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Pharmacology Research & Perspectives

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https://www.readbyqxmd.com/read/28097012/pharmacokinetics-and-pharmacodynamics-of-antibiotics-in-critically-ill-acute-kidney-injury-patients
#1
REVIEW
Welder Zamoner, Fernanda M de Freitas, Durval S S Garms, Mariele Gobo de Oliveira, André L Balbi, Daniela Ponce
Sepsis is the most common cause of death in critically ill patients and is associated with multiorgan failure, including acute kidney injury (AKI). This situation can require acute renal support and increase mortality. Therefore, it is essential to administer antimicrobials in doses that achieve adequate serum levels, avoiding both overdosing and drug toxicity as well as underdosing and the risk of antibiotic resistance and higher mortality. Currently, there are no validated guidelines on antibiotic dose adjustments in septic patients with AKI...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097011/a-selective-gpr40-ffar1-agonist-ly2881835-provides-immediate-and-durable-glucose-control-in-rodent-models-of-type-2-diabetes
#2
Yanyun Chen, Min Song, Jonathan P Riley, Charlie C Hu, Xianbu Peng, Donalyn Scheuner, Krister Bokvist, Pranab Maiti, Steven D Kahl, Chahrzad Montrose-Rafizadeh, Chafiq Hamdouchi, Anne Reifel Miller
LY2881835 is a selective, potent, and efficacious GPR40 agonist. The objective of the studies described here was to examine the pharmacological properties of LY2881835 in preclinical models of T2D. Significant increases in insulin secretion were detected when LY2881835 was tested in primary islets from WT mice but not in islets from GPR40 KO mice. Furthermore, LY2881835 potentiated glucose stimulated insulin secretion in normal lean mice. Acute administration of LY2881835 lowered glucose during OGTTs in WT mice but not in GPR40 KO mice...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097010/corrigendum
#3
(no author information available yet)
[This corrects the article DOI: 10.1002/prp2.248.].
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097009/statin-utilisation-in-a-real-world-setting-a-retrospective-analysis-in-relation-to-arterial-and-cardiovascular-autonomic-function
#4
John D Sluyter, Alun D Hughes, Andrew Lowe, Carlos A Camargo, Robert K R Scragg
Randomized trials suggest that statin treatment may lower blood pressure and influence cardiovascular autonomic function (CVAF), but the impact of duration of usage, discontinuation, and adherence to this therapy is unknown. We examined these issues with regard to blood pressure (BP)-related variables in a large, population-based study. Participants were 4942 adults (58% male; aged 50-84 years): 2179 on statin treatment and 2763 untreated. Days of utilization, adherence (proportion of days covered ≥0.8), and discontinuation (non-use for ≥30 days immediately prior to BP measurement) of three statins (atorvastatin, pravastatin, and simvastatin) over a period of up to 2 years was monitored retrospectively from electronic databases...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097008/preclinical-findings-predicting-efficacy-and-side-effect-profile-of-ly2940094-an-antagonist-of-nociceptin-receptors
#5
Jeffrey M Witkin, Linda M Rorick-Kehn, Mark J Benvenga, Benjamin L Adams, Scott D Gleason, Karen M Knitowski, Xia Li, Steven Chaney, Julie F Falcone, Janice W Smith, Julie Foss, Kirsti Lloyd, John T Catlow, David L McKinzie, Kjell A Svensson, Vanessa N Barth, Miguel A Toledo, Nuria Diaz, Celia Lafuente, Alma Jiménez, Alfonso Benito, Conception Pedregal, Maria A Martínez-Grau, Anke Post, Michael A Ansonoff, John E Pintar, Michael A Statnick
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP (-/-) mice...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097007/safety-assessment-in-rats-and-dogs-of-acoustic-cluster-therapy-a-novel-concept-for-ultrasound-mediated-targeted-drug-delivery
#6
Oddvar Myhre, Marie Bjørgan, Derek Grant, Svein-Olaf Hustvedt, Per C Sontum, Hubert Dirven
Acoustic Cluster Therapy (ACT) represents a novel concept for targeted drug delivery. Ultrasound is applied to activate intravenously administered free-flowing clusters of microbubbles and microdroplets within the target pathology, depositing 20-30 μm large bubbles in the microvasculature for 5-10 min. Further application of ultrasound induces biomechanical effects which increase vascular permeability and enhance localized extravasation of coadministered drugs. Herein we report investigations done to assess the preclinical safety of ACT, using doses up to 1 mL/kg (3 μL perfluoromethyl-cyclopentane/kg)...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097006/contribution-of-sigma-1-receptor-to-cytoprotective-effect-of-afobazole
#7
Mikhail V Voronin, Ilya A Kadnikov
Anxiolytic afobazole (5-Ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihidrochloride) has pronounced ligand properties toward Sigma-1 receptor (σ1 receptor,SigmaR1) and MT 3 receptors. Our previous work demonstrated that afobazole possess cytoprotective effect in the in vitro model of menadione genotoxicity (Woods et al. 1997) through interaction with MT 3 receptor (Kadnikov et al. 2014). Present study utilized previously described models to address the contribution of SigmaR1 to cytoprotective action of afobazole...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097005/the-cardioprotective-efficacy-of-tvp1022-against-ischemia-reperfusion-injury-and-cardiac-remodeling-in-rats
