1,106 results match your criteria Annual Review Of Pharmacology And Toxicology[Journal]


Introduction to the Theme "New Therapeutic Targets".

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

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

"New Therapeutic Targets" is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depression, post-traumatic stress disorder, muscle wasting diseases, cancer, and anemia associated with chronic renal disease. Numerous articles in this volume focus on the identification, validation, and utility of novel therapeutic targets, in particular, ones that involve new or unexpected molecular entities. Read More

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

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

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

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

Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010716-104727DOI Listing
January 2019
13 Reads
18.365 Impact Factor

Metals and Mechanisms of Carcinogenesis.

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

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

Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. Read More

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

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

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

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

The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca channel (LTCC) blocker, for neuroprotective PD therapy. Read More

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

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

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

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

Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration-approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). Read More

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

Pharmacologic Targeting of Hypoxia-Inducible Factors.

Authors:
Gregg L Semenza

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

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

Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O availability. HIFs are heterodimeric proteins composed of an O-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Read More

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

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

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

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

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

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

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

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

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

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of prevalent heart failure (HF) worldwide, and prognosis after hospitalization for HFpEF remains poor. Due, at least in part, to the heterogeneous nature of HFpEF, drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Read More

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

Therapeutic Oligonucleotides: State of the Art.

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

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

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

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

Systems Pharmacology: Defining the Interactions of Drug Combinations.

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

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

The majority of diseases are associated with alterations in multiple molecular pathways and complex interactions at the cellular and organ levels. Single-target monotherapies therefore have intrinsic limitations with respect to their maximum therapeutic benefits. The potential of combination drug therapies has received interest for the treatment of many diseases and is well established in some areas, such as oncology. Read More

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

Modulating NRF2 in Disease: Timing Is Everything.

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

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

The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021856DOI Listing
January 2019
3 Reads

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

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

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

Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Read More

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

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.

Annu Rev Pharmacol Toxicol 2019 Jan 14;59:171-189. Epub 2018 Sep 14.

Clinical Neuroscience Division, Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, USA; email:

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 stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326888PMC
January 2019
35 Reads

The Placebo Effect in Pain Therapies.

Authors:
Luana Colloca

Annu Rev Pharmacol Toxicol 2019 Jan 14;59:191-211. Epub 2018 Sep 14.

Department of Pain and Translational Symptom Science, School of Nursing; Department of Anesthesiology, School of Medicine; and Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland 21201, USA; email:

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 chronicity. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402571PMC
January 2019
3 Reads

Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries.

Annu Rev Pharmacol Toxicol 2019 Jan 12;59:405-421. Epub 2018 Sep 12.

SPARK Translational Research Program, Stanford University School of Medicine, Stanford, California 94305, USA; email:

With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021625DOI Listing
January 2019
2 Reads

Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation.

Annu Rev Pharmacol Toxicol 2019 Jan 12;59:237-261. Epub 2018 Sep 12.

Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; email:

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021807DOI Listing
January 2019
12 Reads

Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain?

Annu Rev Pharmacol Toxicol 2019 Jan 5;59:487-505. Epub 2018 Sep 5.

Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia; email:

Efflux mechanisms situated in various brain barrier interfaces control drug entry into the adult brain; this review considers the effectiveness of these protective mechanisms in the embryo, fetus, and newborn brain. The longstanding belief that the blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statements with potential clinical implications. The immature brain is undoubtedly more vulnerable to damage by drugs and toxins; as is reviewed here, some developmentally regulated normal brain barrier mechanisms probably contribute to this vulnerability. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021430DOI Listing
January 2019
3 Reads

Assessment of Pharmacokinetic Drug-Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited.

Annu Rev Pharmacol Toxicol 2019 Jan 29;59:507-536. Epub 2018 Aug 29.

Institute for Biomedical and Pharmaceutical Research, 90562 Nürnberg-Heroldsberg, Germany.

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug-drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021909DOI Listing
January 2019
10 Reads

Muscle Wasting Diseases: Novel Targets and Treatments.

Annu Rev Pharmacol Toxicol 2019 Jan 27;59:315-339. Epub 2018 Aug 27.

Biozentrum, University of Basel, 4056 Basel, Switzerland; email: ,

Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021041DOI Listing
January 2019
4 Reads

Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.

Annu Rev Pharmacol Toxicol 2019 Jan 22;59:463-486. Epub 2018 Aug 22.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA; email:

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Read More

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https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-0
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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409210PMC
January 2019
19 Reads

Moving from the Trial to the Real World: Improving Medication Adherence Using Insights of Implementation Science.

Annu Rev Pharmacol Toxicol 2019 Jan 20;59:423-445. Epub 2018 Aug 20.

Institute of Nursing Science, Department of Public Health, University of Basel, 4056 Basel, Switzerland; email:

Medication nonadherence is a serious public health concern. Although there are promising interventions that improve medication adherence, most interventions are developed and tested in tightly controlled research environments that are dissimilar from the real-world settings where the majority of patients receive health care. Implementation science methods have the potential to facilitate and accelerate the translation shift from the trial world to the real world. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021348DOI Listing
January 2019
16 Reads

Organoids for Drug Discovery and Personalized Medicine.

Authors:
Toshio Takahashi

Annu Rev Pharmacol Toxicol 2019 Jan 16;59:447-462. Epub 2018 Aug 16.

Suntory Foundation for Life Sciences, Bioorganic Research Institute, Kyoto 619-0284, Japan; email:

A wide variety of organs are in a dynamic state, continuously undergoing renewal as a result of constant growth and differentiation. Stem cells are required during these dynamic events for continuous tissue maintenance within the organs. In a steady state of production and loss of cells within these tissues, new cells are constantly formed by differentiation from stem cells. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021108DOI Listing
January 2019
5 Reads

New Cell Cycle Inhibitors Target Aneuploidy in Cancer Therapy.

