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    1048 results match your criteria Annual Review of Pharmacology and Toxicology [Journal]

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    The Enduring Legacy of 250 Years of Pharmacology in Edinburgh.
    Annu Rev Pharmacol Toxicol 2017 Sep 13. Epub 2017 Sep 13.
    Institute of Mental Health and Wellbeing, College of Medical, Veterinary and Life Sciences, Gartnavel Royal Hospital, University of Glasgow, Glasgow G12 OXH, United Kingdom.
    Two hundred fifty years ago, the University of Edinburgh appointed Francis Home to the first chair of materia medica, the accumulated knowledge of materials used in healing. Francis Home and his colleagues were determined to improve the quality of medical training in Edinburgh by introducing a final examination and compiling a catalog of medicines validated by the Royal College of Physicians of Edinburgh. The catalog, known as the Edinburgh Pharmacopoeia, was a great success, partly due to the orderly nature of its contents, its routine editing to eliminate worthless entries, and the introduction of new treatments whose preparation was precisely documented. Read More

    Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer.
    Annu Rev Pharmacol Toxicol 2017 Sep 15. Epub 2017 Sep 15.
    Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA; email: , and
    Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. Read More

    A Serendipitous Scientist.
    Annu Rev Pharmacol Toxicol 2017 Jul 17. Epub 2017 Jul 17.
    Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710; email:
    Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who were academically inclined fulfilled this obligation by serving in the US Public Health Service as commissioned officers stationed at the National Institutes of Health. Read More

    The Role of Efflux Pumps in Tuberculosis Treatment and Their Promise as a Target in Drug Development: Unraveling the Black Box.
    Annu Rev Pharmacol Toxicol 2017 Jul 17. Epub 2017 Jul 17.
    Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; email:
    Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents. Read More

    Organophosphorus Xenobiotic Toxicology.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:309-327
    Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California, Berkeley, California 94720-3112; email:
    Originally, organophosphorus (OP) toxicology consisted of acetylcholinesterase inhibition by insecticides and chemical threat agents acting as phosphorylating agents for serine in the catalytic triad, but this is no longer the case. Other serine hydrolases can be secondary OP targets, depending on the OP structure, and include neuropathy target esterase, lipases, and endocannabinoid hydrolases. The major OP herbicides are glyphosate and glufosinate, which act in plants but not animals to block aromatic amino acid and glutamine biosynthesis, respectively, with safety for crops conferred by their expression of herbicide-tolerant targets and detoxifying enzymes from bacteria. Read More

    Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:437-454
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; email: ,
    Mitochondria lie at the crossroads of neuronal survival and cell death. They play important roles in cellular bioenergetics, control intracellular Ca(2+) homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Read More

    Aptamers as Therapeutics.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:61-79
    Department of Surgery, Duke University Medical Center, Durham, North Carolina 27705; email:
    Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Read More

    New Targets for Drug Treatment of Obesity.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:585-605
    Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieio University Hospital, Athens Medical School, Athens 11528, Greece; email: , ,
    Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. Read More

    Autophagy: A Druggable Process.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:375-398
    Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, F-75993 Paris, France; email:
    Macroautophagy (hereafter called autophagy) is a vacuolar, lysosomal pathway for catabolism of intracellular material that is conserved among eukaryotic cells. Autophagy plays a crucial role in tissue homeostasis, adaptation to stress situations, immune responses, and the regulation of the inflammatory response. Blockade or uncontrolled activation of autophagy is associated with cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. Read More

    Innovative Approaches to Improve Anti-Infective Vaccine Efficacy.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:189-222
    NovaDigm Therapeutics, Inc., Grand Forks, North Dakota 58202.
    Safe and efficacious vaccines are arguably the most successful medical interventions of all time. Yet the ongoing discovery of new pathogens, along with emergence of antibiotic-resistant pathogens and a burgeoning population at risk of such infections, imposes unprecedented public health challenges. To meet these challenges, innovative strategies to discover and develop new or improved anti-infective vaccines are necessary. Read More

