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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/27903643/effects-of-antihypertensive-agents-on-intestinal-contractility-in-the-spontaneously-hypertensive-rat-angiotensin-receptor-system-down-regulation-by-losartan
#1
Glen S Patten, Mahinda Y Abeywardena
Hypertension is an inflammatory condition controlled by the renin angiotensin system and is linked to kidney disease, diabetes mellitus and recently to dysfunction of the gut. The aim of this study was to determine what effect anti-hypertensive drug treatments may have on intestinal function of the spontaneously hypertensive rat (SHR). In the first experiment SHR were treated with enalapril or hydralazine. In the second experiment SHR were treated with losartan with no-treatment as control for both experiments...
November 30, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27903642/behavioral-characterization-of-kappa-opioid-receptor-agonist-spiradoline-and-cannabinoid-receptor-agonist-cp55940-mixtures-in-rats
#2
Vanessa Minervini, Sujata S Dahal, Charles France
Pain is a significant clinical problem and there is a need for more effective treatments with reduced adverse effects that currently limit the use of mu opioid receptor agonists. Synthetic kappa opioid receptor agonists have no abuse liability and well-documented antinociceptive effects; however, adverse effects (diuresis, dysphoria) preclude their use in the clinic. Combining kappa opioids with non-opioid drugs (cannabinoid receptor agonists) allows for smaller doses of each drug to produce antinociception...
November 30, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27856937/allylpyrocatechol-attenuates-collagen-induced-arthritis-via-attenuation-of-oxidative-stress-secondary-to-modulation-of-the-mapk-jak-stat-and-nrf2-ho-1-pathways
#3
Soumita De, Alak Manna, Sunanda Kundu, Sritama De Sarkar, Uttara Chatterjee, Tuhinadri Sen, Subrata Chattopadhyay, Mitali Chatterjee
Rheumatoid arthritis (RA), an inflammatory autoimmune disorder is characterized by synovial hyperplasia and bony destruction. The pathogenesis of RA includes redox dysregulation, concomitant with increased levels of pro-inflammatory mediators. As the ability of Allylpyrocatechol (APC), a phytoconstituent of Piper betle leaves to alleviate oxidative stress has been demonstrated in patients with RA, its anti-arthritic activity was evaluated in an animal model of arthritis, along with establishment of the underlying mechanism(s) of action...
November 17, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27856936/reveglucosidase-alfa-bmn-701-an-igf-2-tagged-rhacid-%C3%AE-glucosidase-improves-respiratory-functional-parameters-in-a-murine-model-of-pompe-disease
#4
Jeff Peng, Jill Dalton, Mark Butt, Kristin Tracy, Derek Kennedy, Peter Haroldsen, Rhea Cahayag, Stephen Zoog, Charles A O'Neill, Laurie Tsuruda
Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701), is an insulin-like growth factor 2 (IGF2) tagged rhGAA that enhances rhGAA cellular uptake via a glycosylation independent IGF2-binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). These studies evaluated the effects of reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA as well as changes in respiratory function and glycogen clearance in respiratory related tissue in a Pompe mouse model (GAA(tm1Rabn))...
November 16, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27831487/urinary-imidafenacin-contributes-to-the-long-lasting-blockade-of-bladder-muscarinic-receptors-effects-of-bilateral-ligation-of-ureters
#5
Yoshihiko Ito, Shiori Kuraoka, Soma Endo, Ayaka Takahashi, Satomi Onoue, Shizuo Yamada
Imidafenacin, a potent and selective antagonist of the M1 and M3-muscarinic receptor subtypes, is safe, efficacious, and tolerable for controlling the symptoms of overactive bladder (OAB). However, the precise mechanisms responsible for the bladder-selective pharmacological effects of this agent remain unclear. The basis of in vivo pharmacology is that antagonistic effects result from the occupancy of receptors, which may be examined using an in vivo radioligand binding assay. To characterize the in vivo muscarinic receptor binding of the highly specific activity of a new tritium-labeled imidafenacin ([3H]imidafenacin) in the bladder and other tissues of mice, and to clarify the mechanisms underlying the selective binding of bladder muscarinic receptors by imidafenacin...
