1,143 results match your criteria Annual Review Of Pharmacology And Toxicology[Journal]


Drugs that Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option.

Annu Rev Pharmacol Toxicol 2020 Jul 6. Epub 2020 Jul 6.

Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA; email:

Cells 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). Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-022420-112134DOI Listing

Structural Basis of the SARS-CoV-2/SARS-CoV Receptor Binding and Small-Molecule Blockers as Potential Therapeutics.

Annu Rev Pharmacol Toxicol 2020 06 23. Epub 2020 Jun 23.

Department of Biological Sciences, National University of Singapore, Singapore 117543; email:

Over the past two decades, deadly coronaviruses have caused major challenges to public health, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2, 2019) pandemic. 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/or small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-061220-093932DOI Listing

Oral Biologic Delivery: Advances Towards Oral Subunit, DNA and mRNA Vaccines and the Potential for Mass Vaccination During Pandemics.

Annu Rev Pharmacol Toxicol 2020 May 28. Epub 2020 May 28.

Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; email:

Oral vaccination offers the promise of convenient, pain-free and self-administrable vaccine delivery. This is highly attractive in response to pandemic outbreaks where rapid mass vaccination is critical. Furthermore, oral vaccination produces mucosal, as well as systemic, immune responses, which protect against infection at mucosal surfaces. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-030320-092348DOI Listing

Mechanism of Action of TiO: Recommendations to Reduce Uncertainties Related to Carcinogenic Potential.

Annu Rev Pharmacol Toxicol 2020 Apr 13. Epub 2020 Apr 13.

National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands; email:

The Risk Assessment Committee of the European Chemicals Agency issued an opinion on classifying titanium dioxide (TiO) as a suspected human carcinogen upon inhalation. Recent animal studies indicate that TiO may be carcinogenic through the oral route. There is considerable uncertainty on the carcinogenicity of TiO, which may be decreased if its mechanism of action becomes clearer. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-101419-100049DOI Listing

Retinal Pigment Epithelium Replacement Therapy for Age-Related Macular Degeneration: Are We There Yet?

Annu Rev Pharmacol Toxicol 2020 01;60:553-572

Unit on Ocular and Stem Cell Translational Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023245DOI Listing
January 2020

Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies.

Annu Rev Pharmacol Toxicol 2020 01;60:291-309

Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122796PMC
January 2020

Engineered Protein Scaffolds as Next-Generation Therapeutics.

Annu Rev Pharmacol Toxicol 2020 01;60:391-415

Lehrstuhl für Biologische Chemie, Technische Universität München, 85354 Freising, Germany; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021118DOI Listing
January 2020

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders.

Annu Rev Pharmacol Toxicol 2020 01;60:109-131

Department of Pharmacology, School of Pharmacy, University College London, London WC1N 1AX, United Kingdom; email:

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits () 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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023356DOI Listing
January 2020

Neuropathic Pain: Mechanism-Based Therapeutics.

Annu Rev Pharmacol Toxicol 2020 01;60:257-274

Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021524DOI Listing
January 2020

Device-Based Modulation of Neurocircuits as a Therapeutic for Psychiatric Disorders.

Annu Rev Pharmacol Toxicol 2020 01;60:591-614

Noninvasive Neuromodulation Unit, Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023253DOI Listing
January 2020

Neurons, Receptors, and Channels.

Authors:
David A Brown

Annu Rev Pharmacol Toxicol 2020 01;60:9-30

Departments of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023755DOI Listing
January 2020

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders.

Annu Rev Pharmacol Toxicol 2020 01;60:615-636

Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023317DOI Listing
January 2020

Introduction to the Theme "Ion Channels and Neuropharmacology: From the Past to the Future".

Annu Rev Pharmacol Toxicol 2020 01;60:1-6

Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

"Ion Channels and Neuropharmacology: From the Past to the Future" is the main theme of articles in Volume 60 of the . 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 Ca and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L-type Ca channels, and AMPA receptors, as well as the aquaporin channels. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-082719-110050DOI Listing
January 2020

Neonicotinoid Insecticides: Molecular Targets, Resistance, and Toxicity.

Annu Rev Pharmacol Toxicol 2020 01;60:241-255

Centre for Respiratory Biology, UCL Respiratory, University College London, London WC1E 6JF, United Kingdom; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021747DOI Listing
January 2020

Addressing the Challenge of Polypharmacy.

Annu Rev Pharmacol Toxicol 2020 01 7;60:661-681. Epub 2019 Oct 7.

Quality, Safety, and Informatics Research Group, University of Dundee, Dundee DD1 4HN, United Kingdom.

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023508DOI Listing
January 2020

Beyond THC and Endocannabinoids.

Annu Rev Pharmacol Toxicol 2020 01 3;60:637-659. Epub 2019 Oct 3.

