A Chemical Perspective of Pharmacology and Toxicology Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. This article is an attempt to summarize that research and to identify those individuals who made the contributions.
A Serendipitous Scientist Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Robert J. Lefkowitz
Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who were academically inclined fulfilled this obligation by serving in the US Public Health Service as commissioned officers stationed at the National Institutes of Health. This experience would eventually change the entire trajectory of my career. Here I describe how, over a period of years, I transitioned from the life of a physician to that of a physician-scientist; my 50 years of work on cellular receptors; and some miscellaneous thoughts on subjects as varied as Nobel prizes, scientific lineages, mentoring, publishing, and funding.
Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development” Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Such new information energizes discovery efforts in pharmacology and toxicology that seek to improve the efficacy and safety of drugs in patients and to minimize the consequences of exposure to toxins.
Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Recent development of microfluidic Organ-on-a-Chip (Organ Chip) cell culture devices that recapitulate tissue-tissue interfaces, vascular perfusion, and organ-level functionality offer the ability to overcome these limitations when multiple Organ Chips are linked via their endothelium-lined vascular channels. Here, we discuss successes and challenges in the use of existing culture models and vascularized Organ Chips for PBPK and PD modeling of human drug responses, as well as in vitro to in vivo extrapolation (IVIVE) of these results, and how these approaches might advance drug development and regulatory review processes in the future.
Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. By focusing on MPS models that have been developed for these organs, alongside other relevant in vitro models, we review the current state of the art and the challenges that still need to be overcome to ensure application of this technology in enhancing drug discovery.
Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Despite some limitations, human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) are a powerful and evolving technology that has been shown to recapitulate many attributes of human cardiomyocytes and their drug responses. In this review, we discuss the potential impact of the inclusion of the hiPSC-CM platform in premarket candidate drug screening
Precision Medicine Is Not Just Genomics: The Right Dose for Every Patient Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Richard W. Peck
Genomics has helped to initiate the era of precision medicine, with some drugs now prescribed on the basis of molecular genetic tests that indicate which patients are likely to respond or should not receive a drug because of a high risk of adverse effects. However, for precision medicine to realize its potential, the patient's history, environment, and lifestyle must also be taken into account. Improving precision medicine requires a better understanding of the underlying reasons for the variability in drug response so as to better identify which drug or combination of drugs is likely to be most effective for an individual patient, along with consideration of the optimal dose or doses for that patient. Greater individualization of dose will be an important means to achieve more precise medicine and mitigate significant variability in drug response. Achieving this will require changes in how drugs are developed, approved, prescribed, monitored, and paid for. Each of these factors is discussed in this review.
The Genetics of Pain: Implications for Therapeutics Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. We argue that understanding redundancy and plasticity, hallmarks of the nervous system, is critical in developing analgesic drug strategies. 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.
The Opioid Epidemic: Crisis and Solutions Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Phil Skolnick
The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have created what is commonly referred to as the opioid epidemic. The magnitude of this epidemic is startling: About 4% of the adult US population misuses prescription opioids, and in 2015, more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and the adoption of US Centers for Disease Control and Prevention prescribing guidelines all constitute short-term approaches to quell this epidemic. However, with more than 125 million Americans suffering from either acute or chronic pain, the development of effective alternatives to opioids, enabled at least in part by a fuller understanding of the neurobiological bases of pain, offers the best long-term solution for controlling and ultimately eradicating this epidemic.
Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. In addition, emerging methods for detecting epigenetically modified DNA in bodily fluids may provide information about tumor phenotype or drug treatment success. However, it is important to note that many technical pitfalls, such as the nondeconvolution of methylcytosine and hydroxymethylcytosine, compromise epigenetic analyses and the interpretation of results. In this review, we provide an update on the field, with an emphasis on the novel therapeutic opportunities made possible by epidrugs.
Targeting Epigenetics in Cancer Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. In this review, we describe how the writers, readers, and erasers of epigenetic marks are dysregulated in cancer and summarize the development of therapies targeting these mechanisms.
Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Steven P. Angus, Jon S. Zawistowski, Gary L. Johnson
Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change—often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell–like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.
Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Zheng Chen, Seung-Hee Yoo, Joseph S. Takahashi
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 and the cellular networks. Research progress on clock-modulating small molecules is presented, focusing on development strategies and biological efficacies. We highlight the therapeutic potential of small molecules in clock-related pathologies, including jet lag and shiftwork; various chronic diseases, particularly metabolic disease; and aging. Emerging opportunities to identify and exploit clock modulators as novel therapeutic agents are discussed.
Impacts of the Human Gut Microbiome on Therapeutics Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Yoshiki Vázquez-Baeza, Chris Callewaert, Justine Debelius, Embriette Hyde, Clarisse Marotz, James T. Morton, Austin Swafford, Alison Vrbanac, Pieter C. Dorrestein, Rob Knight
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 nonsteroidal anti-inflammatory drugs and cardiac glycosides, and outline the potential of fecal microbiota transplant as a therapeutic. Intriguingly, microbes also alter how hosts respond to therapeutic agents through various pathways acting at distal sites. Finally, we discuss some of the computational and practical issues surrounding use of the microbiome to stratify individuals for drug response, and we envision a future where the microbiome will be modified to increase everyone's potential to benefit from therapy.
The Role of Efflux Pumps in Tuberculosis Treatment and Their Promise as a Target in Drug Development: Unraveling the Black Box Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Lindsey H.M. te Brake, Gerjo J. de Knegt, Jurriaan E. de Steenwinkel, Teunis J.P. van Dam, David M. Burger, Frans G.M. Russel, Reinout van Crevel, Jan B. Koenderink, Rob E. Aarnoutse
Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents. Secondly, human efflux transporters limit the penetration of anti-TB drugs into the brain and cerebrospinal fluid, which is especially important in the treatment of TB meningitis. Finally, efflux transporters located in the macrophage and Mycobacterium tuberculosis cell membranes play a pivotal role in the emergence of phenotypic tolerance and drug resistance, respectively. We review the role of efflux transporters in TB drug disposition and evaluate the promise of efflux pump inhibition from a novel holistic perspective.
The Enduring Legacy of 250 Years of Pharmacology in Edinburgh Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 John S. Kelly, Angus V.P. Mackay
In 1768, 250 years ago, the University of Edinburgh appointed Francis Home to the first chair of materia medica, the accumulated knowledge of materials used in healing. Francis Home and his colleagues were determined to improve the quality of medical training in Edinburgh by introducing a final examination and compiling a catalog of medicines validated by the Royal College of Physicians of Edinburgh. The catalog, known as the Edinburgh Pharmacopoeia, was a great success, partly due to the orderly nature of its contents, its routine editing to eliminate worthless entries, and the introduction of new treatments whose preparation was precisely documented. In a relatively short time, the worth of the Edinburgh Pharmacopoeia was recognized throughout Europe, America, and the British Empire. Today, the British and European Pharmacopoeias are catalogs of publicly available, legally enforceable standards for active pharmaceutical ingredients and finished dosage forms of pharmaceutical products and medical devices. Home and the many luminaries who succeeded him would surely take pleasure and pride in the fact that the mantra of today's medicines regulators worldwide is little different from that of these early visionaries: “To take better advantage of the best possible science in the service of the public health and our health-care systems” (1, p. 492).