November 9, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27831486/ontogeny-of-net-expression-and-antidepressant-like-response-to-desipramine-in-wild-type-and-sert-mutant-mice
#6
Nathan C Mitchell, Melodi A Bowman, Georgianna G Gould, Wouter Koek, Lynette C Daws
Depression is a major public health concern with symptoms that are often poorly controlled by treatment with common antidepressants. This problem is compounded in juveniles and adolescents, where therapeutic options are limited to only two approved antidepressants, both selective serotonin reuptake inhibitors (SSRIs). Moreover, therapeutic benefits of SSRIs are often especially limited in certain subpopulations of depressed patients, including children and carriers of low expressing serotonin transporter (SERT) gene variants...
November 9, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27827303/an-hdac6-inhibitor-confers-protection-and-selectively-inhibits-b-cell-infiltration-in-dss-induced-colitis-in-mice
#7
Anh Do, Robert C Reid, Rink-Jan Lohman, Matthew J Sweet, David P Fairlie, Abishek Iyer
Small molecule histone deacetylase (HDAC) inhibitors with anti-inflammatory activity may be candidates for targeting intestinal inflammatory pathways in inflammatory bowel disease (IBD). This study investigated whether treatment with a potent HDAC6 inhibitor, BML-281, could protect against colonic inflammation and prevent inflammatory cell infiltration into the colon to drive disease pathology in a mouse model of acute DSS-colitis. Control and acute DSS-colitis mice were treated with BML-281 (1mg/kg/day s.c...
November 8, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27821713/quantitative-analyses-of-synergistic-responses-between-cannabidiol-and-dna-damaging-agents-on-the-proliferation-and-viability-of-glioblastoma-and-neural-progenitor-cells-in-culture
#8
Liting Deng, Lindsay Ng, Tatsuya Ozawa, Nephi Stella
Evidence suggests that the non-psychotropic cannabis-derived compound, cannabidiol (CBD), has anti-neoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the anti-proliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27821712/btk-small-molecule-inhibitors-induce-a-distinct-pancreatic-toxicity-in-rats
#9
Rebecca I Erickson, Leah K Schutt, Jacqueline Tarrant, Michelle McDowell, Lichuan Liu, Adam R Johnson, Sock-Cheng Lewin-Koh, Maj Hedehus, Jed Ross, Richard A D Carano, Karin Staflin, Fiona Zhong, James Crawford, Shelly Zhong, Karin Reif, Arna Katewa, Harvey Wong, Wendy Young, Donna Dambach, Dinah Misner
Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematological cancers and autoimmune diseases. GDC-0853 is a selective and reversible oral small molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27821711/low-potential-of-basimglurant-to-be-involved-in-drug-drug-interactions-influence-of-non-michaelis-menten-cyp-kinetics-on-fraction-metabolized
#10
Stephen M Fowler, Elena Guerini, NaHong Qiu, Yumi Cleary, Neil J Parrott, Gerard Greig, Navita L Mallalieu
Basimglurant, a novel mGlu5 negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (CYP) mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominated basimglurant metabolism and highlighted a risk for drug-drug interactions when comedicated with strong CYP3A4/5 inhibitors or inactivators. However, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an AUCi/AUC ratio of only 1...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27821710/exploration-of-%C3%AE-1-antitrypsin-treatment-protocol-for-islet-transplantation-dosing-plan-and-route-of-administration
#11
Boris M Baranovski, Eyal Ozeri, Galit Shahaf, David E Ochayon, Ronen Schuster, Nofar Bahar, Noa Kalay, Pablo Cal, Mark I Mizrahi, Omer Nisim, Pnina Strauss, Eran Schenker, Eli C Lewis
Life-long weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Since the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related injury. Islet-grafted mice were treated with hAAT (Glassia™; i...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27815365/xanthohumol-modulates-calcium-signaling-in-rat-ventricular-myocytes-possible-antiarrhythmic-properties
#12
Juan Jose Arnaiz-Cot, Lars Cleemann, Martin Morad
Cardiac arrhythmia is a major cause of mortality in cardiovascular pathologies. A host of drugs targeted to sarcolemmal Na(+), Ca(2+), and K(+) channels have had limited success clinically. Recently, Ca(2+) signaling has been target of pharmacotherapy based on finding that leaky ryanodine receptors elevate local Ca(2+) concentrations causing membrane depolarizations that trigger arrhythmias. Here we report that xanthohumol, an antioxidant extracted from hops and showing therapeutic effects in other pathologies, may have antiarrhythmic properties by stabilizing ryanodine receptor's activity...
