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Pharmacology Research & Perspectives

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https://www.readbyqxmd.com/read/29417765/conflicting-evidence-for-the-role-of-jnk-as-a-target-in-breast-cancer-cell-proliferation-comparisons-between-pharmacological-inhibition-and-selective-shrna-knockdown-approaches
#1
Rachel A Wood, Mark J Barbour, Gwyn W Gould, Margaret R Cunningham, Robin J Plevin
As a target, the JNK pathway has been implicated in roles including cell death, proliferation, and inflammation in variety of contexts which span cardiovascular disease, neurodegenerative pathologies, and cancer. JNK1 and JNK2 have recently been demonstrated to function independently, highlighting a new parameter in the study of the JNK pathway. In order for JNK1 and JNK2-specific roles to be defined, better tools need to be employed. Previous studies have relied upon the broad spectrum JNK inhibitor, SP600125, to characterize the role of JNK signaling in a number of cell lines, including the breast cancer cell line MCF-7...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417764/prospective-evaluation-of-ceftriaxone-use-in-medical-and-emergency-wards-of-gondar-university-referral-hospital-ethiopia
#2
Asnakew Achaw Ayele, Begashaw Melaku Gebresillassie, Daniel Asfaw Erku, Eyob Alemayehu Gebreyohannes, Dessalegn Getnet Demssie, Amanual Getnet Mersha, Henok Getachew Tegegn
Ceftriaxone is among the most commonly utilized antibiotics owing to its high potency, wide spectrum of activity, and low risk of toxicity. It is used to treat different types of bacterial infections including pneumonia, bone infections, abdominal infections, Skin and soft tissue infections, urinary tract infections. However, evidence around the globe shows the misuse of Ceftriaxone. This study aimed at evaluating the appropriateness of ceftriaxone use in medical and emergency wards of Gondar university referral hospital (GURH), Northwest Ethiopia...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417763/combined-treatment-with-a-selective-pde10a-inhibitor-tak-063-and-either-haloperidol-or-olanzapine-at-subeffective-doses-produces-potent-antipsychotic-like-effects-without-affecting-plasma-prolactin-levels-and-cataleptic-responses-in-rodents
#3
Kazunori Suzuki, Akina Harada, Hirobumi Suzuki, Clizia Capuani, Annarosa Ugolini, Mauro Corsi, Haruhide Kimura
Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417762/improving-the-assessment-of-adverse-drug-reactions-using-the-naranjo-algorithm-in-daily-practice-the-japan-adverse-drug-events-study
#4
Hiroki Murayama, Mio Sakuma, Yuri Takahashi, Takeshi Morimoto
It is difficult to determine adverse drug reactions (ADRs) in daily complicated clinical practice in which many kinds of drugs are prescribed. We evaluated how well the Naranjo Algorithm (NA) categorized ADRs among suspected ADRs. The Japan Adverse Drug Events (JADE) study was a prospective cohort study of 3459 inpatients. After all suspected ADRs were reported from research assistants, a single physician reviewer independently assigned an NA score to each. After all NA score of suspected ADRs were scored, two physician reviewers discussed and determined ADRs based on the literature...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417761/pharmacokinetic-equivalence-comparable-safety-and-immunogenicity-of-an-adalimumab-biosimilar-product-m923-to-humira-in-healthy-subjects
#5
Jan Hillson, Tim Mant, Molly Rosano, Carolyn Huntenburg, Mehrshid Alai-Safar, Siddhesh Darne, Donna Palmer, Borislava G Pavlova, Jennifer Doralt, Russell Reeve, Niti Goel, Doris Weilert, Paul W Rhyne, Kamali Chance, John Caminis, James Roach, Tanmoy Ganguly
The aims of this randomized, double-blind, three-arm, single-dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as "M923") to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration (Cmax ), area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf ), and AUC from time 0 to 336 hours (AUC0-336 ). Secondary endpoints included safety and immunogenicity assessments...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417760/fosfomycin-as-a-potential-therapy-for-the-treatment-of-systemic-infections-a-population-pharmacokinetic-model-to-simulate-multiple-dosing-regimens
#6
Natalia V Ortiz Zacarías, Anneke C Dijkmans, Jacobus Burggraaf, Johan W Mouton, Erik B Wilms, Cees van Nieuwkoop, Daan J Touw, Ingrid M C Kamerling, Jasper Stevens
Fosfomycin has emerged as a potential therapy for multidrug-resistant bacterial infections. In most European countries, the oral formulation is only approved as a 3 g single dose for treatment of uncomplicated cystitis. However, for the treatment of complicated systemic infections, this dose regimen is unlikely to reach efficacious serum and tissue concentrations. This study aims to investigate different fosfomycin-dosing regimens to evaluate its rationale for treatment of systemic infections. Serum concentration-time profiles of fosfomycin were simulated using a population pharmacokinetic model based on published pharmacokinetic parameter values, their uncertainty, inter-individual variability and covariates...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417759/anxiety-and-activity-related-effects-of-paracetamol-on-healthy-and-neuropathic-rats
