journal
MENU ▼
Read by QxMD icon Read
search

Journal of Pharmacology and Experimental Therapeutics

journal
https://www.readbyqxmd.com/read/28819071/genetic-and-non-genetic-factors-associated-with-protein-abundance-of-flavin-containing-monooxygenase-3-in-human-liver
#1
Meijuan Xu, Deepak Kumar Bhatt, Catherine K Yeung, Katrina G Claw, Amarjit S Chaudhry, Andrea Gaedigk, Robin E Pearce, Ulrich Broeckel, Roger Gaedigk, Debbie Nickerson, Erin Schuetz, Allan E Rettie, Steven Leeder, Kenneth E Thummel, Bhagwat Prasad
Hepatic flavin-containing monooxygenase 3 (FMO3) metabolizes a broad array of nucleophilic heteroatom (e.g., N or S)-containing xenobiotics (e.g., amphetamine, sulindac, benzydamine, ranitidine, tamoxifen, nicotine, and ethioniamide), as well as endogenous compounds (e.g., catecholamine and trimethylamine). To predict the effect of genetic and non-genetic factors on the hepatic metabolism of FMO3 substrates, we quantified FMO3 protein abundance in human liver microsomes (HLM; n=445) by LC-MS/MS proteomics. Genotyping/gene-resequencing, mRNA expression, and functional activity (with benzydamine as a probe substrate) of FMO3 were also performed...
August 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28819070/claudin-5-binders-enhance-permeation-of-solutes-across-the-blood-brain-barrier-in-a-mammalian-model
#2
Yosuke Hashimoto, Keisuke Shirakura, Yoshiaki Okada, Hiroyuki Takeda, Kohki Endo, Maki Tamura, Akihiro Watari, Yoshifusa Sadamura, Tatsuya Sawasaki, Takefumi Doi, Kiyohito Yagi, Masuo Kondoh
A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5, a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies specific to the extracellular domains of CLDN-5...
August 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28798030/ethanol-exposure-regulates-gabra1-expression-via-histone-deacetylation-at-the-promoter-in-cultured-cortical-neurons
#3
John Peyton Bohnsack, Vraj K Patel, A Leslie Morrow
GABAA-Rs mediate the majority of inhibitory neurotransmission in the adult brain. α1-containing GABAA-Rs are the most prominent subtype in the adult brain, and are important in both homeostatic function and several disease pathologies including alcohol dependence, epilepsy, and stress. Ethanol exposure causes a decrease of α1 transcription and peptide expression both in vivo and in vitro, but the mechanism that controls the transcriptional regulation is unknown. Since ethanol is known to activate epigenetic regulation of gene expression, we tested the hypothesis that ethanol regulates α1 expression through histone modifications in cerebral cortical cultured neurons...
August 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28790194/characterization-of-the-potent-selective-nrf2-activator-pstc-in-cellular-and-in-vivo-models-of-pulmonary-oxidative-stress
#4
John G Yonchuk, Joseph P Foley, Brian J Bolognese, Gregory A Logan, William E Wixted, Jen-Pyng Kou, Diana G Chalupowicz, Heidi G Feldser, Yolanda Sanchez, Hong Nie, James F Callahan, Jeffrey K Kerns, Patricia L Podolin
Nrf2 is a key regulator of oxidative stress and cellular repair, and can be activated through inhibition of its cytoplasmic repressor, Keap1. Several small molecule disrupters of the Nrf2-Keap1 complex have recently been tested and/or approved for human therapeutic use but lack either potency or selectivity. The main goal of our work was to develop a potent, selective activator of NRF2 as protection against oxidative stress. In human bronchial epithelial cells our Nrf2 activator, PSTC, induced Nrf2 nuclear translocation, Nrf2-regulated gene expression, and downstream signaling events including induction of NQO1 enzyme activity and HO-1 protein expression, in an Nrf2-dependent manner...
August 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28790193/assessing-the-value-of-the-zebrafish-conditioned-place-preference-model-for-predicting-human-abuse-potential
#5
Alistair James Brock, Susan M G Goody, Andrew N Mead, Ari Sudwarts, Matthew O Parker, Caroline H Brennan
Regulatory agencies recommend that centrally-active drugs are tested for abuse potential prior to approval. Standard preclinical assessments are conducted in rats or non-human primates (NHPs). This study evaluated the ability of the zebrafish conditioned place preference (CPP) model to predict human abuse outcomes. Twenty-seven compounds from a variety of pharmacological classes were tested in zebrafish CPP, categorized as positive or negative, and analysed using standard diagnostic tests of binary classification to determine the likelihood that zebrafish correctly predict robust positive signals in human subjective effects studies (+HSE) and/or DEA drug scheduling...