November 4, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27815364/predictors-of-variation-in-cyp2a6-mrna-protein-and-enzyme-activity-in-a-human-liver-bank-influence-of-genetic-and-non-genetic-factors
#13
Julie-Anne Tanner, Bhagwat Prasad, Katrina G Claw, Patricia Stapleton, Amarjit Chaudhry, Erin G Schuetz, Kenneth E Thummel, Rachel F Tyndale
Cytochrome P450 2A6 (CYP2A6) metabolizes several clinically relevant substrates, including nicotine, the primary psychoactive component in cigarette smoke. Smokers vary widely in their rate of inactivation and clearance of nicotine, altering numerous smoking phenotypes. We aimed to characterize independent and shared impact of genetic and non-genetic sources of variation in CYP2A6 mRNA, protein, and enzyme activity in a human liver bank (n=360). We quantified levels of CYP2A6, cytochrome P450 oxidoreductase (POR), and aldo-keto reductase 1D1 (AKR1D1) mRNA, and CYP2A6 and POR protein...
November 4, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27811173/an-allosteric-potentiator-of-the-dopamine-d1-receptor-increases-locomotor-activity-in-human-d1-knock-in-mice-without-causing-stereotypy-or-tachyphylaxis
#14
Kjell A Svensson, Beverly A Heinz, John M Schaus, James P Beck, Junliang Hao, Joseph H Krushinski, Matthew R Reinhard, Michael P Cohen, Sarah L Hellman, Brian G Getman, Xushan Wang, Michelle M Menezes, Deanna L Maren, Julie F Falcone, Wesley H Anderson, Rebecca A Wright, S Michelle Morin, Kelly L Knopp, Benjamin L Adams, Borys Rogovoy, Ilya Okun, Todd M Suter, Michael A Statnick, Donald R Gehlert, David L Nelson, Virginia L Lucaites, Renee Emkey, Neil W DeLapp, Todd R Wiernicki, Jeffrey W Cramer, Charles R Yang, Robert F Bruns
Allosteric potentiators amplify the sensitivity of physiological control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ. In HEK293 cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ~12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ~30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor...
November 3, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27811172/tak-063-a-novel-phosphodiesterase-10a-inhibitor-protects-from-striatal-neurodegeneration-and-ameliorates-behavioral-deficits-in-the-r6-2-mouse-model-of-huntington-s-disease
#15
Akina Harada, Kazunori Suzuki, Haruhide Kimura
Huntington's disease (HD) is characterized by progressive loss of striatal medium spiny neurons (MSNs) that constitute direct and indirect pathways: the indirect pathway MSNs is more vulnerable than the direct pathway MSNs. Impairment of cAMP/cGMP signaling by mutant huntingtin is hypothesized as the molecular mechanism underlying degeneration of MSNs. Phosphodiesterase 10A (PDE10A) is selectively expressed in MSNs and degrades both cAMP and cGMP; thus, PDE10A inhibition can restore impaired cAMP/cGMP signaling...
