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  • Introduction to the Theme “Ion Channels and Neuropharmacology: From the Past to the Future”
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Annette C. Dolphin; Paul A. Insel; Terrence F. Blaschke; Urs A. Meyer

    “Ion Channels and Neuropharmacology: From the Past to the Future” is the main theme of articles in Volume 60 of the Annual Review of Pharmacology and Toxicology. Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of ion channels by second messengers, including Ca2+ and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L-type Ca2+ channels, and AMPA receptors, as well as the aquaporin channels. Molecular identification of exactly where drugs bind in the structure not only elucidates their mechanism of action but also aids future structure-based drug discovery efforts to focus on relevant pharmacophores. The ion channels discussed here are targets for multiple nervous system diseases, including epilepsy and neuropathic pain. This theme complements several previous themes, including “New Therapeutic Targets,” “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development,” and “New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology.”

    更新日期:2020-01-09
  • Neurons, Receptors, and Channels
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    David A. Brown

    Here, I recount some adventures that I and my colleagues have had over some 60 years since 1957 studying the effects of drugs and neurotransmitters on neuronal excitability and ion channel function, largely, but not exclusively, using sympathetic neurons as test objects. Studies include effects of centrally active drugs on sympathetic transmission; neuronal action and neuroglial uptake of GABA in the ganglia and brain; the action of muscarinic agonists on sympathetic neurons; the action of bradykinin on neuroblastoma-derived cells; and the identification of M-current as a target for muscarinic action, including experiments to determine its distribution, molecular composition, neurotransmitter sensitivity, and intracellular regulation by phospholipids and their hydrolysis products. Techniques used include electrophysiological recording (extracellular, intracellular microelectrode, whole-cell, and single-channel patch-clamp), autoradiography, messenger RNA and complementary DNA expression, antibody injection, antisense knockdown, and membrane-targeted lipidated peptides. I finish with some recollections about my scientific career, funding, and changes in laboratory life and pharmacology research over the past 60 years.

    更新日期:2020-01-09
  • Lipid-Dependent Regulation of Ion Channels and G Protein-Coupled Receptors: Insights from Structures and Simulations.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Anna L Duncan,Wanling Song,Mark S P Sansom

    Ion channels and G protein-coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABAA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid-binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Cryo-Electron Microscopy: Moving Beyond X-Ray Crystal Structures for Drug Receptors and Drug Development.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Javier García-Nafría,Christopher G Tate

    Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABAARs) and G protein-coupled receptors (GPCRs). GABAARs are pentameric ion channels, and cryo-EM structures of physiological heteromeric receptors in a lipid environment have uncovered the molecular basis of receptor modulation by drugs such as diazepam. The structures of ten GPCR-G protein complexes from three different classes of GPCRs have now been determined by cryo-EM. These structures give detailed insights into molecular interactions with drugs, GPCR-G protein selectivity, how accessory membrane proteins alter receptor-ligand pharmacology, and the mechanism by which HIV uses GPCRs to enter host cells. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • G Protein-Coupled Receptor Pharmacology at the Single-Molecule Level.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-09-21
    Davide Calebiro,Jak Grimes

    G protein-coupled receptors (GPCRs) mediate the effects of numerous hormones and neurotransmitters and are major pharmacological targets. Classical studies with crude cell lysates or membrane preparations have identified the main biochemical steps involved in GPCR signaling. Moreover, recent studies on purified proteins have provided astounding details at the atomic level of the 3-D structures of receptors in multiple conformations, including in complex with G proteins and β-arrestins. However, several fundamental questions remain regarding the highly specific effects and rapid nature of GPCR signaling. Recent developments in single-molecule microscopy are providing important contributions to answering these questions. Overall, single-molecule studies have revealed unexpected levels of complexity, with receptors existing in different conformations and dynamically interacting among themselves, their signaling partners, and structural elements of the plasma membrane to produce highly localized signals in space and time. These findings may provide a new basis to develop innovative strategies to modulate GPCR function for pharmacological purposes. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-08-28
    Denise Wootten,Laurence J Miller

    Recent advances in our understanding of the structure and function of class B G protein-coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Bina Santoro; Mala M. Shah

    The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits (HCN1–4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.