TRP Channels as Potential Drug Targets Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Magdalene M. Moran
The transient receptor potential (TRP) superfamily of channels comprises a diverse group of cation channels. Four TRP channel subunits coassemble to form functional homo- or heterotetramers that pass sodium, calcium, or both in the inward direction. Modulating TRP channel activity provides an important way to impact cellular function by regulating both membrane excitability and intracellular calcium levels. The import of these channels is underscored by the number of genetic diseases caused when they are mutated: Skeletal, skin, sensory, ocular, cardiac, and neuronal disturbances all arise from aberrant TRP function. Not surprisingly, there has been significant pharmaceutical interest in targeting these fascinating channels. Compounds that modulate TRP vanilloid 1 (TRPV1), TRPV3, TRPV4, TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) have all entered clinical trials. The goal of this review is to familiarize the readers with the rationale behind the pursuit of these channels in drug discovery and the status of those efforts.
Toward Therapy of Human Prion Diseases Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Adriano Aguzzi, Asvin K.K. Lakkaraju, Karl Frontzek
Three decades after the discovery of prions as the cause of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies, we are still nowhere close to finding an effective therapy. Numerous pharmacological interventions have attempted to target various stages of disease progression, yet none has significantly ameliorated the course of disease. We still lack a mechanistic understanding of how the prions damage the brain, and this situation results in a dearth of validated pharmacological targets. In this review, we discuss the attempts to interfere with the replication of prions and to enhance their clearance. We also trace some of the possibilities to identify novel targets that may arise with increasing insights into prion biology.
Repairing Mitochondrial Dysfunction in Disease Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Vincenzo Sorrentino, Keir J. Menzies, Johan Auwerx
Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and preventive strategies aimed at invigorating mitochondrial function by exploiting key components of mitochondrial biogenesis, redox metabolism, dynamics, mitophagy, and the mitochondrial unfolded protein response. As such, new findings linking mitochondrial function to the progression or outcome of this ever-increasing list of diseases has stimulated the discovery and development of the first true mitochondrial drugs, which are now entering the clinic and are discussed in this review.
The Conducted Vasomotor Response: Function, Biophysical Basis, and Pharmacological Control Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Donald G. Welsh, Cam Ha T. Tran, Bjorn O. Hald, Maria Sancho
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 pattern of charge movement along the arterial wall as set by three key parameters (tissue structure, gap junctional resistivity, and ion channel activity). The impact of disease on conduction is carefully discussed, as are potential strategies to restore this key biological response and, along with it, the match of blood flow delivery with tissue energetic demand.
Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. The field of psychoneuroimmunology is one of great therapeutic opportunity, yielding experimental therapeutics for mood disorders, such as peripheral cytokine targeting antibodies, microglia and astrocyte targeting therapies, and probiotic treatments for gut dysbiosis, and producing findings that identify therapeutic targets for future development.
Adhesion G Protein–Coupled Receptors as Drug Targets Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Ryan H. Purcell, Randy A. Hall
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 activity of aGPCRs is largely determined by changes in the interactions among these protomers. We review recent advances in understanding aGPCR activation mechanisms and discuss the physiological roles and pharmacological properties of aGPCRs, with an eye toward the potential utility of these receptors as drug targets.
Harnessing the Properties of Natural Products Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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.
Mechanism of Neonicotinoid Toxicity: Impact on Oxidative Stress and Metabolism Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. This review summarizes the research conducted over the past decade into the production of reactive oxygen species, reactive nitrogen species, and oxidative stress as aresult of neonicotinoid treatments, along with their correlation with the toxicity and metabolism of neonicotinoids. The metabolism of neonicotinoids and protection of various compounds against neonicotinoid-induced toxicity based on their antioxidative effects is also discussed. This review sheds new light on the critical roles of oxidative stress in neonicotinoid-induced toxicity to nontarget species.
The Ethnopharmacologic Contribution to Bioprospecting Natural Products Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Importantly, researchers can now rapidly analyze and identify the multiple, and often synergistic, compounds contained in these natural products. Although we are entering the acme of ethnopharmacology, where information regarding the traditional use of organisms can provide valuable natural product leads and accelerate the identification of new therapeutics, this ethnopharmacologic resource is threatened by the loss of traditional medicine knowledge and extinction of organisms.
