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drug R&D

Hideaki Kagaya, Takenori Niioka, Mitsuru Saito, Takamitsu Inoue, Kazuyuki Numakura, Ryohei Yamamoto, Yumiko Akamine, Tomonori Habuchi, Shigeru Satoh, Masatomo Miura
While tacrolimus and everolimus have common metabolic pathways through CYP3A4/5, tacrolimus is metabolized solely by CYP3A4 in recipients with the CYP3A5*3 / *3 . The purpose of this study was to evaluate how the area under the blood concentration-time curves (AUC) of tacrolimus could be predicted based on CYP3A5 genotype and the AUC of everolimus in renal transplant patients taking both drugs. The dose-adjusted AUC (AUC/D) of tacrolimus and everolimus were calculated at one month and one year after transplantation...
March 16, 2018: International Journal of Molecular Sciences
Elle Wadsworth, Colin Drummond, Paolo Deluca
The Internet has played a major role in the distribution of New Psychoactive Substances (NPS), and crypto markets are increasingly used for the anonymous sale of drugs, including NPS. This study explores the availability of individual NPS and vendors on the crypto markets and considers whether crypto markets are a reliable platform for the sale of NPS. Data was collected from 22 crypto markets that were accessed through the hidden web using the Onion Router (Tor). Data collection took place bimonthly from October 2015 to October 2016 as part of the CASSANDRA ( C omputer A ssisted S olutions for S tudying the A vailability a N d D ist R ibution of novel psycho A ctive substances) project...
March 16, 2018: Brain Sciences
Michaël R Laurent
An overview of selected papers related to bone published in 2017 is provided. PURPOSE: This paper accompanies a lecture at the 2018 Belgian Bone Club annual Clinical Update Symposium held in Brussels on January 20th, discussing the best papers (in the opinion of the author) published in the previous year. METHODS: A PubMed search using the keyword "bone" and articles published in 2017. RESULTS: Hot topics include screening for osteoporosis, novel anabolic drugs such as romosozumab and abaloparatide for osteoporosis and rare metabolic bone diseases, as well as long-term efficacy of denosumab and possible risk of multiple vertebral fractures following its discontinuation...
March 15, 2018: Archives of Osteoporosis
Oliver D Montagnat, Graham R Webster, Jürgen B Bulitta, Cornelia Landersdorfer, Rosemary Wyber, Meru Sheel, Jonathan R Carapetis, Ben J Boyd
Jürgen B. Bulitta's name was misspelled in the original version of the article. It is correct as reflected here. The original article has been revised.
March 15, 2018: Drug Delivery and Translational Research
Shefali Setia Verma, Navya Josyula, Anurag Verma, Xinyuan Zhang, Yogasudha Veturi, Frederick E Dewey, Dustin N Hartzel, Daniel R Lavage, Joe Leader, Marylyn D Ritchie, Sarah A Pendergrass
The DrugBank database consists of ~800 genes that are well characterized drug targets. This list of genes is a useful resource for association testing. For example, loss of function (LOF) genetic variation has the potential to mimic the effect of drugs, and high impact variation in these genes can impact downstream traits. Identifying novel associations between genetic variation in these genes and a range of diseases can also uncover new uses for the drugs that target these genes. Phenome Wide Association Studies (PheWAS) have been successful in identifying genetic associations across hundreds of thousands of diseases...
March 15, 2018: Scientific Reports
Anthony J Kee, Jayshan Chagan, Jeng Yie Chan, Nicole S Bryce, Christine A Lucas, Jun Zeng, Jeff Hook, Herbert Treutlein, D Ross Laybutt, Justine R Stehn, Peter W Gunning, Edna C Hardeman
The development of novel small molecule inhibitors of the cancer-associated tropomyosin 3.1 (Tpm3.1) provides the ability to examine the metabolic function of specific actin filament populations. We have determined the ability of these anti-Tpm (ATM) compounds to regulate glucose metabolism in mice. Acute treatment (1 h) of wild-type (WT) mice with the compounds (TR100 and ATM1001) led to a decrease in glucose clearance due mainly to suppression of glucose-stimulated insulin secretion (GSIS) from the pancreatic islets...
March 15, 2018: Scientific Reports
Tao Yu, Yonglian Zhang, Angela D Kerekes, Jayaram R Tagat, Ronald J Doll, Yushi Xiao, Sara Esposite, Alan Hruza, David B Belanger, Matthew Voss, Matthew P Rainka, Andrea Basso, Ming Liu, Lianzhu Liang, Ning Sui, Daniel Prelusky, Diane Rindgen, Likang Zhang
Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.
