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https://www.readbyqxmd.com/read/28740616/unlocking-the-potential-of-established-products-toward-new-incentives-rewarding-innovation-in-europe
#1
Gabrielle Nayroles, Sandrine Frybourg, Sylvie Gabriel, Åsa Kornfeld, Fernando Antoñanzas-Villar, Jaime Espín, Claudio Jommi, Nello Martini, Gérard de Pouvourville, Keith Tolley, Jürgen Wasem, Mondher Toumi
Background: Many established products (EPs - marketed for eight years or more) are widely used off-label despite little evidence on benefit-risk ratio. This exposes patients to risks related to safety and lack of efficacy, and healthcare providers to liability. Introducing new indications for EPs may represent a high societal value; however, manufacturers rarely invest in R&D for EPs. The objective of this research was to describe incentives and disincentives for developing new indications for EPs in Europe and to investigate consequences of current policies...
2017: Journal of Market Access & Health Policy
https://www.readbyqxmd.com/read/28740608/gne-886-a-potent-and-selective-inhibitor-of-the-cat-eye-syndrome-chromosome-region-candidate-2-bromodomain-cecr2
#2
Terry D Crawford, James E Audia, Steve Bellon, Daniel J Burdick, Archana Bommi-Reddy, Alexandre Côté, Richard T Cummings, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, Hariharan Jayaram, Ying Jiang, Shivangi Joshi, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Arianne Neiss, Eneida Pardo, F Anthony Romero, Peter Sandy, Robert J Sims, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Yongyun Wang, Zhaowu Xu, Laura Zawadzke, Xiaoqin Zhu, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28740525/the-use-of-cholecalciferol-in-patients-with-hip-fracture
#3
Luisella Cianferotti, Simone Parri, Giorgio Gronchi, Roberto Civinini, Maria Luisa Brandi
INTRODUCTION: Major osteoporotic fractures are steadily increasing due to population aging. Programs of secondary prevention against refracture are essential to decrease morbidity and mortality and the cost for individuals and the society. Vitamin D supplementation and optimization of calcium intake are of a pivotal importance to start specific osteoporosis treatment and for its safety and efficacy. Cholecalciferol is the most widely employed drug for vitamin D supplementation. PURPOSE: Aim of this study was to assess the trends in the use of vitamin D supplements containing cholecalciferol in the population of hip fracture patients older than 65 years, resident in the region of Tuscany (Italy) in the years 2011-2015 and to describe vitamin D status in a subgroup of this individuals directly referred to a bone clinic for further evaluation after hip osteoporotic fracture...
January 2017: Clinical Cases in Mineral and Bone Metabolism
https://www.readbyqxmd.com/read/28738861/the-risk-of-hiv-transmission-at-each-step-of-the-hiv-care-continuum-among-people-who-inject-drugs-a-modeling-study
#4
Daniel J Escudero, Mark N Lurie, Kenneth H Mayer, Maximilian King, Sandro Galea, Samuel R Friedman, Brandon D L Marshall
BACKGROUND: People who inject drugs (PWID) are at continued risk for HIV in the U.S., and experience disparities across the HIV care continuum compared to other high-risk groups. Estimates of the risk of HIV transmission at each stage of the care continuum may assist in identifying public health priorities for averting incident infections among PWID, in addition to transmissions to sexual partners of PWID. METHODS: We created an agent-based model simulating HIV transmission and the HIV care continuum for PWID in New York City (NYC) in 2012...
July 25, 2017: BMC Public Health
https://www.readbyqxmd.com/read/28738655/risk-of-false-decision-on-conformity-of-a-multicomponent-material-when-test-results-of-the-components-content-are-correlated
#5
Ilya Kuselman, Francesca R Pennecchi, Ricardo J N B da Silva, D Brynn Hibbert
The probability of a false decision on conformity of a multicomponent material due to measurement uncertainty is discussed when test results are correlated. Specification limits of the components' content of such a material generate a multivariate specification interval/domain. When true values of components' content and corresponding test results are modelled by multivariate distributions (e.g. by multivariate normal distributions), a total global risk of a false decision on the material conformity can be evaluated based on calculation of integrals of their joint probability density function...
