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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/28729456/mechanistic-multi-tissue-modeling-of-gilz-regulation-integrating-circadian-gene-expression-with-receptor-mediated-corticosteroid-pharmacodynamics
#1
Vivaswath S Ayyar, Debra C DuBois, Richard R Almon, William J Jusko
The glucocorticoid-induced leucine zipper (GILZ) is an important mediator of anti-inflammatory corticosteroid action. The pharmacokinetic/pharmacodynamic/pharmacogenomic effects of acute and chronic methylprednisolone (MPL) dosing on the tissue-specific dynamics of GILZ expression were examined in rats. A mechanism-based model was developed to investigate and integrate the role of MPL and circadian rhythms on the transcriptional enhancement of GILZ in multiple tissues. Animals received a single 50 mg/kg intramuscular bolus or a seven-day 0...
July 20, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28724693/new-peptide-inhibitor-of-dipeptidyl-peptidase-iv-emdb-1-extends-the-half-life-of-glp-2-and-attenuates-colitis-in-mice-after-topical-administration
#2
Maciej Salaga, Anna Mokrowiecka, Marta Zielinska, Ewa Malecka-Panas, Radzislaw Kordek, Elzbieta Kamysz, Jakub Fichna
Protease inhibition has become a new possible approach in the inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV) is responsible for inactivation of incretine hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently we showed that the novel peptide analog of endomorphin-2, EMDB-1 is a potent blocker of DPP IV and has an inhibitory effect on gastrointestinal (GI) smooth muscle contractility. The aim of this study was to characterize the anti-inflammatory effect and mechanism of action of EMDB-1 in the mouse GI tract...
July 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28724692/enhancing-studies-of-pharmacodynamic-mechanisms-via-measurements-of-metabolic-flux
#3
Natalie A Daurio, Sheng-Ping Wang, Ying Chen, Haihong Zhou, David G McLaren, Thomas P Roddy, Douglas G Johns, Denise Milot, Takhar Kasumov, Mark D Erion, David E Kelley, Stephen F Previs
Drug discovery and development efforts are largely based around a common expectation, namely, direct or indirect action on a cellular process (e.g. statin-mediated enzyme inhibition or insulin-stimulated receptor activation) will have a beneficial impact on physiological homeostasis. To expand on this, one could argue that virtually all pharmacological interventions attempt to influence the flow of traffic in a biochemical network, irrespective of disease or modality. Since stable isotope tracer kinetic methods provide a measure of traffic flow (i...
July 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28698254/mechanism-based-pharmacokinetic-pharmacodynamic-modeling-of-the-glucagon-like-peptide-1-receptor-agonist-exenatide-to-characterize-its-anti-obesity-effects-in-diet-induced-obese-mice
#4
Shinji Iwasaki, Teruki Hamada, Ikumi Chisaki, Tomohiro Andou, Noriyasu Sano, Atsutoshi Furuta, Nobuyuki Amano
Glucagon-like peptide-1 (GLP-1) analogs lower body weight in humans in addition to their potent anti-diabetic effects. Hence, agonistic targeting of the GLP-1 receptor could be a valid approach to target obesity. However, quantitative analyses of the pharmacokinetic/pharmacodynamic (PK/PD) relationship between GLP-1 analogs and their anti-obesity effect have not been reported in either animals or humans. Therefore, the present study was performed to establish a mechanism-based PK/PD model of GLP-1 receptor agonists using the GLP-1 analog, exenatide, for the development of promising new anti-obesity drugs...
July 11, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28687704/synergistic-cytotoxicity-from-drugs-and-cytokines-in-vitro-as-an-approach-to-classify-drugs-according-to-their-potential-to-cause-idiosyncratic-hepatotoxicity-a-proof-of-concept-study
#5
Ashley R Maiuri, Bronlyn Wassink, Jonathan D Turkus, Anna B Breier, Theresa Lansdell, Gurpreet Kaur, Sarah L Hession, Patricia E Ganey, Robert A Roth
Idiosyncratic, drug-induced liver injury (IDILI) typically occurs in a small fraction of patients and has resulted in removal of otherwise efficacious drugs from the market. Current preclinical testing methods are ineffective in predicting which drug candidates have IDILI liability. Recent results suggest that immune mediators such as tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) interact with drugs that cause IDILI to kill hepatocytes. This proof-of-concept study was designed to test the hypothesis that drugs can be classified according to their ability to cause IDILI in humans using logistic regression modeling with covariates derived from concentration-response relationships that describe cytotoxic interaction with cytokines...