Institute for Drug Research, Faculty of Medicine, Hebrew University, Jerusalem 9112102, Israel; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021441DOI Listing
January 2020
1 Read

Targeting the Trafficking of Kidney Water Channels for Therapeutic Benefit.

Annu Rev Pharmacol Toxicol 2020 01 27;60:175-194. Epub 2019 Sep 27.

Center for Systems Biology, Program in Membrane Biology, and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA; email:

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). Read More

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https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-0
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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334826PMC
January 2020
5 Reads

β Adrenergic Receptor Complexes with the L-Type Ca Channel Ca1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions.

Annu Rev Pharmacol Toxicol 2020 01 27;60:155-174. Epub 2019 Sep 27.

Department of Pharmacology, University of California, Davis, California 95616, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029424PMC
January 2020
1 Read

G Protein-Coupled Receptor Pharmacology at the Single-Molecule Level.

Annu Rev Pharmacol Toxicol 2020 01 20;60:73-87. Epub 2019 Sep 20.

Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham B15 2TT, United Kingdom; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023348DOI Listing
January 2020

Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels.

Annu Rev Pharmacol Toxicol 2020 01 19;60:133-154. Epub 2019 Sep 19.

Department of Pharmacology and Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington 98195, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021757DOI Listing
January 2020

Big Data and Artificial Intelligence Modeling for Drug Discovery.

Authors:
Hao Zhu

Annu Rev Pharmacol Toxicol 2020 01 13;60:573-589. Epub 2019 Sep 13.

Department of Chemistry and Center for Computational and Integrative Biology, Rutgers University, Camden, New Jersey 08102, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010403PMC
January 2020

Lipid-Dependent Regulation of Ion Channels and G Protein-Coupled Receptors: Insights from Structures and Simulations.

Annu Rev Pharmacol Toxicol 2020 01 10;60:31-50. Epub 2019 Sep 10.

Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; email:

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, PIP plays a key role in regulating Kv and Kir channels. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023411DOI Listing
January 2020

Microbiota-Gut-Brain Axis: New Therapeutic Opportunities.

Annu Rev Pharmacol Toxicol 2020 01 10;60:477-502. Epub 2019 Sep 10.

APC Microbiome Ireland, University College Cork, Cork, Ireland; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023628DOI Listing
January 2020
1 Read

Unlocking Personalized Biomedicine and Drug Discovery with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Fit for Purpose or Forever Elusive?

Annu Rev Pharmacol Toxicol 2020 01 10;60:529-551. Epub 2019 Sep 10.

Department of Stem Cell Biology, University of Nottingham, NG7 2RD Nottingham, United Kingdom; email:

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. Read More

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https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-0
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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023309DOI Listing
January 2020
5 Reads

Drug Therapies for Chronic Cholestatic Liver Diseases.

Annu Rev Pharmacol Toxicol 2020 01 10;60:503-527. Epub 2019 Sep 10.

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021059DOI Listing
January 2020
1 Read

Proteasome Inhibitor Drugs.

Authors:
Lloyd D Fricker

Annu Rev Pharmacol Toxicol 2020 01 3;60:457-476. Epub 2019 Sep 3.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023603DOI Listing
January 2020
2 Reads

Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.

Annu Rev Pharmacol Toxicol 2020 01 27;60:89-107. Epub 2019 Aug 27.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville 3052, Australia; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092389PMC
January 2020

Levering Mechanically Activated Piezo Channels for Potential Pharmacological Intervention.

Authors:
Bailong Xiao

Annu Rev Pharmacol Toxicol 2020 01 27;60:195-218. Epub 2019 Aug 27.

State Key Laboratory of Membrane Biology; Tsinghua-Peking Joint Center for Life Sciences; IDG/McGovern Institute for Brain Research; Beijing Advanced Innovation Center for Structural Biology; and School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023703DOI Listing
January 2020

Prospects for Diminishing the Impact of Nonamyloid Small-Vessel Diseases of the Brain.

Authors:
Anne Joutel

Annu Rev Pharmacol Toxicol 2020 01 19;60:437-456. Epub 2019 Aug 19.

Institute of Psychiatry and Neurosciences of Paris, INSERM UMR1266, Paris Descartes University, 75014 Paris, France; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021712DOI Listing
January 2020
2 Reads

(Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease.

Annu Rev Pharmacol Toxicol 2020 01 6;60:371-390. Epub 2019 Aug 6.

Immunogenetics Section, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952538PMC
January 2020

The Role of the Microbiome in Drug Response.

Annu Rev Pharmacol Toxicol 2020 01 6;60:417-435. Epub 2019 Aug 6.

MRC London Institute of Medical Sciences, London W12 0NN, United Kingdom; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023612DOI Listing
January 2020

Cryo-Electron Microscopy: Moving Beyond X-Ray Crystal Structures for Drug Receptors and Drug Development.