    Will There Be a Cure for Ebola?
    Annu Rev Pharmacol Toxicol 2017 Jan 7;57:329-348. Epub 2016 Dec 7.
    US Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702; email:
    Despite the unprecedented Ebola virus outbreak response in West Africa, no Ebola medical countermeasures have been approved by the US Food and Drug Administration. However, multiple valuable lessons have been learned about the conduct of clinical research in a resource-poor, high risk-pathogen setting. Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acid-based drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp). Read More

    Nanobodies to Study G Protein-Coupled Receptor Structure and Function.
    Annu Rev Pharmacol Toxicol 2017 Jan 7;57:19-37. Epub 2016 Dec 7.
    Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; email:
    Ligand-induced activation of G protein-coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently elucidated the structural and dynamic features of GPCR transmembrane signaling. Nanobodies, the recombinant antigen-binding fragments of camelid heavy-chain-only antibodies, have emerged as important research tools to lock GPCRs in particular conformational states. Read More

    Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:535-565
    Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; email:
    Mitochondria have emerged as key participants in and regulators of myocardial injury during ischemia and reperfusion. This review examines the sites of damage to cardiac mitochondria during ischemia and focuses on the impact of these defects. The concept that mitochondrial damage during ischemia leads to cardiac injury during reperfusion is addressed. Read More

    The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia.
    Annu Rev Pharmacol Toxicol 2017 Jan;57:509-533
    Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
    Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Read More

    Harnessing Big Data for Systems Pharmacology.
    Annu Rev Pharmacol Toxicol 2017 Jan 13;57:245-262. Epub 2016 Oct 13.
    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894; email:
    Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). Read More

    GPER (GPR30): A Nongenomic Receptor (GPCR) for Steroid Hormones with Implications for Cardiovascular Disease and Cancer.
    Annu Rev Pharmacol Toxicol 2017 Jan 21;57:567-584. Epub 2016 Oct 21.
    Department of Life and Physical Sciences, Fisk University, Nashville, Tennessee 37208.
    Although the rapid effects of steroids, such as estrogen and aldosterone, were postulated originally to be nongenomic, it is now appreciated that activation of such signaling pathways via a steroid-acting G protein-coupled receptor, the G protein estrogen receptor (GPER), has important transcription-dependent outcomes in the regulation of cell growth and programmed cell death secondary to GPER-regulated second-messenger pathways. GPER is expressed ubiquitously and has diverse biological effects, including regulation of endocrine, immune, neuronal, and cardiovascular functions. Perhaps the most biologically important consequences of GPER activation are the regulation of cell growth, migration, and apoptotic cell death. Read More

    Stem Cell Extracellular Vesicles: Extended Messages of Regeneration.
    Annu Rev Pharmacol Toxicol 2017 Jan 28;57:125-154. Epub 2016 Oct 28.
    Department of Pharmaceutical Sciences, University of California, Irvine, California 92697; email:
    Stem cells are critical to maintaining steady-state organ homeostasis and regenerating injured tissues. Recent intriguing reports implicate extracellular vesicles (EVs) as carriers for the distribution of morphogens and growth and differentiation factors from tissue parenchymal cells to stem cells, and conversely, stem cell-derived EVs carrying certain proteins and nucleic acids can support healing of injured tissues. We describe approaches to make use of engineered EVs as technology platforms in therapeutics and diagnostics in the context of stem cells. Read More

    Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology".
    Annu Rev Pharmacol Toxicol 2017 Jan 12;57:13-17. Epub 2016 Oct 12.
    Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
    Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e. Read More

