Structural Basis of the SARS-CoV-2/SARS-CoV Receptor Binding and Small-Molecule Blockers as Potential Therapeutics.
This article has been accepted for publication on June 23, 2020. Changes may still occur before final publication. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID: 32574109 [PubMed - as supplied by publisher] (Source: Annual Review of Pharmacology and Toxicology)
Source: Annual Review of Pharmacology and Toxicology - June 23, 2020 Category: Drugs & Pharmacology Authors: Sivaraman H, Yin ES, Choong YK, Gavor E, Sivaraman J Tags: Annu Rev Pharmacol Toxicol Source Type: research

Oral Biologic Delivery: Advances Towards Oral Subunit, DNA and mRNA Vaccines and the Potential for Mass Vaccination During Pandemics.
Abstract 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. As the majority of pathogens enter the body through mucosal surfaces this may further enhance protection and minimize the spread of disease. The gastrointestinal (GI) tract presents a number of prospective mucosal inductive sites for targeting orally delivered vaccine...
Source: Annual Review of Pharmacology and Toxicology - May 28, 2020 Category: Drugs & Pharmacology Authors: Coffey JW, Gaiha GD, Traverso G Tags: Annu Rev Pharmacol Toxicol Source Type: research

Mechanism of Action of TiO2: Recommendations to Reduce Uncertainties Related to Carcinogenic Potential.
Abstract The 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 poor...
Source: Annual Review of Pharmacology and Toxicology - April 13, 2020 Category: Drugs & Pharmacology Authors: Braakhuis HM, Gosens I, Heringa MB, Oomen AG, Vandebriel RJ, Groenewold M, Cassee FR Tags: Annu Rev Pharmacol Toxicol Source Type: research

Neonicotinoid Insecticides: Molecular Targets, Resistance, and Toxicity.
Abstract Neonicotinoids have been used to protect crops and animals from insect pests since the 1990s, but there are concerns regarding their adverse effects on nontarget organisms, notably on bees. Enhanced resistance to neonicotinoids in pests is becoming well documented. We address the current understanding of neonicotinoid target site interactions, selectivity, and metabolism not only in pests but also in beneficial insects such as bees. The findings are relevant to the management of both neonicotinoids and the new generation of pesticides targeting insect nicotinic acetylcholine receptors. PMID: 31914891...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Matsuda K, Ihara M, Sattelle DB Tags: Annu Rev Pharmacol Toxicol Source Type: research

Introduction to the Theme "Ion Channels and Neuropharmacology: From the Past to the Future".
Introduction to the Theme "Ion Channels and Neuropharmacology: From the Past to the Future". Annu Rev Pharmacol Toxicol. 2020 Jan 06;60:1-6 Authors: Dolphin AC, Insel PA, Blaschke TF, Meyer UA Abstract "Ion Channels and Neuropharmacology: From the Past to the Future" is the main theme of articles in Volume 60 of the Annual Review of Pharmacology and Toxicology. Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Dolphin AC, Insel PA, Blaschke TF, Meyer UA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders.
Abstract Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opio...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Jacobson ML, Browne CA, Lucki I Tags: Annu Rev Pharmacol Toxicol Source Type: research

Neurons, Receptors, and Channels.
Abstract 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, inc...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Brown DA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Device-Based Modulation of Neurocircuits as a Therapeutic for Psychiatric Disorders.
Abstract Device-based neuromodulation of brain circuits is emerging as a promising new approach in the study and treatment of psychiatric disorders. This work presents recent advances in the development of tools for identifying neurocircuits as therapeutic targets and in tools for modulating neurocircuits. We review clinical evidence for the therapeutic efficacy of circuit modulation with a range of brain stimulation approaches, including subthreshold, subconvulsive, convulsive, and neurosurgical techniques. We further discuss strategies for enhancing the precision and efficacy of neuromodulatory techniques. Final...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Deng ZD, Luber B, Balderston NL, Velez Afanador M, Noh MM, Thomas J, Altekruse WC, Exley SL, Awasthi S, Lisanby SH Tags: Annu Rev Pharmacol Toxicol Source Type: research

Neuropathic Pain: Mechanism-Based Therapeutics.
Abstract Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will ...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Bannister K, Sachau J, Baron R, Dickenson AH Tags: Annu Rev Pharmacol Toxicol Source Type: research

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders.
Abstract The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits (HCN1-4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their ex...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Santoro B, Shah MM Tags: Annu Rev Pharmacol Toxicol Source Type: research