Lung Cancer Heterogeneity and New Strategies for Drug Therapy Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. These results will be more precise if the drugs used in the strategies are selected through protein structure–guided compound screening or a DNA-encoded chemical library before validation in the patient's own cancer cells. Thus, a deeper understanding of heterogeneity mechanisms and improved validation of the therapeutic strategy will result in more precise treatments for patients.
Convergent Neuronal Plasticity and Metaplasticity Mechanisms of Stress, Nicotine, and Alcohol Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Nicotine also activates some of the same signaling molecules, cells, and circuits, producing a convergence of both stress and nicotine onto common plasticity mechanisms that influence alcohol self-administration. 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.
Model-Informed Drug Development for Malaria Therapeutics Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. This could have an enormous impact on the otherwise slow and resource-intensive process of traditional clinical drug development.
Adverse Effects of Nutraceuticals and Dietary Supplements Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. In contrast, a small number of these products have the potential to produce significant toxicity. In addition, patients often do not disclose supplement use to their physicians. Therefore, the risk of adverse drug-supplement interactions is significant. An overview of the major supplement and nutraceutical classes is presented here, together with known toxic effects and the potential for drug interactions.
The Mystery of the Interstitial Cells in the Urinary Bladder Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. A recent report shows that c-Kit+ cells in several species coexpress mast cell tryptase, suggesting that they are likely to be mast cells. In fact, most bladder ICs labeled with vimentin antibodies coexpress platelet-derived growth factor receptor α (PDGFRα). Rather than an excitatory phenotype, PDGFRα+ cells convey inhibitory regulation in the detrusor, and inhibitory mechanisms are activated by purines and stretch. PDGFRα+ cells restrain premature development of contractions during bladder filling, and overactive behavior develops when the inhibitory pathways in these cells are blocked. PDGFRα+ cells are also a prominent cell type in the submucosa and lamina propria, but little is known about their function in these locations. Effective pharmacological manipulation of bladder ICs depends on proper identification and further study of the pathways in these cells that affect bladder functions.
KCNQ-Encoded Potassium Channels as Therapeutic Targets Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 Vincenzo Barrese, Jennifer B. Stott, Iain A. Greenwood
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 prospect for therapeutic development. This review covers the main characteristics of these multifunctional and versatile channels with the aim of providing insight into the therapeutic value of targeting these channels.
Nonalcoholic Steatohepatitis (NASH) and Hepatic Fibrosis: Emerging Therapies Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Novel therapeutic agents are being developed in each of these pathways, and several have shown promise in early phase testing. Given the complexity of the disease, intervention trials are large and long and require histologic confirmation as a primary endpoint for disease improvement or regression. We highlight active Phase 2 and 3 therapeutic trials for NASH as this field rapidly expands in development.
The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2018-01-08 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. Nevertheless, analyses of knockout mice and other data indicate that SLC22 transporters regulate key metabolic pathways and levels of signaling molecules (e.g., gut microbiome products, bile acids, tricarboxylic acid cycle intermediates, dietary flavonoids and other nutrients, prostaglandins, vitamins, short-chain fatty acids, urate, and ergothioneine), as well as uremic toxins associated with chronic kidney disease. Certain SLC22 transporters—such as URAT1 (SLC22A12) and OCTN2 (SLC22A5)—are mutated in inherited metabolic diseases. A new systems biology view of transporters is emerging. As proposed in the remote sensing and signaling hypothesis, SLC22 transporters, together with other SLC and ABC transporters, have key roles in interorgan and interorganism small-molecule communication and, together with the neuroendocrine, growth factor–cytokine, and other homeostatic systems, regulate local and whole-body homeostasis.
New Targets for Drug Treatment of Obesity Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Georgios Valsamakis, Panagiota Konstantakou, George Mastorakos
Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis. Currently, research is focused on the generation of combination treatments based on gut hormones in a way that mimics changes underlying surgically induced weight loss, in addition to centrally acting agents; these aim to restore energy balance disruptions and enhance energy expenditure. Collectively, the pharmacological resolution of obesity could potentially be achieved with combination regimens targeting different molecules and levels of the energy homeostasis system, in parallel with matching patients' needs, resulting in a favorable metabolic profile.