#8
Assaf Malka, Offir Ertracht, Noa Bachner-Hinenzon, Irina Reiter, Ofer Binah
Following acute myocardial infarction (MI), early and successful reperfusion is the most effective strategy for reducing infarct size and improving the clinical outcome. However, immediate restoration of blood flow to the ischemic zone results in myocardial damage, defined as "reperfusion-injury". Whereas we previously reported that TVP1022 (the S-isomer of rasagiline, FDA-approved anti-Parkinson drug) decreased infarct size 24 h post ischemia reperfusion (I/R) in rats, in this study we investigated the chronic cardioprotective efficacy of TVP1022 14 days post-I/R...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097004/rifampicin-decreases-exposure-to-sublingual-buprenorphine-in-healthy-subjects
#9
Nora M Hagelberg, Mari Fihlman, Tuija Hemmilä, Janne T Backman, Jouko Laitila, Pertti J Neuvonen, Kari Laine, Klaus T Olkkola, Teijo I Saari
Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first-pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four-session paired cross-over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6-mg (placebo phase) or 0.8-mg (rifampicin phase) buprenorphine sublingually on day 7...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097003/application-of-a-systems-pharmacology-model-for-translational-prediction-of-herg-mediated-qtc-prolongation
#10
Verena Gotta, Zhiyi Yu, Frank Cools, Karel van Ammel, David J Gallacher, Sandra A G Visser, Frederick Sannajust, Pierre Morissette, Meindert Danhof, Piet H van der Graaf
Drug-induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only)...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097002/ambisome-induced-avascular-necrosis-of-the-alae-of-the-nose-of-a-very-young-girl-suffering-from-kala-azar-a-case-report
#11
Shomik Maruf, Proggananda Nath, Fatima Aktar, Ariful Basher
Although liposomal amphotericin B (AmBisome) is considered as the first-line treatment for New Kala-azar, there is not enough evidence on the dosage formulation in children and its effect on them. Being considered as the safest drug for treatment of Kala-azar, this case of AmBisome-induced avascular necrosis now gives rise to the question; whether it is actually safe enough and if a dosage modification is needed in case of children. This so far, to the best of our knowledge, is the first instance of such severe adverse event due to AmBisome administration...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097001/mag-dpa-curbs-inflammatory-biomarkers-and-pharmacological-reactivity-in-cytokine-triggered-hyperresponsive-airway-models
#12
Rayan Khaddaj-Mallat, Roddy Hiram, Chantal Sirois, Marco Sirois, Edmond Rizcallah, Sofia Marouan, Caroline Morin, Éric Rousseau
Bronchial inflammation contributes to a sustained elevation of airway hyperresponsiveness (AHR) in asthma. Conversely, omega-3 fatty acid derivatives have been shown to resolve inflammation in various tissues. Thus, the effects of docosapentaenoic acid monoacylglyceride (MAG-DPA) were assessed on inflammatory markers and reactivity of human distal bronchi as well as in a cultured model of guinea pig tracheal rings. Human bronchi were dissected and cultured for 48 h with 10 ng/mL TNF-α or IL-13. Guinea pig tracheas were maintained in organ culture for 72 h which was previously shown to trigger spontaneous AHR...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097000/biased-small-molecule-ligands-for-selective-inhibition-of-hiv-1-cell-entry-via-ccr5
#13
Christian Berg, Katja Spiess, Hans R Lüttichau, Mette M Rosenkilde
Since the discovery of HIV's use of CCR5 as the primary coreceptor in fusion, the focus on developing small-molecule receptor antagonists for inhibition hereof has only resulted in one single drug, Maraviroc. We therefore investigated the possibility of using small-molecule CCR5 agonists as HIV-1 fusion inhibitors. A virus-free cell-based fusion reporter assay, based on mixing "effector cells" (expressing HIV Env and luciferase activator) with "target cells" (expressing CD4, CCR5 wild type or a selection of well-described mutations, and luciferase reporter), was used as fusion readout...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27891231/a-pharmacokinetic-evaluation-and-metabolite-identification-of-the-ghb-receptor-antagonist-ncs-382-in-mouse-informs-novel-therapeutic-strategies-for-the-treatment-of-ghb-intoxication
#14
Garrett R Ainslie, K Michael Gibson, Kara R Vogel
Gamma-aminobutyric acid (GABA) is an endogenous inhibitory neurotransmitter and precursor of gamma-hydroxybutyric acid (GHB). NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid), a known GHB receptor antagonist, has shown significant efficacy in a murine model of succinic semialdehyde dehydrogenase deficiency (SSADHD), a heritable neurological disorder featuring chronic elevation of GHB that blocks the final step of GABA degradation. NCS-382 exposures and elimination pathways remain unknown; therefore, the goal of the present work was to obtain in vivo pharmacokinetic data in a murine model and to identify the NCS-382 metabolites formed by mouse and human...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713829/equine-hepatocytes-isolation-cryopreservation-and-applications-to-in%C3%A2-vitro-drug-metabolism-studies
