1,077 results match your criteria Annual Review of Pharmacology and Toxicology [Journal]


A Chemical Perspective of Pharmacology and Toxicology.

Authors:
Arthur K Cho

Annu Rev Pharmacol Toxicol 2018 Jan;58:1-16

Department of Molecular and Medical Pharmacology and Department of Environmental Health Sciences, UCLA Center for the Health Sciences, University of California, Los Angeles, California 90095, USA; email:

My chemical training provided a somewhat different perspective of biolo-gical problems, in the problem itself and approaches to its solution. I was fortunate to have in my laboratory postdocs and students who shared this perspective and used appropriate tools to address problems in amphetamine pharmacology and air pollution toxicology. These apparently disparate areas of research shared two chemical reactions: prooxidant-based generation of reactive oxygen and formation of covalent bonds between electrophiles and biological nucleophiles. Read More

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January 2018
5 Reads

The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease.

Authors:
Sanjay K Nigam

Annu Rev Pharmacol Toxicol 2018 Jan;58:663-687

Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, California 92093, USA; email:

The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)-are widely studied drug transporters. Read More

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January 2018
5 Reads

Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips.

Annu Rev Pharmacol Toxicol 2018 Jan;58:37-64

Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA; email:

Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches are beginning to be integrated into drug development and approval processes because they enable key pharmacokinetic (PK) parameters to be predicted from in vitro data. However, these approaches are hampered by many limitations, including an inability to incorporate organ-specific differentials in drug clearance, distribution, and absorption that result from differences in cell uptake, transport, and metabolism. Moreover, such approaches are generally unable to provide insight into pharmacodynamic (PD) parameters. Read More

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January 2018
4 Reads

The Ethnopharmacologic Contribution to Bioprospecting Natural Products.

Annu Rev Pharmacol Toxicol 2018 Jan 27;58:509-530. Epub 2017 Oct 27.

Mayo Clinic, Rochester, Minnesota 55905, USA; email:

Descriptions of the use of natural products in traditional medicine have served as starting points for new therapeutics. The details of the traditional use of these organisms can provide important information for future drug discovery and development efforts. Recent technologic advances provide the framework to leverage ethnopharmacologic data in the drug discovery process. Read More

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January 2018
3 Reads

Nonalcoholic Steatohepatitis (NASH) and Hepatic Fibrosis: Emerging Therapies.

Annu Rev Pharmacol Toxicol 2018 Jan 20;58:649-662. Epub 2017 Oct 20.

Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA; email: ,

Nonalcoholic fatty liver disease remains a major cause of liver-related morbidity and mortality worldwide. It is a complex disease associated with obesity, diabetes, and dyslipidemia but is increasingly recognized in normal-weight individuals. Its progressive inflammatory phenotype, nonalcoholic steatohepatitis (NASH), currently has no effective treatment apart from lifestyle interventions. Read More

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January 2018
7 Reads

Introduction to the Theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development".

Annu Rev Pharmacol Toxicol 2018 Jan 20;58:33-36. Epub 2017 Oct 20.

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

The theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development" links 13 articles in this volume of the Annual Review of Pharmacology and Toxicology (ARPT). The engaging prefatory articles by Arthur Cho and Robert Lefkowitz set the stage for this theme and for the reviews that insightfully describe new approaches that advance research and discovery in pharmacology and toxicology. Examples include the progress being made in developing Organs-on-Chips/microphysiological systems and human induced pluripotent stem cell-derived cells to aid in understanding cell and tissue pharmacokinetics, action, and toxicity; the recognition of the importance of circadian rhythm, the microbiome, and epigenetics in drug and toxicant responses; and the application of results from new types of patient-derived information to create personalized/precision medicine, including therapeutics for pain, which may perhaps provide help in dealing with the opioid epidemic in the United States. Read More

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January 2018
6 Reads

Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities.

Annu Rev Pharmacol Toxicol 2018 Jan 13;58:161-185. Epub 2017 Oct 13.