GPER (GPR30): A Nongenomic Receptor (GPCR) for Steroid Hormones with Implications for Cardiovascular Disease and Cancer Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Ross D. Feldman, Lee E. Limbird
Although the rapid effects of steroids, such as estrogen and aldosterone, were postulated originally to be nongenomic, it is now appreciated that activation of such signaling pathways via a steroid-acting G protein–coupled receptor, the G protein estrogen receptor (GPER), has important transcription-dependent outcomes in the regulation of cell growth and programmed cell death secondary to GPER-regulated second-messenger pathways. GPER is expressed ubiquitously and has diverse biological effects, including regulation of endocrine, immune, neuronal, and cardiovascular functions. Perhaps the most biologically important consequences of GPER activation are the regulation of cell growth, migration, and apoptotic cell death. These cell growth regulatory effects, important in cancer biology, are also relevant in the regulation of cardiac and vascular hypertrophy and in the response to ischemia. This review provides a summary of relevant findings of the impact of GPER regulation by either estradiol or aldosterone in in vitro model systems and extends those findings to in vivo studies of direct clinical relevance for development of GPER-directed agents for treatment of cancer and cardiovascular diseases associated with cellular proliferation.
Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Edward J. Lesnefsky, Qun Chen, Bernard Tandler, Charles L. Hoppel
Mitochondria have emerged as key participants in and regulators of myocardial injury during ischemia and reperfusion. This review examines the sites of damage to cardiac mitochondria during ischemia and focuses on the impact of these defects. The concept that mitochondrial damage during ischemia leads to cardiac injury during reperfusion is addressed. The mechanisms that translate ischemic mitochondrial injury into cellular damage, during both ischemia and early reperfusion, are examined. Next, we discuss strategies that modulate and counteract these mechanisms of mitochondrial-driven injury. The new concept that mitochondria are not merely stochastic sites of oxidative and calcium-mediated injury but that they activate cellular responses of mitochondrial remodeling and cellular reactions that modulate the balance between cell death and recovery is reviewed, and the therapeutic implications of this concept are discussed.
The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Paul J. Coleman, Anthony L. Gotter, W. Joseph Herring, Christopher J. Winrow, John J. Renger
Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAA receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage–specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.
Critical Functions of the Lysosome in Cancer Biology Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Shawn M. Davidson, Matthew G. Vander Heiden
Lysosomes (or lytic bodies) were so named because they contain high levels of hydrolytic enzymes. Lysosome function and dysfunction have been found to play important roles in human disease, including cancer; however, the ways in which lysosomes contribute to tumorigenesis and cancer progression are still being uncovered. Beyond serving as a cellular recycling center, recent evidence suggests that the lysosome is involved in energy homeostasis, generating building blocks for cell growth, mitogenic signaling, priming tissues for angiogenesis and metastasis formation, and activating transcriptional programs. This review examines emerging knowledge of how lysosomal processes contribute to the hallmarks of cancer and highlights vulnerabilities that might be exploited for cancer therapy.
Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Ted M. Dawson, Valina L. Dawson
Mitochondria lie at the crossroads of neuronal survival and cell death. They play important roles in cellular bioenergetics, control intracellular Ca2+ homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Mitochondria have evolved strategies to kill cells when they are not able to continue their vital functions. This review provides an overview of the role of mitochondria in neurologic disease and the cell death pathways that are mediated through mitochondria, including their role in accidental cell death, the regulated cell death pathways of apoptosis and parthanatos, and programmed cell death. It details the current state of parthanatic cell death and discusses potential therapeutic strategies targeting initiators and effectors of mitochondrial-mediated cell death in neurologic disorders.
