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Journal of Pharmacology and Experimental Therapeutics

Nikolaos Tsamandouras, Tomasz Kostrzewski, Cynthia L Stokes, Linda G Griffith, David J Hughes, Murat Cirit
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from 5 different donors cultured in a perfused 3D human liver microphysiological system and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of 6 compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability (LDH release, albumin and urea production)...
October 19, 2016: Journal of Pharmacology and Experimental Therapeutics
Dan Li, Jie Hong, Weibiao Cao
We have shown that NOX5-S may mediate the acid-induced decrease in cell apoptosis. However, mechanisms of NOX5-S-dependent decrease in cell apoptosis are not fully understood. In this study we found that silencer of death domain (SODD) was significantly increased in esophageal adenocarcinoma (EA) tissues, EA cell lines FLO and OE33, and a dysplastic cell line CP-B. Strong SODD immunostaining was significantly higher in low-grade dysplasia (66.7%), high-grade dysplasia (81.2%) and EA (71.2%) than in Barrett's mucosa (10...
October 18, 2016: Journal of Pharmacology and Experimental Therapeutics
Gretchen Bain, Kristen E Shannon, Fei Huang, Janice Darlington, Lance Goulet, Patricia Prodanovich, Gina L Ma, Angelina M Santini, Adam J Stein, Dave Lonergan, Christopher D King, Imelda Calderon, Andiliy Lai, John H Hutchinson, Jilly F Evans
Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound anti-fibrotic effects in multiple organ systems including the lung, kidney, skin and peritoneum. However, other LPA-generating pathways exist and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacological, pharmacokinetic and pharmacodynamic properties of a novel small-molecule ATX inhibitor [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt] (PAT-505)...
October 17, 2016: Journal of Pharmacology and Experimental Therapeutics
Samina Salim
Biochemical integrity of the brain is vital for normal functioning of the central nervous system (CNS). One of the contributing factors of cerebral biochemical impairment is a chemical process called oxidative stress. Oxidative stress occurs upon excessive free radical production due to insufficiency of counteracting antioxidant response system. The brain with its high oxygen consumption and lipid-rich content is highly susceptible to oxidative stress. Therefore, oxidative stress-induced damage to the brain has a strong potential to negatively impact normal CNS functions...
October 17, 2016: Journal of Pharmacology and Experimental Therapeutics
Haruka Yokota, Ayaka Tsuzuki, Yuki Shimada, Azusa Imai, Daichi Utsumi, Takuya Tsukahara, Misaki Matsumoto, Kikuko Amagase, Kazumi Iwata, Akio Nakamura, Chihiro Yabe-Nishimura, Shinichi Kato
NOX1/NADPH oxidase, a non-phagocytic isoform of reactive oxygen species-producing enzymes, is highly expressed in the colon, but the physiological and pathophysiological roles of this isoform are not fully understood. The present study investigated the role of NOX1 in the development of colonic inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. Intrarectal injection of TNBS caused severe colitis accompanied by body weight loss, diarrhea, and increased MPO activity in wild-type (WT) mice...
October 17, 2016: Journal of Pharmacology and Experimental Therapeutics
Zoltan Patai, Andras Guttman, Endre G Mikus
Drotaverine is considered to evoke a spasmolytic effect through the inhibition of cyclic-3',5'-nucleotide-phophodiesterase (PDE) enzymes. However, published receptor binding data supports the potential L-type Voltage Operated Calcium Channel (L-VOCC) blocking effect of drotaverine as well. Hence, in this work we are focusing on the potential L-VOCC blocking effect of drotaverine using L-VOCC associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction...
October 13, 2016: Journal of Pharmacology and Experimental Therapeutics
Martin J Bobak, Matthew W Weber, Melissa A Doellman, Douglas R Schuweiler, Jeana M Athens, Steven A Juliano, Paul A Garris
Modafinil (MOD) exhibits therapeutic efficacy for treating sleep and psychiatric disorders, but its mechanism is incompletely understood. Compared to other psychostimulants inhibiting dopamine (DA) uptake, MOD weakly interacts with the dopamine transporter (DAT) and modestly elevates striatal dialysate DA, suggesting additional targets besides DAT. However, the ability of MOD to induce wakefulness is abolished with DAT knockout, conversely suggesting that DAT is necessary for MOD action. Another psychostimulant target, but one not established for MOD, is activation of phasic DA signaling...
