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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/29453199/simultaneous-assessment-of-clearance-metabolism-induction-and-drug-drug-interaction-potential-using-a-long-term-in-vitro-liver-model-for-a-novel-hepatitis-b-virus-inhibitor
#1
Nicole A Kratochwil, Miriam Triyatni, Martina B Mueller, Florian Klammers, Brian Leonard, Dan Turley, Josephine Schmaler, Aynur Ekiciler, Birgit Molitor, Isabelle Walter, Pierre-Alexis Gonsard, Charles A Tournillac, Alexandre Durrwell, Michaela Marschmann, Russell Jones, Mohammed Ullah, Franziska Boess, Giorgio Ottaviani, Yuyan Yin, Neil J Parrott, Stephen Fowler
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism, comparison of low clearance drugs as well as induction studies. Here, we present studies using a long-term liver model which show how metabolism and active transport, drug-drug interactions and enzyme induction in healthy and diseased states, e.g. hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for PBPK modeling...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29453198/targeting-kca1-1-channels-with-a-scorpion-venom-peptide-for-the-therapy-of-rat-models-of-rheumatoid-arthritis
#2
Mark R Tanner, Michael W Pennington, Brayden H Chamberlain, Redwan Huq, Elizabeth J Gehrmann, Teresina Laragione, Percio S Gulko, Christine Beeton
Fibroblast-like synoviocytes (FLS) are a key cell-type involved in rheumatoid arthritis (RA) progression. We previously identified the KCa1.1 potassium channel (Maxi-K, BK, Slo 1, KCNMA1) as a regulator of FLS and that KCa1.1 inhibition reduces disease severity in RA animal models. However, systemic KCa1.1 block causes multiple side effects and in this study, we aimed to determine whether the KCa1.1 β1-3-specific venom peptide blocker iberiotoxin (IbTX) reduces disease severity in animal models of RA without inducing major side effects...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29440309/the-phosphodiesterase-2a-inhibitor-tak-915-ameliorates-cognitive-impairments-and-social-withdrawal-in-n-methyl-d-aspartate-receptor-antagonist-induced-rat-models-of-schizophrenia
#3
Masato Nakashima, Haruka Imada, Eri Shiraishi, Yuki Ito, Noriko Suzuki, Maki Miyamoto, Takahiko Taniguchi, Hiroki Iwashita
The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N-methyl-D-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain penetrant PDE2A inhibitor, (N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide) (TAK-915) as a novel treatment for schizophrenia...
February 13, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29440451/establishing-transcriptional-signatures-to-differentiate-pxr-car-and-ahr-mediated-regulation-of-drug-metabolism-and-transport-genes-in-cryopreserved-human-hepatocytes
#4
Jamie E Moscovitz, Amit S Kalgutkar, Kelly Nulick, Nathaniel Johnson, Zhiwu Lin, Theunis C Goosen, Yan Weng
The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug disposition genes via activation of nuclear receptors (NRs) such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and/or aryl hydrocarbon receptor (AhR) remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR/CAR/AhR-specific drug metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO) and AhR (omeprazole)...
February 12, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29440450/pharmacokinetic-assessment-of-cooperative-efflux-of-the-multi-targeted-kinase-inhibitor-ponatinib-across-the-blood-brain-barrier
#5
Janice K Laramy, Minjee Kim, Karen E Parrish, Jann N Sarkaria, William F Elmquist
A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multi-kinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and free brain-to-plasma ratios (Kp or Kp,uu) were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp ( Mdr1a/b(-/-)Bcrp1(-/-) ) compared to the wild-type mice...
February 12, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29438988/flavopiridol-inhibits-tgf-%C3%AE-stimulated-biglycan-synthesis-by-blocking-linker-region-phosphorylation-and-nuclear-translocation-of-smad2
#6
Muhamad Ashraf Rostam, Aravindra Shajimoon, Danielle Kamato, Partha Mitra, Terrence Piva, Robel Getachew, Yingnan Cao, Wenhua Zheng, Narin Osman, Peter James Little
Transforming Growth Factor (TGF) β is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that leads to increased binding of atherogenic lipoproteins in the wall of blood vessels. TGF-β signalling pathway components leading to the modification of GAG chains on biglcyan are therefore potential targets for the treatment of atherosclerosis. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signalling pathways that control the synthesis of biglycan, both the core protein and the GAG chains...
February 9, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29438998/hydroxychloroquine-a-physiologically-based-pharmacokinetic-model-in-the-context-of-cancer-related-autophagy-modulation
#7
Keagan P Collins, Kristen M Jackson, Daniel L Gustafson
Hydroxychloroquine (HCQ) is a lysosomotropic autophagy inhibitor being used in over 50 clinical trials either alone or in combination with chemotherapy. Pharmacokinetic (PK) and pharmacodynamic (PD) studies with HCQ have shown that drug exposure in the blood does not correlate with autophagy inhibition in either peripheral blood mononuclear cells (PBMCs) or tumor tissue. To better explain this PK/PD disconnect a physiologically-based pharmacokinetic model (PBPK) was developed for HCQ describing the tissue-specific absorption, distribution, metabolism, and excretion as well as lysosome-specific sequestration...