#7
Zuyue Chen, Hong Wei, Antti Pertovaara, Jianhong Wang, Synnöve Carlson
Paracetamol has recently been suggested to affect emotion processing in addition to alleviating pain in humans. We investigated in adult male Hannover-Wistar rats whether acute intraperitoneally administrated paracetamol affects behavior in tests measuring anxiety, mood, motor activity, and memory. Unoperated rats received saline or a low (50 mg/kg) or high (300 mg/kg) dose of paracetamol, while rats with a spared nerve injury (SNI) model of neuropathy and sham-operated rats received saline or the low dose of paracetamol...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417758/protective-effect-of-carvedilol-alone-and-coadministered-with-diltiazem-and-prednisolone-on-doxorubicin-and-5-fluorouracil-induced-hepatotoxicity-and-nephrotoxicity-in-rats
#8
Abidemi J Akindele, Gabriel O Oludadepo, Kennedy I Amagon, Dhirendra Singh, Daniel D Osiagwu
This study investigated the protective effects of carvedilol alone and coadministered with prednisolone and diltiazem on doxorubicin (DOX) and 5-fluorouracil (5-FU)-induced toxicity. Each of 2 pools of 70 female rats were randomly allotted into 10 groups of 7 animals each and treated as follows: Group 1: normal saline (10 mL/kg); Group 2: normal saline and DOX (40 mg/kg)/5-FU (20 mg/kg) alone; Group 3: gallic acid (200 mg/kg) and DOX/5-FU; Group 4: carvedilol (0.075 mg/kg) and DOX/5-FU; Group 5: carvedilol (0...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417757/natriuretic-peptide-receptor-c-mediated-attenuation-of-vascular-smooth-muscle-cell-hypertrophy-involves-gq%C3%AE-plc%C3%AE-1-proteins-and-ros-associated-signaling
#9
Ashish Jain, Madhu B Anand-Srivastava
Hypertension is associated with vascular remodeling due to hyperproliferation and hypertrophy of vascular smooth muscle cells (VSMC). Recently, we showed the implication of enhanced expression of Gqα and PLCβ1 proteins in hypertrophy of VSMCs from 16-week-old spontaneously hypertensive rats (SHR). The aim of this study was to investigate whether C-ANP4-23 , a natriuretic peptide receptor-C (NPR-C) ligand that was shown to inhibit vasoactive peptide-induced enhanced protein synthesis in A10 VSMC could also attenuate hypertrophy of VSMC isolated from rat model of cardiac hypertrophy and to further explore the possible involvement of Gqα/PLCβ1 proteins and ROS-mediated signaling in this effect...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417756/darrell-r-abernethy-1949-2017
#10
(no author information available yet)
No abstract text is available yet for this article.
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417755/safety-signal-detection-and-evaluation-in-clinical-development-programs-a-case-study-of-tofacitinib
#11
Gorana Dasic, Thomas Jones, Vera Frajzyngier, Ricardo Rojo, Ann Madsen, Hernan Valdez
Adverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in-depth case review and external expert consultation. The magnitude of the signal was quantified...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226628/modeling-of-prolactin-response-following-dopamine-d2-receptor-antagonists-in-rats-can-it-be-translated-to-clinical-dosing
#12
Amit Taneja, An Vermeulen, Dymphy R H Huntjens, Meindert Danhof, Elizabeth C M De Lange, Johannes H Proost
Prolactin release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe prolactin response in rats and subsequently be translated to predict pituitary dopamine D2 receptor occupancy and plasma prolactin concentrations in humans following administration of paliperidone or remoxipride. Data on male Wistar rats receiving single or multiple doses of risperidone, paliperidone, or remoxipride was described by two semimechanistic models, the precursor pool model and the agonist-antagonist interaction model...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226627/data-visualizations-to-detect-systematic-errors-in-laboratory-assay-results
#13
Jörn Lötsch
The measurement of concentrations of drugs and endogenous substances is widely used in basic and clinical pharmacology research and service tasks. Using data science-derived visualizations of laboratory data, it is demonstrated on a real-life example that basic statistical exploration of laboratory assay results or advised standard visual methods of data inspection may fall short in detecting systematic laboratory errors. For example, data pathologies such as generating always the same value in all probes of a particular assay run may pass undetected when using standard methods of data quality check...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226626/randomized-clinical-study-of-safety-pharmacokinetics-and-pharmacodynamics-of-ripk1-inhibitor-gsk2982772-in-healthy-volunteers
