journal
MENU ▼
Read by QxMD icon Read
search

Journal of Pharmacology and Experimental Therapeutics

journal
https://www.readbyqxmd.com/read/28642233/sembragiline-a-novel-selective-monoamine-oxidase-type-b-inhibitor-for-the-treatment-of-alzheimer-s-disease
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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/28592614/the-cannabinoid-cb2-agonist-gw405833-suppresses-inflammatory-and-neuropathic-pain-through-a-cb1-mechanism-that-is-independent-of-cb2-receptors-in-mice
#10
Ai-Ling Li, Lawrence M Carey, Ken Mackie, Andrea G Hohmann
GW405833, widely accepted as a cannabinoid CB2 agonist, suppresses pathological pain in preclinical models without unwanted central side effects of CB1 agonists. However, recent in vitro studies suggest that GW405833 may also behave as a non-competitive CB1 antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacological specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e. partial sciatic nerve ligation (PSNL) model) and inflammatory (i...
June 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28576976/pleiotropic-and-adverse-effects-of-statins-do-epigenetics-play-a-role
#11
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
https://www.readbyqxmd.com/read/28576975/route-of-administration-affects-corticosteroid-sensitivity-of-a-combined-ovalbumin-and-lipopolysaccharide-model-of-asthma-exacerbation-in-guinea-pigs
#12
Alexander P P Lowe, Rhian S Thomas, Anthony T Nials, Emma J Kidd, Kenneth J Broadley, William R Ford
Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare and most patients lie on a continuum of steroid responsiveness. The objective of this study was to examine the sensitivity of combined ovalbumin- (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea-pigs, to test the hypothesis that the route of administration affects its sensitivity...
June 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28576974/lecithin-cholesterol-acyltransferase-activation-by-sulfhydryl-reactive-small-molecules-role-of-cysteine-31
#13
Lita A Freeman, Stephen J Demosky, Monika Konaklieva, Rostislav Kuskovsky, Angel Aponte, Alice F Ossoli, Scott M Gordon, Ross F Koby, Kelly A Manthei, Min Shen, Boris Vaisman, Robert D Shamburek, Ajit Jadhav, Laura Calabresi, Marjan Gucek, John J G Tesmer, Rodney L Levine, Alan T Remaley
BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) catalyzes plasma cholesteryl ester formation and is defective in Familial LCAT Deficiency (FLD), an autosomal recessive disorder characterized by low HDL, anemia and renal disease. OBJECTIVE: To investigate the mechanism by which Compound A, a small heterocyclic amine, activates LCAT. METHODS: Effect of Compound A on LCAT was tested in human plasma and with recombinant LCAT. Mass spectrometry and NMR was used to determine Compound A adduct formation with LCAT...
June 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28559480/in-vitro-and-in-silico-characterization-of-lemborexant-e2006-a-novel-dual-orexin-receptor-antagonist
#14
Carsten Theodor Beuckmann, Michiyuki Suzuki, Takashi Ueno, Kazuya Nagaoka, Tohru Arai, Hiroyuki Higashiyama
Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder, rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant (E2006: (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic for the symptomatic treatment of insomnia disorder, and compare its properties to two other DORAs, almorexant and suvorexant...
May 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28559479/modelling-human-myocardium-exposure-to-doxorubicin-defines-the-risk-of-heart-failure-from-low-dose-doxorubicin
#15
Emanuela Salvatorelli, Pierantonio Menna, Massimo Chello, Elvio Covino, Giorgio Minotti
The antitumor anthracycline, doxorubicin (DOX), can cause heart failure (HF) upon cumulative administration. Lowering the cumulative dose of DOX proved useful to minimize HF risk and yet, there is a growing concern that HF might occur after doses that were thought to be safe. Clinical trials that prospectively address such concerns are lacking. Because HF risk correlates with cardiac exposure to DOX, cumulative doses associated with HF risk were re-explored by modelling the accumulation of anthracycline pools in human myocardium...