Engineered Protein Scaffolds as Next-Generation Therapeutics.
Abstract The concept of engineering robust protein scaffolds for novel binding functions emerged 20 years ago, one decade after the advent of recombinant antibody technology. Early examples were the Affibody, Monobody (Adnectin), and Anticalin proteins, which were derived from fragments of streptococcal protein A, from the tenth type III domain of human fibronectin, and from natural lipocalin proteins, respectively. Since then, this concept has expanded considerably, including many other protein templates. In fact, engineered protein scaffolds with useful binding specificities, mostly directed against targets of b...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Gebauer M, Skerra A Tags: Annu Rev Pharmacol Toxicol Source Type: research

Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies.
Abstract Cerebral edema, a common and often fatal companion to most forms of acute central nervous system disease, has been recognized since the time of ancient Egypt. Unfortunately, our therapeutic armamentarium remains limited, in part due to historic limitations in our understanding of cerebral edema pathophysiology. Recent advancements have led to a number of clinical trials for novel therapeutics that could fundamentally alter the treatment of cerebral edema. In this review, we discuss these agents, their targets, and the data supporting their use, with a focus on agents that have progressed to clinical trial...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Stokum JA, Gerzanich V, Sheth KN, Kimberly WT, Simard JM Tags: Annu Rev Pharmacol Toxicol Source Type: research

Retinal Pigment Epithelium Replacement Therapy for Age-Related Macular Degeneration: Are We There Yet?
Abstract Pluripotent stem cells (PSCs) are a potential replacement tissue source for degenerative diseases. Age-related macular degeneration (AMD) is a blinding disease triggered by degeneration of the retinal pigment epithelium (RPE), a monolayer tissue that functionally supports retinal photoreceptors. Recently published clinical and preclinical studies have tested PSC-derived RPE as a potential treatment for AMD. Multiple approaches have been used to manufacture RPE cells, to validate them functionally, to confirm their safety profile, and to deliver them to patients either as suspension or as a monolayer patch...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2020 Category: Drugs & Pharmacology Authors: Sharma R, Bose D, Maminishkis A, Bharti K Tags: Annu Rev Pharmacol Toxicol Source Type: research

Addressing the Challenge of Polypharmacy.
This article outlines lessons from two programs that aim to address these challenges: the Scottish polypharmacy guidance on realistic prescribing and the European Union SIMPATHY project. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID: 31589822 [PubMed - as supplied by publisher] (Source: Annual Review of Pharmacology and Toxicology)
Source: Annual Review of Pharmacology and Toxicology - October 7, 2019 Category: Drugs & Pharmacology Authors: Mair A, Wilson M, Dreischulte T Tags: Annu Rev Pharmacol Toxicol Source Type: research

Beyond THC and Endocannabinoids.
Abstract 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....
Source: Annual Review of Pharmacology and Toxicology - October 3, 2019 Category: Drugs & Pharmacology Authors: Pacher P, Kogan NM, Mechoulam R Tags: Annu Rev Pharmacol Toxicol Source Type: research

β2 Adrenergic Receptor Complexes with the L-Type Ca2+ Channel CaV1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions.
β2 Adrenergic Receptor Complexes with the L-Type Ca2+ Channel CaV1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions. Annu Rev Pharmacol Toxicol. 2019 Sep 27;: Authors: Man KNM, Navedo MF, Horne MC, Hell JW Abstract 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 epin...
Source: Annual Review of Pharmacology and Toxicology - September 27, 2019 Category: Drugs & Pharmacology Authors: Man KNM, Navedo MF, Horne MC, Hell JW Tags: Annu Rev Pharmacol Toxicol Source Type: research

Targeting the Trafficking of Kidney Water Channels for Therapeutic Benefit.
Abstract The ability to regulate water movement is vital for the survival of cells and organisms. In addition to passively crossing lipid bilayers by diffusion, water transport is also driven across cell membranes by osmotic gradients through aquaporin water channels. There are 13 aquaporins in human tissues, and of these, aquaporin-2 (AQP2) is the most highly regulated water channel in the kidney: The expression and trafficking of AQP2 respond to body volume status and plasma osmolality via the antidiuretic hormone, vasopressin (VP). Dysfunctional VP signaling in renal epithelial cells contributes to disorders of...
Source: Annual Review of Pharmacology and Toxicology - September 27, 2019 Category: Drugs & Pharmacology Authors: Cheung PW, Bouley R, Brown D Tags: Annu Rev Pharmacol Toxicol Source Type: research