February 23, 2018: Bioorganic & Medicinal Chemistry Letters
A J Ullmann, J M Aguado, S Arikan-Akdagli, D W Denning, A H Groll, K Lagrou, C Lass-Flörl, R E Lewis, P Munoz, P E Verweij, A Warris, F Ader, M Akova, M C Arendrup, R A Barnes, C Beigelman-Aubry, S Blot, E Bouza, R J M Brüggemann, D Buchheidt, J Cadranel, E Castagnola, A Chakrabarti, M Cuenca-Estrella, G Dimopoulos, J Fortun, J-P Gangneux, J Garbino, W J Heinz, R Herbrecht, C P Heussel, C C Kibbler, N Klimko, B J Kullberg, C Lange, T Lehrnbecher, J Löffler, O Lortholary, J Maertens, O Marchetti, J F Meis, L Pagano, P Ribaud, M Richardson, E Roilides, M Ruhnke, M Sanguinetti, D C Sheppard, J Sinkó, A Skiada, M J G T Vehreschild, C Viscoli, O A Cornely
The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended...
March 12, 2018: Clinical Microbiology and Infection
Shan Xing, Gregory S Calip, Alex D Leow, Shiyun Kim, Glen T Schumock, Daniel R Touchette, Todd A Lee
AIMS: To compare adherence and persistence to oral antidiabetic drugs (OAD) between patients who are new users of second generation antipsychotics (SGA) versus new users of other depression therapies in adults with type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD). METHODS: Adults 18-64 years with previously-treated T2DM and MDD (past OAD and SSRI/SNRI use) who are new users of SGA or non-SGA therapies (bupropion, lithium, mirtazapine, thyroid hormone, tricyclic antidepressant) were identified in the 2009-2015 MarketScan® Commercial Claims and Encounters database...
December 27, 2017: Journal of Diabetes and its Complications
Catherine R Lesko, Bryan Lau, Geetanjali Chander, Richard D Moore
Persons with HIV who have entered care but have viral load > 1500 copies/mL may be the source of the majority of new HIV infections in the United States. We followed patients engaged in continuity care in the Johns Hopkins HIV Clinical Cohort between January 2010 and August 2015. We estimated person-time spent with viral load > 1500 copies/mL while in care after antiretroviral therapy (ART) initiation, while in care, and while alive. Person-time was classified according to the most recent viral load measurement...
March 14, 2018: AIDS and Behavior
D Burkard, T Beckett, E Kourtjian, C Messingschlager, R Sipahi, M Padley, J Stubbart
Teriparatide is an anabolic therapy used to treat patients with osteoporosis and is only approved for 2 years of treatment. This is the first study to look at two common osteoporosis drugs in maintaining its beneficial effects: denosumab and zoledronic acid. Denosumab treatment was associated with the greatest increase in bone mineral density (BMD) at the femoral neck and lumbar spine, an amount that was statistically greater than no treatment and zoledronic acid treatment. INTRODUCTION: Teriparatide, a hallmark treatment for osteoporosis, has been shown to increase BMD and bone turnover...
March 14, 2018: Osteoporosis International
Colin R O'Dowd, Matthew D Helm, J S Shane Rountree, Jakub T Flasz, Elias Arkoudis, Hugues Miel, Peter R Hewitt, Linda Jordan, Oliver Barker, Caroline Hughes, Ewelina Rozycka, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Stephanie Feutren-Burton, Scarlett Dvorkin, Gerald Gavory, Timothy Harrison
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography...
March 8, 2018: ACS Medicinal Chemistry Letters
Collin D Edington, Wen Li Kelly Chen, Emily Geishecker, Timothy Kassis, Luis R Soenksen, Brij M Bhushan, Duncan Freake, Jared Kirschner, Christian Maass, Nikolaos Tsamandouras, Jorge Valdez, Christi D Cook, Tom Parent, Stephen Snyder, Jiajie Yu, Emily Suter, Michael Shockley, Jason Velazquez, Jeremy J Velazquez, Linda Stockdale, Julia P Papps, Iris Lee, Nicholas Vann, Mario Gamboa, Matthew E LaBarge, Zhe Zhong, Xin Wang, Laurie A Boyer, Douglas A Lauffenburger, Rebecca L Carrier, Catherine Communal, Steven R Tannenbaum, Cynthia L Stokes, David J Hughes, Gaurav Rohatgi, David L Trumper, Murat Cirit, Linda G Griffith
Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs...
