Annual Review of Pharmacology and Toxicology - Volume 61, 2021
Volume 61, 2021
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Introduction to the Theme “Old and New Toxicology: Interfaces with Pharmacology”
Vol. 61 (2021), pp. 1–7More LessThe theme of Volume 61 is “Old and New Toxicology: Interfaces with Pharmacology.” Old toxicology is exemplified by the authors of the autobiographical articles: B.M. Olivera's work on toxins and venoms from cone snails and P. Taylor's studies of acetylcholinesterase and the nicotinic cholinergic receptor, which serve as sites of action for numerous pesticides and venoms. Other articles in this volume focus on new understanding and new types of toxicology, including (a) arsenic toxicity, which is an ancient poison that, through evolution, has caused most multicellular organisms to express an active arsenic methyltransferase to methylate arsenite, which accelerates the excretion of arsenic from the body; (b) small molecules that react with lipid dicarbonyls, which are now considered the most toxic oxidative stress end products; (c) immune checkpoint inhibitors (ICIs), which have revolutionized cancer therapy but have numerous immune-related adverse events, including cardiovascular complications; (d) autoimmunity caused by the environment; (e) idiosyncratic drug-induced liver disease, which together with the toxicity of ICIs represents new toxicology interfacing with pharmacology; and (f) sex differences in the development of cardiovascular disease, with men more susceptible than women to vascular inflammation that initiates and perpetuates disease. These articles and others in Volume 61 reflect the interface and close integration of pharmacology and toxicology that began long ago but continues today.
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A Serendipitous Path to Pharmacology
Vol. 61 (2021), pp. 9–23More LessMy path to research in neuropharmacology has been a coalescing of my training as a molecular biologist and my intense interest in an esoteric group of animals, the fish-hunting cone snails. Attempting to bridge these two disparate worlds has led me to an idiosyncratic career as a pharmacologist.
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Cholinergic Capsules and Academic Admonitions
Vol. 61 (2021), pp. 25–46More LessHerein, I intend to capture highlights shared with my academic and research colleagues over the 60 years I devoted initially to my graduate and postdoctoral training and then to academic endeavors starting as an assistant professor in a new medical school at the University of California, San Diego (UCSD). During this period, the Department of Pharmacology emerged from a division within the Department of Medicine to become the first basic science department, solely within the School of Medicine at UCSD in 1979. As part of the school's plans to reorganize and to retain me at UCSD, I was appointed as founding chair. Some years later in 2002, faculty, led largely within the Department of Pharmacology and by practicing pharmacists within UCSD Healthcare, started the independent Skaggs School of Pharmacy and Pharmaceutical Sciences with a doctor of pharmacy (PharmD) program, where I served as the founding dean. My career pathway, from working at my family-owned pharmacy to chairing a department in a school of medicine and then becoming the dean of a school of pharmacy at a research-intensive, student-centered institution, involved some risky decisions. But the academic, curricular, and accreditation challenges posed were met by a cadre of creative faculty colleagues. I offer my experiences to individuals confronted with a multiplicity of real or imagined opportunities in academic health sciences, the related pharmaceutical industry, and government oversight agencies.
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Arsenic: A Global Environmental Challenge
Qiao Yi Chen, and Max CostaVol. 61 (2021), pp. 47–63More LessArsenic is a naturally occurring metalloid and one of the few metals that can be metabolized inside the human body. The pervasive presence of arsenic in nature and anthropogenic sources from agricultural and medical use have perpetuated human exposure to this toxic and carcinogenic element. Highly exposed individuals are susceptible to various illnesses, including skin disorders; cognitive impairment; and cancers of the lung, liver, and kidneys. In fact, across the globe, approximately 200 million people are exposed to potentially toxic levels of arsenic, which has prompted substantial research and mitigation efforts to combat this extensive public health issue. This review provides an up-to-date look at arsenic-related challenges facing the global community, including current sources of arsenic, global disease burden, arsenic resistance, and shortcomings of ongoing mitigation measures, and discusses potential next steps.