August 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28784820/urolithin-a-mitigates-cisplatin-induced-nephrotoxicity-by-inhibiting-renal-inflammation-and-apoptosis-in-an-experimental-rat-model
#6
Melissa Guada, Raghu Ganugula, Manicka Vadhanam, Ravi Kumar Majeti
Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways, therefore regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential of urolithin A for prevention of cisplatin-induced nephrotoxicity in an experimental rat model...
August 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28778859/nktr-181-a-novel-mu-opioid-analgesic-with-inherently-low-abuse-potential
#7
Takahiro Miyazaki, Irene Y Choi, Werner Rubas, Neel K Anand, Cherie Ali, Juli Evans, Hema Gursahani, Marlene Hennessy, Grace Kim, Daniel McWeeney, Juergen Pfeiffer, Phi Quach, David Gauvin, Timothy A Riley, Jennifer A Riggs, Kathleen Gogas, Jonathan Zalevsky, Stephen K Doberstein
The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADF) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within...
August 4, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28768817/cxcr4-specific-nanobodies-as-potential-therapeutics-for-whim-syndrome
#8
Raymond H de Wit, Raimond Heukers, Hendrik Brink, Angela Arsova, David Maussang, Pasquale Cutolo, Beatrijs Strubbe, Henry Vischer, Francoise Bachelerie, Martine J Smit
WHIM syndrome is a rare congenital immunodeficiency disease, named after its main clinical manifestations: Warts, Hypogammaglobulinemia, Infections and Myelokathexis. The disease is primarily caused by C-terminal truncation mutations of the chemokine receptor CXCR4. Consequently, these CXCR4-WHIM mutants have a gain of function in response to its ligand CXCL12, which results in abnormal leukocyte migration and thereby immune system dysfunctions. Treatment of WHIM patients currently consists of symptom relief, leading to unsatisfactory clinical responses...
August 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28760737/docetaxel-reverses-pulmonary-vascular-remodeling-by-decreasing-autophagy-and-resolves-right-ventricular-fibrosis
#9
Yasmine F Ibrahim, Nataliia V Shults, Vladyslava Rybka, Yuichiro J Suzuki
Pulmonary arterial hypertension remains a fatal disease despite the availability of approved vasodilators. Since vascular remodeling contributes to increased pulmonary arterial pressure, new agents that reduce the thickness of pulmonary vascular walls have therapeutic potential. Thus, anti-tumor agents that are capable of killing cells were investigated. Testing of various anti-tumor drugs identified that docetaxel is a superior drug for killing proliferating pulmonary artery smooth muscle cells compared with other drugs including gemcitabine, methotrexate and ifosfamide...
July 31, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28729456/mechanistic-multi-tissue-modeling-of-gilz-regulation-integrating-circadian-gene-expression-with-receptor-mediated-corticosteroid-pharmacodynamics
#10
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
#11
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
#12
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/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
#13
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/28663311/the-use-of-physiology-based-pk-and-pd-modeling-in-the-discovery-of-the-dual-orexin-receptor-antagonist-act-541468
#14
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/28698254/mechanism-based-pharmacokinetic-pharmacodynamic-modeling-of-the-glucagon-like-peptide-1-receptor-agonist-exenatide-to-characterize-its-antiobesity-effects-in-diet-induced-obese-mice
#15
Shinji Iwasaki, Teruki Hamada, Ikumi Chisaki, Tomohiro Andou, Noriyasu Sano, Atsutoshi Furuta, Nobuyuki Amano
In addition to their potent antidiabetic effects, glucagon-like peptide-1 (GLP-1) analogs lower body weight in humans. 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 antiobesity 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 antiobesity drugs...
September 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
#16
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 1-g oral dose...
September 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28652388/optimization-of-thermolytic-response-to-a1-adenosine-receptor-agonists-in-rats
#17
Isaac R Bailey, Bernard Laughlin, Lucille A 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, limit application and benefit of TTM. Stimulating central nervous system A1 adenosine receptors (A1AR) inhibits shivering and nonshivering thermogenesis in rats and induces a hibernation-like response in hibernating species...
September 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
#18
Giordano de Guglielmo, Alessandra Matzeu, Jenni Kononoff, Julia Mattioni, Rémi 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...
September 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28645914/bile-salt-homeostasis-in-normal-and-bsep-gene-knockout-rats-with-single-and-repeated-doses-of-troglitazone
#19
Yaofeng Cheng, Shenjue Chen, Chris Freeden, Weiqi Chen, Yueping Zhang, Pamela Abraham, David M Nelson, W Griffith Humphreys, Jinping Gan, Yurong Lai
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is 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 knockout (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...
September 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
#20
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 Pähler, Julie K Andersen, 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 hypothesized 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...
September 2017: Journal of Pharmacology and Experimental Therapeutics
journal
journal
23880
1
2
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"