate eCB signaling, and enhanced eCB tone can reduce the effects of chronic stress on avoidance behaviors and anhedonia. Studies in healthy humans generally align with these preclinical findings. Type 1 cannabinoid receptors (CB1Rs) and fatty acid amide hydrolase (FAAH), the enzyme that degrades the eCB <i>N</i>-arachidonoylethanolamine (AEA), are present in circuits that regulate emotion, and pharmacological and genetic manipulations of these proteins affect anxiety, stress responses, and reward. However, FAAH inhibitors have largely failed to demonstrate efficacy, and CB1R agonists have only modest effects in individuals with mood disorders. Advancing the therapeutic potential of CB1R/eCB signaling likely will require a deeper understanding of the factors contributing to inconsistencies between model systems and individuals with mood disorders.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Small Interfering RNA in Cardiovascular Disease: A New Frontier in Precision Medicine. 小干扰RNA在心血管疾病中的应用：精准医学的新前沿。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-07 DOI: 10.1146/annurev-pharmtox-062124-023947
Kaavya Paruchuri, Jaiden Busso, Pradeep Natarajan
{"title":"Small Interfering RNA in Cardiovascular Disease: A New Frontier in Precision Medicine.","authors":"Kaavya Paruchuri, Jaiden Busso, Pradeep Natarajan","doi":"10.1146/annurev-pharmtox-062124-023947","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062124-023947","url":null,"abstract":"<p><p>Despite advances in traditional lipid-lowering, antithrombotic, and antihypertensive therapies, cardiovascular disease remains the leading cause of mortality worldwide. Small interfering RNA (siRNA) therapeutics harness the endogenous RNA interference pathway to degrade target messenger RNA, thereby reducing synthesis of disease-associated proteins. Because gene silencing occurs intracellularly and persists beyond circulating drug exposure, siRNA agents result in sustained effects with infrequent dosing. Hepatocyte-directed agents targeting PCSK9, LPA, ANGPTL3, APOC3, angiotensinogen, and transthyretin have demonstrated robust and durable reductions in several measures, including atherogenic lipoproteins, blood pressure, and amyloid precursors. Ongoing trials will determine whether these biomarker effects translate into improvements in cardiovascular outcomes. Key challenges include delivery beyond the liver, long-term safety monitoring, off-target mitigation, and economic considerations. Advances in chemical modification, ligand-directed targeting, artificial intelligence-guided sequence design, and reversal strategies are expanding the therapeutic landscape. siRNA-based interventions hold promise as a precision modality capable of reshaping prevention and treatment across the spectrum of cardiovascular disease.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacological Individuality: The Twists and Turns of My Journey. 药理学个性：我旅程的曲折。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-07 DOI: 10.1146/annurev-pharmtox-062425-044036
Urs Albert Meyer
{"title":"Pharmacological Individuality: The Twists and Turns of My Journey.","authors":"Urs Albert Meyer","doi":"10.1146/annurev-pharmtox-062425-044036","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-062425-044036","url":null,"abstract":"<p><p>The intent of this review is a nearly chronicle tale of my life as a physician-scientist, recounting the events, fortuitous encounters, and sites that shaped my career. Intrigued as a clinician by the large individual variation in response to drug therapy, my research efforts centered on finding the causes for this individuality, including genetic, environmental, and other influences. The ultimate goal was to better predict drug responses in an individual patient and allow decisions on drug choice and drug dose to optimize the clinical outcomes of therapies. The results of my research have contributed to the emergence of pharmacogenomics, personalized medicine, and precision medicine.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Placebo Pain Relief: Mechanisms and Therapeutic Opportunities. 安慰剂缓解疼痛：机制和治疗机会。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-05 DOI: 10.1146/annurev-pharmtox-060225-124705
Chong Chen, Grégory Scherrer
{"title":"Placebo Pain Relief: Mechanisms and Therapeutic Opportunities.","authors":"Chong Chen, Grégory Scherrer","doi":"10.1146/annurev-pharmtox-060225-124705","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060225-124705","url":null,"abstract":"<p><p>The placebo effect has accompanied medicine throughout its history and remains a powerful modulator of health and disease. While the rise of double-blind, randomized, placebo-controlled trials has positioned placebo effects primarily as methodological controls, accumulating evidence has prompted a reassessment of their underlying mechanisms and therapeutic value. Over the past several decades, substantial progress has been made in elucidating the psychological, neural circuit, and molecular bases of placebo effects. In this review, we summarize recent clinical and preclinical findings that reveal how cognitive processes engage endogenous pain-modulatory circuits to shape pain perception. We further discuss strategies for leveraging placebo-related mechanisms in current clinical practice and outline potential future directions in which a more precise mechanistic understanding may enable targeted, ethical, and effective approaches to pain management.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Introduction to the Theme "Context Is Everything: Defining the Factors That Contribute to Variability in Drug Response". 主题介绍“环境决定一切：确定导致药物反应变异性的因素”。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-05 DOI: 10.1146/annurev-pharmtox-090826-125709
Susan G Amara, Amrita Ahluwalia, Paul A Insel
{"title":"Introduction to the Theme \"Context Is Everything: Defining the Factors That Contribute to Variability in Drug Response\".","authors":"Susan G Amara, Amrita Ahluwalia, Paul A Insel","doi":"10.1146/annurev-pharmtox-090826-125709","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-090826-125709","url":null,"abstract":"<p><p>Drug response is shaped by far more than the interaction between a drug and its molecular target. The reviews in Volume 67 of the <i>Annual Review of Pharmacology and Toxicology</i> examine how temporal, pharmacokinetic, genetic, physiological, environmental, cellular, and psychosocial factors contribute to variability in drug efficacy, toxicity, and tolerability. This volume's reviews highlight emerging approaches for understanding these influences, including untargeted mass spectrometry-based technologies, artificial intelligence, and therapeutic drug monitoring, as well as the context-dependent actions of specific drug targets and physiological states. Together, these perspectives emphasize the dynamic and multifactorial nature of pharmacological and toxicological responses and the need to consider not only what a drug does, but also when, where, in whom, and under what conditions it acts.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nanobodies as Versatile Next-Generation Biologics. 纳米体作为多功能下一代生物制剂。
IF 19 1区 医学
Annual review of pharmacology and toxicology Pub Date : 2026-10-02 DOI: 10.1146/annurev-pharmtox-060425-094846
Serge Muyldermans, Jan Steyaert
{"title":"Nanobodies as Versatile Next-Generation Biologics.","authors":"Serge Muyldermans, Jan Steyaert","doi":"10.1146/annurev-pharmtox-060425-094846","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060425-094846","url":null,"abstract":"<p><p>Nanobodies, also known as single-domain antibodies or variable domains of heavy-chain-only antibodies (VHHs), are the antigen-binding domains derived from heavy-chain-only antibodies that naturally occur in camelids. Since their discovery in the early 1990s, Nanobodies have attracted significant attention in the fields of biotechnology, structural biology, diagnostics, and therapeutics. Their unique structural and biochemical properties distinguish them from conventional antibodies and offer several practical advantages as versatile modular units in next-generation biologics. We discuss the most important and useful properties of Nanobodies, including their generation, physicochemical characteristics, manufacturability, stability, immunogenicity, antigen recognition capabilities, functional modulation, and engineering flexibility. We review the development and production of multivalent and multispecific Nanobody constructs; strategies to extend their in vivo half-life; and various functional fusions, including immunotoxins, imaging agents, and cellular therapies such as CAR T cell constructs.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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