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Journal of Pharmacology and Experimental Therapeutics

Yunshan Zhang, Mei Wang, Qiuhua Lu, Qi Li, Mingyan Lin, Jianzhong Huang, Yanguo Hong
Glial activation plays a pivotal role in morphine tolerance. This study investigated effect of Mas-related gene (Mrg) C receptor on morphine-induced activation of microglia and astrocytes in the spinal cord and its underlying mechanisms. Intrathecal (i.t.) administration of morphine (20 µg, daily) for 6 days induced a great decline of morphine antinociception and increased expression of GFAP and OX-42 in the spinal dorsal horn. These changes were greatly attenuated by the intermittent co-injection of bovine adrenal medulla 8-22 (BAM8-22, 1 nmol), a specific agonist of MrgC receptor...
November 28, 2018: Journal of Pharmacology and Experimental Therapeutics
Cecilia Karlsson, Peter J Greasley, David Gustafsson, Karin Wahlander
Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase which later on in clinical development would demonstrate efficacy. A cross-functional team at AstraZeneca with extensive experience of drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation (HTV; the relevance of the target from a human perspective)...
November 27, 2018: Journal of Pharmacology and Experimental Therapeutics
Lisa R Gerak, David R Maguire, James H Woods, Stephen M Husbands, Alex Disney, Charles P France
One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory-depressant effects (minute volume [VE]) of heroin in 5 monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared to those of naltrexone (0...
November 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Afshin T Ebrahimpour, Samana Shrestha, Mark D Bonnen, N Tony T Eissa, Ganesh Raghu, Yohannes T Ghebre
Idiopathic pulmonary fibrosis (IPF) is a fatal disease that destroys the structure and function of the lungs. Risk factors include advanced age and genetic predisposition. However, tobacco use is the chief modifiable risk factor. The prevalence of tobacco use in IPF reaches up to 80%. Although tobacco smoke contains over 5,000 chemicals, nicotine is a major component. Nicotine is a bioactive molecule that acts upon nicotinic acetylcholine receptors expressed on neuronal and non-neuronal cells including endothelial cells...
November 16, 2018: Journal of Pharmacology and Experimental Therapeutics
Anna Kothencz, Judit Hajagos-Toth, Kalman F Szucs, Annamaria Schaffer, Robert Gaspar
Vitamin E and their analogues as antioxidant and lipid soluble compounds can have diverse effects on the physiological processes. By binding to receptors and enzymes, they may modify the action of drugs. It has been proved that alpha-tocopherol succinate modifies the effects of β2 agonist terbutaline and cyclooxygenase (COX) inhibitors on rat trachea and myometrium. Our aim was to investigate how alpha-tocopherol and COX inhibitors may influence cervical resistance in rats. The cervical resistance of non-pregnant and 22-day-pregnant Sprague-Dawley rats was determined in an isolated organ bath in vitro...
November 15, 2018: Journal of Pharmacology and Experimental Therapeutics
Albert Dahan, Anne Olesen, Suzanne Broens, Soren Olesen, Monique van Velzen, Asbjorn Drewes, Marieke Niesters, Erik Olofsen
It is not straightforward to simultaneously evaluate benefits and harms of pain management, as different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here we construct "pragmatic" utility functions based on measurements of benefit and harms, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics...
November 15, 2018: Journal of Pharmacology and Experimental Therapeutics
Raziye Mohammadpour, Mostafa Yazdimamaghani, Christopher Reilly, Hamid Ghandehari
Fundamental to the design and development of nanoparticles for applications in nanomedicine is a detailed understanding of their biological fate and potential toxic effects. Transient receptor potential (TRP) ion channels are a large superfamily of cation channels with varied physiological functions. This superfamily is classified into six related subfamilies; TRPC (canonical), V (vanilloid), M (melastatin), A (ankyrin), P (polycystin) and ML (mucolipin). TRPA1, M2 and M8 are nonselective Ca2+-permeable cation channels which regulate calcium pathways under oxidative stress...
