Pub Date : 2024-01-23Epub Date: 2023-07-28DOI: 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.
{"title":"High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions.","authors":"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","doi":"10.1146/annurev-pharmtox-112122-104310","DOIUrl":"10.1146/annurev-pharmtox-112122-104310","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10822017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10246325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-23Epub Date: 2023-07-14DOI: 10.1146/annurev-pharmtox-030823-111731
Manuel Corpas, Moneeza K Siddiqui, Opeyemi Soremekun, Rohini Mathur, Dipender Gill, Segun Fatumo
The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcaseCYP2D6, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males.
{"title":"Addressing Ancestry and Sex Bias in Pharmacogenomics.","authors":"Manuel Corpas, Moneeza K Siddiqui, Opeyemi Soremekun, Rohini Mathur, Dipender Gill, Segun Fatumo","doi":"10.1146/annurev-pharmtox-030823-111731","DOIUrl":"10.1146/annurev-pharmtox-030823-111731","url":null,"abstract":"<p><p>The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcase<i>CYP2D6</i>, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9779570","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}
Pub Date : 2024-01-23Epub Date: 2023-08-16DOI: 10.1146/annurev-pharmtox-032723-110507
Ivan K H Poon, Kodi S Ravichandran
Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells can contribute to the low-grade chronic inflammation that occurs during aging, described as inflammaging. Lastly, we explore opportunities in targeting and harnessing the efferocytic machinery to limit aging-associated inflammatory diseases.
吞噬细胞快速清除凋亡细胞的过程被称为 "排出细胞",是维持组织平衡、消除炎症和组织修复的关键。然而,渗出功能受损会导致凋亡细胞堆积,随后通过从膜通透的凋亡细胞中释放 DNA 和核蛋白等内源性因子引发无菌性炎症。在此,我们回顾了流出吞噬三个关键阶段的分子基础,即吞噬细胞对凋亡物质的检测、摄取和降解。我们还讨论了由于吞噬细胞和凋亡细胞的改变而导致的渗出缺陷如何导致衰老过程中出现的低度慢性炎症,即炎症衰老。最后,我们探讨了针对和利用流出细胞机制限制衰老相关炎症疾病的机会。
{"title":"Targeting Efferocytosis in Inflammaging.","authors":"Ivan K H Poon, Kodi S Ravichandran","doi":"10.1146/annurev-pharmtox-032723-110507","DOIUrl":"10.1146/annurev-pharmtox-032723-110507","url":null,"abstract":"<p><p>Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells can contribute to the low-grade chronic inflammation that occurs during aging, described as inflammaging. Lastly, we explore opportunities in targeting and harnessing the efferocytic machinery to limit aging-associated inflammatory diseases.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10013250","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}
Pub Date : 2024-01-23Epub Date: 2023-10-03DOI: 10.1146/annurev-pharmtox-022323-082311
Daniel W Nebert
I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (a) discovery and characterization of the AHR/CYP1 axis, (b) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (c) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (d) discovery and characterization of the SLC39A8 gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.
{"title":"Gene-Environment Interactions: My Unique Journey.","authors":"Daniel W Nebert","doi":"10.1146/annurev-pharmtox-022323-082311","DOIUrl":"10.1146/annurev-pharmtox-022323-082311","url":null,"abstract":"<p><p>I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (<i>a</i>) discovery and characterization of the AHR/CYP1 axis, (<i>b</i>) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (<i>c</i>) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (<i>d</i>) discovery and characterization of the <i>SLC39A8</i> gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41091887","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}
Pub Date : 2024-01-23Epub Date: 2023-09-08DOI: 10.1146/annurev-pharmtox-040623-115054
Martin J Lohse, Andreas Bock, Manuela Zaccolo
G protein-coupled receptors are the largest and pharmacologically most important receptor family and are involved in the regulation of most cell functions. Most of them reside exclusively at the cell surface, from where they signal via heterotrimeric G proteins to control the production of second messengers such as cAMP and IP3 as well as the activity of several ion channels. However, they may also internalize upon agonist stimulation or constitutively reside in various intracellular locations. Recent evidence indicates that their function differs depending on their precise cellular localization. This is because the signals they produce, notably cAMP and Ca2+, are mostly bound to cell proteins that significantly reduce their mobility, allowing the generation of steep concentration gradients. As a result, signals generated by the receptors remain confined to nanometer-sized domains. We propose that such nanometer-sized domains represent the basic signaling units in a cell and a new type of target for drug development.