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Challenges and Opportunities in Implementing Pharmacogenetic Testing in Clinical Settings
Vol. 61 (2021), pp. 65–84More LessThe clinical implementation of pharmacogenetic biomarkers continues to grow as new genetic variants associated with drug outcomes are discovered and validated. The number of drug labels that contain pharmacogenetic information also continues to expand. Published, peer-reviewed clinical practice guidelines have also been developed to support the implementation of pharmacogenetic tests. Incorporating pharmacogenetic information into health care benefits patients as well as clinicians by improving drug safety and reducing empiricism in drug selection. Barriers to the implementation of pharmacogenetic testing remain. This review explores current pharmacogenetic implementation initiatives with a focus on the challenges of pharmacogenetic implementation and potential opportunities to overcome these challenges.
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Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance
Vol. 61 (2021), pp. 85–112More LessT cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system.CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases.
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Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure
Vol. 61 (2021), pp. 113–134More LessImmune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by loweringbarriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity.
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Mechanisms of Environment-Induced Autoimmunity
Vol. 61 (2021), pp. 135–157More LessAlthough numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation. Coincident with exposure and resulting pathological processes is the posttranslational modification of self-antigens, which, in concert with the formation of tertiary lymphoid structures containing abundant B cells, is thought to promote the generation of autoantibodies that in some instances demonstrate major histocompatibility complex restriction. Under appropriate gene-environment interactions, these responses can have diagnostic specificity. Greater insight into the molecular and cellular requirements governing this process, especially those that distinguish preclinical autoimmunity from clinical autoimmunedisease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.
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Engineering the Microbiome to Prevent Adverse Events: Challenges and Opportunities
Vol. 61 (2021), pp. 159–179More LessIn the past decade of microbiome research, we have learned about numerous adverse interactions between the microbiome and medical interventions such as drugs, radiation, and surgery. What if we could alter our microbiomes to prevent these events? In this review, we discuss potential routes to mitigate microbiome adverse events, including applications from the emerging field of microbiome engineering. We highlight cases where the microbiome acts directly on a treatment, such as via differential drug metabolism, and cases where a treatment directly harms the microbiome, such as in radiation therapy. Understanding and preventing microbiome adverse events is a difficult challenge that will require a data-driven approach involving causal statistics, multiomics techniques, and a personalized means of mitigating adverse events. We propose research considerations to encourage productive work in preventing microbiome adverse events, and we highlight the many challenges and opportunities that await.
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Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain
Vol. 61 (2021), pp. 181–201More LessThis review explores how different classes of drugs, including those with therapeutic and abuse potential, alter brain functions and behavior via the epigenome. Epigenetics, in its simplest interpretation, is the study of the regulation of a genes’ transcriptional potential. The epigenome is established during development but is malleable throughout life by a wide variety of drugs, with both clinical utility and abuse potential. An epigenetic effect can be central to the drug's therapeutic or abuse potential, or it can be independent from the main effect but nevertheless produce beneficial or adverse side effects. Here, I discuss the various epigenetic effects of main pharmacological drug classes, including antidepressants, antiepileptics, and drugs of abuse.
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Mechanism of Action of TiO2: Recommendations to Reduce Uncertainties Related to Carcinogenic Potential
Vol. 61 (2021), pp. 203–223More LessThe Risk Assessment Committee of the European Chemicals Agency issued an opinion on classifying titanium dioxide (TiO2) as a suspected human carcinogen upon inhalation. Recent animal studies indicate that TiO2 may be carcinogenic through the oral route. There is considerable uncertainty on the carcinogenicity of TiO2, which may be decreased if its mechanism of action becomes clearer. Here we consider adverse outcome pathways and present the available information on each of the key events (KEs). Inhalation exposure to TiO2 can induce lung tumors in rats via a mechanism that is also applicable to other poorly soluble, low-toxicity particles. To reduce uncertainties regarding human relevance, we recommend gathering information on earlier KEs such as oxidative stress in humans. For oral exposure, insufficient information is available to conclude whether TiO2 can induce intestinal tumors. An oral carcinogenicity study with well-characterized (food-grade) TiO2 is needed, including an assessment of toxicokinetics and early KEs.
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Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy
Vol. 61 (2021), pp. 225–245More LessModel-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health economics, and drug regulations.