Nanodomain Regulation of Cardiac Cyclic Nucleotide Signaling by Phosphodiesterases Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Kristen Kokkonen, David A. Kass
Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3′,5′-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP. New insights regarding the different roles of PDEs in health and disease and their local signaling control are broadening the potential therapeutic utility for PDE-selective inhibitors. In this review, we discuss these PDEs, focusing on the different mechanisms by which they control cardiac function in health and disease by regulating intracellular nanodomains.
Adipose-Vascular Coupling and Potential Therapeutics Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Maik Gollasch
Excess visceral adipose tissue is associated with increased risk of high blood pressure, lipid disorders, type 2 diabetes, and cardiovascular disease. Adipose tissue is an endocrine organ with multiple humoral and metabolic roles in regulating whole-body physiology. However, perivascular adipose tissue (PVAT) also plays a functional role in regulating the contractile state of the underlying smooth muscle cell layer. Work during the past decade has shown that this adipose-vascular coupling is achieved by production of numerous substances released from PVAT. Animal disease models have been instrumental in identifying biological and pathophysiological functions of this regulation. These studies have produced strong evidence that alterations in the paracrine control of PVAT in the regulation of arterial tone contribute to vascular dysfunction in obesity, hypertension, and cardiometabolic disease. Perivascular relaxing factors, or perhaps their putative targets, might represent exciting new targets for the prevention and treatment of cardiovascular and metabolic diseases.
Intestinal and Hepatocellular Transporters: Therapeutic Effects and Drug Interactions of Herbal Supplements Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Bruno Stieger, Zainab M. Mahdi, Walter Jäger
Herbal supplements are generally considered safe; however, drug disposition is influenced by the interactions of herbal supplements and food constituents with transport and metabolic processes. Although the interference of herbal supplements with drug metabolism has been studied extensively, knowledge of how they interact with the drug transport processes is less advanced. Therefore, we describe here specific examples of experimental and human interaction studies of herbal supplement components with drug transporters addressing, for example, organic anion transporting polypeptides or P-glycoprotein, as such interactions may lead to severe side effects and altered drug efficacy. Hence, it is clearly necessary to increase the awareness of the clinical relevance of the interference of herbal supplements with the drug transport processes.
Autophagy: A Druggable Process Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Etienne Morel, Maryam Mehrpour, Joëlle Botti, Nicolas Dupont, Ahmed Hamaï, Anna Chiara Nascimbeni, Patrice Codogno
Macroautophagy (hereafter called autophagy) is a vacuolar, lysosomal pathway for catabolism of intracellular material that is conserved among eukaryotic cells. Autophagy plays a crucial role in tissue homeostasis, adaptation to stress situations, immune responses, and the regulation of the inflammatory response. Blockade or uncontrolled activation of autophagy is associated with cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. During the past decade, researchers have made major progress in understanding the three levels of regulation of autophagy in mammalian cells: signaling, autophagosome formation, and autophagosome maturation and lysosomal degradation. As we discuss in this review, each of these levels is potentially druggable, and, depending on the indication, may be able to stimulate or inhibit autophagy. We also summarize the different modulators of autophagy and their potential and limitations in the treatment of life-threatening diseases.
Challenges and Opportunities in Protease-Activated Receptor Drug Development Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Justin R. Hamilton, JoAnn Trejo
Protease-activated receptors (PARs) are a unique class of G protein–coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.
Will There Be a Cure for Ebola? Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Anthony P. Cardile, Travis K. Warren, Karen A. Martins, Ronald B. Reisler, Sina Bavari
Despite the unprecedented Ebola virus outbreak response in West Africa, no Ebola medical countermeasures have been approved by the US Food and Drug Administration. However, multiple valuable lessons have been learned about the conduct of clinical research in a resource-poor, high risk–pathogen setting. Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acid–based drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp). We review Ebola therapeutics progress in the aftermath of the West Africa Ebola virus outbreak and attempt to offer a glimpse of a path forward.