November 1, 2017: Talanta
https://www.readbyqxmd.com/read/28738235/treatment-decisions-in-metastatic-colorectal-cancer-beyond-first-and-second-line-combination-therapies
#6
REVIEW
A Vogel, R D Hofheinz, S Kubicka, D Arnold
Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has reached up to 30months in recent clinical trials of first line therapies. Following disease progression after the standard in both, 1st and 2nd line, combination chemotherapy with monoclonal antibodies, many patients maintain a good performance status and a significant proportion is motivated to undergo further therapy. Choices of treatment beyond the second line setting for mCRC are therefore becoming increasingly important...
May 4, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28737971/fluticasone-furoate-vilanterol-and-lung-function-decline-in-patients-with-moderate-copd-and-heightened-cardiovascular-risk
#7
Peter M A Calverley, Julie A Anderson, Robert D Brook, Courtney Crim, Natacha Gallot, Sally Kilbride, Fernando Martinez, Julie Yates, David E Newby, Jørgen Vestbo, Robert Wise, Bartolome R Celli
RATIONALE: Many patients with chronic obstructive pulmonary disease (COPD) have an accelerated loss of lung function. It is unclear whether drug treatment can modify this in moderately severe disease. OBJECTIVES: In a pre-specified analysis of the key secondary outcome in the Study to Understand Mortality and MorbidITy (SUMMIT), we investigated whether the inhaled corticosteroid fluticasone furoate 100 μg (FF), the long-acting beta-agonist vilanterol 25 µg (VI) or the combination (FF/VI) modified the rate of decline in FEV1 compared with placebo...
July 24, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28736929/impact-of-cost-sharing-increases-on-continuity-of-specialty-drug-use-a-quasi-experimental-study
#8
Pengxiang Li, Tianyan Hu, Xinyan Yu, Salim Chahin, Nabila Dahodwala, Marissa Blum, Amy R Pettit, Jalpa A Doshi
OBJECTIVE: To examine the impact of cost-sharing increases on continuity of specialty drug use in Medicare beneficiaries with multiple sclerosis (MS) or rheumatoid arthritis (RA). DATA SOURCES/STUDY SETTING: Five percent Medicare claims data (2007-2010). STUDY DESIGN: Quasi-experimental study examining changes in specialty drug use among a group of Medicare Part D beneficiaries without low-income subsidies (non-LIS) as they transitioned from a 5 percent cost-sharing preperiod to a ≥25 percent cost-sharing postperiod, as compared to changes among a disease-matched contemporaneous control group of patients eligible for full low-income subsidies (LIS), who faced minor cost sharing (≤$6...
July 24, 2017: Health Services Research
https://www.readbyqxmd.com/read/28736828/genomic-and-metabolic-characterization-of-a-chromophobe-renal-cell-carcinoma-cell-line-model-uok276
#9
Youfeng Yang, Cathy D Vocke, Christopher J Ricketts, Darmood Wei, Hesed M Padilla-Nash, Martin Lang, Carole Sourbier, J Keith Killian, Shawna L Boyle, Robert Worrell, Paul S Meltzer, Thomas Ried, Maria J Merino, Adam R Metwalli, W Marston Linehan
Chromophobe renal cell carcinoma (ChRCC) represents 5% of all RCC cases and frequently demonstrates multiple chromosomal losses and an indolent pattern of local growth, but can demonstrate aggressive features and resistance to treatment in a metastatic setting. Cell line models are an important tool for the investigation of tumor biology and therapeutic drug efficacy. Currently, there are few ChRCC-derived cell lines and none is well characterized. This study characterizes a novel ChRCC-derived cell line model, UOK276...