    更新日期:2020-01-09
  • Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    William A Catterall,Michael J Lenaeus,Tamer M Gamal El-Din

    Voltage-gated sodium and calcium channels are evolutionarily related transmembrane signaling proteins that initiate action potentials, neurotransmission, excitation-contraction coupling, and other physiological processes. Genetic or acquired dysfunction of these proteins causes numerous diseases, termed channelopathies, and sodium and calcium channels are the molecular targets for several major classes of drugs. Recent advances in the structural biology of these proteins using X-ray crystallography and cryo-electron microscopy have given new insights into the molecular basis for their function and pharmacology. Here we review this recent literature and integrate findings on sodium and calcium channels to reveal the structural basis for their voltage-dependent activation, fast and slow inactivation, ion conductance and selectivity, and complex pharmacology at the atomic level. We conclude with the theme that new understanding of the diseases and therapeutics of these channels will be derived from application of the emerging structural principles from these recent structural analyses. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • β2 Adrenergic Receptor Complexes with the L-Type Ca2+ Channel CaV1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Kwun Nok Mimi Man,Manuel F Navedo,Mary C Horne,Johannes W Hell

    Formation of signaling complexes is crucial for the orchestration of fast, efficient, and specific signal transduction. Pharmacological disruption of defined signaling complexes has the potential for specific intervention in selected regulatory pathways without affecting organism-wide disruption of parallel pathways. Signaling by epinephrine and norepinephrine through α and β adrenergic receptors acts on many signaling pathways in many cell types. Here, we initially provide an overview of the signaling complexes formed between the paradigmatic β2 adrenergic receptor and two of its most important targets, the L-type Ca2+ channel CaV1.2 and the AMPA-type glutamate receptor. Importantly, both complexes contain the trimeric Gs protein, adenylyl cyclase, and the cAMP-dependent protein kinase, PKA. We then discuss the functional implications of the formation of these complexes, how those complexes can be specifically disrupted, and how such disruption could be utilized in the pharmacological treatment of disease. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Targeting the Trafficking of Kidney Water Channels for Therapeutic Benefit.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Pui W Cheung,Richard Bouley,Dennis Brown

    The ability to regulate water movement is vital for the survival of cells and organisms. In addition to passively crossing lipid bilayers by diffusion, water transport is also driven across cell membranes by osmotic gradients through aquaporin water channels. There are 13 aquaporins in human tissues, and of these, aquaporin-2 (AQP2) is the most highly regulated water channel in the kidney: The expression and trafficking of AQP2 respond to body volume status and plasma osmolality via the antidiuretic hormone, vasopressin (VP). Dysfunctional VP signaling in renal epithelial cells contributes to disorders of water balance, and research initially focused on regulating the major cAMP/PKA pathway to normalize urine concentrating ability. With the discovery of novel and more complex signaling networks that regulate AQP2 trafficking, promising therapeutic targets have since been identified. Several strategies based on data from preclinical studies may ultimately translate to the care of patients with defective water homeostasis. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Levering Mechanically Activated Piezo Channels for Potential Pharmacological Intervention.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-08-28
    Bailong Xiao

    The mechanically activated Piezo channels, including Piezo1 and Piezo2 in mammals, function as key mechanotransducers for converting mechanical force into electrochemical signals. This review highlights key evidence for the potential of Piezo channel drug discovery. First, both mouse and human genetic studies have unequivocally demonstrated the prominent role of Piezo channels in various mammalian physiologies and pathophysiologies, validating their potential as novel therapeutic targets. Second, the cryo-electron microscopy structure of the 2,547-residue mouse Piezo1 trimer has been determined, providing a solid foundation for studying its structure-function relationship and drug action mechanisms and conducting virtual drug screening. Third, Piezo1 chemical activators, named Yoda1 and Jedi1/2, have been identified through high-throughput screening assays, demonstrating the drugability of Piezo channels. However, the pharmacology of Piezo channels is in its infancy. By establishing an integrated drug discovery platform, we may hopefully discover and develop a fleet of Jedi masters for battling Piezo-related human diseases. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-07-25
    Brandon M Brown,Heesung Shim,Palle Christophersen,Heike Wulff

    The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Neonicotinoid Insecticides: Molecular Targets, Resistance, and Toxicity
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Kazuhiko Matsuda; Makoto Ihara; David B. Sattelle

    Neonicotinoids have been used to protect crops and animals from insect pests since the 1990s, but there are concerns regarding their adverse effects on nontarget organisms, notably on bees. Enhanced resistance to neonicotinoids in pests is becoming well documented. We address the current understanding of neonicotinoid target site interactions, selectivity, and metabolism not only in pests but also in beneficial insects such as bees. The findings are relevant to the management of both neonicotinoids and the new generation of pesticides targeting insect nicotinic acetylcholine receptors.

    更新日期:2020-01-09
  • Neuropathic Pain: Mechanism-Based Therapeutics
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Kirsty Bannister; Juliane Sachau; Ralf Baron; Anthony H. Dickenson

    Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.

