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Journal of Pharmacology and Experimental Therapeutics

Shelby Barnett, Kayode Ogungbenro, Karelle Menochet, Hong Shen, Griffith W Humphreys, Aleksandra Galetin
Endogenous biomarkers can be clinically relevant tools for the assessment of transporter function in vivo and corresponding drug-drug interactions (DDIs). The aim of this study was to perform systematic evaluation of plasma data obtained for 20 endogenous molecules in the same healthy subjects (n=8-12) in the absence and presence of OATP inhibitor rifampicin (600mg s.d.). The extent of rifampicin DDI magnitude (AUCR), estimated fraction transported (fT) and baseline variability were compared across the biomarkers and relative to rosuvastatin and coproporphyrin I (CPI)...
October 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Jason R Clapper, Cassandra L Henry, Micah J Niphakis, Anna M Knize, Aundrea R Coppola, Gabriel M Simon, Nhi Ngo, Rachel A Herbst, Dylan M Herbst, Alex W Reed, Justin S Cisar, Olivia D Weber, Andreu Viader, Jessica P Alexander, Mark L Cunningham, Todd K Jones, Iain P Fraser, Cheryl A Grice, R Alan B Ezekowitz, Gary P O'Neill, Jacqueline L Blankman
Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurological disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 (1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate). We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations and efficacy...
October 10, 2018: Journal of Pharmacology and Experimental Therapeutics
Wen-Liang Song, Emanuela Ricciotti, Xue Liang, Tilo Grosser, Gregory R Grant, Garret A FitzGerald
Prostaglandin (PG) D2 is formed by two distinct prostaglandin D synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2 producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a sigma glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of LPGDS and HPGDS dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDSs, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds KO mice...
October 10, 2018: Journal of Pharmacology and Experimental Therapeutics
Babak Baban, Cristina Marchetti, Hesam Khodadadi, Aneeq Maliq, Golnaz Emami, Ping-Chang Lin, Ali S Arbab, Carlo Riccardi, Mahmood S Mozaffari
The glucocorticoid-induced leucine zipper (GILZ) mediates anti-inflammatory effects of glucocorticoids. Acute kidney injury (AKI) mobilizes immune/inflammatory mechanisms, causing tissue injury, but GILZ's impact in AKI is not known. Neutrophils play context-specific pro- (N1) and anti-inflammatory (N2) functional roles. Also, regulatory T lymphocytes (Tregs) and regulatory T-17 (Treg17) cells exert counter-inflammatory effects including suppression of effector T lymphocytes, e.g., Th-17 cells. Thus, utilizing cell preparations of mice kidneys subjected to AKI or sham operation, we determined the effects of GILZ on T cells and neutrophil subtypes in the context of its renoprotective effect; these studies utilized the trans activator of transcription (TAT)-GILZ or the TAT peptide...
October 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Maria Santos-Galdiano, Diego Perez-Rodriguez, Berta Anuncibay-Soto, Enrique Font-Belmonte, Irene F Ugidos, Carlos Cesar Perez-Garcia, Arsenio Fernandez-Lopez
BACKGROUND: Areas of selective neuronal loss (SNL) represent the first morphological signs of damage in the penumbra region and are considered putative targets for ischemic stroke therapy. Here we performed a novel assessment of measuring the effects of the anti-inflammatory agent, celecoxib, analyzing simultaneously the different neural populations (neurons, astrocytes and microglia cells) in SNL and non-SNL areas. METHODS: Rats were subjected to 1 hour of middle cerebral artery occlusion (MCAO) and treated with celecoxib 1 h and 24 h after ischemia...
October 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Fabrizio Gardoni, Michele Morari, James Kulisevsky, Andrea Brugnoli, Salvatore Novello, Clarissa A Pisano, Carla Caccia, Manuela Mellone, Elsa Melloni, Gloria Padoani, Victoria Sosti, Silvia Vailati, Charlotte Keywood
Safinamide (Xadago®) is a novel dual mechanism drug which has been approved in the EU and US as add-on treatment to levodopa in Parkinson's disease (PD) therapy. In addition to its selective and reversible monoamine oxidase B (MAO-B) inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA) lesioned rats, evaluating behavioural, molecular and neurochemical parameters associated with LID appearance...
October 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Wei Ling Lau, Nosratola D Vaziri, Ane Cf Nunes, Andre M Comeau, Morgan Gi Langille, Whitney England, Mahyar Khazaeli, Yasunori Suematsu, Joann Phan, Katrine Whiteson
In chronic kidney disease (CKD), the gut microbiome is altered and bacterial-derived uremic toxins promote systemic inflammation and cardiovascular disease. Ferric citrate complex is a dietary phosphate binder prescribed in end-stage kidney disease patients to treat hyperphosphatemia and secondary hyperparathyroidism. Iron is an essential nutrient in both microbes and mammals. The present study was undertaken to test the hypothesis that the large iron load administered with ferric citrate in CKD may significantly change the gut microbiome...