    Adipose-Vascular Coupling and Potential Therapeutics.
    Annu Rev Pharmacol Toxicol 2017 Jan 10;57:417-436. Epub 2016 Oct 10.
    Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, and Experimental and Clinical Research Center, a joint cooperation of the Charité - University Medicine Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; email:
    Excess visceral adipose tissue is associated with increased risk of high blood pressure, lipid disorders, type 2 diabetes, and cardiovascular disease. Adipose tissue is an endocrine organ with multiple humoral and metabolic roles in regulating whole-body physiology. However, perivascular adipose tissue (PVAT) also plays a functional role in regulating the contractile state of the underlying smooth muscle cell layer. Read More

    Pharmacology of Antisense Drugs.
    Annu Rev Pharmacol Toxicol 2017 Jan 10;57:81-105. Epub 2016 Oct 10.
    Ionis Pharmaceuticals, Carlsbad, California 92010; email:
    Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Read More

    Critical Functions of the Lysosome in Cancer Biology.
    Annu Rev Pharmacol Toxicol 2017 Jan 12;57:481-507. Epub 2016 Oct 12.
    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; email: ,
    Lysosomes (or lytic bodies) were so named because they contain high levels of hydrolytic enzymes. Lysosome function and dysfunction have been found to play important roles in human disease, including cancer; however, the ways in which lysosomes contribute to tumorigenesis and cancer progression are still being uncovered. Beyond serving as a cellular recycling center, recent evidence suggests that the lysosome is involved in energy homeostasis, generating building blocks for cell growth, mitogenic signaling, priming tissues for angiogenesis and metastasis formation, and activating transcriptional programs. Read More

    Targeted Protein Degradation by Small Molecules.
    Annu Rev Pharmacol Toxicol 2017 Jan 12;57:107-123. Epub 2016 Oct 12.
    Department of Molecular, Cellular, and Developmental Biology, Department of Chemistry, and Department of Pharmacology, Yale University, New Haven, Connecticut 06511; email:
    Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. Read More

    Nanodomain Regulation of Cardiac Cyclic Nucleotide Signaling by Phosphodiesterases.
    Annu Rev Pharmacol Toxicol 2017 Jan 12;57:455-479. Epub 2016 Oct 12.
    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; email:
    Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3',5'-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP. Read More

    Intestinal and Hepatocellular Transporters: Therapeutic Effects and Drug Interactions of Herbal Supplements.
    Annu Rev Pharmacol Toxicol 2017 Jan 14;57:399-416. Epub 2016 Sep 14.
    Division of Clinical Pharmacy and Diagnostics, Department of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria; email:
    Herbal supplements are generally considered safe; however, drug disposition is influenced by the interactions of herbal supplements and food constituents with transport and metabolic processes. Although the interference of herbal supplements with drug metabolism has been studied extensively, knowledge of how they interact with the drug transport processes is less advanced. Therefore, we describe here specific examples of experimental and human interaction studies of herbal supplement components with drug transporters addressing, for example, organic anion transporting polypeptides or P-glycoprotein, as such interactions may lead to severe side effects and altered drug efficacy. Read More

    Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward.
    Annu Rev Pharmacol Toxicol 2017 Jan 2;57:285-308. Epub 2016 Sep 2.
    National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland 20892; email:
    Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. Read More

    Changing Provider Behavior in the Context of Chronic Disease Management: Focus on Clinical Inertia.
    Annu Rev Pharmacol Toxicol 2017 Jan 7;57:263-283. Epub 2016 Sep 7.
    Department of Psychology, University of Calgary, Calgary, Alberta T2N 1N4, Canada; email:
    Widespread acceptance of evidence-based medicine has led to the proliferation of clinical practice guidelines as the primary mode of communicating current best practices across a range of chronic diseases. Despite overwhelming evidence supporting the benefits of their use, there is a long history of poor uptake by providers. Nonadherence to clinical practice guidelines is referred to as clinical inertia and represents provider failure to initiate or intensify treatment despite a clear indication to do so. Read More