July 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28663312/race-gender-and-genetic-polymorphism-contribute-to-variability-in-acetaminophen-pharmacokinetics-metabolism-and-protein-adduct-concentrations-in-healthy-african-american-and-european-american-volunteers
#6
Michael H Court, Zhaohui Zhu, Gina Masse, Su X Duan, Laura P James, Jerold S Harmatz, David J Greenblatt
Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a one-gram oral dose...
June 29, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28663311/the-use-of-physiology-based-pk-and-pd-modeling-in-the-discovery-of-the-dual-orexin-receptor-antagonist-act-541468
#7
Alexander Treiber, Ruben de Kanter, Catherine Roch, John Gatfield, Christoph Boss, Markus von Raumer, Benno Schindelholz, Clemens Muehlan, Joop van Gerven, Francois Jenck
The identification of new sleep drugs poses particular challenges in drug discovery due to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging in case inter-species differences are prominent...
June 29, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28652388/optimization-of-thermolytic-response-to-a1-adenosine-receptor-agonists-in-rats
#8
Isaac R Bailey, Bernard Laughlin, Lucille Moore, Lori K Bogren, Zeinab Barati, Kelly L Drew
Cardiac arrest is a leading cause of death in the United States and currently, therapeutic hypothermia, now called targeted temperature management (TTM), is the only recent treatment modality proven to increase survival rates and reduce morbidity for this condition. Shivering and subsequent metabolic stress, however, limits application and benefit of TTM. Stimulating CNS A1 adenosine receptors inhibits shivering and non-shivering thermogenesis in rats and induces a hibernation-like response in hibernating species...
June 26, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28645915/cebranopadol-blocks-the-escalation-of-cocaine-intake-and-conditioned-reinstatement-of-cocaine-seeking-in-rats
#9
Giordano de Guglielmo, Alessandra Matzeu, Jenni Kononoff, Julia Mattioni, Remi Martin-Fardon, Olivier George
Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine...
June 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28645914/bile-salt-homeostasis-in-normal-and-bsep-gene-knock-out-rats-with-single-and-repeated-doses-of-troglitazone
#10
Yaofeng Cheng, Shenjue Chen, Chris Freeden, Weiqi Chen, Yueping Zhang, Pamela Abraham, David Nelson, William G Humphreys, Jinpin Gan, Yurong Lai
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition was one of the mechanisms for troglitazone (TGZ) induced hepatotoxicity. Here we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep KO rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on Day-1 and Day-7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7...
June 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28642233/sembragiline-a-novel-selective-monoamine-oxidase-type-b-inhibitor-for-the-treatment-of-alzheimer-s-disease
#11
Edilio Borroni, Bernd Bohrmann, Fiona Grueninger, Eric Prinssen, Stephane Nave, Hansruedi Loetscher, Shankar J Chinta, Subramanian Rajagopalan, Anand Rane, Almas Siddiqui, Bart Ellenbroek, Juerg Messer, Axel Pahler, Julie K Anderson, Rene Wyler, Andrea M Cesura
Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesised to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease...
June 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28642232/a-single-amino-acid-residue-at-transmembrane-domain-4-of-the-alpha-subunit-influences-carisoprodol-direct-gating-efficacy-at-gabaa-receptors
#12
Manoj Kumar, Manish Kumar, John Freund, Glenn H Dillon
The muscle relaxant carisoprodol (CSP, trade name Soma) has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures and even death. Recent work has shown that carisoprodol can directly gate and allosterically modulate the GABAA receptor. These actions are subunit-dependent; compared to other GABAA receptors, carisoprodol has nominal direct gating effects in α3β2γ2receptors. Here, using site-directed-mutagenesis and whole cell patch clamp electrophysiology in transiently transfected HEK293 cells, we examined the role of GABAA receptor α subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of carisoprodol...
June 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28630284/differential-interaction-of-dantrolene-glafenine-nalidixic-acid-and-prazosin-with-human-organic-anion-transporters-1-and-3-oat1-oat3
#13
Birgitta C Burckhardt, Maja Henjakovic, Yohannes Hagos, Gerhard Burckhardt
In renal proximal tubule cells, the organic anion transporters 1 and 3 (OAT1 and OAT3) in the basolateral membrane and the multi drug resistance-associated protein 4 (MRP4) in the apical membrane share substrates and co-operate in renal drug secretion. We hypothetized that recently identified MRP4 inhibitors, dantrolene, glafenine, nalidixic acid, and prazosin, also interact with human OAT1 and/or OAT3 stably transfected in HEK293 cells. These four drugs were tested as possible inhibitors of p-[3H]aminohippurate (PAH) and [14C]glutarate uptake by OAT1, and of [3H]estrone-3-sulfate (ES) uptake by OAT3...