Organophosphorus Xenobiotic Toxicology Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 John E. Casida
Originally, organophosphorus (OP) toxicology consisted of acetylcholinesterase inhibition by insecticides and chemical threat agents acting as phosphorylating agents for serine in the catalytic triad, but this is no longer the case. Other serine hydrolases can be secondary OP targets, depending on the OP structure, and include neuropathy target esterase, lipases, and endocannabinoid hydrolases. The major OP herbicides are glyphosate and glufosinate, which act in plants but not animals to block aromatic amino acid and glutamine biosynthesis, respectively, with safety for crops conferred by their expression of herbicide-tolerant targets and detoxifying enzymes from bacteria. OP fungicides, pharmaceuticals including calcium retention agents, industrial chemicals, and cytochrome P450 inhibitors act by multiple noncholinergic mechanisms, often with high potency and specificity. One type of OP-containing fire retardant forms a highly toxic bicyclophosphate γ-aminobutyric acid receptor antagonist upon combustion. Some OPs are teratogenic, mutagenic, or carcinogenic by known mechanisms that can be avoided as researchers expand knowledge of OP chemistry and toxicology for future developments in bioregulation.
Changing Provider Behavior in the Context of Chronic Disease Management: Focus on Clinical Inertia Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Kim L. Lavoie, Joshua A. Rash, Tavis S. Campbell
Widespread acceptance of evidence-based medicine has led to the proliferation of clinical practice guidelines as the primary mode of communicating current best practices across a range of chronic diseases. Despite overwhelming evidence supporting the benefits of their use, there is a long history of poor uptake by providers. Nonadherence to clinical practice guidelines is referred to as clinical inertia and represents provider failure to initiate or intensify treatment despite a clear indication to do so. Here we review evidence for the ubiquity of clinical inertia across a variety of chronic health conditions, as well as the organizational and system, patient, and provider factors that serve to maintain it. Limitations are highlighted in the emerging literature examining interventions to reduce clinical inertia. An evidence-based framework to address these limitations is proposed that uses behavior change theory and advocates for shared decision making and enhanced guideline development and dissemination.
Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Nora D. Volkow, Aidan J. Hampson, Ruben D. Baler
Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-á-vis the ECS's modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions.
Harnessing Big Data for Systems Pharmacology Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Lei Xie, Eli J. Draizen, Philip E. Bourne
Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.
PCSK9: Regulation and Target for Drug Development for Dyslipidemia Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Amy C. Burke, Jacqueline S. Dron, Robert A. Hegele, Murray W. Huff
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.
Innovative Approaches to Improve Anti-Infective Vaccine Efficacy Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Michael R. Yeaman, John P. Hennessey Jr.
Safe and efficacious vaccines are arguably the most successful medical interventions of all time. Yet the ongoing discovery of new pathogens, along with emergence of antibiotic-resistant pathogens and a burgeoning population at risk of such infections, imposes unprecedented public health challenges. To meet these challenges, innovative strategies to discover and develop new or improved anti-infective vaccines are necessary. These approaches must intersect the most meaningful insights into protective immunity and advanced technologies with capabilities to deliver immunogens for optimal immune protection. This goal is considered through several recent advances in host-pathogen relationships, conceptual strides in vaccinology, and emerging technologies. Given a clear and growing risk of pandemic disease should the threat of infection go unmet, developing vaccines that optimize protective immunity against high-priority and antibiotic-resistant pathogens represents an urgent and unifying imperative.
CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism? Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 P.H. Hutson, J.A. Clark, A.J. Cross
There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success. In this review, we outline previous methods for identifying and validating novel targets for CNS drug discovery, and, cognizant of previous failures, we discuss potential new strategies that may improve the probability of success of developing novel treatments for CNS disorders.
Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Maaike Everts, Tomas Cihlar, J. Robert Bostwick, Richard J. Whitley
Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Together, these steps could result in accelerated timelines for bringing antiviral therapies to market so they can treat emerging infections and reduce human suffering.