G 蛋白偶联受体是最大的受体家族,也是药理学上最重要的受体家族,参与调节大多数细胞功能。它们中的大多数只存在于细胞表面,通过异三聚 G 蛋白发出信号,控制 cAMP 和 IP3 等第二信使的产生以及几种离子通道的活性。不过,它们也可能在激动剂刺激下内化或持续存在于细胞内的不同位置。最近的证据表明,它们的功能因其精确的细胞定位而有所不同。这是因为它们产生的信号,特别是 cAMP 和 Ca2+,大多与细胞蛋白结合,从而大大降低了它们的流动性,从而产生陡峭的浓度梯度。因此,受体产生的信号被限制在纳米级的区域内。我们认为,这种纳米级结构域是细胞中的基本信号传递单元,也是药物开发的新型靶点。
{"title":"G Protein-Coupled Receptor Signaling: New Insights Define Cellular Nanodomains.","authors":"Martin J Lohse, Andreas Bock, Manuela Zaccolo","doi":"10.1146/annurev-pharmtox-040623-115054","DOIUrl":"10.1146/annurev-pharmtox-040623-115054","url":null,"abstract":"<p><p>G protein-coupled receptors are the largest and pharmacologically most important receptor family and are involved in the regulation of most cell functions. Most of them reside exclusively at the cell surface, from where they signal via heterotrimeric G proteins to control the production of second messengers such as cAMP and IP<sub>3</sub> as well as the activity of several ion channels. However, they may also internalize upon agonist stimulation or constitutively reside in various intracellular locations. Recent evidence indicates that their function differs depending on their precise cellular localization. This is because the signals they produce, notably cAMP and Ca<sup>2+</sup>, are mostly bound to cell proteins that significantly reduce their mobility, allowing the generation of steep concentration gradients. As a result, signals generated by the receptors remain confined to nanometer-sized domains. We propose that such nanometer-sized domains represent the basic signaling units in a cell and a new type of target for drug development.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10187019","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}
Pub Date : 2024-01-23Epub Date: 2023-08-09DOI: 10.1146/annurev-pharmtox-051921-023858
Eric J Nunes, Nii A Addy, P Jeffrey Conn, Daniel J Foster
Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.
胆碱能对多巴胺(DA)信号传导的调节对精神分裂症、药物使用障碍和情绪相关障碍等多种疾病具有重要影响。中脑 DA 神经元的活动和末端区域的 DA 释放模式受到纹状体和后脑中胆碱能神经元的严格调控。这些胆碱能神经元可通过激活包括毒蕈碱乙酰胆碱受体(mAChR)亚型在内的多种受体来调节 DA 电路。本综述特别关注 M2、M4 和 M5 mAChR 亚型在调节 DA 神经元活动和 DA 释放中的复杂作用,以及靶向这些 mAChR 亚型的潜在临床意义。
{"title":"Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.","authors":"Eric J Nunes, Nii A Addy, P Jeffrey Conn, Daniel J Foster","doi":"10.1146/annurev-pharmtox-051921-023858","DOIUrl":"10.1146/annurev-pharmtox-051921-023858","url":null,"abstract":"<p><p>Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10219282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-23Epub Date: 2023-07-31DOI: 10.1146/annurev-pharmtox-022823-113946
Ruth Nussinov, Hyunbum Jang
Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-RasG12C. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-RasG12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in cis, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.
{"title":"Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance.","authors":"Ruth Nussinov, Hyunbum Jang","doi":"10.1146/annurev-pharmtox-022823-113946","DOIUrl":"10.1146/annurev-pharmtox-022823-113946","url":null,"abstract":"<p><p>Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-Ras<sup>G12C</sup>. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-Ras<sup>G12C</sup> with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in <i>cis</i>, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9902032","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}
Pub Date : 2024-01-23Epub Date: 2023-09-18DOI: 10.1146/annurev-pharmtox-051623-091038
Ekaterini Tiligada, Daria Gafarov, Maria Zaimi, Joana Vitte, Francesca Levi-Schaffer
The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.
