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Annual Review of Pharmacology and Toxicology

Arthur K Cho
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Sanjay K Nigam
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Rachelle Prantil-Baun, Richard Novak, Debarun Das, Mahadevabharath R Somayaji, Andrzej Przekwas, Donald E Ingber
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Eric J Buenz, Rob Verpoorte, Brent A Bauer
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Julia Wattacheril, Danny Issa, Arun Sanyal
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. 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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Paul A Insel, Susan G Amara, Terrence F Blaschke, Urs A Meyer
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Volker M Lauschke, Isabel Barragan, Magnus Ingelman-Sundberg
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Lorna Ewart, Eva-Maria Dehne, Kristin Fabre, Susan Gibbs, James Hickman, Ellinor Hornberg, Magnus Ingelman-Sundberg, Kyung-Jin Jang, David R Jones, Volker M Lauschke, Uwe Marx, Jerome T Mettetal, Amy Pointon, Dominic Williams, Wolfram-Hubertus Zimmermann, Peter Newham
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Richard L Bennett, Jonathan D Licht
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Vincenzo Barrese, Jennifer B Stott, Iain A Greenwood
Kv 7 channels are voltage-gated potassium channels encoded by KCNQ genes that have a considerable physiological impact in many cell types. This reliance upon Kv 7 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 Kv 7 channel activity have been developed. Moreover, Kv 7 channels are influenced by many disparate intracellular mediators and trafficking processes, making upstream targeting an appealing prospect for therapeutic development...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Sang Don Koh, Haeyeong Lee, Sean M Ward, Kenton M Sanders
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Kayla Ann Andrews, David Wesche, James McCarthy, Jörg J Möhrle, Joel Tarning, Luann Phillips, Steven Kern, Thaddeus Grasela
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 would be a valuable tool across all stages of drug development...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Tarek Magdy, Adam J T Schuldt, Joseph C Wu, Daniel Bernstein, Paul W Burridge
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Martin J J Ronis, Kim B Pedersen, James Watt
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Madeline L Pfau, Caroline Ménard, Scott J Russo
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Alexey Ostroumov, John A Dani
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. Stress modulates alcohol-evoked plasticity via the release of signaling molecules that influence synaptic transmission...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Diane C Wang, William Wang, Bijun Zhu, Xiangdong Wang
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 of the strategies in the patient's own cancer cells or in patient-derived xenografts using their own cancer cells isolated during surgery or biopsies...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Xu Wang, Arturo Anadón, Qinghua Wu, Fang Qiao, Irma Ares, María-Rosa Martínez-Larrañaga, Zonghui Yuan, María-Aránzazu Martínez
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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Asmaa Boufridi, Ronald J Quinn
Natural products (NPs) have been used as traditional medicines since antiquity. With more than 1060 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...
January 6, 2018: Annual Review of Pharmacology and Toxicology
Jane E Sexton, James J Cox, Jing Zhao, John N Wood
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. Here, we summarize what we know about the genetics of pain and implications for drug development. We make the case that chronic pain is not one but a set of disease states, with peripheral drive a key element in most...
January 6, 2018: Annual Review of Pharmacology and Toxicology
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