February 8, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29434053/a-model-mechanism-based-explanation-of-an-in-vitro-in-vivo-disconnect-for-improving-extrapolation-and-translation
#8
Andrew K Smith, Yanli Xu, Glen E P Ropella, C Anthony Hunt
An improved understanding of in vivo-to-in vitro hepatocyte changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based in vitro-to-in vivo extrapolations to human targets. We demonstrate using virtual experiments as a means to help untangle plausible causes of inaccurate extrapolations. We start with virtual mice that use biomimetic software livers. Earlier, using those mice, we discovered model mechanisms that enabled achieving quantitative validation targets while also providing plausible causal explanations for temporal characteristics of acetaminophen hepatotoxicity...
February 6, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29434052/in-vitro-and-in-vivo-anti-tumor-and-anti-inflammatory-capabilities-of-the-novel-gsk3-and-ckd9-inhibitor-abc1183
#9
Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines, Charles D Smith
Glycogen synthase kinase-3s (GSK3α and GSK3β) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate vital cellular functions such as proliferation, apoptosis and inflammation. Cyclin-dependent kinase 9 (CDK9) regulates RNA production as a component of positive transcription elongation factor b and promotes expression of oncogenic and inflammatory genes. Simultaneous inhibition of these signaling nodes is a promising approach for drug discovery, although previous compounds exhibit limited selectivity and clinical efficacy...
February 6, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29431616/role-of-the-pregnane-x-receptor-in-binge-ethanol-induced-steatosis-and-hepatotoxicity
#10
Sora Choi, Afua A Gyamfi, Prince Neequaye, Samuel Addo, Frank J Gonzalez, Maxwell A Gyamfi
The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1)...
February 5, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29420256/nicotinamide-phosphoribosyltransferase-deficiency-potentiates-the-anti-proliferative-activity-of-methotrexate-through-enhanced-depletion-of-intracellular-atp
#11
Rakesh K Singh, Leon van Haandel, Daniel P Heruth, Shui Q Ye, J Steven Leeder, Mara L Becker, Ryan S Funk
Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA). Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX, however the mechanism of this interaction has yet to be defined. Therefore, in this study we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells. The siRNA-based silencing of NAMPT expression resulted in a greater than three-fold increase in the sensitivity to MTX (p<0...
February 2, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29420255/development-and-translational-application-of-a-minimal-physiologically-based-pharmacokinetic-mpbpk-model-for-a-monoclonal-antibody-mab-against-interleukin-23-il-23-in-il-23-induced-psoriasis-like-psl-mice
#12
Xi Chen, Xiling Jiang, Rajitha Janssen R D Doddareddy, Brian Geist, Thomas McIntosh, William J Jusko, Honghui Zhou, Weirong Wang
The IL-23/Th17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic PK/PD study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like (PsL) mouse model. A minimal physiologically-based pharmacokinetic (mPBPK) model with target-mediated drug disposition (TMDD) features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 (rmIL-23) in both serum and lesional skin site...
February 2, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29437915/cyp4x1-inhibition-by-flavonoid-ch625-normalizes-glioma-vasculature-through-reprogramming-tams-via-cb2-and-egfr-stat3-axis
#13
Chenlong Wang, Ying Li, Honglei Chen, Keqing Huang, Xiaoxiao Liu, Miao Qiu, Yanzhuo Liu, Yuqing Yang, Jing Yang
Tumor-associated macrophages (TAMs) are pivotal effector cells in angiogenesis. Here, we tested whether CYP4X1 inhibition in TAMs by flavonoid CH625 prolongs survival and normalizes glioma vasculature. CH625 was selected against the CYP4X1 3D model by virtual screening, and showed inhibitory activity on the CYP4X1 catalytic production of 14, 15-EET-EA in the M2-polarized human peripheral blood mononuclear cells (IC50= 16.5 μM). CH625 improved survival and reduced tumor burden in the C6 and GL261 glioma intracranial and subcutaneous model...
February 1, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29367277/targeting-glycine-reuptake-in-alcohol-seeking-and-relapse
#14
Valentina Vengeliene, Martin Rossmanith, Tatiane T Takahashi, Daniela Alberati, Berthold Behl, Anton Bespalov, Rainer Spanagel
It has recently been demonstrated that pharmacological blockade of the glycine transporter 1 (GlyT1) reduced alcohol intake and relapse in rats. The aim of the present study was to further explore the role of GlyT1 in alcohol relapse-like behaviour. For this purpose we used three different GlyT1 blockers - SSR504734, A-1246399 and RO4993850 - and tested their effect on alcohol-seeking and relapse-like consumption. Two behavioural models, the alcohol deprivation effect (ADE) model and the cue-induced reinstatement model, were used...