G Protein-Coupled Receptor Pharmacology at the Single-Molecule Level.
Abstract G protein-coupled receptors (GPCRs) mediate the effects of numerous hormones and neurotransmitters and are major pharmacological targets. Classical studies with crude cell lysates or membrane preparations have identified the main biochemical steps involved in GPCR signaling. Moreover, recent studies on purified proteins have provided astounding details at the atomic level of the 3-D structures of receptors in multiple conformations, including in complex with G proteins and β-arrestins. However, several fundamental questions remain regarding the highly specific effects and rapid nature of GPCR signali...
Source: Annual Review of Pharmacology and Toxicology - September 20, 2019 Category: Drugs & Pharmacology Authors: Calebiro D, Grimes J Tags: Annu Rev Pharmacol Toxicol Source Type: research

Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels.
Abstract 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 pharmac...
Source: Annual Review of Pharmacology and Toxicology - September 19, 2019 Category: Drugs & Pharmacology Authors: Catterall WA, Lenaeus MJ, El-Din TMG Tags: Annu Rev Pharmacol Toxicol Source Type: research

Big Data and Artificial Intelligence Modeling for Drug Discovery.
Abstract Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, heterogeneous, and large nature of drug data sets. As a result, recently developed artificial intelligence approaches such as deep learning and relevant modeling studies provide new solutions to efficacy and safety evaluations of drug candidates based on big data modeling and analysis. The resulting models provided deep insights into the continuum from chem...
Source: Annual Review of Pharmacology and Toxicology - September 13, 2019 Category: Drugs & Pharmacology Authors: Zhu H Tags: Annu Rev Pharmacol Toxicol Source Type: research

Drug Therapies for Chronic Cholestatic Liver Diseases.
Abstract 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...
Source: Annual Review of Pharmacology and Toxicology - September 10, 2019 Category: Drugs & Pharmacology Authors: Wagner M, Fickert P Tags: Annu Rev Pharmacol Toxicol Source Type: research

Unlocking Personalized Biomedicine and Drug Discovery with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Fit for Purpose or Forever Elusive?
Abstract 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 platform...
Source: Annual Review of Pharmacology and Toxicology - September 10, 2019 Category: Drugs & Pharmacology Authors: de Korte T, Katili PA, Mohd Yusof NAN, van Meer BJ, Saleem U, Burton FL, Smith GL, Clements P, Mummery CL, Eschenhagen T, Hansen A, Denning C Tags: Annu Rev Pharmacol Toxicol Source Type: research

Microbiota-Gut-Brain Axis: New Therapeutic Opportunities.
Abstract 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 bact...
Source: Annual Review of Pharmacology and Toxicology - September 10, 2019 Category: Drugs & Pharmacology Authors: Long-Smith C, O'Riordan KJ, Clarke G, Stanton C, Dinan TG, Cryan JF Tags: Annu Rev Pharmacol Toxicol Source Type: research

Lipid-Dependent Regulation of Ion Channels and G Protein-Coupled Receptors: Insights from Structures and Simulations.
Abstract Ion channels and G protein-coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., for...
Source: Annual Review of Pharmacology and Toxicology - September 10, 2019 Category: Drugs & Pharmacology Authors: Duncan AL, Song W, Sansom MSP Tags: Annu Rev Pharmacol Toxicol Source Type: research

Proteasome Inhibitor Drugs.
Abstract Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are...
Source: Annual Review of Pharmacology and Toxicology - September 3, 2019 Category: Drugs & Pharmacology Authors: Fricker LD Tags: Annu Rev Pharmacol Toxicol Source Type: research

Levering Mechanically Activated Piezo Channels for Potential Pharmacological Intervention.
Abstract The mechanically activated Piezo channels, including Piezo1 and Piezo2 in mammals, function as key mechanotransducers for converting mechanical force into electrochemical signals. This review highlights key evidence for the potential of Piezo channel drug discovery. First, both mouse and human genetic studies have unequivocally demonstrated the prominent role of Piezo channels in various mammalian physiologies and pathophysiologies, validating their potential as novel therapeutic targets. Second, the cryo-electron microscopy structure of the 2,547-residue mouse Piezo1 trimer has been determined, providing...
Source: Annual Review of Pharmacology and Toxicology - August 27, 2019 Category: Drugs & Pharmacology Authors: Xiao B Tags: Annu Rev Pharmacol Toxicol Source Type: research

Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.
Abstract 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...
Source: Annual Review of Pharmacology and Toxicology - August 27, 2019 Category: Drugs & Pharmacology Authors: Wootten D, Miller LJ Tags: Annu Rev Pharmacol Toxicol Source Type: research