June 9, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28736108/chronic-intermittent-ethanol-exposure-selectively-alters-the-expression-of-g%C3%AE-subunit-isoforms-and-rgs-subtypes-in-rat-prefrontal-cortex
#10
D Jluessen, H Sun, M M McGinnis, B A McCool, R Chen
Chronic alcohol exposure induces pronounced changes in GPCR-mediated G-protein signaling. Recent microarray and RNA-seq analyses suggest associations between alcohol abuse and the expression of genes involved in G-protein signaling. The activity of G-proteins (e.g. Gαi/o and Gαq) is negatively modulated by regulator of G-protein signaling (RGS) proteins which are implicated in drugs of abuse including alcohol. The present study used 7 days of chronic intermittent ethanol exposure followed by 24 hour withdrawal (CIE) to investigate changes in mRNA and protein levels of G-protein subunit isoforms and RGS protein subtypes in rat prefrontal cortex, a region associated with cognitive deficit attributed to excessive alcohol drinking...
July 20, 2017: Brain Research
https://www.readbyqxmd.com/read/28736028/association-between-tacrolimus-pharmacokinetics-and-cytochrome-p450-3a5-and-multidrug-resistance-protein-1-exon-21-polymorphisms
#11
M Soda, M Fujitani, R Michiuchi, A Shibayama, K Kanamori, S Yoshikuni, Y Ohno, T Tsuchiya, A Suzuki, K Horie, T Deguchi, Y Itoh, K Kitaichi
BACKGROUND: Individual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single-nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. METHODS: Thirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction-restriction fragment length polymorphism analysis...
July 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28736024/effects-of-sildenafil-and-tadalafil-on-edema-and-reactive-oxygen-species-production-in-an-experimental-model-of-lung-ischemia-reperfusion-injury
#12
J R Guerra-Mora, E Perales-Caldera, D Aguilar-León, C Nava-Sanchez, A Díaz-Cruz, N E Díaz-Martínez, P Santillán-Doherty, G Torres-Villalobos, C C Bravo-Reyna
BACKGROUND: Lung ischemia-reperfusion injury is characterized by formation of reactive oxygen species and cellular swelling leading to pulmonary edema and primary graft dysfunction. Phosphodiesterase 5 inhibitors could ameliorate lung ischemia-reperfusion injury by interfering in many molecular pathways. The aim of this work was to evaluate and compare the effects of sildenafil and tadalafil on edema and reactive oxygen species formation in an ex vivo nonhuman animal model of lung ischemia-reperfusion injury...
July 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28735423/the-anticoagulant-effect-of-heparin-during-radiofrequency-ablation-rfa-in-patients-taking-apixaban-or-rivaroxaban
#13
L C Brendel, F Dobler, G Hessling, J Michel, S L Braun, A L Steinsiek, P Groha, R Eckl, I Deisenhofer, A Hyseni, M Roest, I Ott, B Steppich
PURPOSE: Measuring the anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban and rivaroxaban is challenging, since the activated coagulation time (ACT) does not seem to reflect the true anticoagulant activity of these drugs. We therefore evaluated coagulation properties of apixaban and rivaroxaban during RFA by different coagulation assays to better monitor periprocedural hemostasis. METHODS: The study included 90 patients (61 ± 12 years) with atrial fibrillation who underwent RFA procedures...
July 22, 2017: Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing
https://www.readbyqxmd.com/read/28735185/mil-101-cr-go-for-dispersive-micro-solid-phase-extraction-of-pharmaceutical-residue-in-chicken-breast-used-in-microwave-assisted-coupling-with-hplc-ms-ms-detection
#14
Yudan Wang, Xinpeng Dai, Xi He, Lin Chen, Xiaohong Hou
In this work, MIL-101(Cr)@GO (Graphite Oxide) was synthesized using a hydrothermal synthesis method and was applied as a dispersive micro-solid-phase extraction (D-μ-SPE) sorbent for the efficient concentration of four residual drugs (metronidazole, MNZ; tinidazole, TNZ; chloramphenicol, CAP; sulfamethoxazole, SMX). Meanwhile, the extraction process was optimized by combining it with microwave-assisted extraction. Factors affecting the D-μ-SPE efficiency, such as selection of sorbent materials, pH of the sample solution, salting-out effect, amount of used material, extraction time, desorption solvent and desorption time, were studied...