    更新日期:2020-01-09
  • Barriers to Ensuring Access to Affordable Prescription Drugs.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-05-29
    Michelle M Mello

    High and rising prescription drug costs have become a preoccupying policy problem in the United States. Notwithstanding broad, bipartisan interest in finding effective policy solutions, several aspects of the drug affordability problem make it an uncommonly difficult one to solve. This article reviews the moral, market, and political factors contributing to the difficulty. Among the moral problems is lack of agreement about how to weigh the fundamental tradeoff involved in regulating drug prices-affordability versus incentives for innovation-and about what constitutes a fair price. Market-related factors include the lack of price transparency and a myriad of perverse incentives in the system through which prescription drugs are supplied to patients. Finally, current policy choices are constrained by past political compromises, and an atmosphere of scandal focusing on egregious instances of price gouging has made rational deliberation about fixes to deeper problems in the system difficult. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Jesse A. Stokum; Volodymyr Gerzanich; Kevin N. Sheth; W. Taylor Kimberly; J. Marc Simard

    Cerebral edema, a common and often fatal companion to most forms of acute central nervous system disease, has been recognized since the time of ancient Egypt. Unfortunately, our therapeutic armamentarium remains limited, in part due to historic limitations in our understanding of cerebral edema pathophysiology. Recent advancements have led to a number of clinical trials for novel therapeutics that could fundamentally alter the treatment of cerebral edema. In this review, we discuss these agents, their targets, and the data supporting their use, with a focus on agents that have progressed to clinical trials.

    更新日期:2020-01-09
  • Gene-Based Dose Optimization in Children.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-07-10
    Laura B Ramsey,Jacob T Brown,Susan I Vear,Jeffrey R Bishop,Sara L Van Driest

    Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Using What We Already Have: Uncovering New Drug Repurposing Strategies in Existing Omics Data.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-07-25
    Jill M Pulley,Jillian P Rhoads,Rebecca N Jerome,Anup P Challa,Kevin B Erreger,Meghan M Joly,Robert R Lavieri,Kelly E Perry,Nicole M Zaleski,Jana K Shirey-Rice,David M Aronoff

    The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity. This review summarizes drug repurposing strategies and methodologies in the context of the following omics fields: genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, phenomics, pregomics, and personomics. While each omics field has specific strengths and limitations, incorporating omics into the drug repurposing landscape is integral to its success. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Artificial Intelligence in Drug Treatment.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Eden L Romm,Igor F Tsigelny

    The most common applications of artificial intelligence (AI) in drug treatment have to do with matching patients to their optimal drug or combination of drugs, predicting drug-target or drug-drug interactions, and optimizing treatment protocols. This review outlines some of the recently developed AI methods aiding the drug treatment and administration process. Selection of the best drug(s) for a patient typically requires the integration of patient data, such as genetics or proteomics, with drug data, like compound chemical descriptors, to score the therapeutic efficacy of drugs. The prediction of drug interactions often relies on similarity metrics, assuming that drugs with similar structures or targets will have comparable behavior or may interfere with each other. Optimizing the dosage schedule for administration of drugs is performed using mathematical models to interpret pharmacokinetic and pharmacodynamic data. The recently developed and powerful models for each of these tasks are addressed, explained, and analyzed here. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • (Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-08-07
    Anton M Jetten,Donald N Cook

    Retinoic acid-related orphan receptor γt (RORγt) functions as a ligand-dependent transcription factor that regulates multiple proinflammatory genes and plays a critical role in several inflammatory and autoimmune diseases. Various endogenous and synthetic RORγ (inverse) agonists have been identified that regulate RORγ transcriptional activity, including many cholesterol intermediates and oxysterols. Changes in cholesterol biosynthesis and metabolism can therefore have a significant impact on the generation of oxysterol RORγ ligands and, consequently, can control RORγt activity and inflammation. These observations contribute to a growing literature that connects cholesterol metabolism to the regulation of immune responses and autoimmune disease. Loss of RORγ function in knockout mice and in mice treated with RORγ inverse agonists results in reduced production of proinflammatory cytokines, such as IL-17A/F, and increased resistance to autoimmune disease in several experimental rodent models. Thus, RORγt inverse agonists might provide an attractive therapeutic approach to treat a variety of autoimmune diseases.Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Engineered Protein Scaffolds as Next-Generation Therapeutics
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Michaela Gebauer; Arne Skerra

    The concept of engineering robust protein scaffolds for novel binding functions emerged 20 years ago, one decade after the advent of recombinant antibody technology. Early examples were the Affibody, Monobody (Adnectin), and Anticalin proteins, which were derived from fragments of streptococcal protein A, from the tenth type III domain of human fibronectin, and from natural lipocalin proteins, respectively. Since then, this concept has expanded considerably, including many other protein templates. In fact, engineered protein scaffolds with useful binding specificities, mostly directed against targets of biomedical relevance, constitute an area of active research today, which has yielded versatile reagents as laboratory tools. However, despite strong interest from basic science, only a handful of those protein scaffolds have undergone biopharmaceutical development up to the clinical stage. This includes the abovementioned pioneering examples as well as designed ankyrin repeat proteins (DARPins). Here we review the current state and clinical validation of these next-generation therapeutics.