October 12, 2016: Journal of Pharmacology and Experimental Therapeutics
Xuewen Jiang, Thomas W Fuller, Jathin Bandari, Utsav Bansal, Zhaocun Zhang, Bing Shen, Jicheng Wang, James R Roppolo, William C de Groat, Changfeng Tai
In α-chloralose anesthetized cats, we examined the role GABAA, glycine, and opioid receptors in sacral neuromodulation-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.5% acetic acid (AA). AA irritation significantly (p<0.01) reduced bladder capacity to 59.5±4.8% of saline control. S1 or S2 dorsal root stimulation at threshold intensity for inducing reflex twitching of the anal sphincter or toe significantly (p<0.01) increased bladder capacity to 105.3±9.0% and 134...
October 11, 2016: Journal of Pharmacology and Experimental Therapeutics
Therese S Salameh, Gul N Shah, Tulin O Price, Melvin R Hayden, William A Banks
All forms of diabetes mellitus are characterized by chronic hyperglycemia resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature, leading to dysfunctions and ultimately disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. In diabetes, BBB damage is associated with increased oxidative stress and reactive oxygen species (ROS). This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia...
October 11, 2016: Journal of Pharmacology and Experimental Therapeutics
Jia Yin, Haichuan Duan, Joanne Wang
Renal transporter-mediated drug-drug interactions (DDIs) are of significant clinical concerns as they can adversely impact drug disposition, efficacy and toxicity. Emerging evidence suggests that human renal organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) exhibit substrate-dependent inhibition but the impact on renal drug secretion and intracellular accumulation is unknown. Using metformin and atenolol as the probe substrates, we found that the classic inhibitors (e...
October 6, 2016: Journal of Pharmacology and Experimental Therapeutics
Edwin K Jackson, Delbert G Gillespie, Zaichuan Mi
In vivo, guanine moieties in DNA, RNA, guanine nucleotides, guanosine or guanine can undergo nitration (for example by peroxynitrite) or hydroxylation (for example by superoxide anion) on position 8 of the purine ring. Subsequent catabolism of these modified biomolecules leads to the production of a diverse group of 8-nitro, 8-amino and 8-hydroxy guanosine and guanine compounds. Indeed, studies suggest the in vivo existence of 8-nitroguanosine, 8-nitroguanine, 8-aminoguanosine, 8-aminoguanine, 8-hydroxyguanosine, 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanine...
September 27, 2016: Journal of Pharmacology and Experimental Therapeutics
Li-Li Gong, Guang-Run Li, Wen Zhang, He Liu, Ya-Li Lv, Fei-Fei Han, Zi-Rui Wan, Ming-Biao Shi, Li-Hong Liu
Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing. However, there is a lack of appropriate drugs for the therapy of NAFLD. In the present article, we aimed to elucidate the protective effects and mechanisms of Akebia saponin D (ASD) against NAFLD on ob/ob mice and BRL cells. ASD significantly decreased hepatic steatosis and heptocyte apoptosis in ob/ob mice. Furthermore, ASD significantly activated the autophagic flux assessed by decreased the expression of LC3-II, p62 accumulation of autophagosomes...
September 26, 2016: Journal of Pharmacology and Experimental Therapeutics
Laura C Sullivan, Teresa A Chavera, Raehannah J Jamshidi, Kelly A Berg, William P Clarke
Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions, however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a non-responsive state to a functionally competent state. Here we tested the hypothesis that the basal, non-responsive state of the mu and delta opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized...
September 22, 2016: Journal of Pharmacology and Experimental Therapeutics
Lisa R Gerak, Gregory T Collins, Charles P France
Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin2C (5-HT2C) receptor agonist lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32-320 μg/kg/infusion)...
September 20, 2016: Journal of Pharmacology and Experimental Therapeutics
Naama Levy-Cooperman, Gail McIntyre, Laura Bonifacio, Michael McDonnell, J Michael Davenport, Paul S Covington, Leonard S Dove, Edward M Sellers
Drugs with μ-opioid receptor (OR) activity can be associated with abuse and misuse. The peripherally acting mixed μ-OR and κ-OR agonist and δ-OR antagonist, eluxadoline, is approved in the US for the treatment of irritable bowel syndrome with diarrhea. In two separate crossover studies, we evaluated the oral and intranasal abuse potential of eluxadoline versus placebo and the active control oxycodone. Healthy recreational opioid users received eluxadoline 100, 300, and 1000 mg, oxycodone 30 and 60 mg, and placebo (oral study), or eluxadoline 100 and 200 mg, oxycodone 15 and 30 mg, and placebos matched to eluxadoline and oxycodone (intranasal study)...