July 11, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28735046/ceftolozane-tazobactam-activity-against-drug-resistant-enterobacteriaceae-and-pseudomonas-aeruginosa-causing-healthcare-associated-infections-in-australia-and-new-zealand-report-from-an-antimicrobial-surveillance-program-2013-2015
#15
M A Pfaller, D Shortridge, H S Sader, R K Flamm, M Castaneheira
OBJECTIVES: To evaluate the in vitro activity of ceftolozane-tazobactam and comparator agents tested against isolates of Enterobacteriaceae and Pseudomonas aeruginosa from patients in Australia and New Zealand with healthcare-associated infection. METHODS: A total of 1,459 gram-negative organisms (440P. aeruginosa and 1,019 Enterobacteriaceae) were consecutively collected from 11 medical centers located in Australia and New Zealand. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A10 document and the results interpreted according to EUCAST and CLSI breakpoint criteria...
July 19, 2017: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/28734777/inhibitor-mechanisms-in-the-s1-binding-site-of-the-dopamine-transporter-defined-by-multi-site-molecular-tethering-of-photoactive-cocaine-analogs
#16
Danielle Krout, Akula Bala Pramod, Rejwi Acharya Dahal, Michael J Tomlinson, Babita Sharma, James D Foster, Mu-Fa Zou, Comfort Boatang, Amy Hauck Newman, John R Lever, Roxanne A Vaughan, L Keith Henry
Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints...
July 19, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28734581/discovery-of-r-5-benzo-d-1-3-dioxol-5-yl-7-1-vinylsulfonyl-pyrrolidin-2-yl-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-amine-b6-as-a-potent-bmx-inhibitor-for-the-treatment-of-nsclc
#17
Linhong He, Da Li, Chufeng Zhang, Peng Bai, Lijuan Chen
Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2...
July 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28733560/mir-122-socs1-jak2-axis-regulates-allergic-inflammation-and-allergic-inflammation-promoted-cellular-interactions
#18
Kyeonga Noh, Misun Kim, Youngmi Kim, Hanearl Kim, Hyuna Kim, Jaehwan Byun, Yeongseo Park, Hansoo Lee, Yun Sil Lee, Jongseon Choe, Young Myeong Kim, Dooil Jeoung
The regulatory role of suppressor of cytokine signaling 1 (SOCS1) in inflammation has been reported. However, its role in allergic inflammation has not been previously reported. SOCS1 mediated in vitro and in vivo allergic inflammation. Histone deacetylase-3 (HDAC3), a mediator of allergic inflammation, interacted with SOCS1, and miR-384 inhibitor, a positive regulator of HDAC3, induced features of allergic inflammation in an SOCS1-dependent manner. miRNA array analysis showed that the expression of miR-122 was decreased by antigen-stimulation...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28733355/erk-mapk-signaling-is-required-for-pathway-specific-striatal-motor-functions
#19
Scott R Hutton, James M Otis, Erin M Kim, Yashna Lamsal, Garret D Stuber, William D Snider
The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell type-specific roles of ERK/MAPK signaling due to the reliance on globally-administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity...
July 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28733286/the-regulator-ldhr-and-the-d-lactate-dehydrogenase-ldha-of-burkholderia-multivorans-play-a-role-in-carbon-overflow-and-in-planktonic-cellular-aggregates-formation
#20
Inês N Silva, Marcelo J Ramires, Lisa A Azevedo, Ana R Guerreiro, Andreia C Tavares, Jörg D Becker, Leonilde M Moreira
LysR-type transcriptional regulators (LTTR) are the most commonly found regulators in Burkholderia cepacia complex, comprising opportunistic pathogens causing chronic respiratory infections in cystic fibrosis (CF) patients. Despite LTTRs being global regulators of pathogenicity in several bacteria, few have been characterized in Burkholderia Here, we showed that gene ldhR of B. multivorans encoding a LTTR is co-transcribed with ldhA encoding a d-lactate dehydrogenase, and evaluate their implication in virulence traits like exopolysaccharide (EPS) synthesis and biofilm formation...
July 21, 2017: Applied and Environmental Microbiology
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