Stem Cell Extracellular Vesicles: Extended Messages of Regeneration Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Milad Riazifar, Egest J. Pone, Jan Lötvall, Weian Zhao
Stem cells are critical to maintaining steady-state organ homeostasis and regenerating injured tissues. Recent intriguing reports implicate extracellular vesicles (EVs) as carriers for the distribution of morphogens and growth and differentiation factors from tissue parenchymal cells to stem cells, and conversely, stem cell–derived EVs carrying certain proteins and nucleic acids can support healing of injured tissues. We describe approaches to make use of engineered EVs as technology platforms in therapeutics and diagnostics in the context of stem cells. For some regenerative therapies, natural and engineered EVs from stem cells may be superior to single-molecule drugs, biologics, whole cells, and synthetic liposome or nanoparticle formulations because of the ease of bioengineering with multiple factors while retaining superior biocompatibility and biostability and posing fewer risks for abnormal differentiation or neoplastic transformation. Finally, we provide an overview of current challenges and future directions of EVs as potential therapeutic alternatives to cells for clinical applications.
Targeted Protein Degradation by Small Molecules Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Daniel P. Bondeson, Craig M. Crews
Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application. Second, we describe techniques that may find broader acceptance in the biomedical research community that require little or no synthetic chemistry. In addition to serving as innovative research tools, these new approaches to control intracellular protein levels offer the potential to develop novel therapeutics targeting proteins that are not currently pharmaceutically vulnerable.
Pharmacology of Antisense Drugs Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 C. Frank Bennett, Brenda F. Baker, Nguyen Pham, Eric Swayze, Richard S. Geary
Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Antisense drugs utilizing various antisense mechanisms are demonstrating therapeutic potential for the treatment of a broad variety of diseases. This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.
Aptamers as Therapeutics Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Shahid M. Nimjee, Rebekah R. White, Richard C. Becker, Bruce A. Sullenger
Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.
Strategies to Develop Inhibitors of Motif-Mediated Protein-Protein Interactions as Drug Leads Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Carles Corbi-Verge, Michael Garton, Satra Nim, Philip M. Kim
Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has been increased interest in targeting them using peptide-based therapeutics. Peptides benefit from being specific, relatively safe, and easy to produce. They are also easy to modify using chemical synthesis and molecular biology techniques. However, significant challenges remain regarding the use of peptides as therapeutic agents. Identification of peptide motifs is difficult, and peptides typically display low cell permeability and sensitivity to enzymatic degradation. In this review, we outline the principal high-throughput methodologies for motif discovery and describe current methods for overcoming pharmacokinetic and bioavailability limitations.
Nanobodies to Study G Protein–Coupled Receptor Structure and Function Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Aashish Manglik, Brian K. Kobilka, Jan Steyaert
Ligand-induced activation of G protein–coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently elucidated the structural and dynamic features of GPCR transmembrane signaling. Nanobodies, the recombinant antigen–binding fragments of camelid heavy-chain-only antibodies, have emerged as important research tools to lock GPCRs in particular conformational states. Active-state stabilizing nanobodies have elucidated several agonist-bound structures of hormone-activated GPCRs and have provided insight into the dynamic character of receptors. Nanobodies have also been used to stabilize transient GPCR transmembrane signaling complexes, yielding the first structural insights into GPCR signal transduction across the cellular membrane. Beyond their in vitro uses, nanobodies have served as conformational biosensors in living systems and have provided novel ways to modulate GPCR function. Here, we highlight several examples of how nanobodies have enabled the study of GPCR function and give insights into potential future uses of these important tools.
Introduction to the Theme “New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology” Annu. Rev. Pharmacol. Toxicol. (IF 12.877) Pub Date : 2017-01-06 Paul A. Insel, Susan G. Amara, Terrence F. Blaschke, Urs A. Meyer
Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen “New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology” as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e.g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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