June 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28630283/molecular-behavioral-and-physiological-consequences-methamphetamine-neurotoxicity-implications-for-treatment
#14
Anna Moszczynska, Sean P Callan
Understanding the relationship between the molecular mechanisms underlying neurotoxicity of high-dose methamphetamine (METH) and related clinical manifestations is imperative for providing more effective treatments for human METH users. This article provides overview of neurobiology underlying consequences of administration of neurotoxic METH doses.
June 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28620120/ethyl-vanillin-activates-trpa1
#15
Shaw-Wen Wu, Daniel K Fowler, Forrest J Shaffer, Jonathon E M Lindberg, James Henry Peters
The non-selective cation channel TRPA1 is expressed in neurons of dorsal root ganglia and trigeminal ganglia and also in vagal afferent neurons that innervate the lungs and gastrointestinal tract. Many TRPA1 agonists are also reactive electrophilic compounds which form covalent adducts with TRPA1. Allyl isothiocyanate (AITC), the common reference agonist used to identify TRPA1, contains a reactive electrophilic group that covalently binds with cysteine residues of TRPA1 and confers a structural change on the channel...
June 15, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28615288/correlation-between-apparent-substrate-affinity-and-oct2-transporter-turnover
#16
Alyscia Cory Severance, Philip J Sandoval, Stephen H Wright
Organic cation transporter 2 (OCT2) mediates the first step in the renal secretion of many cationic drugs: basolateral uptake from blood into proximal tubule cells. The impact of this process on the pharmacokinetics of drug clearance as estimated using a physiologically-based pharmacokinetic (PBPK) approach relies on an accurate understanding of the kinetics of transport because the ratio of the maximal rate of transport to the Michaelis constant (i.e., Jmax/Kt) provides an estimate of the intrinsic clearance (Clint) used in in vitro-in vivo extrapolation of experimentally determined transport data...
June 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28611093/danirixin-a-reversible-and-selective-antagonist-of-the-cxc-chemokine-receptor-2
#17
Jakob Busch-Petersen, Donald C Carpenter, Miriam Burman, James Foley, Gerald E Hunsberger, David J Kilian, Michael Salmon, Ruth J Mayer, John G Yonchuk, Ruth Tal-Singer
CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC50) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca2+ mobilization assays, with a Kb of 6...
June 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28611092/altering-metabolic-profiles-of-drugs-by-precision-deuteration-2-discovery-of-a-deuterated-analog-of-ivacaftor-with-differentiated-pharmacokinetics-for-clinical-development
#18
Scott L Harbeson, Adam J Morgan, Julie F Liu, Ara M Aslanian, Sophia Nguyen, Gary W Bridson, Christopher L Brummel, Lijun Wu, Roger D Tung, Lana Pilja, Virginia Braman, Vinita Uttamsingh
Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco®) and combination therapy with lumacaftor (Orkambi®). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR), while Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor...
June 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28600397/semi-mechanistic-bone-marrow-exhaustion-pharmacokinetic-pharmacodynamic-model-for-chemotherapy-induced-cumulative-neutropenia
#19
Andrea Henrich, Markus Joerger, Stefanie Kraff, Ulrich Jaehde, Wilhelm Huisinga, Charlotte Kloft, Zinnia Patricia Parra-Guillen
Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. A dose individualization algorithm was developed by Joerger et al. based on a pharmacokinetic/pharmacodynamic (PK/PD) model describing paclitaxel and neutrophil concentrations. Further, the algorithm was prospectively compared in a clinical trial against standard dosing (CEPAC-TDM study, npatients=365, ncycles=720) but did not substantially improve neutropenia...
June 9, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28576976/pleiotropic-and-adverse-effects-of-statins-do-epigenetics-play-a-role
#20
Stephanie C Allen, Cyril Ds Mamotte
Statins are widely used to prevent major cardiovascular events through the lowering of serum cholesterol. There is evidence that statins have pleiotropic effects, that is cholesterol-independent effects, that may also confer protection from cardiovascular disease and potentially numerous other pathologies including cancer. Statins also have a number of well described adverse effects including myopathy, rhabdomyolysis, liver damage and type 2 diabetes. This paper examines the evidence of epigenetic modifications as a contributory factor to the pleiotropic and adverse effects of statins...
June 2, 2017: Journal of Pharmacology and Experimental Therapeutics
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