January 24, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29367276/regulation-of-udp-glucuronosyltransferase-2b15-by-mir-331-5p-in-prostate-cancer-cells-involves-canonical-and-non-canonical-target-sites
#15
Dhilushi Wijayakumara, Peter Ian Mackenzie, Ross A McKinnon, Dong Gui Hu, Robyn Meech
UGT2B15 is an important androgen metabolizing UGT and the mechanisms controlling its expression are of considerable interest. Recent studies showed that miR-376c regulates UGT2B15 in prostate cancer cells via a canonical target site in the 3'untranslated region (3'UTR). The UGT2B15 3'UTR also contains a canonical miR-331-5p target site; previous work indicated that deleting this site reduced, but did not abolish, the ability of miR-331-5p to repress a luciferase reporter carrying the UGT2B15 3'UTR. We report here the discovery and characterization of a second, non-canonical miR-331-5p target site in the UGT2B15 3'UTR...
January 24, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29363579/repeated-morphine-produces-sensitization-to-reward-and-tolerance-to-anti-allodynia-in-male-and-female-rats-with-chemotherapy-induced-neuropathy
#16
Luke P Legakis, S Stevens Negus
Paclitaxel is a cancer chemotherapy drug with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or following chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase risk of opioid abuse. In this study, male and female Sprague Dawley rats were used to test the hypothesis that repeated 3.2 mg/kg morphine would induce tolerance to its antinociceptve effects in a mechanical sensitivity assay and increased expression of its abuse-related rewarding effects in an assay of intracranial self-stimulation (ICSS)...
January 23, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29363578/in-silico-screening-identified-novel-small-molecule-antagonists-of-pac1-receptor
#17
Ichiro Takasaki, Ai Watanabe, Masafumi Yokai, Yurie Watanabe, Daichi Hayakawa, Ryota Nagashima, Mamoru Fukuchi, Takuya Okada, Naoki Toyooka, Atsuro Miyata, Hiroaki Gouda, Takashi Kurihara
Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are present in the spinal dorsal horn and dorsal root ganglia, suggesting an important role of PACAP signaling systems in the modulation of spinal nociceptive transmission. Previously, we found that intrathecal (i.t.) injection of PACAP or maxadilan, a selective PACAP type I (PAC1) receptor agonist, induced transient aversive responses followed by a long-lasting mechanical allodynia in mice, suggesting that PACAP-PAC1 receptor systems are involved in chronic pain and that selective PAC1 antagonists may become a new class of analgesics...
January 23, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29348267/toll-like-receptor-9-dependent-ampk%C3%AE-activation-occurs-via-tak1-and-contributes-to-rhoa-rock-signaling-and-actin-polymerization-in-vascular-smooth-muscle-cells
#18
Cameron G McCarthy, Camilla Ferreira Wenceslau, Safia Ogbi, Theodora Szasz, R Clinton Webb
Traditionally, Toll-like receptor (TLR)9 signals through a MyD88-dependent cascade that results in pro-inflammatory gene transcription. Recently it was reported that TLR9 also participates in a stress tolerance signaling cascade in non-immune cells. In this non-canonical pathway, TLR9 binds to and inhibits sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), modulating intracellular calcium handling, and subsequently resulting in the activation of 5'-AMP-activated protein kinase (AMPK)α. We have previously reported TLR9 causes increased contraction in isolated arteries; however, the mechanisms underlying this vascular dysfunction need to be further clarified...
January 18, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29348266/dopamine-receptor-agonist-treatment-for-idiopathic-dystonia-a-reappraisal-in-humans-and-mice
#19
Xueliang Fan, Yuping Donsante, H A Jinnah, Ellen J Hess
Although dystonia is often associated with abnormal dopamine neurotransmission, dopaminergic drugs are not currently used to treat dystonia because there is a general view that dopaminergic drugs are ineffective. However, there is little conclusive evidence to support or refute this assumption. Therefore, to assess the therapeutic potential of these compounds, we analyzed results from multiple trials of dopamine receptor agonists in patients with idiopathic dystonias and also tested the efficacy of dopamine receptor agonists in a mouse model of generalized dystonia...
January 18, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29339457/curcumin-acts-as-a-positive-allosteric-modulator-of-%C3%AE-7-nicotinic-acetylcholine-receptors-and-reverses-nociception-in-mouse-models-of-inflammatory-pain
#20
Eslam Gaber El Nebrisi, Deniz Bagdas, Wisam Toma, Halima Al Samri, Anna Brodzik, Yasmin Alkhlaif, Keun-Hang Susan Yang, Frank C Howarth, Imad M Damaj, Murat Oz
Effects of curcumin, a major ingredient of turmeric, were tested on the function of α7 subunit of the human nicotinic acetylcholine (α7 nACh) receptor expressed in Xenopus oocytes and on nociception in mouse models of tonic and visceral pain. Curcumin caused a significant potentiation of ACh (100 μM)-induced currents with an EC50 value of 0.2 µM. The effect of curcumin was not dependent on the activation of G-proteins and protein kinases and did not involve Ca2+-dependent Cl- channels expressed endogenously in oocytes...
January 16, 2018: Journal of Pharmacology and Experimental Therapeutics
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