    Strategies to Develop Inhibitors of Motif-Mediated Protein-Protein Interactions as Drug Leads.
    Annu Rev Pharmacol Toxicol 2017 Jan 8;57:39-60. Epub 2016 Sep 8.
    Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada; email: , , ,
    Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has been increased interest in targeting them using peptide-based therapeutics. Peptides benefit from being specific, relatively safe, and easy to produce. Read More

    Challenges and Opportunities in Protease-Activated Receptor Drug Development.
    Annu Rev Pharmacol Toxicol 2017 Jan 9;57:349-373. Epub 2016 Sep 9.
    Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093; email:
    Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Read More

    PCSK9: Regulation and Target for Drug Development for Dyslipidemia.
    Annu Rev Pharmacol Toxicol 2017 Jan 8;57:223-244. Epub 2016 Aug 8.
    Department of Biochemistry, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7; email: , , ,
    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Read More

    CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism?
    Annu Rev Pharmacol Toxicol 2017 Jan 15;57:171-187. Epub 2016 Aug 15.
    Neuroscience Innovative Medicines, AstraZeneca, Cambridge, Massachusetts 01239; email:
    There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. Read More

    A Life of Neurotransmitters.
    Annu Rev Pharmacol Toxicol 2017 Jan 22;57:1-11. Epub 2016 Jul 22.
    Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205; email:
    Development of scientific creativity is often tied closely to mentorship. In my case, two years with Julius Axelrod, the sum total of my research training, was transformative. My mentoring generations of graduate students and postdoctoral fellows has been as nurturing for me as it has been for them. Read More

    Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model.
    Annu Rev Pharmacol Toxicol 2017 Jan 22;57:155-169. Epub 2016 Jul 22.
    Department of Pediatrics, Division of Infectious Diseases, University of Alabama, Birmingham, Alabama 35233; email: ,
    Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Read More

    Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?
    Annu Rev Pharmacol Toxicol 2016 ;56:605-626
    Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut 06269.
    Nuclear receptors (NR) are ligand-modulated transcription factors that play diverse roles in cell differentiation, development, proliferation, and metabolism and are associated with numerous liver pathologies such as cancer, steatosis, inflammation, fibrosis, cholestasis, and xenobiotic/drug-induced liver injury. The network of target proteins associated with NRs is extremely complex, comprising coregulators, small noncoding microRNAs, and long noncoding RNAs. The importance of NRs as targets of liver disease is exemplified by the number of NR ligands that are currently used in the clinics or in clinical trials with promising results. Read More

    Design of Next-Generation G Protein-Coupled Receptor Drugs: Linking Novel Pharmacology and In Vivo Animal Models.
    Annu Rev Pharmacol Toxicol 2016 ;56:535-59
    MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN United Kingdom; email: ,
    Despite the fact that G protein-coupled receptors (GPCRs) are the most successful drug targets in history, this supergene family of cell surface receptors has yet to be fully exploited as targets in the treatment of human disease. Here, we present optimism that this may change in the future by reviewing the substantial progress made in the understanding of GPCR molecular pharmacology that has generated an extensive toolbox of ligand types that include orthosteric, allosteric, and bitopic ligands, many of which show signaling bias. We discuss how combining these advances with recently described transgenic, chemical genetic, and optogenetic animal models will provide the framework to allow for the rational design of next-generation GPCR drugs that possess increased therapeutic efficacy and decreased adverse/toxic responses. Read More

    The Emerging Role of Spinal Dynorphin in Chronic Pain: A Therapeutic Perspective.
    Annu Rev Pharmacol Toxicol 2016 ;56:511-33
    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093; email:
    Notable findings point to the significance of the dynorphin peptide neurotransmitter in chronic pain. Spinal dynorphin neuropeptide levels are elevated during development of chronic pain and sustained during persistent chronic pain. Importantly, knockout of the dynorphin gene prevents development of chronic pain in mice, but acute nociception is unaffected. Read More