November 15, 2018: Journal of Pharmacology and Experimental Therapeutics
Cathryn D Wilson, Sherrica Tai, Laura Ewing, Jasmine Crane, Taylor Lockhart, Azure L Yarbrough, Ryoichi Fujiwara, Anna Radominska-Pandya, William E Fantegrossi
Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of partial CB1R agonist ∆9-tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classical chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively and more potently than PTZ. SCB-elicited convulsions were attenuated by the CB1R antagonist rimonabant or by THC, or by dose regimens of THC and JWH-018 which downregulate and desensitize CB1Rs...
November 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Takeo Nakanishi, Hiroki Takashima, Yuka Uetoko, Hisakazu Komori, Ikumi Tamai
Prostaglandin transporter Oatp2a1/ Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in PGE2 handling by alveolar epithelium, we studied PGE2 transport across and secretion from monolayers of rat AT1-like (AT1-L) cells obtained by trans-differentiation of type-2 alveolar epithelial cells (AT2) isolated from male Wistar rats. Rat AT1-L cells expressed Oatp2a1/ Slco2a1 , together with smaller amounts of Mrp4/ Abcc4 and Oct1/ Slc22a1 PGE2 uptake was saturable with Km 43...
November 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Takanobu Matsuzaki, Daniel Scotcher, Adam Darwich, Aleksandra Galetin, Amin Rostami-Hodjegan
In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically-based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule. However, the ability of these models to quantitatively capture the impact of perturbed conditions (e.g., urine flow/ urine pH changes) on CLR has not been fully evaluated. The current work aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples)...
November 9, 2018: Journal of Pharmacology and Experimental Therapeutics
John Russell, Ehsan Mohammadi, Casey O Ligon, Anthony C Johnson, Michael D Gershon, Meenakshi Rao, Yuhong Shen, Chi-Chung Chan, Hilary S Eidam, Michael P DeMartino, Mui Cheung, Allen I Oliff, Sanjay Kumar, Beverley Greenwood-Van Meerveld
Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal (GI) inflammation or psychological stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor (GDNF), rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae...
November 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Aaron M Teitelbaum, Matthew G McDonald, John P Kowalski, Oliver T Parkinson, Michele Scian, Dale Whittington, Katharina Roellecke, Helmut Hanenberg, Constanze Wiek, Allan E Rettie
A potential CYP4B1 suicide gene application in engineered T-cell treatment of blood cancers has revived interest in the use of 4-Ipomeanol (IPO) in gene-directed enzyme prodrug therapy, where disposition of the administered compound may be critical. IPO contains one chiral center at the carbon bearing a secondary alcohol group; it was of interest to determine the effect of stereochemistry on (i) CYP4B1-mediated bioactivation and (ii) UGT-mediated glucuronidation. (R)-IPO and (S)-IPO were synthesized and utilized, firstly, to assess cytotoxicity in HepG2 cells expressing rabbit CYP4B1 and re-engineered human CYP4B1, where the enantiomers were found to be equipotent...
November 8, 2018: Journal of Pharmacology and Experimental Therapeutics
Michael D Raleigh, Federico Baruffaldi, Samantha J Peterson, Morgan Le Naour, Theresa M Harmon, Jennifer R Vigliaturo, Paul R Pentel, Marco Pravetoni
Fentanyl is an extremely potent synthetic opioid that has been increasingly used to adulterate heroin, cocaine and counterfeit prescription pills leading to an increase in opioid-induced fatal overdoses in the US, Canada, and Europe. A vaccine targeting fentanyl could offer protection against fatal overdoses in both recreational drug users and others in professions at risk of accidental exposure. This study focuses on the development of a vaccine consisting of a fentanyl hapten (F) conjugated to keyhole limpet hemocyanin (KLH) carrier protein or to GMP-grade subunit KLH (sKLH)...
November 8, 2018: Journal of Pharmacology and Experimental Therapeutics
Hao Zhang, Toshihide Kashihara, Tsutomu Nakada, Satoshi Tanaka, Kumiko Ishida, Satoshi Fuseya, Hiroyuki Kawagishi, Kenkichi Kiyosawa, Mikito Kawamata, Mitsuhiko Yamada
An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. After 10 days of the surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side...