Pharmacogenetics Section, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; email:

Pharmacological treatment and exposure to xenobiotics can cause substantial changes in epigenetic signatures. The majority of these epigenetic changes, caused by the compounds in question, occur downstream of transcriptional activation mechanisms, whereby the epigenetic alterations can create a transcriptional memory and stably modulate cell function. The increasing understanding of epigenetic mechanisms and their importance in disease has prompted the development of therapeutic interventions that target epigenetic modulatory mechanisms, particularly in oncology where inhibitors of epigenetic-modifying proteins (epidrugs) have been successfully used in treatment, mostly in combination with standard-of-care chemotherapy, either provoking direct cytotoxicity or inhibiting resistance to anticancer drugs. Read More

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January 2018
5 Reads

Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery.

Annu Rev Pharmacol Toxicol 2018 Jan 13;58:65-82. Epub 2017 Oct 13.

Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca, Cambridge CB4 0WG, United Kingdom; email:

Enhancing the early detection of new therapies that are likely to carry a safety liability in the context of the intended patient population would provide a major advance in drug discovery. Microphysiological systems (MPS) technology offers an opportunity to support enhanced preclinical to clinical translation through the generation of higher-quality preclinical physiological data. In this review, we highlight this technological opportunity by focusing on key target organs associated with drug safety and metabolism. Read More

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January 2018
16 Reads

Targeting Epigenetics in Cancer.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:187-207. Epub 2017 Oct 6.

Division of Hematology & Oncology, Department of Medicine, University of Florida Health Cancer Center, University of Florida, Gainesville, Florida 32606, USA; email:

Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors. Read More

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January 2018
5 Reads

KCNQ-Encoded Potassium Channels as Therapeutic Targets.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:625-648. Epub 2017 Oct 6.

Vascular Biology Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, SW17 0RE, United Kingdom; email: , ,

K7 channels are voltage-gated potassium channels encoded by KCNQ genes that have a considerable physiological impact in many cell types. This reliance upon K7 channels for normal cellular function, as well as the existence of hereditary disorders caused by mutations to KCNQ genes, means that pharmacological targeting of these channels has broad appeal. Consequently, a plethora of chemical entities that modulate K7 channel activity have been developed. Read More

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January 2018
4 Reads

The Mystery of the Interstitial Cells in the Urinary Bladder.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:603-623. Epub 2017 Oct 6.

Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada 89557, USA; email:

Intrinsic mechanisms to restrain smooth muscle excitability are present in the bladder, and premature contractions during filling indicate a pathological phenotype. Some investigators have proposed that c-Kit interstitial cells (ICs) are pacemakers and intermediaries in efferent and afferent neural activity, but recent findings suggest these cells have been misidentified and their functions have been misinterpreted. Cells reported to be c-Kit cells colabel with vimentin antibodies, but vimentin is not a specific marker for c-Kit cells. Read More

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January 2018
10 Reads

Model-Informed Drug Development for Malaria Therapeutics.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:567-582. Epub 2017 Oct 6.

Cognigen Corporation, a subsidiary of Simulations Plus, Buffalo, New York 14221, USA; email: , ,

Malaria is a critical public health problem resulting in substantial morbidity and mortality, particularly in developing countries. Owing to the development of resistance toward current therapies, novel approaches to accelerate the development efforts of new malaria therapeutics are urgently needed. There have been significant advancements in the development of in vitro and in vivo experiments that generate data used to inform decisions about the potential merit of new compounds. Read More

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January 2018
2 Reads

Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:83-103. Epub 2017 Oct 6.

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

Billions of US dollars are invested every year by the pharmaceutical industry in drug development, with the aim of introducing new drugs that are effective and have minimal side effects. Thirty percent of in-pipeline drugs are excluded in an early phase of preclinical and clinical screening owing to cardiovascular safety concerns, and several lead molecules that pass the early safety screening make it to market but are later withdrawn owing to severe cardiac side effects. Although the current drug safety screening methodologies can identify some cardiotoxic drug candidates, they cannot accurately represent the human heart in many aspects, including genomics, transcriptomics, and patient- or population-specific cardiotoxicity. Read More

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January 2018
7 Reads

Adverse Effects of Nutraceuticals and Dietary Supplements.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:583-601. Epub 2017 Oct 6.