May 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28550055/potential-drug-interactions-mediated-by-renal-organic-anion-transporter-oatp4c1
#16
Toshihiro Sato, Eikan Mishima, Nariyasu Mano, Takaaki Abe, Hiroaki Yamaguchi
OATP4C1 is an organic anion transporter expressed in the basolateral membrane of the renal proximal tubules. It plays a major role in the urinary excretion of both exogenous drugs and endogenous compounds. Our previous studies have indicated the importance of OATP4C1 in pathological and physiological conditions; however, the majority of its pharmacological characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we, in this study, attempted to clarify drug interactions mediated by OATP4C1...
May 26, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28533288/apparent-affinity-estimates-and-reversal-of-the-effects-of-synthetic-cannabinoids-am-2201-cp-47-497-jwh-122-and-jwh-250-by-rimonabant-in-rhesus-monkeys
#17
Lenka Hruba, Lance R McMahon
Synthetic cannabinoids have been prohibited due to abuse liability and toxicity. Four such synthetic cannabinoids, AM-2201, CP-47,497, JWH-122, and JWH-250, were tested for their capacity to produce CB1 receptor-mediated discriminative stimulus effects in two groups of rhesus monkeys. One group (n=4) discriminated ∆9-THC (0.1 mg/kg i.v.) and a second group (n=4) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving 1 mg/kg/12 h of ∆9-THC. AM-2201, JWH-122, CP-47,497, JWH-250, and ∆9-THC increased ∆9-THC-lever responding...
May 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28533287/trv0109101-a-g-protein-biased-agonist-of-the-%C3%A2%C2%B5-opioid-receptor-does-not-promote-opioid-induced-mechanical-allodynia-following-chronic-administration
#18
Michael Koblish, Richard Carr, Edward R Siuda, David H Rominger, William Gowen-MacDonald, Conrad L Cowan, Aimee L Crombie, Jonathan D Violin, Michael W Lark
Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients experiencing OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon...
May 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28515158/the-anti-psoriatic-drug-monomethylfumarate-increases-nuclear-factor-erythroid-2-related-factor-2-nrf2-levels-and-induces-aquaporin-3-aqp3-mrna-and-protein-expression
#19
Inas Helwa, Vivek Choudhary, Xunsheng Chen, Ismail Kaddour-Djebbar, Wendy B Bollag
BACKGROUND: Oxidative stress contributes to inflammatory skin diseases including psoriasis. Monomethylfumarate (MMF) is an anti-psoriatic agent with a poorly understood mechanism of action. In other cell types MMF increases the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcription factor that regulates cellular anti-oxidant responses, to reduce oxidative stress like that observed in inflammatory disorders such as multiple sclerosis. OBJECTIVE: We tested the hypothesis that MMF enhances Nrf2 activity in keratinocytes, thereby improving their capacity to counteract environmental stresses...
May 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28515157/carboxyamidotriazole-synergizes-with-sorafenib-to-combat-non-small-cell-lung-cancer-through-inhibition-of-nanog-and-aggravation-of-apoptosis
#20
Chen Chen, Rui Ju, Jing Shi, Wei Chen, Fangrui Sun, Lei Zhu, Juan Li, Dechang Zhang, Caiying Ye, Lei Guo
Lung cancer is the leading cause of cancer-related deaths in the world. In this study, we investigated the combination of carboxyamidotriazole (CAI) and sorafenib in NSCLC in vitro and in vivo, to test whether CAI enhances the antitumor effects of sorafenib and reduces its side effects. The combination index (CI) showed that co-administration of CAI and sorafenib synergistically inhibited the proliferation of NSCLC cells (Lewis lung carcinoma, A549, NCI-H1975). The cell death led by the treatment of combination drugs was attributed to apoptosis which was accompanied with activation of caspase 3 and poly ADP-ribose polymerase...
May 17, 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"