September 19, 2016: Journal of Pharmacology and Experimental Therapeutics
Giulia Donvito, Jenny L Wilkerson, M Imad Damaj, Aron H Lichtman
Chemotherapy-induced peripheral neuropathy (CIPN) represents a serious complication associated with anticancer drugs. Although there are no medications available that effectively prevent CIPN, many classes of drugs have been used to treat this condition, including anticonvulsants, serotonin and noradrenaline reuptake inhibitors, and opioids. However, these theraputic options yielded inconclusive results in CIPN clincal trials and produce assorted side effects with their prolonged use. Thus, there is an urgent need to develop efficacious and safe treatments for CIPN...
September 8, 2016: Journal of Pharmacology and Experimental Therapeutics
Raehanna J Jamshidi, Laura C Sullivan, Blaine A Jacobs, Teresa A Chavera, Kelly A Berg, William P Clarke
A single administration of the kappa opioid receptor (KOR) antagonist, norbinaltorphimine (norBNI), produces long-term reduction in KOR function in heterologous expression systems and brain that is mediated by activation of c-Jun N-terminal Kinase (JNK). In this study, we examined the long-term effects of norBNI on adult rat peripheral sensory neurons in vivo and ex vivo. Following a single intraplantar ( injection of norBNI into the hindpaw, peripheral KOR-mediated antinociception in the ipsilateral, but not the contralateral, hindpaw was abolished for at least 9 days...
September 7, 2016: Journal of Pharmacology and Experimental Therapeutics
Maria Concetta Olianas, Simona Dedoni, Pier Luigi Onali
Antidepressants have been shown to affect glial cell functions and intracellular signalling through mechanisms still not completely understood. In the present study, we provide evidence that in glial cells the lysophosphatidic acid (LPA) receptor LPA1 mediates antidepressant-induced growth factor receptor transactivation, ERK1/2 signalling, and protection from oxidative stress. Thus, in C6 glioma cells and rat cortical astrocytes ERK1/2 activation induced by either amitriptyline or mianserin was antagonized by Ki16425 and VPC 12249 (S), which block LPA1 and LPA3 receptors, and by AM966, which selectively blocks LPA1 Cell depletion of LPA1 with siRNA treatment markedly reduced antidepressant- and LPA-induced ERK1/2 phosphorylation...
September 7, 2016: Journal of Pharmacology and Experimental Therapeutics
Travis W Grim, Anthony J Morales, Maciej M Gonek, Jenny L Wiley, Brian F Thomas, Gregory W Endres, Laura J Sim-Selley, Dana E Selley, Sidney S Negus, Aron H Lichtman
Synthetic cannabinoids (SCs) represent an emerging new class of abused drugs that widely differ from each other and from the phytocannabinoid Δ9-tetrahydrocannabinol (THC) in cannabinoid-1 receptor (CB1R) selectivity, potency, and efficacy. As these pharmacological parameters offer critical information to understand drug action, the present study investigated in vivo CB1R efficacy and selectivity of THC, two well-characterized SCs (WIN55,212-2 and CP55,940), and three abused SCs possessing largely unknown pharmacology (JWH-073, CP47,497, and A-834,735-D) in CB1 (+/+), (+/-), and (-/-) mice...
August 17, 2016: Journal of Pharmacology and Experimental Therapeutics
Kwok H C Choy, David M Shackleford, Daniel T Malone, Shailesh N Mistry, Rahul T Patil, Peter J Scammells, Christopher J Langmead, Christos Pantelis, Patrick M Sexton, Johnathan R Lane, Arthur Christopoulos
Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M1 muscarinic acetylcholine receptor (mAChR) may provide a novel means of improving cognition. However, very little is known about the potential of combination therapies in extending coverage across schizophrenic symptom domains. This study investigated the effect of the M1 mAChR positive allosteric modulator BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], alone or in combination with haloperidol (a first-generation antipsychotic), clozapine (a second-generation atypical antipsychotic), or aripiprazole (a third-generation atypical antipsychotic), in reversing deficits in sensorimotor gating and spatial memory induced by the N-methyl-d-aspartate receptor antagonist, MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]...
November 2016: Journal of Pharmacology and Experimental Therapeutics
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