    更新日期:2020-01-09
  • The Role of the Microbiome in Drug Response.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-08-07
    Rosina Pryor,Daniel Martinez-Martinez,Leonor Quintaneiro,Filipe Cabreiro

    The microbiome is known to regulate many aspects of host health and disease and is increasingly being recognized as a key mediator of drug action. However, investigating the complex multidirectional relationships between drugs, the microbiota, and the host is a challenging endeavor, and the biological mechanisms that underpin these interactions are often not well understood. In this review, we outline the current evidence that supports a role for the microbiota as a contributor to both the therapeutic benefits and side effects of drugs, with a particular focus on those used to treat mental disorders, type 2 diabetes, and cancer. We also provide a snapshot of the experimental and computational tools that are currently available for the dissection of drug-microbiota-host interactions. The advancement of knowledge in this area may ultimately pave the way for the development of novel microbiota-based strategies that can be used to improve treatment outcomes. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Prospects for Diminishing the Impact of Nonamyloid Small-Vessel Diseases of the Brain.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-08-20
    Anne Joutel

    Small-vessel diseases (SVDs) of the brain are involved in about one-fourth of ischemic strokes and a vast majority of intracerebral hemorrhages and are responsible for nearly half of dementia cases in the elderly. SVDs are a heavy burden for society, a burden that is expected to increase further in the absence of significant therapeutic advances, given the aging population. Here, we provide a critical appraisal of currently available therapeutic approaches for nonamyloid sporadic SVDs that are largely based on targeting modifiable risk factors. We review what is known about the pathogenic mechanisms of vascular risk factor-related SVDs and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most frequent hereditary SVD, and elaborate on two mechanism-based therapeutic approaches worth exploring in sporadic SVD and CADASIL. We conclude by discussing opportunities and challenges that need to be tackled if efforts to achieve significant therapeutic advances for these diseases are to be successful. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Proteasome Inhibitor Drugs.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-09-04
    Lloyd D Fricker

    Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Microbiota-Gut-Brain Axis: New Therapeutic Opportunities.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Caitríona Long-Smith,Kenneth J O'Riordan,Gerard Clarke,Catherine Stanton,Timothy G Dinan,John F Cryan

    The traditional fields of pharmacology and toxicology are beginning to consider the substantial impact our gut microbiota has on host physiology. The microbiota-gut-brain axis is emerging as a particular area of interest and a potential new therapeutic target for effective treatment of central nervous system disorders, in addition to being a potential cause of drug side effects. Microbiota-gut-brain axis signaling can occur via several pathways, including via the immune system, recruitment of host neurochemical signaling, direct enteric nervous system routes and the vagus nerve, and the production of bacterial metabolites. Altered gut microbial profiles have been described in several psychiatric and neurological disorders. Psychobiotics, live biotherapeutics or substances whose beneficial effects on the brain are bacterially mediated, are currently being investigated as direct and/or adjunctive therapies for psychiatric and neurodevelopmental disorders and possibly for neurodegenerative disease, and they may emerge as new therapeutic options in the clinical management of brain disorders. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Drug Therapies for Chronic Cholestatic Liver Diseases.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Martin Wagner,Peter Fickert

    Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Unlocking Personalized Biomedicine and Drug Discovery with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Fit for Purpose or Forever Elusive?
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : null
    Tessa de Korte,Puspita A Katili,Nurul A N Mohd Yusof,Berend J van Meer,Umber Saleem,Francis L Burton,Godfrey L Smith,Peter Clements,Christine L Mummery,Thomas Eschenhagen,Arne Hansen,Chris Denning

    In recent decades, drug development costs have increased by approximately a hundredfold, and yet about 1 in 7 licensed drugs are withdrawn from the market, often due to cardiotoxicity. This review considers whether technologies using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could complement existing assays to improve discovery and safety while reducing socioeconomic costs and assisting with regulatory guidelines on cardiac safety assessments. We draw on lessons from our own work to suggest a panel of 12 drugs that will be useful in testing the suitability of hiPSC-CM platforms to evaluate contractility. We review issues, including maturity versus complexity, consistency, quality, and cost, while considering a potential need to incorporate auxiliary approaches to compensate for limitations in hiPSC-CM technology. We give examples on how coupling hiPSC-CM technologies with Cas9/CRISPR genome engineering is starting to be used to personalize diagnosis, stratify risk, provide mechanistic insights, and identify new pathogenic variants for cardiovascular disease. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Retinal Pigment Epithelium Replacement Therapy for Age-Related Macular Degeneration: Are We There Yet?
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Ruchi Sharma; Devika Bose; Arvydas Maminishkis; Kapil Bharti

    Pluripotent stem cells (PSCs) are a potential replacement tissue source for degenerative diseases. Age-related macular degeneration (AMD) is a blinding disease triggered by degeneration of the retinal pigment epithelium (RPE), a monolayer tissue that functionally supports retinal photoreceptors. Recently published clinical and preclinical studies have tested PSC-derived RPE as a potential treatment for AMD. Multiple approaches have been used to manufacture RPE cells, to validate them functionally, to confirm their safety profile, and to deliver them to patients either as suspension or as a monolayer patch. Since most of these studies are at an early regulatory approval stage, the primary outcome has been to determine the safety of RPE transplants in patients. However, preliminary signs of efficacy were observed in a few patients. Here, we review the current progress in the PSC-derived RPE transplantation field and provide a comparative assessment of various approaches under development as potential therapeutics for AMD.

