Read by QxMD icon Read

Annual Review of Pharmacology and Toxicology

Paul A Insel, Susan G Amara, Terrence F Blaschke, Urs A Meyer
"New Therapeutic Targets" is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depression, post-traumatic stress disorder, muscle wasting diseases, cancer, and anemia associated with chronic renal disease...
January 6, 2019: Annual Review of Pharmacology and Toxicology
Leigh Goedeke, Rachel J Perry, Gerald I Shulman
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed...
January 6, 2019: Annual Review of Pharmacology and Toxicology
Qiao Yi Chen, Thomas DesMarais, Max Costa
Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis...
January 6, 2019: Annual Review of Pharmacology and Toxicology
Birgit Liss, Jörg Striessnig
The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects...
January 6, 2019: Annual Review of Pharmacology and Toxicology
Jerold Chun, Yasuyuki Kihara, Deepa Jonnalagadda, Victoria A Blaho
Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration-approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS)...
January 6, 2019: Annual Review of Pharmacology and Toxicology
Gregg L Semenza
Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O2 availability. HIFs are heterodimeric proteins composed of an O2 -regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease...
January 6, 2019: Annual Review of Pharmacology and Toxicology
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...
January 6, 2019: Annual Review of Pharmacology and Toxicology
Todd D Gould, Carlos A Zarate, Scott M Thompson
For decades, symptoms of depression have been treated primarily with medications that directly 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...
January 6, 2019: Annual Review of Pharmacology and Toxicology
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 stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD...
January 6, 2019: Annual Review of Pharmacology and Toxicology
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...
January 6, 2019: Annual Review of Pharmacology and Toxicology
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
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
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
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
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
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
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
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
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
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
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"