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

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

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

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

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

Introduction to the Theme "New Therapeutic Targets".
Introduction to the Theme "New Therapeutic Targets". Annu Rev Pharmacol Toxicol. 2019 Jan 06;59:15-20 Authors: Insel PA, Amara SG, Blaschke TF, Meyer UA Abstract "New Therapeutic Targets" is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depre...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2019 Category: Drugs & Pharmacology Authors: Insel PA, Amara SG, Blaschke TF, Meyer UA Tags: Annu Rev Pharmacol Toxicol Source Type: research

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

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

Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?
Abstract Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, m...
Source: Annual Review of Pharmacology and Toxicology - October 8, 2018 Category: Drugs & Pharmacology Authors: De T, Park CS, Perera MA Tags: Annu Rev Pharmacol Toxicol Source Type: research

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

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

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

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

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

Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation.
Abstract 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. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this s...
Source: Annual Review of Pharmacology and Toxicology - September 12, 2018 Category: Drugs & Pharmacology Authors: Moutinho M, Codocedo JF, Puntambekar SS, Landreth GE Tags: Annu Rev Pharmacol Toxicol Source Type: research

Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries.
Abstract 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...
Source: Annual Review of Pharmacology and Toxicology - September 12, 2018 Category: Drugs & Pharmacology Authors: Parrish MC, Tan YJ, Grimes KV, Mochly-Rosen D Tags: Annu Rev Pharmacol Toxicol Source Type: research

Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain?
Habgood MD Abstract 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 long-standing 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. ...
Source: Annual Review of Pharmacology and Toxicology - September 5, 2018 Category: Drugs & Pharmacology Authors: Saunders NR, Dziegielewska KM, Møllgârd K, Habgood MD Tags: Annu Rev Pharmacol Toxicol Source Type: research

Assessment of Pharmacokinetic Drug-Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited.
l F Abstract 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. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are t...
Source: Annual Review of Pharmacology and Toxicology - August 29, 2018 Category: Drugs & Pharmacology Authors: Fuhr U, Hsin CH, Li X, Jabrane W, Sörgel F Tags: Annu Rev Pharmacol Toxicol Source Type: research

Muscle Wasting Diseases: Novel Targets and Treatments.
Abstract 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. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular patho...
Source: Annual Review of Pharmacology and Toxicology - August 27, 2018 Category: Drugs & Pharmacology Authors: Furrer R, Handschin C Tags: Annu Rev Pharmacol Toxicol Source Type: research

Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.
Abstract 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. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present t...
Source: Annual Review of Pharmacology and Toxicology - August 22, 2018 Category: Drugs & Pharmacology Authors: Karnes JH, Miller MA, White KD, Konvinse KC, Pavlos RK, Redwood AJ, Peter JG, Lehloenya R, Mallal SA, Phillips EJ Tags: Annu Rev Pharmacol Toxicol Source Type: research

Moving from the Trial to the Real World: Improving Medication Adherence Using Insights of Implementation Science.
This article is a call to action for researchers, clinicians, policy makers, pharmaceutical companies, and others involved in the delivery of care to adopt the implementation science paradigm in the scale-up of adherence (research) programs. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID: 30125127 [PubMed - as supplied by publisher] (Source: Annual Review of Pharmacology and Toxicology)
Source: Annual Review of Pharmacology and Toxicology - August 20, 2018 Category: Drugs & Pharmacology Authors: Zullig L, Deschodt M, Liska J, Bosworth HB, De Geest S Tags: Annu Rev Pharmacol Toxicol Source Type: research

Organoids for Drug Discovery and Personalized Medicine.
Abstract 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. Today, organoids derived from either adult stem cells or pluripotent stem cells can be grown to resemble various organs. As they are similar to their original organs, organoids hold great promise for use in medical research and the de...
Source: Annual Review of Pharmacology and Toxicology - August 16, 2018 Category: Drugs & Pharmacology Authors: Takahashi T Tags: Annu Rev Pharmacol Toxicol Source Type: research

New Cell Cycle Inhibitors Target Aneuploidy in Cancer Therapy.
Abstract 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. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cel...
Source: Annual Review of Pharmacology and Toxicology - August 15, 2018 Category: Drugs & Pharmacology Authors: Kawakami M, Liu X, Dmitrovsky E Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Exposome: Molecules to Populations.
Abstract 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. Emerging technologies make it possible to obtain detailed information on drugs, toxicants, pollutants, nutrients, and physical and psychological stressors on an omic scale. These forces can also be assessed at systems and network levels, providin...
Source: Annual Review of Pharmacology and Toxicology - August 10, 2018 Category: Drugs & Pharmacology Authors: Niedzwiecki MM, Walker DI, Vermeulen R, Chadeau-Hyam M, Jones DP, Miller GW Tags: Annu Rev Pharmacol Toxicol Source Type: research

Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips.
Abstract 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. Recent develo...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2018 Category: Drugs & Pharmacology Authors: Prantil-Baun R, Novak R, Das D, Somayaji MR, Przekwas A, Ingber DE Tags: Annu Rev Pharmacol Toxicol Source Type: research

The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease.
Abstract 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. Nevertheless, analyses of knockout mice and other data indica...
Source: Annual Review of Pharmacology and Toxicology - January 6, 2018 Category: Drugs & Pharmacology Authors: Nigam SK Tags: Annu Rev Pharmacol Toxicol Source Type: research

A Chemical Perspective of Pharmacology and Toxicology.
This article is an attempt to summarize that research and to identify those individuals who made the contributions. PMID: 29309258 [PubMed - in process] (Source: Annual Review of Pharmacology and Toxicology)
Source: Annual Review of Pharmacology and Toxicology - January 6, 2018 Category: Drugs & Pharmacology Authors: Cho AK Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Ethnopharmacologic Contribution to Bioprospecting Natural Products.
Abstract 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. Information on the traditional harvest, preparation, storage, and administration of the organisms, and the natural products they contain, provides valuable details regarding characteristics of the active compounds. Importantly, researc...
Source: Annual Review of Pharmacology and Toxicology - October 27, 2017 Category: Drugs & Pharmacology Authors: Buenz EJ, Verpoorte R, Bauer BA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Introduction to the Theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development".
Introduction to the Theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development". Annu Rev Pharmacol Toxicol. 2017 Oct 20;: Authors: Insel PA, Amara SG, Blaschke TF, Meyer UA Abstract 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 app...
Source: Annual Review of Pharmacology and Toxicology - October 20, 2017 Category: Drugs & Pharmacology Authors: Insel PA, Amara SG, Blaschke TF, Meyer UA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Nonalcoholic Steatohepatitis (NASH) and Hepatic Fibrosis: Emerging Therapies.
Abstract 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 normalweight individuals. Its progressive inflammatory phenotype, nonalcoholic steatohepatitis (NASH), currently has no effective treatment apart from lifestyle interventions. Multiple pathogenic pathways are involved in disease progression, and targets for intervention have been identified. These targets mediate glucose, lipid, and bile acid metabolism; inflammation; apoptosis; and fibrosis....
Source: Annual Review of Pharmacology and Toxicology - October 20, 2017 Category: Drugs & Pharmacology Authors: Wattacheril J, Issa D, Sanyal A Tags: Annu Rev Pharmacol Toxicol Source Type: research

Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery.
Abstract 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. By focusing on MPS models that have been developed for these organs, alongside other relev...
Source: Annual Review of Pharmacology and Toxicology - October 13, 2017 Category: Drugs & Pharmacology Authors: Ewart L, Dehne EM, Fabre K, Gibbs S, Hickman J, Hornberg E, Ingelman-Sundberg M, Jang KJ, Jones DR, Lauschke VM, Marx U, Mettetal JT, Pointon A, Williams D, Zimmermann WH, Newham P Tags: Annu Rev Pharmacol Toxicol Source Type: research

Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities.
Abstract 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 pr...
Source: Annual Review of Pharmacology and Toxicology - October 13, 2017 Category: Drugs & Pharmacology Authors: Lauschke VM, Barragan I, Ingelman-Sundberg M Tags: Annu Rev Pharmacol Toxicol Source Type: research

Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities.
so SJ Abstract 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...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Pfau ML, Ménard C, Russo SJ Tags: Annu Rev Pharmacol Toxicol Source Type: research

Adverse Effects of Nutraceuticals and Dietary Supplements.
Abstract 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. Despite widespread consumption, there is limited evidence of health benefits related to nutraceutical or supplement use in well-nourished adults. In contrast...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Ronis MJJ, Pedersen KB, Watt J Tags: Annu Rev Pharmacol Toxicol Source Type: research

Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems.
Abstract 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 represen...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Magdy T, Schuldt AJT, Wu JC, Bernstein D, Burridge PW Tags: Annu Rev Pharmacol Toxicol Source Type: research

Model-Informed Drug Development for Malaria Therapeutics.
a T Abstract 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. A comprehensive disease-drug model capable of integrating discrete data from different preclinical and clinical components ...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Andrews KA, Wesche D, McCarthy J, Möhrle JJ, Tarning J, Phillips L, Kern S, Grasela T Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Mystery of the Interstitial Cells in the Urinary Bladder.
Abstract 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. A recent report shows that c-Kit(+) cells in several species ...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Koh SD, Lee H, Ward SM, Sanders KM Tags: Annu Rev Pharmacol Toxicol Source Type: research