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA; email: , ,

Over 70% of Americans take some form of dietary supplement every day, and the supplement industry is currently big business, with a gross of over $28 billion. However, unlike either foods or drugs, supplements do not need to be registered or approved by the US Food and Drug Administration (FDA) prior to production or sales. Under the Dietary Supplement Health and Education Act of 1994, the FDA is restricted to adverse report monitoring postmarketing. Read More

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January 2018
4 Reads

Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities.

Annu Rev Pharmacol Toxicol 2018 Jan 6;58:411-428. Epub 2017 Oct 6.

Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA; email:

Mood disorders such as depression are among the most prevalent psychiatric disorders in the United States, but they are inadequately treated in a substantial proportion of patients. Accordingly, neuropsychiatric research has pivoted from investigation of monoaminergic mechanisms to exploration of novel mediators, including the role of inflammatory processes. Subsets of mood disorder patients exhibit immune-related abnormalities, including elevated levels of proinflammatory cytokines, monocytes, and neutrophils in the peripheral circulation; dysregulation of neuroglia and blood-brain barrier function; and disruption of gut microbiota. Read More

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January 2018
9 Reads

Convergent Neuronal Plasticity and Metaplasticity Mechanisms of Stress, Nicotine, and Alcohol.

Annu Rev Pharmacol Toxicol 2018 Jan 4;58:547-566. Epub 2017 Oct 4.

Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, Philadelphia, Pennsylvania 19104, USA; email: ,

Stress and tobacco smoking are risk factors for alcoholism, but the underlying neural mechanisms are not well understood. Although stress, nicotine, and alcohol have broad, individual effects in the brain, some of their actions converge onto the same mechanisms and circuits. Stress and nicotine augment alcohol-related behaviors, in part via modulation of alcohol-evoked neuronal plasticity and metaplasticity mechanisms. Read More

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January 2018
4 Reads

Lung Cancer Heterogeneity and New Strategies for Drug Therapy.

Annu Rev Pharmacol Toxicol 2018 Jan 4;58:531-546. Epub 2017 Oct 4.

Zhongshan Hospital Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Shanghai 200032, China; email:

Lung cancer heterogeneity plays an important role in the development of drug resistance. Comprehensive molecular characterizations of lung cancer can describe hereditary and somatic gene changes, mutation, and heterogeneity. We discuss heterogeneity specificity, characterization, and roles of PIK3CD, TP53, and KRAS, as well as target-driven therapies and strategies applied in clinical trials based on a proposed precise self-validation system. Read More

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January 2018
8 Reads

Mechanism of Neonicotinoid Toxicity: Impact on Oxidative Stress and Metabolism.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:471-507. Epub 2017 Oct 2.

Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain; email:

Thousands of tons of neonicotinoids are widely used around the world as broad-spectrum systemic insecticides and veterinary drugs. Researchers originally thought that neonicotinoids exhibited low mammalian toxicity. However, following their widespread use, it became increasingly evident that neonicotinoids could have various toxic effects on vertebrates and invertebrates. Read More

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January 2018
10 Reads

Harnessing the Properties of Natural Products.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:451-470. Epub 2017 Oct 2.

Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia; email: ,

Natural products (NPs) have been used as traditional medicines since antiquity. With more than 10 estimated compounds with molecular weights less than 500 Da representing chemical space, NPs occupy a very small percentage; however, they are significantly overrepresented in biologically relevant chemical space. The classical approach concentrates on identifying one or more NPs with biological activity from a source organism. Read More

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January 2018
5 Reads

The Genetics of Pain: Implications for Therapeutics.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:123-142. Epub 2017 Oct 2.

Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom; email:

Pain is an increasing clinical challenge affecting about half the population, with a substantial number of people suffering daily intense pain. Such suffering can be linked to the dramatic rise in opioid use and associated deaths in the United States. There is a pressing need for new analgesics with limited side effects. Read More

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January 2018
20 Reads

The Conducted Vasomotor Response: Function, Biophysical Basis, and Pharmacological Control.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:391-410. Epub 2017 Oct 2.

Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5B7, Canada; email:

Arterial tone is coordinated among vessel segments to optimize nutrient transport and organ function. Coordinated vasomotor activity is remarkable to observe and depends on stimuli, sparsely generated in tissue, eliciting electrical responses that conduct lengthwise among electrically coupled vascular cells. The conducted response is the focus of this topical review, and in this regard, the authors highlight literature that advances an appreciation of functional significance, cellular mechanisms, and biophysical principles. Read More

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January 2018
3 Reads

Impacts of the Human Gut Microbiome on Therapeutics.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:253-270. Epub 2017 Oct 2.

Department of Computer Science and Engineering, University of California, San Diego, California 92093, USA; email:

The human microbiome contains a vast source of genetic and biochemical variation, and its impacts on therapeutic responses are just beginning to be understood. This expanded understanding is especially important because the human microbiome differs far more among different people than does the human genome, and it is also dramatically easier to change. Here, we describe some of the major factors driving differences in the human microbiome among individuals and populations. Read More

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January 2018
11 Reads

The Opioid Epidemic: Crisis and Solutions.

Authors:
Phil Skolnick

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:143-159. Epub 2017 Oct 2.

Opiant Pharmaceuticals, Santa Monica, California 09401, USA; email:

The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have created what is commonly referred to as the opioid epidemic. The magnitude of this epidemic is startling: About 4% of the adult US population misuses prescription opioids, and in 2015, more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and the adoption of US Centers for Disease Control and Prevention prescribing guidelines all constitute short-term approaches to quell this epidemic. Read More

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January 2018
42 Reads

Adhesion G Protein-Coupled Receptors as Drug Targets.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:429-449. Epub 2017 Oct 2.

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA; email:

The adhesion G protein-coupled receptors (aGPCRs) are an evolutionarily ancient family of receptors that play key roles in many different physiological processes. These receptors are notable for their exceptionally long ectodomains, which span several hundred to several thousand amino acids and contain various adhesion-related domains, as well as a GPCR autoproteolysis-inducing (GAIN) domain. The GAIN domain is conserved throughout almost the entire family and undergoes autoproteolysis to cleave the receptors into two noncovalently-associated protomers. Read More

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January 2018
4 Reads

Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems.

Annu Rev Pharmacol Toxicol 2018 Jan 2;58:231-252. Epub 2017 Oct 2.

Department of Neuroscience and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Circadian timekeeping systems drive oscillatory gene expression to regulate essential cellular and physiological processes. When the systems are perturbed, pathological consequences ensue and disease risks rise. A growing number of small-molecule modulators have been reported to target circadian systems. Read More

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January 2018
12 Reads

Precision Medicine Is Not Just Genomics: The Right Dose for Every Patient.

Authors:
Richard W Peck

Annu Rev Pharmacol Toxicol 2018 Jan 27;58:105-122. Epub 2017 Sep 27.

Pharma Research and Exploratory Development, Roche Innovation Center Basel, 4070 Basel, Switzerland; email:

Genomics has helped to initiate the era of precision medicine, with some drugs now prescribed on the basis of molecular genetic tests that indicate which patients are likely to respond or should not receive a drug because of a high risk of adverse effects. However, for precision medicine to realize its potential, the patient's history, environment, and lifestyle must also be taken into account. Improving precision medicine requires a better understanding of the underlying reasons for the variability in drug response so as to better identify which drug or combination of drugs is likely to be most effective for an individual patient, along with consideration of the optimal dose or doses for that patient. Read More

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January 2018
2 Reads

Toward Therapy of Human Prion Diseases.