    Oxysterols: Old Tale, New Twists.
    Annu Rev Pharmacol Toxicol 2016 ;56:447-67
    School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia; email: , , ,
    Oxysterols have long been known for their important role in cholesterol homeostasis, where they are involved in both transcriptional and posttranscriptional mechanisms for controlling cholesterol levels. However, they are increasingly associated with a wide variety of other, sometimes surprising cell functions. They are activators of the Hedgehog pathway (important in embryogenesis), and they act as ligands for a growing list of receptors, including some that are of importance to the immune system. Read More

    Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders.
    Annu Rev Pharmacol Toxicol 2016 ;56:339-60
    Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510; email: ,
    Medications to treat cognitive disorders are increasingly needed, yet researchers have had few successes in this challenging arena. Cognitive abilities in primates arise from highly evolved N-methyl-d-aspartate (NMDA) receptor circuits in layer III of the dorsolateral prefrontal cortex. These circuits have unique modulatory needs that can differ from the layer V neurons that predominate in rodents, but they offer multiple therapeutic targets. Read More

    Triclosan: A Widespread Environmental Toxicant with Many Biological Effects.
    Annu Rev Pharmacol Toxicol 2016 ;56:251-72
    Laboratory of Environmental Toxicology, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California, San Diego, La Jolla, California 92093; email: ,
    Triclosan (TCS) is a broad-spectrum antimicrobial agent that has been added to personal care products, including hand soaps and cosmetics, and impregnated in numerous different materials ranging from athletic clothing to food packaging. The constant disposal of TCS into the sewage system is creating a major environmental and public health hazard. Owing to its chemical properties of bioaccumulation and resistance to degradation, TCS is widely detected in various environmental compartments in concentrations ranging from nanograms to micrograms per liter. Read More

    Structure-Driven Developments of 26S Proteasome Inhibitors.
    Annu Rev Pharmacol Toxicol 2016 ;56:191-209
    Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; email:
    The 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the treatment of some cancers and autoimmune diseases, and moreover, it has potential as a target of antibacterial agents. Read More

    RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?
    Annu Rev Pharmacol Toxicol 2016 ;56:103-22
    Beckman Research Institute, City of Hope, Duarte, California 91010; email:
    A resurgence in clinical trials using RNA interference (RNAi) occurred in 2012. Although there were initial difficulties in achieving efficacious results with RNAi without toxic side effects, advances in delivery and improved chemistry made this resurgence possible. More than 20 RNAi-based therapeutics are currently in clinical trials, and several of these are Phase III trials. Read More

    Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy.
    Annu Rev Pharmacol Toxicol 2016 ;56:59-83
    Center of Cancer Research, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
    A chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Read More

    Mitochondrial Biogenesis as a Pharmacological Target: A New Approach to Acute and Chronic Diseases.
    Annu Rev Pharmacol Toxicol 2016 4;56:229-49. Epub 2015 Nov 4.
    Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina and.
    Mitochondrial dysfunction is a key pathophysiological component of many acute and chronic diseases. Maintenance of mitochondrial homeostasis through the balance of mitochondrial turnover, fission and fusion, and generation of new mitochondria via mitochondrial biogenesis is critical for tissue health. Pharmacological activation of mitochondrial biogenesis can enhance oxidative metabolism and tissue bioenergetics, and improve organ function in conditions characterized by mitochondrial dysfunction. Read More

    The Cellular Thermal Shift Assay: A Novel Biophysical Assay for In Situ Drug Target Engagement and Mechanistic Biomarker Studies.
    Annu Rev Pharmacol Toxicol 2016 9;56:141-61. Epub 2015 Nov 9.
    Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; email:
    A drug must engage its intended target to achieve its therapeutic effect. However, conclusively measuring target engagement (TE) in situ is challenging. This complicates preclinical development and is considered a key factor in the high rate of attrition in clinical trials. Read More

