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Annual Review of Pharmacology and Toxicology

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https://www.readbyqxmd.com/read/30296897/cardiovascular-pharmacogenomics-does-it-matter-if-you-re-black-or-white
#1
Tanima De, C Sehwan Park, Minoli A Perera
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...
October 8, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30296896/molecular-pharmacology-and-neurobiology-of-rapid-acting-antidepressants
#2
Todd D Gould, Carlos A Zarate, Scott M Thompson
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 more effectively treated in the future...
October 8, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30296895/drug-targets-for-heart-failure-with-preserved-ejection-fraction-a-mechanistic-approach-and-review-of-contemporary-clinical-trials
#3
Ravi B Patel, Sanjiv J Shah
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 new therapeutic targets for HFpEF...
October 8, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30285540/therapeutic-oligonucleotides-state-of-the-art
#4
C I Edvard Smith, Rula Zain
Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, spliceswitching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNAdecoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. DNAtargeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines...
October 4, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30260737/systems-pharmacology-defining-the-interactions-of-drug-combinations
#5
J G Coen van Hasselt, Ravi Iyengar
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...
September 27, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30256716/modulating-nrf2-in-disease-timing-is-everything
#6
Matthew Dodson, Montserrat Rojo de la Vega, Aram B Cholanians, Cody J Schmidlin, Eli Chapman, Donna D Zhang
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...
September 26, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30230960/novel-clinical-toxicology-and-pharmacology-of-organophosphorus-insecticide-self-poisoning
#7
Michael Eddleston
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...
September 19, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30216745/the-neurobiology-and-pharmacotherapy-of-posttraumatic-stress-disorder
#8
Chadi G Abdallah, Lynnette A Averill, Teddy J Akiki, Mohsin Raza, Christopher L Averill, Hassaan Gomaa, Archana Adikey, John H Krystal
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...
September 14, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30216744/the-placebo-effect-in-pain-therapies
#9
Luana Colloca
Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor-mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients' positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and chronicity...
September 14, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30208282/surviving-in-the-valley-of-death-opportunities-and-challenges-in-translating-academic-drug-discoveries
#10
Marcus C Parrish, Yuan Jin Tan, Kevin V Grimes, Daria Mochly-Rosen
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...
September 12, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30208281/nuclear-receptors-as-therapeutic-targets-for-neurodegenerative-diseases-lost-in-translation
#11
Miguel Moutinho, Juan F Codocedo, Shweta S Puntambekar, Gary E Landreth
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 strategy to clinical practice has been unsuccessful...
September 12, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30183506/recent-developments-in-understanding-barrier-mechanisms-in-the-developing-brain-drugs-and-drug-transporters-in-pregnancy-susceptibility-or-protection-in-the-fetal-brain
#12
Norman R Saunders, Katarzyna M Dziegielewska, Kjeld Møllgârd, Mark D Habgood
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...
September 5, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30156973/assessment-of-pharmacokinetic-drug-drug-interactions-in-humans-in-vivo-probe-substrates-for-drug-metabolism-and-drug-transport-revisited
#13
Uwe Fuhr, Chih-Hsuan Hsin, Xia Li, Wafaâ Jabrane, Fritz Sörgel
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 the main challenges...
August 29, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30148697/muscle-wasting-diseases-novel-targets-and-treatments
#14
Regula Furrer, Christoph Handschin
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 pathologies, current treatments are mostly targeted on non-muscle tissues...
August 27, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30134124/applications-of-immunopharmacogenomics-predicting-preventing-and-understanding-immune-mediated-adverse-drug-reactions
#15
Jason H Karnes, Matthew A Miller, Katie D White, Katherine C Konvinse, Rebecca K Pavlos, Alec J Redwood, Jonathan G Peter, Rannakoe Lehloenya, Simon A Mallal, Elizabeth J Phillips
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...
August 22, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30125127/moving-from-the-trial-to-the-real-world-improving-medication-adherence-using-insights-of-implementation-science
#16
Leah Zullig, Mieke Deschodt, Jan Liska, Hayden B Bosworth, Sabina De Geest
Medication nonadherence is a serious public health concern. Although there are promising interventions that improve medication adherence, most interventions are developed and tested in tightly controlled research environments that are dissimilar from the real-world settings where the majority of patients receive health care. Implementation science methods have the potential to facilitate and accelerate the translation shift from the trial world to the real world. We demonstrate their potential by reviewing published, high-quality medication adherence studies that could potentially be translated into clinical practice yet lack essential implementation science building blocks...
August 20, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30113875/organoids-for-drug-discovery-and-personalized-medicine
#17
Toshio Takahashi
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 development of new treatments...
August 16, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30110577/new-cell-cycle-inhibitors-target-aneuploidy-in-cancer-therapy
#18
Masanori Kawakami, Xi Liu, Ethan Dmitrovsky
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 cells...
August 15, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30095351/the-exposome-molecules-to-populations
#19
Megan M Niedzwiecki, Douglas I Walker, Roel Vermeulen, Marc Chadeau-Hyam, Dean P Jones, Gary W Miller
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...
August 10, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30044728/challenges-in-orphan-drug-development-identification-of-effective-therapy-for-thyroid-associated-ophthalmopathy
#20
Terry J Smith
Thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves' disease, is a process in which orbital connective tissues and extraocular muscles undergo inflammation and remodeling. The condition seems to result from autoimmune responses to antigens shared by the thyroid and orbit. The thyrotropin receptor (TSHR), expressed at low levels in orbital tissues, is a leading candidate antigen. Recent evidence suggests that another protein, the insulin-like growth factor-I receptor (IGF-IR), is overexpressed in TAO, and antibodies against IGF-IR have been detected in patients with the disease...
July 25, 2018: Annual Review of Pharmacology and Toxicology
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