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Models of Idiosyncratic Drug-Induced Liver Injury
Tsuyoshi Yokoi, and Shingo OdaVol. 61 (2021), pp. 247–268More LessDrug-induced liver injury (DILI) is a leading cause of attrition during the early and late stages of drug development and after a drug is marketed. DILI is generally classified as either intrinsic or idiosyncratic. Intrinsic DILI is dose dependent and predictable (e.g., acetaminophen toxicity). However, predicting the occurrence of idiosyncratic DILI, which has a very low incidence and is associated with severe liver damage, is difficult because of its complex nature and the poor understanding of its mechanism. Considering drug metabolism and pharmacokinetics, we established experimental animal models of DILI for 14 clinical drugs that cause idiosyncratic DILI in humans, which is characterized by the formation of reactive metabolites and the involvement of both innate and adaptive immunity. On the basis of the biomarker data obtained from the animal models, we developed a cell-based assay system that predicts the potential risks of drugs for inducing DILI. These findings increase our understanding of the mechanisms of DILI and may help predict and prevent idiosyncratic DILI due to certain drugs.
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Nanoparticle Toxicology
Vol. 61 (2021), pp. 269–289More LessNanoparticles from natural and anthropogenic sources are abundant in the environment, thus human exposure to nanoparticles is inevitable. Due to this constant exposure, it is critically important to understand the potential acute and chronic adverse effects that nanoparticles may cause to humans. In this review, we explore and highlight the current state of nanotoxicology research with a focus on mechanistic understanding of nanoparticle toxicity at organ, tissue, cell, and biomolecular levels. We discuss nanotoxicity mechanisms, including generation of reactive oxygen species, nanoparticle disintegration, modulation of cell signaling pathways, protein corona formation, and poly(ethylene glycol)-mediated immunogenicity. We conclude with a perspective on potential approaches to advance current understanding of nanoparticle toxicity. Such improved understanding may lead to mitigation strategies that could enable safe application of nanoparticles in humans. Advances in nanotoxicity research will ultimately inform efforts to establish standardized regulatory frameworks with the goal of fully exploiting the potential of nanotechnology while minimizing harm to humans.
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Scavenging Reactive Lipids to Prevent Oxidative Injury
Vol. 61 (2021), pp. 291–308More LessOxidative injury due to elevated levels of reactive oxygen species is implicated in cardiovascular diseases, Alzheimer's disease, lung and liver diseases, and many cancers. Antioxidant therapies have generally been ineffective at treating these diseases, potentially due to ineffective doses but also due to interference with critical host defense and signaling processes. Therefore, alternative strategies to prevent oxidative injury are needed. Elevated levels of reactive oxygen species induce lipid peroxidation, generating reactive lipid dicarbonyls. These lipid oxidation products may be the most salient mediators of oxidative injury, as they cause cellular and organ dysfunction by adducting to proteins, lipids, and DNA. Small-molecule compounds have been developed in the past decade to selectively and effectively scavenge these reactive lipid dicarbonyls. This review outlines evidence supporting the role of lipid dicarbonyls in disease pathogenesis, as well as preclinical data supporting the efficacy of novel dicarbonyl scavengers in treating or preventing disease.
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Preventing and Treating Anthracycline Cardiotoxicity: New Insights
Vol. 61 (2021), pp. 309–332More LessAnthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood. In this review, we discuss the incidence, risk factors, types, and pathophysiology of anthracycline cardiotoxicity, as well as methods to prevent and treat this condition. We also summarize and discuss advances made in the last decade in the comprehension of the molecular mechanisms underlying the pathology.
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Sex Differences in the Inflammatory Response: Pharmacological Opportunities for Therapeutics for Coronary Artery Disease
Vol. 61 (2021), pp. 333–359More LessCoordinated molecular responses are key to effective initiation and resolution of both acute and chronic inflammation. Vascular inflammation plays an important role in initiating and perpetuating atherosclerotic disease, specifically at the site of plaque and subsequent fibrous cap rupture. Both men and women succumb to this disease process, and although management strategies have focused on revascularization and pharmacological therapies in the acute situation to reverse vessel closure and prevent thrombogenesis, data now suggest that regulation of host inflammation may improve both morbidity and mortality, thus supporting the notion that prevention is better than cure. There is a clear sex difference in the incidence of vascular disease, and data confirm biological differences in inflammatory initiation and resolution between men and women. This article reviews contemporary opinions describing the sex difference in the initiation and resolution of inflammatory responses, with a view to explore potential targets for pharmacological intervention.