    更新日期:2020-01-09
  • Big Data and Artificial Intelligence Modeling for Drug Discovery.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-09-14
    Hao Zhu

    Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, heterogeneous, and large nature of drug data sets. As a result, recently developed artificial intelligence approaches such as deep learning and relevant modeling studies provide new solutions to efficacy and safety evaluations of drug candidates based on big data modeling and analysis. The resulting models provided deep insights into the continuum from chemical structure to in vitro, in vivo, and clinical outcomes. The relevant novel data mining, curation, and management techniques provided critical support to recent modeling studies. In summary, the new advancement of artificial intelligence in the big data era has paved the road to future rational drug development and optimization, which will have a significant impact on drug discovery procedures and, eventually, public health. Expected final online publication date for the Annual Review of Psychology, Volume 71 is January 4, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Device-Based Modulation of Neurocircuits as a Therapeutic for Psychiatric Disorders
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Zhi-De Deng; Bruce Luber; Nicholas L. Balderston; Melbaliz Velez Afanador; Michelle M. Noh; Jeena Thomas; William C. Altekruse; Shannon L. Exley; Shriya Awasthi; Sarah H. Lisanby

    Device-based neuromodulation of brain circuits is emerging as a promising new approach in the study and treatment of psychiatric disorders. This work presents recent advances in the development of tools for identifying neurocircuits as therapeutic targets and in tools for modulating neurocircuits. We review clinical evidence for the therapeutic efficacy of circuit modulation with a range of brain stimulation approaches, including subthreshold, subconvulsive, convulsive, and neurosurgical techniques. We further discuss strategies for enhancing the precision and efficacy of neuromodulatory techniques. Finally, we survey cutting-edge research in therapeutic circuit modulation using novel paradigms and next-generation devices.

    更新日期:2020-01-09
  • Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2020-01-08
    Moriah L. Jacobson; Caroline A. Browne; Irwin Lucki

    Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.

    更新日期:2020-01-09
  • Beyond THC and Endocannabinoids.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-10-04
    Pal Pacher,Natalya M Kogan,Raphael Mechoulam

    Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Addressing the Challenge of Polypharmacy.
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-10-08
    Alpana Mair,Martin Wilson,Tobias Dreischulte

    Polypharmacy describes the concomitant use of multiple medicines and represents a growing global challenge attributable to aging populations with an increasing prevalence of multimorbidity. Polypharmacy can be appropriate but is problematic when the increased risk of harm from interactions between drugs or between drugs and diseases or the burden of administering and monitoring medicines outweighs plausible benefits. Polypharmacy has a substantial economic impact in service demand and hospitalization as well as a detrimental impact on patients' quality of life. Apart from causing avoidable harm, polypharmacy can also lead to therapeutic failure, with up to 50% of patients who take four or more medications not taking them as prescribed. Guidance is needed to support patients and clinicians in defining and achieving realistic goals of drug treatment, and system change is necessary to aid implementation. This article outlines lessons from two programs that aim to address these challenges: the Scottish polypharmacy guidance on realistic prescribing and the European Union SIMPATHY project. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2020-01-09
  • Role of Cell Death in Toxicology: Does It Matter How Cells Die?
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Sten Orrenius

    My research activity started with studies on drug metabolism in rat liver microsomes in the early 1960s. The CO-binding pigment (cytochrome P450) had been discovered a few years earlier and was subsequently found to be involved in steroid hydroxylation in adrenal cortex microsomes. Our early studies suggested that it also participated in the oxidative demethylation of drugs catalyzed by liver microsomes, and that prior treatment of the animals with phenobarbital caused increased levels of the hemoprotein in the liver, and similarly enhanced rates of drug metabolism. Subsequent studies of cytochrome P450-mediated metabolism of toxic drugs in freshly isolated rat hepatocytes characterized critical cellular defense systems and identified mechanisms by which accumulating toxic metabolites could damage and kill the cells. These studies revealed that multiple types of cell death could result from the toxic injury, and that it is important to know which type of cell death results from the toxic injury.