    Genome Editing: A New Approach to Human Therapeutics.
    Annu Rev Pharmacol Toxicol 2016 9;56:163-90. Epub 2015 Nov 9.
    Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University, Stanford, California 94305; email:
    The ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. Read More

    Epidermal Growth Factor Receptor Transactivation: Mechanisms, Pathophysiology, and Potential Therapies in the Cardiovascular System.
    Annu Rev Pharmacol Toxicol 2016 9;56:627-53. Epub 2015 Nov 9.
    Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140; email:
    Epidermal growth factor receptor (EGFR) activation impacts the physiology and pathophysiology of the cardiovascular system, and inhibition of EGFR activity is emerging as a potential therapeutic strategy to treat diseases including hypertension, cardiac hypertrophy, renal fibrosis, and abdominal aortic aneurysm. The capacity of G protein-coupled receptor (GPCR) agonists, such as angiotensin II (AngII), to promote EGFR signaling is called transactivation and is well described, yet delineating the molecular processes and functional relevance of this crosstalk has been challenging. Moreover, these critical findings are dispersed among many different fields. Read More

    Sleep Pharmacogenetics: Personalized Sleep-Wake Therapy.
    Annu Rev Pharmacol Toxicol 2016 2;56:577-603. Epub 2015 Nov 2.
    Institute of Pharmacology and Toxicology and Zürich Center for Interdisciplinary Sleep Research, University of Zürich, CH-8057 Zürich, Switzerland; email:
    Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordered patients has identified the neurotransmitters and neuromodulators dopamine, serotonin, norepinephrine, histamine, hypocretin, melatonin, glutamate, acetylcholine, γ-amino-butyric acid, and adenosine as important players in the regulation and maintenance of sleep-wake-dependent changes in neuronal activity and the sleep-wake continuum. Dysregulation of these neurochemical systems leads to sleep-wake disorders. Most currently available pharmacological treatments are symptomatic rather than causal, and their beneficial and adverse effects are often variable and in part genetically determined. Read More

    Drugging Undruggable Molecular Cancer Targets.
    Annu Rev Pharmacol Toxicol 2016 2;56:23-40. Epub 2015 Nov 2.
    Fiske Drug Discovery Laboratory, Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908-0735; email: ,
    Cancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. Read More

    Can Humanized Mice Predict Drug "Behavior" in Humans?
    Annu Rev Pharmacol Toxicol 2016 22;56:323-38. Epub 2015 Oct 22.
    Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305; email:
    Most of what we know about a drug prior to human clinical studies is derived from animal testing. Because animals and humans have substantial differences in their physiology and in their drug metabolism pathways, we do not know very much about the pharmacokinetic and pharmacodynamic behavior of a drug in humans until after it is administered to many people. Hence, drug-induced liver injury has become a significant public health problem, and we have a very inefficient drug development process with a high failure rate. Read More

    Existing and Future Drugs for the Treatment of the Dark Side of Addiction.
    Annu Rev Pharmacol Toxicol 2016 22;56:299-322. Epub 2015 Oct 22.
    Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037; email: ,
    The identification of a heuristic framework for the stages of the addiction cycle that are linked to neurocircuitry changes in pathophysiology includes the binge/intoxication stage, the withdrawal/negative affect stage, and the preoccupation/anticipation (craving) stage, which represent neuroadaptations in three neurocircuits (basal ganglia, extended amygdala, and frontal cortex, respectively). The identification of excellent and validated animal models, the development of human laboratory models, and an enormous surge in our understanding of neurocircuitry and neuropharmacological mechanisms have provided a revisionist view of addiction that emphasizes the loss of brain reward function and gain of stress function that drive negative reinforcement (the dark side of addiction) as a key to compulsive drug seeking. Reversing the dark side of addiction not only explains much of the existing successful pharmacotherapies for addiction but also points to vast new opportunities for future medications to alleviate this major source of human suffering. Read More

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