Annu Rev Pharmacol Toxicol 2019 Jan 15;59:361-377. Epub 2018 Aug 15.

Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.

Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021649DOI Listing
January 2019
2 Reads

The Exposome: Molecules to Populations.

Annu Rev Pharmacol Toxicol 2019 Jan 10;59:107-127. Epub 2018 Aug 10.

Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.

Derived from the term exposure, the exposome is an omic-scale characterization of the nongenetic drivers of health and disease. With the genome, it defines the phenome of an individual. The measurement of complex environmental factors that exert pressure on our health has not kept pace with genomics and historically has not provided a similar level of resolution. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021315DOI Listing
January 2019
17 Reads

Challenges in Orphan Drug Development: Identification of Effective Therapy for Thyroid-Associated Ophthalmopathy.

Authors:
Terry J Smith

Annu Rev Pharmacol Toxicol 2019 Jan 25;59:129-148. Epub 2018 Jul 25.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, and Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA; email:

Thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves' disease, is a process in which orbital connective tissues and extraocular muscles undergo inflammation and remodeling. The condition seems to result from autoimmune responses to antigens shared by the thyroid and orbit. The thyrotropin receptor (TSHR), expressed at low levels in orbital tissues, is a leading candidate antigen. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052509DOI Listing
January 2019
8 Reads

Therapeutic Approaches to the Treatment of Tinnitus.

Annu Rev Pharmacol Toxicol 2019 Jan 25;59:291-313. Epub 2018 Jul 25.

Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.

Tinnitus is a highly prevalent condition that is associated with hearing loss in most cases. In the absence of external stimuli, phantom perceptions of sounds emerge from alterations in neuronal activity within central auditory and nonauditory structures. Pioneering studies using lidocaine revealed that tinnitus is susceptible to pharmacological interventions. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021556DOI Listing
January 2019
30 Reads

Environmental Obesogens: Mechanisms and Controversies.

Annu Rev Pharmacol Toxicol 2019 Jan 25;59:89-106. Epub 2018 Jul 25.

Department of Developmental and Cell Biology, Department of Pharmaceutical Sciences, and Department of Biomedical Engineering, University of California, Irvine, California 92697, USA; email:

Obesity is a worldwide pandemic in adults as well as children and adds greatly to health care costs through its association with type 2 diabetes, metabolic syndrome, cardiovascular disease, and cancers. The prevailing medical view of obesity is that it results from a simple imbalance between caloric intake and energy expenditure. However, numerous other factors are important in the etiology of obesity. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021304DOI Listing
January 2019
4 Reads

Role of Cell Death in Toxicology: Does It Matter How Cells Die?

Authors:
Sten Orrenius

Annu Rev Pharmacol Toxicol 2019 Jan 25;59:1-14. Epub 2018 Jul 25.

Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden; email:

My research activity started with studies on drug metabolism in rat liver microsomes in the early 1960s. The CO-binding pigment (cytochrome P450) had been discovered a few years earlier and was subsequently found to be involved in steroid hydroxylation in adrenal cortex microsomes. Our early studies suggested that it also participated in the oxidative demethylation of drugs catalyzed by liver microsomes, and that prior treatment of the animals with phenobarbital caused increased levels of the hemoprotein in the liver, and similarly enhanced rates of drug metabolism. Read More

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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021725DOI Listing
January 2019
3 Reads

A Chemical Perspective of Pharmacology and Toxicology.

Authors:
Arthur K Cho

Annu Rev Pharmacol Toxicol 2018 01;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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-053205DOI Listing
January 2018
11 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 01;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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225997PMC
January 2018
10 Reads

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

Annu Rev Pharmacol Toxicol 2018 01;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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http://dx.doi.org/10.1146/annurev-pharmtox-010716-104748DOI Listing
January 2018
16 Reads

The Ethnopharmacologic Contribution to Bioprospecting Natural Products.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052703DOI Listing
January 2018
8 Reads

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

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052545DOI Listing
January 2018
32 Reads

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

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-092617-121952DOI Listing
January 2018
18 Reads

Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-053021DOI Listing
January 2018
17 Reads

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

Annu Rev Pharmacol Toxicol 2018 01 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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http://www.annualreviews.org/doi/10.1146/annurev-pharmtox-01
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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052722DOI Listing
January 2018
54 Reads

Targeting Epigenetics in Cancer.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010716-105106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800772PMC
January 2018
9 Reads

KCNQ-Encoded Potassium Channels as Therapeutic Targets.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052912DOI Listing
January 2018
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The Mystery of the Interstitial Cells in the Urinary Bladder.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052615DOI Listing
January 2018
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Model-Informed Drug Development for Malaria Therapeutics.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010715-103429DOI Listing
January 2018
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Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-053110DOI Listing
January 2018
20 Reads

Adverse Effects of Nutraceuticals and Dietary Supplements.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380172PMC
January 2018
8 Reads

Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826556PMC
January 2018
13 Reads

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

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052735DOI Listing
January 2018
8 Reads

Lung Cancer Heterogeneity and New Strategies for Drug Therapy.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010716-104523DOI Listing
January 2018
33 Reads

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

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052429DOI Listing
January 2018
38 Reads

Harnessing the Properties of Natural Products.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010716-105029DOI Listing
January 2018
16 Reads

The Genetics of Pain: Implications for Therapeutics.

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052554DOI Listing
January 2018
53 Reads

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

Annu Rev Pharmacol Toxicol 2018 01 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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http://dx.doi.org/10.1146/annurev-pharmtox-010617-052623DOI Listing
January 2018
7 Reads