October 4, 2018: Journal of Pharmacology and Experimental Therapeutics
Eleonora Zorzan, Silvia Da Ros, Mery Giantin, Lara Zorro Shahidian, Giorgia Guerra, Manlio Palumbo, Claudia Sissi, Mauro Dacasto
G-quadruplexes (G4) are nucleic acid secondary structures frequently assumed by G-rich sequences located mostly at telomeres and proto-oncogenes promoters. Recently, we identified, in canine KIT promoter, two G-rich sequences able to fold into G4: d_kit1 and d_kit2_A16. In this study, an anthraquinone (AQ1) and an anthracene derivative (AN6), known to stabilize the G4 structures of the corresponding human h_kit1 and h_kit2, were tested on the canine G4 and in two canine mast cell tumor (MCT) cell lines (C2 and NI-1) to verify their capability to downregulate KIT expression...
October 1, 2018: Journal of Pharmacology and Experimental Therapeutics
Richard A Slivicki, Shahin Saberi, Vishakh Iyer, Kiran Vemuri, Alexandros Makriyannis, Andrea G Hohmann
Opioid-based therapies remain a mainstay for chronic pain management, but unwanted side-effects limit therapeutic use. We compared efficacies of brain permeant and impermeant inhibitors of fatty-acid amide hydrolase (FAAH) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Paclitaxel produced mechanical and cold allodynia without altering nestlet shredding or marble burying behaviors. We compared FAAH inhibitors that differ in their ability to penetrate the central nervous system for anti-allodynic efficacy, pharmacological specificity and synergism with the opioid analgesic morphine...
October 1, 2018: Journal of Pharmacology and Experimental Therapeutics
Pierantonio Menna, Emanuela Salvatorelli, Grazia Armento, Ombretta Annibali, Carlo Greco, Francesco Marchesi, Vito Calabrese, Giorgio Reggiardo, Giorgio Minotti
We reported that cancer patients treated by anthracycline-based or nonanthracycline chemotherapy developed an early impairment of myocardial relaxation at echocardiography or persistent elevations of the cardiac hormone, B-type natriuretic peptide (BNP). Post hoc pharmacologic analyses showed that BNP elevations were induced by impaired relaxation and caused positive lusitropic effects that maintained a normal relaxation. High BNP and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction but high BNP caused positive chronotropism and inappropriate tachycardia...
October 1, 2018: Journal of Pharmacology and Experimental Therapeutics
Jeremy Carlier, Ariane Wohlfarth, Bonita D Salmeron, Karl B Scheidweiler, Marilyn A Huestis, Michael H Baumann
Novel synthetic cannabinoids are appearing in recreational drug markets worldwide. Pharmacological characterization of these new drugs is needed to inform clinicians, toxicologists and policy makers who monitor public health. 1-[(5-Fluoropentyl)-1H-indol-3-yl]-(naphthalen-1-yl)methanone (AM-2201) is an abused synthetic cannabinoid that was initially created as a research tool for investigating the endocannabinoid system. Here we measured pharmacodynamic effects of AM-2201 in rats, and simultaneously determined plasma pharmacokinetics for the parent drug and its metabolites...
September 28, 2018: Journal of Pharmacology and Experimental Therapeutics
Saadet Inan, Toby K Eisenstein, Mia N Watson, Menahem Doura, Joseph J Meissler, Christopher S Tallarida, Xiaohong Chen, Ellen B Geller, Scott M Rawls, Alan Cowan, Martin W Adler
Cross-desensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if co-administration of chemokine receptor antagonists (CRAs) with morphine would enhance the analgesic potency of morphine on incisional pain in rats. Animals underwent incisional surgery on the left hind paw and pain responses were evaluated using von Frey filaments at various time points post-surgery between 15 and 360 minutes and daily between 24 and 72 hours...
September 24, 2018: Journal of Pharmacology and Experimental Therapeutics
Na Gao, Jing Li, Ming-Rui Li, Bing Qi, Zhao Wang, Gao-Ju Wang, Jie Gao, Hai-Ling Qiao
Hepatofibrosis can progress to cirrhosis and hepatocellular carcinoma (HCC). Prevention, stabilization and reversal disease progression is vital for patients with hepatofibrosis, and identifying risk factors for hepatofibrosis is urgently needed. This study examines the activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in the fibrotic livers from HCC patients (n=88) with comparison to the activities found in patients with normal livers (n=74). A fibrosis-carcinoma rat model was used to study activity of ADH in fibrosis and HCC, and relationship between innate ADH activity and extent of hepatofibrosis or HCC...