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Drugs That Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option
Vol. 61 (2021), pp. 361–379More LessCells respond to environmental cues by mobilizing signal transduction cascades that engage protein kinases and phosphoprotein phosphatases. Correct organization of these enzymes in space and time enables the efficient and precise transmission of chemical signals. The cyclic AMP-dependent protein kinase A is compartmentalized through its association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of multivalent scaffolds that constrain signaling enzymes and effectors at subcellular locations to drive essential physiological events. More recently, it has been recognized that defective signaling in certain endocrine disorders and cancers proceeds through pathological AKAP complexes. Consequently, pharmacologically targeting these macromolecular complexes unlocks new therapeutic opportunities for a growing number of clinical indications. This review highlights recent findings on AKAP signaling in disease, particularly in certain cancers, and offers an overview of peptides and small molecules that locally regulate AKAP-binding partners.
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Hormonal Signaling Actions on Kv7.1 (KCNQ1) Channels
Vol. 61 (2021), pp. 381–400More LessKv7 channels (Kv7.1–7.5) are voltage-gated K+ channels that can be modulated by five β-subunits (KCNE1–5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K+ current, IKs, which is important during the repolarization phase of the cardiac action potential. Kv7.2–7.5 are predominantly neuronally expressed and constitute the muscarinic M-current and control the resting membrane potential in neurons. Kv7.1 produces drastically different currents as a result of modulation by KCNE subunits. This flexibility allows the Kv7.1 channel to have many roles depending on location and assembly partners. The pharmacological sensitivity of Kv7.1 channels differs from that of Kv7.2–7.5 and is largely dependent upon the number of β-subunits present in the channel complex. As a result, the development of pharmaceuticals targeting Kv7.1 is problematic. This review discusses the roles and the mechanisms by which different signaling pathways affect Kv7.1 and KCNE channels and could potentially provide different ways of targeting the channel.
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Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond
Vol. 61 (2021), pp. 401–420More LessTwo-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.
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Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs
Vol. 61 (2021), pp. 421–440More LessG protein–coupled receptors (GPCRs) form a superfamily of plasma membrane receptors that couple to four major families of heterotrimeric G proteins, Gs, Gi, Gq, and G12. GPCRs represent excellent targets for drug therapy. Since the individual GPCRs are expressed by many different cell types, the in vivo metabolic roles of a specific GPCR expressed by a distinct cell type are not well understood. The development of designer GPCRs known as DREADDs (designer receptors exclusively activated by a designer drug) that selectively couple to distinct classes of heterotrimeric G proteins has greatly facilitated studies in this area. This review focuses on the use of DREADD technology to explore the physiological and pathophysiological roles of distinct GPCR/G protein cascades in several metabolically important cell types. The novel insights gained from these studies should stimulate the development of GPCR-based treatments for major metabolic diseases such as type 2 diabetes and obesity.
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Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors
Vol. 61 (2021), pp. 441–463More LessInspired by the medicinal properties of the plant Cannabis sativa and its principal component (−)-trans-Δ9-tetrahydrocannabinol (THC), researchers have developed a variety of compounds to modulate the endocannabinoid system in the human brain. Inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are the enzymes responsible for the inactivation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, respectively, may exert therapeutic effects without inducing the adverse side effects associated with direct cannabinoid CB1 receptor stimulation by THC. Here we review the FAAH and MAGL inhibitors that have reached clinical trials, discuss potential caveats, and provide an outlook on where the field is headed.
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Structural Basis of SARS-CoV-2– and SARS-CoV–Receptor Binding and Small-Molecule Blockers as Potential Therapeutics
Vol. 61 (2021), pp. 465–493More LessOver the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other hosts is mediated by host–pathogen interactions, specifically virus–receptor binding. An in-depth understanding of the virus–receptor binding mechanism is a prerequisite for the discovery of vaccines, antibodies, and small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. In this review, we discuss the viral entry mechanism, the known structural aspects of virus–receptor interactions (SARS-CoV-2 S/humanACE2, SARS-CoV S/humanACE2, and MERS-CoV S/humanDPP4), the key protein domains and amino acid residues involved in binding, and the small-molecule inhibitors and other drugs that have (as of June 2020) exhibited therapeutic potential. Specifically, we review the potential clinical utility of two transmembrane serine protease 2 (TMPRSS2)-targeting protease inhibitors, nafamostat mesylate and camostat mesylate, as well as two novel potent fusion inhibitors and the repurposed Ebola drug, remdesivir, which is specific to RNA-dependent RNA polymerase, against human coronaviruses, including SARS-CoV-2.