    更新日期:2019-11-18
  • Introduction to the Theme “New Therapeutic Targets”
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Paul A. Insel, Susan G. Amara, Terrence F. Blaschke, Urs A. Meyer

    “New Therapeutic Targets” is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depression, post-traumatic stress disorder, muscle wasting diseases, cancer, and anemia associated with chronic renal disease. Numerous articles in this volume focus on the identification, validation, and utility of novel therapeutic targets, in particular, ones that involve new or unexpected molecular entities. This theme complements several previous themes, including “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development,” “Precision Medicine and Prediction in Pharmacology,” and “New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology.”

    更新日期:2019-11-18
  • Systems Pharmacology: Defining the Interactions of Drug Combinations
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    J.G. Coen van Hasselt, Ravi Iyengar

    The majority of diseases are associated with alterations in multiple molecular pathways and complex interactions at the cellular and organ levels. Single-target monotherapies therefore have intrinsic limitations with respect to their maximum therapeutic benefits. The potential of combination drug therapies has received interest for the treatment of many diseases and is well established in some areas, such as oncology. Combination drug treatments may allow us to identify synergistic drug effects, reduce adverse drug reactions, and address variability in disease characteristics between patients. Identification of combination therapies remains challenging. We discuss current state-of-the-art systems pharmacology approaches to enable rational identification of combination therapies. These approaches, which include characterization of mechanisms of disease and drug action at a systems level, can enable understanding of drug interactions at the molecular, cellular, physiological, and organismal levels. Such multiscale understanding can enable precision medicine by promoting the rational development of combination therapy at the level of individual patients for many diseases.

    更新日期:2019-11-18
  • Drug Targets for Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach and Review of Contemporary Clinical Trials
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Ravi B. Patel, Sanjiv J. Shah

    Heart failure with preserved ejection fraction (HFpEF) accounts for over half of prevalent heart failure (HF) worldwide, and prognosis after hospitalization for HFpEF remains poor. Due, at least in part, to the heterogeneous nature of HFpEF, drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Despite these challenges, important mechanistic understandings of the disease have revealed that the pathophysiology of HFpEF is distinct from that of HF with reduced ejection fraction and have also highlighted potential new therapeutic targets for HFpEF. Of note, HFpEF is a systemic syndrome affecting multiple organ systems. Depending on the organ systems involved, certain novel therapies offer promise in reducing the morbidity of the HFpEF syndrome. In this review, we aim to discuss novel pharmacotherapies for HFpEF based on its unique pathophysiology and identify key research strategies to further elucidate mechanistic pathways to develop novel therapeutics in the future.

    更新日期:2019-11-18
  • Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2016-01-20
    Leigh Goedeke, Rachel J. Perry, Gerald I. Shulman

    Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.

    更新日期:2019-11-18
  • Environmental Obesogens: Mechanisms and Controversies
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Jerrold J. Heindel, Bruce Blumberg

    Obesity is a worldwide pandemic in adults as well as children and adds greatly to health care costs through its association with type 2 diabetes, metabolic syndrome, cardiovascular disease, and cancers. The prevailing medical view of obesity is that it results from a simple imbalance between caloric intake and energy expenditure. However, numerous other factors are important in the etiology of obesity. The obesogen hypothesis proposes that environmental chemicals termed obesogens promote obesity by acting to increase adipocyte commitment, differentiation, and size by altering metabolic set points or altering the hormonal regulation of appetite and satiety. Many obesogens are endocrine disrupting chemicals that interfere with normal endocrine regulation. Endocrine disrupting obesogens are abundant in our environment, used in everyday products from food packaging to fungicides. In this review, we explore the evidence supporting the obesogen hypothesis, as well as the gaps in our knowledge that are currently preventing a complete understanding of the extent to which obesogens contribute to the obesity pandemic.

    更新日期:2019-11-18
  • The Exposome: Molecules to Populations
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Megan M. Niedzwiecki, Douglas I. Walker, Roel Vermeulen, Marc Chadeau-Hyam, Dean P. Jones, Gary W. Miller

    Derived from the term exposure, the exposome is an omic-scale characterization of the nongenetic drivers of health and disease. With the genome, it defines the phenome of an individual. The measurement of complex environmental factors that exert pressure on our health has not kept pace with genomics and historically has not provided a similar level of resolution. Emerging technologies make it possible to obtain detailed information on drugs, toxicants, pollutants, nutrients, and physical and psychological stressors on an omic scale. These forces can also be assessed at systems and network levels, providing a framework for advances in pharmacology and toxicology. The exposome paradigm can improve the analysis of drug interactions and detection of adverse effects of drugs and toxicants and provide data on biological responses to exposures. The comprehensive model can provide data at the individual level for precision medicine, group level for clinical trials, and population level for public health.