#14
Kathleen Weisel, Nicola E Scott, Debra J Tompson, Bartholomew J Votta, Sujith Madhavan, Kat Povey, Allen Wolstenholme, Monica Simeoni, Todd Rudo, Lauren Richards-Peterson, Tarjinder Sahota, J Gene Wang, John Lich, Joshua Finger, Adeline Verticelli, Michael Reilly, Peter J Gough, Philip A Harris, John Bertin, Mei-Lun Wang
GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226625/identification-of-an-antibody-based-immunoassay-for-measuring-direct-target-binding-of-ripk1-inhibitors-in-cells-and-tissues
#15
Joshua N Finger, Jean-Marie Brusq, Nino Campobasso, Michael N Cook, Jennifer Deutsch, Heather Haag, Philip A Harris, Earl L Jenkins, Devika Joglekar, John D Lich, Sean Maguire, Rakesh Nagilla, Elizabeth J Rivera, Helen Sun, Bartholomew J Votta, John Bertin, Peter J Gough
Therapies that suppress RIPK1 kinase activity are emerging as promising therapeutic agents for the treatment of multiple inflammatory disorders. The ability to directly measure drug binding of a RIPK1 inhibitor to its target is critical for providing insight into pharmacokinetics, pharmacodynamics, safety and clinical efficacy, especially for a first-in-class small-molecule inhibitor where the mechanism has yet to be explored. Here, we report a novel method for measuring drug binding to RIPK1 protein in cells and tissues...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226624/burden-of-health-care-costs-for-patients-with-heparin-replacement-for-colorectal-emr-in-japan
#16
LETTER
Shiro Hayashi, Dai Nakamatsu, Tokuhiro Matsubara, Masashi Yamamoto, Tsutomu Nishida
No abstract text is available yet for this article.
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226623/distortion-of-kb-estimates-of-endothelin-1-eta-and-etb-receptor-antagonists-in-pulmonary-arteries-possible-role-of-an-endothelin-1-clearance-mechanism
#17
James A Angus, Richard J A Hughes, Christine E Wright
Dual endothelin ETA and ETB receptor antagonists are approved therapy for pulmonary artery hypertension (PAH). We hypothesized that ETB receptor-mediated clearance of endothelin-1 at specific vascular sites may compromise this targeted therapy. Concentration-response curves (CRC) to endothelin-1 or the ETB agonist sarafotoxin S6c were constructed, with endothelin receptor antagonists, in various rat and mouse isolated arteries using wire myography or in rat isolated trachea. In rat small mesenteric arteries, bosentan displaced endothelin-1 CRC competitively indicative of ETA receptor antagonism...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226622/pde4-inhibitor-rolipram-inhibits-the-expression-of-microsomal-prostaglandin-e-synthase-1-by-a-mechanism-dependent-on-map-kinase-phosphatase-1
#18
Lauri Tuure, Mari Hämäläinen, Eeva Moilanen
Phosphodiesterase-4 (PDE4) inhibitors have recently been introduced to the treatment of COPD and psoriatic arthritis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme synthesizing PGE2 , the most abundant prostanoid related to inflammation and inflammatory pain. mPGES-1 is a potential drug target for novel anti-inflammatory treatments aiming at an improved safety profile as compared to NSAIDs. Here we investigated the effect of the PDE4 inhibitor rolipram on the expression of mPGES-1 in macrophages; and a potential mediator role in the process for MAP kinase phosphatase-1 (MKP-1) which is an endogenous factor limiting the activity of the proinflammatory MAP kinases p38 and JNK...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226621/cenerimod-a-novel-selective-s1p1-receptor-modulator-with-unique-signaling-properties
#19
Luca Piali, Magdalena Birker-Robaczewska, Cyrille Lescop, Sylvie Froidevaux, Nicole Schmitz, Keith Morrison, Christopher Kohl, Markus Rey, Rolf Studer, Enrico Vezzali, Patrick Hess, Martine Clozel, Beat Steiner, Martin H Bolli, Oliver Nayler
Sphingosine-1-phosphate receptor 1 (S1P1 ) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1-5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side-effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29226620/comparative-potency-of-obeticholic-acid-and-natural-bile-acids-on-fxr-in-hepatic-and-intestinal-in%C3%A2-vitro-cell-models
#20
Yuanyuan Zhang, Carl LaCerte, Sanjay Kansra, Jonathan P Jackson, Kenneth R Brouwer, Jeffrey E Edwards
Obeticholic acid (OCA) is a semisynthetic farnesoid X receptor (FXR) agonist, an analogue of chenodeoxycholic acid (CDCA) which is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA). OCA efficiently inhibits bile acid synthesis and promotes bile acid efflux via activating FXR-mediated mechanisms in a physiologically relevant in vitro cell system, Sandwich-cultured Transporter Certified ™ human primary hepatocytes (SCHH). The study herein evaluated the effects of UDCA alone or in combination with OCA in SCHH...
December 2017: Pharmacology Research & Perspectives
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