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Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis
Vol. 61 (2021), pp. 495–516More LessTuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly recognized as a method capable of drug prioritization and regimen optimization to efficiently progress compounds through TB drug development phases. In this review, we examine translational models and tools, including plasma PK scaling, site-of-disease lesion PK, host-immune and bacteria interplay, combination PK-PD models of multidrug regimens, resistance formation, and integration of data across nonclinical and clinical phases.We propose a workflow that integrates these tools with computational platforms to identify drug combinations that have the potential to accelerate sterilization, reduce relapse rates, and limit the emergence of resistance.
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Oral Biologic Delivery: Advances Toward Oral Subunit, DNA, and mRNA Vaccines and the Potential for Mass Vaccination During Pandemics
Vol. 61 (2021), pp. 517–540More LessOral vaccination enables pain-free and self-administrable vaccine delivery for rapid mass vaccination during pandemic outbreaks. Furthermore, it elicits systemic and mucosal immune responses. This protects against infection at mucosal surfaces, which may further enhance protection and minimize the spread of disease. The gastrointestinal (GI) tract presents a number of prospective mucosal inductive sites for vaccine targeting, including the oral cavity, stomach, and small intestine. However, currently available oral vaccines are effectively limited to live-attenuated and inactivated vaccines against enteric diseases. The GI tract poses a number of challenges,including degradative processes that digest biologics and mucosal barriers that limit their absorption. This review summarizes the approaches currently under development and future opportunities for oral vaccine delivery to established (intestinal) and relatively new (oral cavity, stomach) mucosal targets. Special consideration is given to recent advances in oral biologic delivery that offer promise as future platforms for the administration of oral vaccines.
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The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting
Vol. 61 (2021), pp. 541–563More LessElevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.
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Pharmacogenomics of Antiretroviral Drug Metabolism and Transport
Vol. 61 (2021), pp. 565–585More LessAntiretroviral therapy has markedly reduced morbidity and mortality for persons living with human immunodeficiency virus (HIV). Individual tailoring of antiretroviral regimens has the potential to further improve the long-term management of HIV through the mitigation of treatment failure and drug-induced toxicities. While the mechanisms underlying anti-HIV drug adverse outcomes are multifactorial, the application of drug-specific pharmacogenomic knowledge is required in order to move toward the personalization of HIV therapy. Thus, detailed understanding of the metabolism and transport of antiretrovirals and the influence of genetics on these pathways is important. To this end, this review provides an up-to-date overview of the metabolism of anti-HIV therapeutics and the impact of genetic variation in drug metabolism and transport on the treatment of HIV. Future perspectives on and current challenges in pursuing personalized HIV treatment are also discussed.
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Signaling Microdomains in the Spotlight: Visualizing Compartmentalized Signaling Using Genetically Encoded Fluorescent Biosensors
Vol. 61 (2021), pp. 587–608More LessHow cells muster a network of interlinking signaling pathways to faithfully convert diverse external cues to specific functional outcomes remains a central question in biology. Through their ability to convert dynamic biochemical activities to rapid and precise optical readouts, genetically encoded fluorescent biosensors have become instrumental in unraveling the molecular logic controlling the specificity of intracellular signaling. In this review, we discuss how the use of genetically encoded fluorescent biosensors to visualize dynamic signaling events within their native cellular context is elucidating the different strategies employed by cells to organize signaling activities into discrete compartments, or signaling microdomains, to ensure functional specificity.
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New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders
Vol. 61 (2021), pp. 609–628More LessThe abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D3 receptors are described as two promising targets for future drug development.
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Store-Operated Ca2+ Channels: Mechanism, Function, Pharmacology, and Therapeutic Targets
Vol. 61 (2021), pp. 629–654More LessCalcium (Ca2+) release–activated Ca2+ (CRAC) channels are a major route for Ca2+ entry in eukaryotic cells. These channels are store operated, opening when the endoplasmic reticulum (ER) is depleted of Ca2+, and are composed of the ER Ca2+ sensor protein STIM and the pore-forming plasma membrane subunit Orai. Recent years have heralded major strides in our understanding of the structure, gating, and function of the channels. Loss-of-function and gain-of-function mutants combined with RNAi knockdown strategies have revealed important roles for the channel in numerous human diseases, making the channel a clinically relevant target. Drugs targeting the channels generally lack specificity or exhibit poor efficacy in animal models. However, the landscape is changing, and CRAC channel blockers are now entering clinical trials. Here, we describe the key molecular and biological features of CRAC channels, consider various diseases associated with aberrant channel activity, and discuss targeting of the channels from a therapeutic perspective.