    更新日期:2019-11-18
  • Challenges in Orphan Drug Development: Identification of Effective Therapy for Thyroid-Associated Ophthalmopathy
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Terry J. Smith

    Thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves’ disease, is a process in which orbital connective tissues and extraocular muscles undergo inflammation and remodeling. The condition seems to result from autoimmune responses to antigens shared by the thyroid and orbit. The thyrotropin receptor (TSHR), expressed at low levels in orbital tissues, is a leading candidate antigen. Recent evidence suggests that another protein, the insulin-like growth factor-I receptor (IGF-IR), is overexpressed in TAO, and antibodies against IGF-IR have been detected in patients with the disease. Furthermore, TSHR and IGF-IR form a physical and functional complex, and signaling initiated at TSHR requires IGF-IR activity. Identification of therapy for this rare disease has proven challenging and currently relies on nonspecific and inadequate agents, thus representing an important unmet need. A recently completed therapeutic trial suggests that inhibiting IGF-IR activity with a monoclonal antibody may be an effective and safe treatment for active TAO.

    更新日期:2019-11-18
  • Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Jerold Chun, Yasuyuki Kihara, Deepa Jonnalagadda, Victoria A. Blaho

    Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration–approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other LP receptor modulators. Fingolimod's direct CNS activities likely contribute to its efficacy in MS, with particular relevance to treating progressive disease stages and forms that involve neurodegeneration. The evolving understanding of fingolimod's MOA has provided strategies for developing next-generation compounds with superior attributes, suggesting new ways to target S1P as well as other LP receptor modulators for novel therapeutics in the CNS and other organ systems.

    更新日期:2019-11-18
  • The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Chadi G. Abdallah, Lynnette A. Averill, Teddy J. Akiki, Mohsin Raza, Christopher L. Averill, Hassaan Gomaa, Archana Adikey, John H. Krystal

    New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD. Here, we integrate this perspective within a broader framework—in other words, a dual pathology model of (a) stress-related synaptic loss arising from amino acid–based pathology and (b) stress-related synaptic gain related to monoamine-based pathology. Then, we summarize the standard and experimental (e.g., ketamine) pharmacotherapeutic options for PTSD and discuss their putative mechanism of action and clinical efficacy.

    更新日期:2019-11-18
  • The Placebo Effect in Pain Therapies
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Luana Colloca

    Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor–mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients’ positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and chronicity. Expectancy-induced analgesia and placebo effects in general have emerged as useful models to assess individual endogenous pain modulatory systems. Different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes, and sense of well-being. This review illustrates critical elements of placebo mechanisms that inform the methodology of clinical trials, the discovery of new therapeutic targets, and the advancement of personalized pain management.

    更新日期:2019-11-18
  • Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Todd D. Gould, Carlos A. Zarate Jr., Scott M. Thompson

    For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of (R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.

    更新日期:2019-11-18
  • Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Miguel Moutinho, Juan F. Codocedo, Shweta S. Puntambekar, Gary E. Landreth

    Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.

    更新日期:2019-11-18
  • The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Birgit Liss, Jörg Striessnig

    The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.

    更新日期:2019-11-18
  • Therapeutic Approaches to the Treatment of Tinnitus
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Berthold Langguth, Ana Belen Elgoyhen, Christopher R. Cederroth

    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.

    更新日期:2019-11-18
  • Muscle Wasting Diseases: Novel Targets and Treatments
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Regula Furrer, Christoph Handschin

    Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.

    更新日期:2019-11-18
  • Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Michael Eddleston

    Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides—in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus—results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Current treatment is modestly effective, aiming only to reactivate acetylcholinesterase and counter the effects of excess acetylcholine at muscarinic receptors. Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen. The role of oximes in therapy remains unclear. Novel antidotes have been tested in small trials, but the great variability in poisoning makes interpretation of such trials difficult. More effort is required to test treatments in adequately powered studies.

    更新日期:2019-11-18
  • New Cell Cycle Inhibitors Target Aneuploidy in Cancer Therapy
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Masanori Kawakami, Xi Liu, Ethan Dmitrovsky

    Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cells. Based on this concept, proteins and pathways engaged in chromosome segregation are being exploited as candidate therapeutic targets for aneuploid cancers. Agents that induce chromosome missegregation and aneuploidy now exist, including SAC inhibitors, those that alter centrosome fidelity and others that are under active study in preclinical and clinical contexts. This review explores the therapeutic potentials of such new agents, including the benefits of combining them with other antineoplastic agents.

    更新日期:2019-11-18
  • Pharmacologic Targeting of Hypoxia-Inducible Factors
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Gregg L. Semenza

    Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O2 availability. HIFs are heterodimeric proteins composed of an O2-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease. HIFs contribute to the pathogenesis of many cancers, particularly the clear cell type of renal cell carcinoma in which loss of function of the von Hippel-Lindau tumor suppressor blocks HIF-2α degradation. A small molecule inhibitor that binds to HIF-2α and blocks dimerization with HIF-1β is in clinical trials for the treatment of renal cell carcinoma. Targeting HIFs for stabilization or inhibition may improve outcomes in diseases that are common causes of mortality in the US population.