September 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Philippe B Pierrillas, Emilie Henin, Julien Ogier, Laurence Kraus-Berthier, Marylore Chenel, Francois Bouzom, Michel Tod
The Bcl-2 inhibitor, S 55746, is able to restore apoptosis functions impaired by tumorigenesis in mice. Data from pharmacokinetic (PK), biomarker, and tumor growth studies in a xenograft mouse model were considered for population modeling. The aim of the modeling exercise was to link the kinetics of the drug to the biomarker and tumor size time profiles to better understand its dose-effect relationship. The PK, caspase kinetics, and tumor dynamics were successfully characterized by the proposed pharmacokinetic-pharmacodynamic model...
September 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Sanjeev Khindri, Anthony Cahn, Malcolm Begg, Mickael Montembault, Claudia Leemereise, Yi Cui, Annabel Hogg, Hannah Wajdner, Shuying Yang, Jon Roberston, J Nicole Hamblin, Andrea Ludwig-Sengpiel, Oliver Kornmann, Edith Hessel
Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3Kδ has been linked to airway inflammation and asthma pathogenesis. This randomised, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability and pharmacokinetics of a PI3Kδ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n=50) received once-daily inhaled nemiralisib (1000 µg) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period...
September 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Koji Matsumoto, Tomomi Yoshitomi, Yoko Ishimoto, Naomi Tanaka, Kanako Takahashi, Akiko Watanabe, Katsuyoshi Chiba
G protein-coupled receptor 119 (GPR119) has been shown to be highly expressed in small intestinal L-cells and pancreatic β-cells and mediates intracellular cyclic adenosine monophosphate (cAMP) concentration, glucagon like peptide (GLP-1) secretion, and glucose-stimulated insulin secretion (GSIS). This study examined the pharmacological effects of 4-(5-{(1R)-1-[4-(Cyclopropylcarbonyl) phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(2R)-1-hydroxypropan-2-yl]benzamide (DS-8500a), a novel, orally available, selective GPR119 agonist...
September 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Samantha K Saland, Mohamed Kabbaj
Recent work from our group and others has revealed a higher sensitivity of female rodents to the antidepressant-like effects of N-methyl d-aspartate receptor (NMDAR) antagonist, ketamine, strongly influenced by circulating estrogen (E2) and progesterone (P4) levels. However, in the absence of any preclinical studies of pharmacokinetic sex differences using low-dose ketamine in rats, it is unclear whether the effects of sex and hormonal milieu on ketamine's behavioral actions are influenced by differences in ketamine metabolism between male and female rats...
September 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Mami Nakamura, Kaori Shintani-Ishida, Hiroshi Ikegaya
Recreational drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, induce hyperthermia, which is affected by ambient temperature. 2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe), a selective agonist of 5-HT2A receptor used as a recreational drug, reportedly induces hyperthermia. This study aimed to verify whether 25B-NBOMe induces ambient temperature-dependent hyperthermia and to clarify its mechanism. Eight-week-old male Sprague-Dawley rats were administered intraperitoneal injection of 25B-NBOMe at an ambient temperature of 23°C or 29°C...
September 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Yu-Hsin Hsieh, Hui-Chun Huang, Ching-Chih Chang, Chiao-Lin Chuang, Fa-Yauh Lee, Shao-Jung Hsu, Yi-Hsiang Huang, Ming-Chih Hou, Shou-Dong Lee
Chronic hepatitis is the major cause of liver cirrhosis and portal hypertension. Several factors affect portal pressure, including liver fibrosis, splanchnic vasodilatation and pathological angiogenesis. Nucleos(t)ide analogs (NUCs), the oral antiviral agents, effectively attenuate chronic hepatitis B-related liver cirrhosis and portal hypertension via viral suppression and alleviation of hepatitis. On the other hand, NUCs affect TNF-α, vascular endothelial growth factor (VEGF) and nitric oxide, which participate in fibrogenesis, vasodilatation and angiogenesis...
September 7, 2018: Journal of Pharmacology and Experimental Therapeutics
Jason A Justice, Daniel T Manjooran, Chung-Yang Yeh, Karen A Hartnett-Scott, Anthony J Schulien, Gabrielle J Kosobucki, Shalom Mammen, Michael J Palladino, Elias Aizenman
We present the design of an innovative molecular neuroprotective strategy, and provide proof-of-concept for its implementation, relying on the injury-mediated activation of an ectopic gene construct. As oxidative injury leads to the intracellular liberation of zinc, we hypothesize that tapping onto the zinc-activated metal regulatory element ( MRE ) transcription factor 1 (MTF-1) system to drive expression of the Kv2.1-targeted hepatitis C protein NS5A, will provide neuroprotection by preventing cell death-enabling cellular potassium loss in rat cortical neurons in vitro...
September 6, 2018: Journal of Pharmacology and Experimental Therapeutics
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