November 8, 2018: Journal of Pharmacology and Experimental Therapeutics
David R Maguire, Lisa R Gerak, James H Woods, Stephen M Husbands, Alex Disney, Charles P France
Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu opioid receptor antagonist (methocinnamox; MCAM) as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n=5) or cocaine (n=4) under a fixed-ratio schedule...
November 6, 2018: Journal of Pharmacology and Experimental Therapeutics
Jacopo Lucchetti, Claudia Fracasso, Claudia Balducci, Alice Passoni, Gianluigi Forloni, Mario Salmona, Marco Gobbi
Repurposing doxycycline for the treatment of amyloidosis has recently been put forward based on the anti-aggregating and anti-inflammatory properties of this drug. Most of the investigations on the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g. prion and Alzheimer disease (AD), are carried out in mouse models but, surprisingly, no data are available as regards the concentrations reached in the brain after systemic administration. We filled this gap by analysing the pharmacokinetic profile of doxycycline in plasma and brain after single and repeated intraperitoneal injections of 10 and 100 mg/kg, in wild-type mice and the APP23 mouse model of the AD...
November 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Yoo-Kyung Song, Ji Eun Park, Yunseok Oh, Sungwoo Hyung, Yoo-Seong Jeong, Min-Soo Kim, Wooin Lee, Suk-Jae Chung
Endogenous cABCB1 is expressed abundantly in MDCKII cells, and its presence often complicates the phenotyping of the transport process. Errors in estimating cER, as the result of the variable expression of cABCB1, were examined for the dual substrates of ABCB1 and ABCG2 in MDCKII cells expressing hABCG2. The mRNA and protein expression of cABCB1 was 60% and 55% lower, respectively, in MDCKII cells expressing hABCG2 compared to the values for the wild type, suggesting that the expression of endogenous cABCB1 became variable after the expression of hABCG2...
November 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Yiwei Liao, Xiang Liu, Youssef Jounaidi, Stuart A Forman, Hua-Jun Feng
Central α4βδ receptors are the most abundant isoform of δ subunit-containing extrasynaptic GABAA receptors that mediate tonic inhibition. Although the amplitude of GABA-activated currents through α4βδ receptors is modulated by multiple general anesthetics, the effects of general anesthetics on desensitization and deactivation of α4βδ receptors remain unknown. In the current study, we investigated the effect of etomidate, a potent general anesthetic, on the kinetics and the pseudo steady-state current amplitude of α4β3δ receptors inducibly expressed in HEK293 TetR cells...
November 2, 2018: Journal of Pharmacology and Experimental Therapeutics
Jean A Boutin, Gilles Ferry
In the 1980s, researchers used binding studies to show that there was a melatonin binding site in addition to the receptors described previously. It was first termed ML2 and then, in 1999, was termed MT3. Purification efforts led to its identification as quinone reductase 2. Several lines of evidence support the notion that MT3 is the same as quinone reductase 2, including the detection and characterization of MT3 whenever quinone reductase 2 was added to various systems under various conditions. This evidence is discussed in this review, which summarizes the results of relevant cellular and animal experiments...
November 2, 2018: Journal of Pharmacology and Experimental Therapeutics
Yan-Mei Liu, Hui-Ran Fan, Shining Deng, Tailin Zhu, Yuhua Yan, Wei-Hong Ge, Wei-Guang Li, Fei Li
Central amygdala (CeA) plays a critical role in the expression of emotional behaviors including pathological anxiety disorders. The present study demonstrated that the GABAergic inhibition in CeA was significantly increased by methyleugenol (ME), a natural constituent isolated from the essential oils of several plants. The electrophysiological recordings showed that ME increased both tonic and miniature inhibitory postsynaptic GABAergic currents (mIPSCs) in CeA slices, especially the tonic currents, while the miniature excitatory postsynaptic currents (mEPSCs) were not affected...
November 2, 2018: Journal of Pharmacology and Experimental Therapeutics
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