KCNQ-Encoded Potassium Channels as Therapeutic Targets.
Abstract Kv7 channels are voltage-gated potassium channels encoded by KCNQ genes that have a considerable physiological impact in many cell types. This reliance upon Kv7 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 Kv7 channel activity have been developed. Moreover, Kv7 channels are influenced by many disparate intracellular mediators and trafficking processes, making upstream targeting an appealing prospec...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Barrese V, Stott JB, Greenwood IA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Targeting Epigenetics in Cancer.
Abstract 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. In this review, we describe how the writers, reade...
Source: Annual Review of Pharmacology and Toxicology - October 6, 2017 Category: Drugs & Pharmacology Authors: Bennett RL, Licht JD Tags: Annu Rev Pharmacol Toxicol Source Type: research

Lung Cancer Heterogeneity and New Strategies for Drug Therapy.
Abstract 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. The system is a specifically selected strategy of treatment for patients with cancer gene mutations and heterogeneity based on gene sequencing, following validation ...
Source: Annual Review of Pharmacology and Toxicology - October 4, 2017 Category: Drugs & Pharmacology Authors: Wang DC, Wang W, Zhu B, Wang X Tags: Annu Rev Pharmacol Toxicol Source Type: research

Convergent Neuronal Plasticity and Metaplasticity Mechanisms of Stress, Nicotine, and Alcohol.
We describe several forms of alcohol-induced plasticity, including classic Hebbian plasticity at glutamatergic synapses, and we highlight less appreciated forms, such as non-Hebbian and GABAergic synaptic plasticity. Risk factors such as stress and nicotine initiate lasting neural changes that modify subsequent alcohol-induced synaptic plasticity and increase the vulnerability to alcohol addiction. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID: 28977763 [...
Source: Annual Review of Pharmacology and Toxicology - October 4, 2017 Category: Drugs & Pharmacology Authors: Ostroumov A, Dani JA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems.
Abstract 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. Such small molecules, identified via high-throughput screening or derivatized from known scaffolds, have shown promise as drug candidates to improve biological timing and physiological outputs in disease models. In this review, we first briefly describe the circadian system, including the core oscillator ...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Chen Z, Yoo SH, Takahashi JS Tags: Annu Rev Pharmacol Toxicol Source Type: research

Adhesion G Protein-Coupled Receptors as Drug Targets.
Abstract 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. Recent studies have revealed that the signaling acti...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Purcell RH, Hall RA Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Opioid Epidemic: Crisis and Solutions.
Abstract 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 guideli...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Skolnick P Tags: Annu Rev Pharmacol Toxicol Source Type: research

Impacts of the Human Gut Microbiome on Therapeutics.
ght R Abstract 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. We then describe some of the many ways in which gut microbes modify the action of specific chemotherapeutic agents, including no...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Vázquez-Baeza Y, Callewaert C, Debelius J, Hyde E, Marotz C, Morton JT, Swafford A, Vrbanac A, Dorrestein PC, Knight R Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Conducted Vasomotor Response: Function, Biophysical Basis, and Pharmacological Control.
Abstract 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. Of particular note, this review stresses that conduction is enabled by a defined p...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Welsh DG, Tran CHT, Hald BO, Sancho M Tags: Annu Rev Pharmacol Toxicol Source Type: research

The Genetics of Pain: Implications for Therapeutics.
We describe the exploitation of monogenic pain syndromes and genetic association studies to define analgesic targets, as well as issues associated with animal models of pain. We appraise present-day screening technologies and describe recent approaches to pain treatment that hold promise. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID: 28968191 [PubMed - as supplied by publisher] (Source: Annual Review of Pharmacology and Toxicology)
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Sexton JE, Cox JJ, Zhao J, Wood JN Tags: Annu Rev Pharmacol Toxicol Source Type: research

Harnessing the Properties of Natural Products.
Abstract Natural products (NPs) have been used as traditional medicines since antiquity. With more than 10(60) 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. There is much more to be learned from NPs than we can discover this narrow view. In this review, we discuss ways to harness the global properties of NPs. Expected final online publ...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Boufridi A, Quinn RJ Tags: Annu Rev Pharmacol Toxicol Source Type: research

Mechanism of Neonicotinoid Toxicity: Impact on Oxidative Stress and Metabolism.
n Z, Martínez MA Abstract 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. The primary focus of this review is to summarize the research progress associated with oxidative stress as a plausible mechanism for neonicotinoid-induced toxicity as well as neonicotinoid metabolism. This review ...
Source: Annual Review of Pharmacology and Toxicology - October 2, 2017 Category: Drugs & Pharmacology Authors: Wang X, Anadón A, Qinghua W, Qiao F, Ares I, Martínez-Larrañaga MR, Yuan Z, Martínez MA Tags: Annu Rev Pharmacol Toxicol Source Type: research

Repairing Mitochondrial Dysfunction in Disease.
Abstract 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 also expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and prevent...
Source: Annual Review of Pharmacology and Toxicology - September 27, 2017 Category: Drugs & Pharmacology Authors: Sorrentino V, Menzies KJ, Auwerx J Tags: Annu Rev Pharmacol Toxicol Source Type: research