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TRP Channel Cooperation for Nociception: Therapeutic Opportunities
Vol. 61 (2021), pp. 655–677More LessChronic pain treatment remains a sore challenge, and in our aging society, the number of patients reporting inadequate pain relief continues to grow. Current treatment options all have their drawbacks, including limited efficacy and the propensity of abuse and addiction; the latter is exemplified by the ongoing opioid crisis. Extensive research in the last few decades has focused on mechanisms underlying chronic pain states, thereby producing attractive opportunities for novel, effective and safe pharmaceutical interventions. Members of the transient receptor potential (TRP) ion channel family represent innovative targets to tackle pain sensation at the root. Three TRP channels, TRPV1, TRPM3, and TRPA1, are of particular interest, as they were identified as sensors of chemical- and heat-induced pain in nociceptor neurons. This review summarizes the knowledge regarding TRP channel–based pain therapies, including the bumpy road of the clinical development of TRPV1 antagonists, the current status of TRPA1 antagonists, and the future potential of targeting TRPM3.
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Pharmacogenomics in Pediatric Oncology: Mitigating Adverse Drug Reactions While Preserving Efficacy
Vol. 61 (2021), pp. 679–699More LessCancer is the leading cause of death in American children older than 1 year of age. Major developments in drugs such as thiopurines and optimization in clinical trial protocols for treating cancer in children have led to a remarkable improvement in survival, from approximately 30% in the 1960s to more than 80% today. Short-term and long-term adverse effects of chemotherapy still affect most survivors of childhood cancer. Pharmacogenetics plays a major role in predicting the safety of cancer chemotherapy and, in the future, its effectiveness. Treatment failure in childhood cancer—due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission—warrants development of new strategies for treatment. Here, we summarize the current knowledge of the pharmacogenomics of cancer drug treatment in children and of statistically and clinically relevant drug–gene associations and the mechanistic understandings that underscore their therapeutic value in the treatment of childhood cancer.
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Novel Therapeutic Approach for Excitatory/Inhibitory Imbalance in Neurodevelopmental and Neurodegenerative Diseases
Vol. 61 (2021), pp. 701–721More LessExcitatory/inhibitory (E/I) balance, defined as the balance between excitation and inhibition of synaptic activity in a neuronal network, accounts in part for the normal functioning of the brain, controlling, for example, normal spike rate. In many pathological conditions, this fine balance is perturbed, leading to excessive or diminished excitation relative to inhibition, termed E/I imbalance, reflected in network dysfunction. E/I imbalance has emerged as a contributor to neurological disorders that occur particularly at the extremes of life, including autism spectrum disorder and Alzheimer's disease, pointing to the vulnerability of neuronal networks at these critical life stages. Hence, it is important to develop approaches to rebalance neural networks. In this review, we describe emerging therapies that can normalize the E/I ratio or the underlying abnormality that contributes to the imbalance in electrical activity, thus improving neurological function in these maladies.
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PHLPPing the Script: Emerging Roles of PHLPP Phosphatases in Cell Signaling
Vol. 61 (2021), pp. 723–743More LessWhereas protein kinases have been successfully targeted for a variety of diseases, protein phosphatases remain an underutilized therapeutic target, in part because of incomplete characterization of their effects on signaling networks. The pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) is a relatively new player in the cell signaling field, and new roles in controlling the balance among cell survival, proliferation, and apoptosis are being increasingly identified. Originally characterized for its tumor-suppressive function in deactivating the prosurvival kinase Akt, PHLPP may have an opposing role in promoting survival, as recent evidence suggests. Additionally, identification of the transcription factor STAT1 as a substrate unveils a role for PHLPP as a critical mediator of transcriptional programs in cancer and the inflammatory response. This review summarizes the current knowledge of PHLPP as both a tumor suppressor and an oncogene and highlights emerging functions in regulating gene expression and the immune system. Understanding the context-dependent functions of PHLPP is essential for appropriate therapeutic intervention.
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Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?
Vol. 61 (2021), pp. 745–756More LessLong-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients’ access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.