Annu Rev Pharmacol Toxicol 2020 01 26;60:51-71. Epub 2019 Jul 26.

MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; email:

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 (GABARs) and G protein-coupled receptors (GPCRs). Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023545DOI Listing
January 2020
1 Read

Artificial Intelligence in Drug Treatment.

Annu Rev Pharmacol Toxicol 2020 01 26;60:353-369. Epub 2019 Jul 26.

CureMatch Inc., San Diego, California 92121, USA.

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023746DOI Listing
January 2020
9 Reads

Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels.

Annu Rev Pharmacol Toxicol 2020 01 23;60:219-240. Epub 2019 Jul 23.

Department of Pharmacology, University of California, Davis, California 95616, USA; email:

The three small-conductance calcium-activated potassium (K2) channels and the related intermediate-conductance K3.1 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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023420DOI Listing
January 2020
1 Read

Using What We Already Have: Uncovering New Drug Repurposing Strategies in Existing Omics Data.

Annu Rev Pharmacol Toxicol 2020 01 23;60:333-352. Epub 2019 Jul 23.

Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023537DOI Listing
January 2020
3 Reads

Gene-Based Dose Optimization in Children.

Annu Rev Pharmacol Toxicol 2020 01 5;60:311-331. Epub 2019 Jul 5.

Departments of Pediatrics and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023459DOI Listing
January 2020
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Barriers to Ensuring Access to Affordable Prescription Drugs.

Authors:
Michelle M Mello

Annu Rev Pharmacol Toxicol 2020 01 28;60:275-289. Epub 2019 May 28.

Department of Health Research and Policy, Stanford University School of Medicine, and Stanford Law School, Stanford University, Stanford, California 94305, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010919-023518DOI Listing
January 2020
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Introduction to the Theme "New Therapeutic Targets".

Annu Rev Pharmacol Toxicol 2019 01;59:15-20

Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

"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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-101018-112717DOI Listing
January 2019
15 Reads

Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes.

Annu Rev Pharmacol Toxicol 2019 01;59:65-87

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA; email: , ,

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010716-104727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198260PMC
January 2019
31 Reads
18.365 Impact Factor

Metals and Mechanisms of Carcinogenesis.

Annu Rev Pharmacol Toxicol 2019 01;59:537-554

Departments of Environmental Medicine, and Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10010, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348465PMC
January 2019
15 Reads

The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease.

Annu Rev Pharmacol Toxicol 2019 01;59:263-289

Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, and Center for Molecular Biosciences Innsbruck, Universität Innsbruck, A-6020 Innsbruck, Austria; email:

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 Ca channel (LTCC) blocker, for neuroprotective PD therapy. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021214DOI Listing
January 2019
5 Reads

Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders.

Annu Rev Pharmacol Toxicol 2019 01;59:149-170

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA; email:

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). Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392001PMC
January 2019
27 Reads

Pharmacologic Targeting of Hypoxia-Inducible Factors.

Authors:
Gregg L Semenza

Annu Rev Pharmacol Toxicol 2019 01;59:379-403

Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; email:

Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O availability. HIFs are heterodimeric proteins composed of an O-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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021637DOI Listing
January 2019
27 Reads

Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?

Annu Rev Pharmacol Toxicol 2019 01 8;59:577-603. Epub 2018 Oct 8.

Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA; email:

Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021154DOI Listing
January 2019
4 Reads

Drug Targets for Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach and Review of Contemporary Clinical Trials.

Annu Rev Pharmacol Toxicol 2019 01 8;59:41-63. Epub 2018 Oct 8.

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327844PMC
January 2019
10 Reads
18.365 Impact Factor

Therapeutic Oligonucleotides: State of the Art.

Annu Rev Pharmacol Toxicol 2019 01 9;59:605-630. Epub 2018 Oct 9.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden; email:

Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, splice-switching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNA decoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021050DOI Listing
January 2019
7 Reads

Systems Pharmacology: Defining the Interactions of Drug Combinations.

Annu Rev Pharmacol Toxicol 2019 01 27;59:21-40. Epub 2018 Sep 27.

Department of Pharmacological Sciences, Systems Biology Center, Mount Sinai Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021511DOI Listing
January 2019
35 Reads

Modulating NRF2 in Disease: Timing Is Everything.

Annu Rev Pharmacol Toxicol 2019 01 26;59:555-575. Epub 2018 Sep 26.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538038PMC
January 2019
5 Reads

Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning.

Annu Rev Pharmacol Toxicol 2019 01 19;59:341-360. Epub 2018 Sep 19.

Pharmacology, Toxicology, and Therapeutics Unit, Centre for Cardiovascular Science, and Centre for Pesticide Suicide Prevention, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; email:

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. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021842DOI Listing
January 2019
5 Reads