Prospects for Diminishing the Impact of Nonamyloid Small-Vessel Diseases of the Brain.
Abstract Small-vessel diseases (SVDs) of the brain are involved in about one-fourth of ischemic strokes and a vast majority of intracerebral hemorrhages and are responsible for nearly half of dementia cases in the elderly. SVDs are a heavy burden for society, a burden that is expected to increase further in the absence of significant therapeutic advances, given the aging population. Here, we provide a critical appraisal of currently available therapeutic approaches for nonamyloid sporadic SVDs that are largely based on targeting modifiable risk factors. We review what is known about the pathogenic mechanisms of va...
Source: Annual Review of Pharmacology and Toxicology - August 19, 2019 Category: Drugs & Pharmacology Authors: Joutel A Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Role of the Microbiome in Drug Response.
Abstract 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...
Source: Annual Review of Pharmacology and Toxicology - August 6, 2019 Category: Drugs & Pharmacology Authors: Pryor R, Martinez-Martinez D, Quintaneiro L, Cabreiro F Tags: Annu Rev Pharmacol Toxicol Source Type: research

(Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease.
(Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease. Annu Rev Pharmacol Toxicol. 2019 Aug 06;: Authors: Jetten AM, Cook DN Abstract 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 chole...
Source: Annual Review of Pharmacology and Toxicology - August 6, 2019 Category: Drugs & Pharmacology Authors: Jetten AM, Cook DN Tags: Annu Rev Pharmacol Toxicol Source Type: research

Artificial Intelligence in Drug Treatment.
Abstract The most common applications of artificial intelligence (AI) in drug treatment have to do with matching patients to their optimal drug or combination of drugs, predicting drug-target or drug-drug interactions, and optimizing treatment protocols. This review outlines some of the recently developed AI methods aiding the drug treatment and administration process. Selection of the best drug(s) for a patient typically requires the integration of patient data, such as genetics or proteomics, with drug data, like compound chemical descriptors, to score the therapeutic efficacy of drugs. The prediction of drug in...
Source: Annual Review of Pharmacology and Toxicology - July 26, 2019 Category: Drugs & Pharmacology Authors: Romm EL, Tsigelny IF Tags: Annu Rev Pharmacol Toxicol Source Type: research

Cryo-Electron Microscopy: Moving Beyond X-Ray Crystal Structures for Drug Receptors and Drug Development.
J, Tate CG Abstract Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABAARs) and G protein-coupled receptors (GPCRs). GABAARs are pentameric ion channels, and cryo-EM structures of phy...
Source: Annual Review of Pharmacology and Toxicology - July 26, 2019 Category: Drugs & Pharmacology Authors: García-Nafría J, Tate CG Tags: Annu Rev Pharmacol Toxicol Source Type: research

Using What We Already Have: Uncovering New Drug Repurposing Strategies in Existing Omics Data.
Abstract The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity. This review summarizes drug repurposing strategies and methodologies in the context of the following omics fields: genomics, epigenomics, transcriptomic...
Source: Annual Review of Pharmacology and Toxicology - July 23, 2019 Category: Drugs & Pharmacology Authors: Pulley JM, Rhoads JP, Jerome RN, Challa AP, Erreger KB, Joly MM, Lavieri RR, Perry KE, Zaleski NM, Shirey-Rice JK, Aronoff DM Tags: Annu Rev Pharmacol Toxicol Source Type: research

Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels.
Abstract The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review...
Source: Annual Review of Pharmacology and Toxicology - July 23, 2019 Category: Drugs & Pharmacology Authors: Brown BM, Shim H, Christophersen P, Wulff H Tags: Annu Rev Pharmacol Toxicol Source Type: research

Gene-Based Dose Optimization in Children.
Abstract Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxet...
Source: Annual Review of Pharmacology and Toxicology - July 5, 2019 Category: Drugs & Pharmacology Authors: Ramsey LB, Brown JT, Vear SI, Bishop JR, Van Driest SL Tags: Annu Rev Pharmacol Toxicol Source Type: research

Barriers to Ensuring Access to Affordable Prescription Drugs.
This article reviews the moral, market, and political factors contributing to the difficulty. Among the moral problems is lack of agreement about how to weigh the fundamental tradeoff involved in regulating drug prices-affordability versus incentives for innovation-and about what constitutes a fair price. Market-related factors include the lack of price transparency and a myriad of perverse incentives in the system through which prescription drugs are supplied to patients. Finally, current policy choices are constrained by past political compromises, and an atmosphere of scandal focusing on egregious instances of price gou...
Source: Annual Review of Pharmacology and Toxicology - May 28, 2019 Category: Drugs & Pharmacology Authors: Mello MM Tags: Annu Rev Pharmacol Toxicol Source Type: research