    更新日期:2019-11-18
  • Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Marcus C. Parrish, Yuan Jin Tan, Kevin V. Grimes, Daria Mochly-Rosen

    With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need.

    更新日期:2019-11-18
  • Moving from the Trial to the Real World: Improving Medication Adherence Using Insights of Implementation Science
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Leah L. Zullig, Mieke Deschodt, Jan Liska, Hayden B. Bosworth, Sabina De Geest

    Medication nonadherence is a serious public health concern. Although there are promising interventions that improve medication adherence, most interventions are developed and tested in tightly controlled research environments that are dissimilar from the real-world settings where the majority of patients receive health care. Implementation science methods have the potential to facilitate and accelerate the translation shift from the trial world to the real world. We demonstrate their potential by reviewing published, high-quality medication adherence studies that could potentially be translated into clinical practice yet lack essential implementation science building blocks. We further illustrate this point by describing an adherence study that demonstrates how implementation science creates a junction between research and real-world settings. This article is a call to action for researchers, clinicians, policy makers, pharmaceutical companies, and others involved in the delivery of care to adopt the implementation science paradigm in the scale-up of adherence (research) programs.

    更新日期:2019-11-18
  • Organoids for Drug Discovery and Personalized Medicine
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Toshio Takahashi

    A wide variety of organs are in a dynamic state, continuously undergoing renewal as a result of constant growth and differentiation. Stem cells are required during these dynamic events for continuous tissue maintenance within the organs. In a steady state of production and loss of cells within these tissues, new cells are constantly formed by differentiation from stem cells. Today, organoids derived from either adult stem cells or pluripotent stem cells can be grown to resemble various organs. As they are similar to their original organs, organoids hold great promise for use in medical research and the development of new treatments. Furthermore, they have already been utilized in the clinic, enabling personalized medicine for inflammatory bowel disease. In this review, I provide an update on current organoid technology and summarize the application of organoids in basic research, disease modeling, drug development, personalized treatment, and regenerative medicine.

    更新日期:2019-11-18
  • Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Jason H. Karnes, Matthew A. Miller, Katie D. White, Katherine C. Konvinse, Rebecca K. Pavlos, Alec J. Redwood, Jonathan G. Peter, Rannakoe Lehloenya, Simon A. Mallal, Elizabeth J. Phillips

    Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen (HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell–mediated ADRs.

    更新日期:2019-11-18
  • Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain?
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Norman R. Saunders, Katarzyna M. Dziegielewska, Kjeld Møllgård, Mark D. Habgood

    Efflux mechanisms situated in various brain barrier interfaces control drug entry into the adult brain; this review considers the effectiveness of these protective mechanisms in the embryo, fetus, and newborn brain. The longstanding belief that the blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statements with potential clinical implications. The immature brain is undoubtedly more vulnerable to damage by drugs and toxins; as is reviewed here, some developmentally regulated normal brain barrier mechanisms probably contribute to this vulnerability. We propose that the functional status of brain barrier efflux mechanisms should be investigated at different stages of brain development to provide a rational basis for the use of drugs in pregnancy and in newborns, especially in those prematurely born, where protection usually provided by the placenta is no longer present.

    更新日期:2019-11-18
  • Assessment of Pharmacokinetic Drug–Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Uwe Fuhr, Chih-hsuan Hsin, Xia Li, Wafaâ Jabrane, Fritz Sörgel

    Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug–drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.

    更新日期:2019-11-18
  • Metals and Mechanisms of Carcinogenesis
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Qiao Yi Chen, Thomas DesMarais, Max Costa

    Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis. Specifically, we focus on the five most prevalent carcinogenic metals, arsenic, nickel, cadmium, chromium, and beryllium, and their potential to drive carcinogenesis in humans. A comprehensive understanding of the mechanisms behind the development of metal-induced cancer can provide valuable insights for therapeutic intervention involving molecular targets in metal-induced carcinogenesis.

    更新日期:2019-11-18
  • Modulating NRF2 in Disease: Timing Is Everything
    Annu. Rev. Pharmacol. Toxicol. (IF 12.103) Pub Date : 2019-01-09
    Matthew Dodson, Montserrat Rojo de la Vega, Aram B. Cholanians, Cody J. Schmidlin, Eli Chapman, Donna D. Zhang

    The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation of the NRF2 pathway is critical in creating effective therapeutic regimens. In this review, we summarize the regulation and downstream targets of NRF2. Furthermore, we discuss the role of NRF2 in cancer, neurodegeneration, and diabetes as well as cardiovascular, kidney, and liver disease, with a special emphasis on NRF2-based therapeutics, including those that have made it into clinical trials.

    更新日期:2019-11-18
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