Annu Rev Pharmacol Toxicol 2018 Jan 27;58:331-351. Epub 2017 Sep 27.

Institute of Neuropathology, University of Zurich, CH-8091 Zürich, Switzerland; email:

Three decades after the discovery of prions as the cause of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies, we are still nowhere close to finding an effective therapy. Numerous pharmacological interventions have attempted to target various stages of disease progression, yet none has significantly ameliorated the course of disease. We still lack a mechanistic understanding of how the prions damage the brain, and this situation results in a dearth of validated pharmacological targets. Read More

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January 2018
4 Reads

Repairing Mitochondrial Dysfunction in Disease.

Annu Rev Pharmacol Toxicol 2018 Jan 27;58:353-389. Epub 2017 Sep 27.

Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; email:

Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. Read More

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January 2018
12 Reads

TRP Channels as Potential Drug Targets.

Annu Rev Pharmacol Toxicol 2018 Jan 25;58:309-330. Epub 2017 Sep 25.

Hydra Biosciences, Cambridge, Massachusetts 02138, USA; email:

The transient receptor potential (TRP) superfamily of channels comprises a diverse group of cation channels. Four TRP channel subunits coassemble to form functional homo- or heterotetramers that pass sodium, calcium, or both in the inward direction. Modulating TRP channel activity provides an important way to impact cellular function by regulating both membrane excitability and intracellular calcium levels. Read More

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January 2018
11 Reads

The Enduring Legacy of 250 Years of Pharmacology in Edinburgh.

Annu Rev Pharmacol Toxicol 2018 Jan 13;58:293-307. 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.

In 1768, 250 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

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January 2018
4 Reads

Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer.

Annu Rev Pharmacol Toxicol 2018 Jan 15;58:209-229. 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: , ,

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

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January 2018
3 Reads

A Serendipitous Scientist.

Annu Rev Pharmacol Toxicol 2018 Jan 17;58:17-32. Epub 2017 Jul 17.

Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA; 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

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January 2018
6 Reads

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 2018 Jan 17;58:271-291. 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

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January 2018
8 Reads

Organophosphorus Xenobiotic Toxicology.

Authors:
John E Casida

Annu Rev Pharmacol Toxicol 2017 01;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

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January 2017
7 Reads

Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics.

Annu Rev Pharmacol Toxicol 2017 01;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 homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Read More

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January 2017
8 Reads

Aptamers as Therapeutics.

Annu Rev Pharmacol Toxicol 2017 01;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

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January 2017
6 Reads

New Targets for Drug Treatment of Obesity.

Annu Rev Pharmacol Toxicol 2017 01;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

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January 2017
5 Reads

Autophagy: A Druggable Process.

Annu Rev Pharmacol Toxicol 2017 01;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

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January 2017
6 Reads

Innovative Approaches to Improve Anti-Infective Vaccine Efficacy.

Annu Rev Pharmacol Toxicol 2017 01;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

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January 2017
4 Reads
18.36 Impact Factor

Will There Be a Cure for Ebola?

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
6 Reads

Nanobodies to Study G Protein-Coupled Receptor Structure and Function.

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
6 Reads

Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies.

Annu Rev Pharmacol Toxicol 2017 01;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

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January 2017
12 Reads

The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia.

Annu Rev Pharmacol Toxicol 2017 01;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 (GABA) 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

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January 2017
18 Reads

Harnessing Big Data for Systems Pharmacology.

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
4 Reads

GPER (GPR30): A Nongenomic Receptor (GPCR) for Steroid Hormones with Implications for Cardiovascular Disease and Cancer.

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
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Stem Cell Extracellular Vesicles: Extended Messages of Regeneration.

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
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Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology".

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
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Adipose-Vascular Coupling and Potential Therapeutics.

Authors:
Maik Gollasch

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
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Pharmacology of Antisense Drugs.

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
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Critical Functions of the Lysosome in Cancer Biology.

Annu Rev Pharmacol Toxicol 2017 01 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

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January 2017
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