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Pharmacologic Approach to Sinoatrial Node Dysfunction
Vol. 61 (2021), pp. 757–778More LessThe spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the heart's inability to generate a normal sinoatrial node action potential. In clinical practice, SND is generally considered an age-related pathology, secondary to degenerative fibrosis of the heart pacemaker tissue. However, other forms of SND exist, including idiopathic primary SND, which is genetic, and forms that are secondary to cardiovascular or systemic disease. The incidence of SND in the general population is expected to increase over the next half century, boosting the need to implant electronic pacemakers. During the last two decades, our knowledge of sino-atrial node physiology and of the pathophysiological mechanisms underlying SND has advanced considerably. This review summarizes the current knowledge about SND mechanisms and discusses the possibility of introducing new pharmacologic therapies for treating SND.
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Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
Vol. 61 (2021), pp. 779–803More LessSenescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.
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Pharmacology of Chimeric Antigen Receptor–Modified T Cells
Vol. 61 (2021), pp. 805–829More LessCell-based immunotherapies using T cells that are engineered to express a chimeric antigen receptor (CAR-T cells) are an effective treatment option for several B cell malignancies. Compared with most drugs, CAR-T cell products are highly complex, as each cell product is composed of a heterogeneous mixture of millions of cells. The biodistribution and kinetics of CAR-T cells, following administration, are unique given the ability of T cells to actively migrate as well as replicate within the patient. CAR-T cell therapies also have multiple mechanisms of action that contribute to both their antitumor activity and their toxicity. This review provides an overview of the unique pharmacology of CAR-T cells, with a focus on CD19-targeting and B cell maturation antigen (BCMA)-targeting CAR-T cells.
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Antisense Drugs Make Sense for Neurological Diseases
Vol. 61 (2021), pp. 831–852More LessThe genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of drugs—antisense oligonucleotides (ASOs)—show promise as a therapeutic platform for treating neurological diseases. ASOs are designed to bind to the RNAs either by promoting degradation of the targeted RNA or by elevating expression by RNA splicing. Intrathecal injection into the cerebral spinal fluid results in broad distribution of antisense drugs and long-term effects. Approval of nusinersen in 2016 demonstrated that effective treatments for neurodegenerative diseases can be identified and that treatments not only slow disease progression but also improve some symptoms. Antisense drugs are currently in development for amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and Angelman syndrome, and several drugs are in late-stage research for additional neurological diseases. This review highlights the advances in antisense technology as potential treatments for neurological diseases.
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Previous Volumes
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Volume 64 (2024)
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Volume 63 (2023)
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Volume 62 (2022)
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Volume 61 (2021)
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Volume 60 (2020)
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Volume 59 (2019)
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Volume 58 (2018)
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Volume 57 (2017)
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Volume 56 (2016)
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Volume 55 (2015)
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Volume 54 (2014)
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Volume 53 (2013)
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Volume 52 (2012)
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Volume 51 (2011)
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Volume 50 (2010)
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Volume 49 (2009)
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Volume 48 (2008)
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Volume 47 (2007)
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Volume 46 (2006)
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Volume 45 (2005)
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Volume 44 (2004)
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Volume 43 (2003)
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Volume 42 (2002)
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Volume 41 (2001)
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Volume 40 (2000)
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Volume 39 (1999)
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Volume 38 (1998)
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Volume 37 (1997)
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Volume 36 (1996)
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Volume 35 (1995)
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Volume 34 (1994)
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Volume 33 (1993)
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Volume 32 (1992)
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Volume 31 (1991)
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Volume 30 (1990)
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Volume 29 (1989)
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Volume 28 (1988)
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Volume 27 (1987)
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Volume 26 (1986)
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Volume 25 (1985)
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Volume 24 (1984)
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Volume 23 (1983)
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Volume 22 (1982)
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Volume 21 (1981)
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Volume 20 (1980)
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Volume 19 (1979)
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Volume 18 (1978)
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Volume 17 (1977)
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Volume 16 (1976)
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Volume 15 (1975)
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Volume 14 (1974)
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Volume 13 (1973)
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Volume 12 (1972)
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Volume 11 (1971)
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Volume 10 (1970)
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Volume 9 (1969)
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Volume 8 (1968)
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Volume 7 (1967)
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Volume 6 (1966)
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Volume 5 (1965)
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Volume 4 (1964)
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Volume 3 (1963)
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Volume 2 (1962)
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Volume 1 (1961)
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Volume 0 (1932)