#15
Khaled A Shibany, Sabine Tötemeyer, Stefanie L Pratt, Stuart W Paine
Despite reports of the successful isolation of primary equine hepatocytes, there are no published data regarding the successful cryopreservation of these isolated cells. In this study, a detailed description of the procedures for isolation, cryopreservation, and recovery of equine hepatocytes are presented. Furthermore, the intrinsic clearance (Clint) and production of metabolites for three drugs were compared between freshly isolated and recovered cryopreserved hepatocytes. Primary equine hepatocytes were isolated using a two-step collagenase perfusion method, with an average cell yield of 2...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713828/efficacy-and-safety-evaluation-of-claudin-4-targeted-antitumor-therapy-using-a-human-and-mouse-cross-reactive-monoclonal-antibody
#16
Yosuke Hashimoto, Yumi Kawahigashi, Tomoyuki Hata, Xiangru Li, Akihiro Watari, Minoru Tada, Akiko Ishii-Watabe, Yoshiaki Okada, Takefumi Doi, Masayoshi Fukasawa, Hiroki Kuniyasu, Kiyohito Yagi, Masuo Kondoh
Claudin-4 (CLDN-4), a tight-junction protein, is overexpressed in various malignant tumors, including gastric, colorectal, pancreatic, and breast cancers. However, CLDN-4 is also expressed in normal tissues, including the liver, pancreas, kidney, and small intestine. Whether CLDN-4 is an effective and safe target for cancer therapy has been unclear owing to the lack of a binder with both CLDN-4 specificity and cross-reactivity to human and murine cells. In this study, we successfully generated a rat anti-CLDN-4 monoclonal antibody (5D12) that was specific to, and cross-reactive with, human and mouse CLDN-4...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713827/evaluation-of-a-novel-pxr-knockout-in-heparg-%C3%A2-cells
#17
Beth Williamson, Mathias Lorbeer, Michael D Mitchell, Timothy G Brayman, Robert J Riley
The nuclear pregnane X receptor (PXR) regulates the expression of genes involved in the metabolism, hepatobiliary disposition, and toxicity of drugs and endogenous compounds. PXR is a promiscuous nuclear hormone receptor (NHR) with significant ligand and DNA-binding crosstalk with the constitutive androstane receptor (CAR); hence, defining the precise role of PXR in gene regulation is challenging. Here, utilising a novel PXR-knockout (KO) HepaRG cell line, real-time PCR analysis was conducted to determine PXR involvement for a range of inducers...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713826/soluble-guanylate-cyclase-redox-state-under-oxidative-stress-conditions-in-isolated-monkey-coronary-arteries
#18
Masashi Tawa, Tomio Okamura
Coronary artery disease is associated with oxidative stress due to the excessive generation of free radicals in the vascular wall. This study investigated the impact of tert-butyl hydroperoxide (t-BuOOH), a peroxyl radical generator, on the redox state of soluble guanylate cyclase (sGC) in isolated monkey coronary arteries. Helically cut strips of endothelium-intact monkey coronary arteries treated with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (10 μmol/L) were exposed for approximately 60 min to either no drug or t-BuOOH (100 μmol/L) in the presence and absence of α-tocopherol (300 μmol/L)...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713825/frequency-and-trends-of-disease-modifying-antirheumatic-drug-dmard-use-in-germany
#19
Alexander M Fassmer, Edeltraut Garbe, Niklas Schmedt
The aim of this study was to analyze the population-based frequency of classic (c-) and biologic (b-) disease-modifying antirheumatic drug (DMARD) use over time, selected underlying indications and the specialty of the prescribing physicians in Germany. Based on the claims data of the German Pharmacoepidemiological Research Database (GePaRD), yearly cross-sectional studies were conducted from 2004 to 2011. The prevalence of DMARD use was calculated as the number of persons with at least one dispensation per 1000 persons stratified by sex and age...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713824/comparison-of-11-c-tz1964b-and-18-f-mni659-for-pet-imaging-brain-pde10a-in-nonhuman-primates
#20
Hui Liu, Hongjun Jin, Xuyi Yue, Junbin Han, Hao Yang, Hubert Flores, Yi Su, David Alagille, Joel S Perlmutter, Gilles Tamagnan, Zhude Tu
Phosphodiesterase 10A (PDE10A) inhibitors show therapeutic effects for diseases with striatal pathology. PET radiotracers have been developed to quantify in vivo PDE10A levels and target engagement for therapeutic interventions. The aim of this study was to compare two potent and selective PDE10A radiotracers, [(11)C]TZ1964B and [(18)F]MNI659 in the nonhuman primate (NHP) brain. Double scans in the same cynomolgus monkey on the same day were performed after injection of [(11)C]TZ1964B and [(18)F]MNI659. Specific uptake was determined in two ways: nondisplaceable binding potential (BPND) was calculated using cerebellum as the reference region and the PDE-10A enriched striatum as the target region of interest (ROI); the area under the time-activity curve (AUC) for the striatum to cerebellum ratio was also calculated...
October 2016: Pharmacology Research & Perspectives
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