November 3, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27807008/role-of-equilibrative-nucleobase-transporter-1-slc43a3-as-a-ganciclovir-transporter-in-the-induction-of-cytotoxic-effect-of-ganciclovir-in-a-suicide-gene-therapy-with-herpes-simplex-virus-thymidine-kinase
#16
Junji Furukawa, Katsuhisa Inoue, Kinya Ohta, Tomoya Yasujima, Yoshihisa Mimura, Hiroaki Yuasa
A suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV) has been under development as a tumor-targeted therapy. However, the mechanism of cellular GCV uptake, which is prerequisite in the therapy, has not been clarified. In an attempt to resolve this situation and gain information to optimize HSV-TK/GCV system for cancer therapy, we found that human equilibrative nucleobase transporter 1 (ENBT1) can transport GCV with a Michaelis constant of 2.75 mM in Madin-Darby canine kidney II (MDCKII) cells stably transfected with this transporter...
November 2, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27807007/hormonal-and-chemical-regulation-of-glut9-transporter-in-mice
#17
Pengli Bu, Yuan Le, Yue Zhang, Xingguo Cheng
Glucose transporter (Glut) 9 plays an important role in the homeostasis of uric acid in the liver and kidney. Although the physiological functions of Glut9 have been well established, the regulation of Glut9 expression is less well understood. In the present study, we showed that the mRNA and protein expression of Glut9 in mouse liver and kidney are female-predominant. Ontogeny studies further revealed that the female-predominant Glut9 expression in mouse liver only occurs in the adults, which is primarily due to the fact that Glut9 expression sustains in females but gradually decreases in males after it reaches the peak level at day 22...
November 2, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27799295/the-m1-muscarinic-receptor-antagonist-vu0255035-delays-the-development-of-status-epilepticus-after-organophosphate-exposure-and-prevents-hyperexcitability-in-the-basolateral-amygdala
#18
Steven L Miller, Vassiliki Aroniadou-Anderjaska, Volodymyr I Pidoplichko, Taiza H Figueiredo, James P Apland, Jishnu K S Krishnan, Maria F M Braga
Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1 receptor antagonist VU0255035, significantly suppressed seizure severity and prevented the development of SE for about 40 min after exposure to paraoxon or soman, suggesting an important role of the M1 receptor in the early phases of seizure generation...
October 31, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27799294/structure-activity-relationships-of-substituted-cathinones-with-transporter-binding-uptake-and-release
#19
Amy J Eshleman, Katherine M Wolfrum, John F Reed, Sunyoung O Kim, Tracy Swanson, Robert A Johnson, Aaron J Janowsky
Synthetic cathinones are components of "bath salts" and have physical and psychological side effects including hypertension, paranoia, and hallucinations. Herein we report interactions of 20 "bath salt" components with human dopamine, serotonin, and norepinephrine transporters (hDAT, hSERT, and hNET, respectively) heterologously expressed in HEK 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (Ki values) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-PPP, α-PBP, α-PHP, PV-8, 3,4-MDPPP, 3,4-MDPBP, 4-MePPP, α-PVP, 4-MeO- α-PVP, α-PVT and pentedrone, and hDAT>hSERT>hNET for pentylone...
October 31, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27789682/disrupted-murine-gut-to-human-liver-signaling-alters-bile-acid-homeostasis-in-humanized-mouse-liver-models
#20
Edwin C Y Chow, Holly P Quach, Yueping Zhang, Jason Z Y Wang, David C Evan, Albert P Li, Jose Silva, Rommel G Tirona, Yurong Lai, K Sandy Pang
The humanized liver mouse model is increasingly being exploited for human drug metabolism studies. However, its model stability, inter-communication between human hepatocytes and mouse non-parenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expression has not been investigated. We examined these issues in FRGN [Fah(-/-), Rag2(-/-), and IL-2rg(-/-) on NOD background] and chimeric mice: mFRGN, and hFRGN (repopulated with mouse or human hepatocytes, respectively)...
October 27, 2016: Journal of Pharmacology and Experimental Therapeutics
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