{"title":"Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases.","authors":"Ekaterini Tiligada, Daria Gafarov, Maria Zaimi, Joana Vitte, Francesca Levi-Schaffer","doi":"10.1146/annurev-pharmtox-051623-091038","DOIUrl":"10.1146/annurev-pharmtox-051623-091038","url":null,"abstract":"<p><p>The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10311550","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}
Pub Date : 2024-01-23Epub Date: 2023-08-10DOI: 10.1146/annurev-pharmtox-022123-022046
Kaushik P Venkatesh, Gabriel Brito, Maged N Kamel Boulos
Health digital twins (HDTs) are virtual representations of real individuals that can be used to simulate human physiology, disease, and drug effects. HDTs can be used to improve drug discovery and development by providing a data-driven approach to inform target selection, drug delivery, and design of clinical trials. HDTs also offer new applications into precision therapies and clinical decision making. The deployment of HDTs at scale could bring a precision approach to public health monitoring and intervention. Next steps include challenges such as addressing socioeconomic barriers and ensuring the representativeness of the technology based on the training and validation data sets. Governance and regulation of HDT technology are still in the early stages.
{"title":"Health Digital Twins in Life Science and Health Care Innovation.","authors":"Kaushik P Venkatesh, Gabriel Brito, Maged N Kamel Boulos","doi":"10.1146/annurev-pharmtox-022123-022046","DOIUrl":"10.1146/annurev-pharmtox-022123-022046","url":null,"abstract":"<p><p>Health digital twins (HDTs) are virtual representations of real individuals that can be used to simulate human physiology, disease, and drug effects. HDTs can be used to improve drug discovery and development by providing a data-driven approach to inform target selection, drug delivery, and design of clinical trials. HDTs also offer new applications into precision therapies and clinical decision making. The deployment of HDTs at scale could bring a precision approach to public health monitoring and intervention. Next steps include challenges such as addressing socioeconomic barriers and ensuring the representativeness of the technology based on the training and validation data sets. Governance and regulation of HDT technology are still in the early stages.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9964722","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}
Pub Date : 2024-01-23Epub Date: 2023-09-14DOI: 10.1146/annurev-pharmtox-051921-093711
Sarah L Withey, Diego A Pizzagalli, Jack Bergman
The failure of preclinical research to advance successful candidate medications in psychiatry has created a paradigmatic crisis in psychiatry. The Research Domain Criteria (RDoC) initiative was designed to remedy this situation with a neuroscience-based approach that employs multimodal and cross-species in vivo methodology to increase the probability of translational findings and, consequently, drug discovery. The present review underscores the feasibility of this methodological approach by briefly reviewing, first, the use of multidimensional and cross-species methodologies in traditional behavioral pharmacology and, subsequently, the utility of this approach in contemporary neuroimaging and electrophysiology research-with a focus on the value of functionally homologous studies in nonhuman and human subjects. The final section provides a brief review of the RDoC, with a focus on the potential strengths and weaknesses of its domain-based underpinnings. Optimistically, this mechanistic and multidimensional approach in neuropsychiatric research will lead to novel therapeutics for the management of neuropsychiatric disorders.
{"title":"Translational In Vivo Assays in Behavioral Biology.","authors":"Sarah L Withey, Diego A Pizzagalli, Jack Bergman","doi":"10.1146/annurev-pharmtox-051921-093711","DOIUrl":"10.1146/annurev-pharmtox-051921-093711","url":null,"abstract":"<p><p>The failure of preclinical research to advance successful candidate medications in psychiatry has created a paradigmatic crisis in psychiatry. The Research Domain Criteria (RDoC) initiative was designed to remedy this situation with a neuroscience-based approach that employs multimodal and cross-species in vivo methodology to increase the probability of translational findings and, consequently, drug discovery. The present review underscores the feasibility of this methodological approach by briefly reviewing, first, the use of multidimensional and cross-species methodologies in traditional behavioral pharmacology and, subsequently, the utility of this approach in contemporary neuroimaging and electrophysiology research-with a focus on the value of functionally homologous studies in nonhuman and human subjects. The final section provides a brief review of the RDoC, with a focus on the potential strengths and weaknesses of its domain-based underpinnings. Optimistically, this mechanistic and multidimensional approach in neuropsychiatric research will lead to novel therapeutics for the management of neuropsychiatric disorders.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10233152","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}