Pharmacologic Targeting of Hypoxia-Inducible Factors.
Abstract Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O2 availability. HIFs are heterodimeric proteins composed of an O2-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease. HIFs contri...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Semenza GL Tags: Annu Rev Pharmacol Toxicol Source Type: research

Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders.
Abstract Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration-approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other L...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Chun J, Kihara Y, Jonnalagadda D, Blaho VA Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease.
Abstract The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vi...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Liss B, Striessnig J Tags: Annu Rev Pharmacol Toxicol Source Type: research

Metals and Mechanisms of Carcinogenesis.
Abstract Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis. Specifically, we focus on the five most preval...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Chen QY, DesMarais T, Costa M Tags: Annu Rev Pharmacol Toxicol Source Type: research

Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes.
Abstract Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this ...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Goedeke L, Perry RJ, Shulman GI Tags: Annu Rev Pharmacol Toxicol Source Type: research

Introduction to the Theme "New Therapeutic Targets".
Introduction to the Theme "New Therapeutic Targets". Annu Rev Pharmacol Toxicol. 2019 Jan 06;59:15-20 Authors: Insel PA, Amara SG, Blaschke TF, Meyer UA Abstract "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, depre...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Insel PA, Amara SG, Blaschke TF, Meyer UA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Drug Targets for Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach and Review of Contemporary Clinical Trials.
Abstract Heart failure with preserved ejection fraction (HFpEF) accounts for over half of prevalent heart failure (HF) worldwide, and prognosis after hospitalization for HFpEF remains poor. Due, at least in part, to the heterogeneous nature of HFpEF, drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Despite these challenges, important mechanistic understandings of the disease have revealed that the pathophysiology of HFpEF is distinct from that of HF with reduced ejection fraction and have also highlighted potential ne...
Source: Annual Review of Pharmacology and Toxicology - October 8, 2018 Category: Drugs & Pharmacology Authors: Patel RB, Shah SJ Tags: Annu Rev Pharmacol Toxicol Source Type: research

Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants.
Abstract For decades, symptoms of depression have been treated primarily with medications that target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of (R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be...
Source: Annual Review of Pharmacology and Toxicology - October 8, 2018 Category: Drugs & Pharmacology Authors: Gould TD, Zarate CA, Thompson SM Tags: Annu Rev Pharmacol Toxicol Source Type: research

Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?
Abstract 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. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, m...
Source: Annual Review of Pharmacology and Toxicology - October 8, 2018 Category: Drugs & Pharmacology Authors: De T, Park CS, Perera MA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Systems Pharmacology: Defining the Interactions of Drug Combinations.
Abstract The majority of diseases are associated with alterations in multiple molecular pathways and complex interactions at the cellular and organ levels. Singletarget monotherapies therefore have intrinsic limitations with respect to their maximum therapeutic benefits. The potential of combination drug therapies has received interest for the treatment of many diseases and is well established in some areas, such as oncology. Combination drug treatments may allow us to identify synergistic drug effects, reduce adverse drug reactions, and address variability in disease characteristics between patients. Identificati...
Source: Annual Review of Pharmacology and Toxicology - September 27, 2018 Category: Drugs & Pharmacology Authors: van Hasselt JGC, Iyengar R Tags: Annu Rev Pharmacol Toxicol Source Type: research

Modulating NRF2 in Disease: Timing Is Everything.
Abstract The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation o...
Source: Annual Review of Pharmacology and Toxicology - September 26, 2018 Category: Drugs & Pharmacology Authors: Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD Tags: Annu Rev Pharmacol Toxicol Source Type: research

Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning.
Abstract Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Current treatment is modestly effective,...
Source: Annual Review of Pharmacology and Toxicology - September 19, 2018 Category: Drugs & Pharmacology Authors: Eddleston M Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Placebo Effect in Pain Therapies.
Abstract Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor-mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients' positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and ch...
Source: Annual Review of Pharmacology and Toxicology - September 14, 2018 Category: Drugs & Pharmacology Authors: Colloca L Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.
Abstract New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stressrelated synaptic dysconnectivity in the neurobiology and treatment ofPTSD. Here, we integrate this perspe...
Source: Annual Review of Pharmacology and Toxicology - September 14, 2018 Category: Drugs & Pharmacology Authors: Abdallah CG, Averill LA, Akiki TJ, Raza M, Averill CL, Gomaa H, Adikey A, Krystal JH Tags: Annu Rev Pharmacol Toxicol Source Type: research