March 14, 2018: Scientific Reports
Gabriela Nestal de Moraes, Zongling Ji, Lavender Y-N Fan, Shang Yao, Stefania Zona, Andrew D Sharrocks, Eric W-F Lam
The forkhead transcription factor FOXK2 plays a critical role in suppressing tumorigenesis and mediating cytotoxic drug action in breast cancer. However, the mechanism by which the biological function of FOXK2 is regulated remains poorly understood. Here, we investigated the role of SUMOylation in modulating FOXK2-mediated drug sensitivity. We identified SUMOylation consensus motifs within the FOXK2 sequence and constructed two SUMOylation-defective double mutants by converting lysine 527 and 633 to arginines and glutamic acid 529 and 635 to alanines, respectively...
March 13, 2018: Oncogenesis
D Marshall Brinkley, David DeNofrio, Robin Ruthazer, Amanda R Vest, Navin K Kapur, Gregory S Couper, Michael S Kiernan
BACKGROUND: Since Food and Drug Administration's approval of the HeartMate II left ventricular assist device (LVAD) as destination therapy, the number of hospitals offering LVAD therapy has grown rapidly. A rising number are performed at centers without internal transplant programs. We sought to determine whether outcomes after destination therapy LVAD implantation are similar at transplant and nontransplant centers. METHODS AND RESULTS: Adult recipients of a primary, continuous-flow LVAD as destination therapy between January 2012 and March 2014 from the Interagency Registry for Mechanically Assisted Circulatory Support were included...
March 2018: Circulation. Heart Failure
Michael Hallek, Bruce D Cheson, Daniel Catovsky, Federico Caligaris-Cappio, Guillermo Dighiero, Hartmut Döhner, Peter Hillmen, Michael Keating, Emili Montserrat, Nicholas Chiorazzi, Stephan Stilgenbauer, Kanti R Rai, John C Byrd, Barbara Eichhorst, Susan O'Brien, Tadeusz Robak, John F Seymour, Thomas J Kipps
In 2008, International Workshop on CLL (iwCLL) published consensus guidelines for the design and conduct of clinical trials for patients with chronic lymphocytic leukemia (CLL) that were revised from those previously published by the National Cancer Institute-sponsored Working Group. These guidelines provided definitions intended to standardize the assessment of patients that were adopted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the evaluation of new drugs. Since the publication of these guidelines there have been major advances in the biology and treatment of patients with CLL, prompting the iwCLL to evaluate and revise the 2008 criteria...
March 14, 2018: Blood
Seyedmojtaba Seyedmousavi, Sandra de M G Bosco, Sybren de Hoog, Frank Ebel, Daniel Elad, Renata R Gomes, Ilse D Jacobsen, An Martel, Bernard Mignon, Frank Pasmans, Elena Piecková, Anderson Messias Rodrigues, Karuna Singh, Vania A Vicente, Gudrun Wibbelt, Nathan P Wiederhold, Jacques Guillot
The importance of fungal infections in both human and animals has increased over the last decades. This article represents an overview of the different categories of fungal infections that can be encountered in animals originating from environmental sources without transmission to humans. In addition, the endemic infections with indirect transmission from the environment, the zoophilic fungal pathogens with near-direct transmission, the zoonotic fungi that can be directly transmitted from animals to humans, mycotoxicoses and antifungal resistance in animals will also be discussed...
April 1, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
John R Horton, Xu Liu, Lizhen Wu, Kai Zhang, John Shanks, Xing Zhang, Ganesha Rai, Bryan T Mott, Daniel J Jansen, Stephen C Kales, Mark J Henderson, Katherine Pohida, Yuhong Fang, Xin Hu, Ajit Jadhav, David J Maloney, Matthew D Hall, Anton Simeonov, Haian Fu, Paula M Vertino, Qin Yan, Xiaodong Cheng
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropane-carboxamide (compounds N54 and N55)...
March 14, 2018: Journal of Medicinal Chemistry
Jing Lu, Dong Lu, Zunyun Fu, Mingyue Zheng, Xiaomin Luo
Toxicity is an important reason for the failure of drug research and development (R&D). The traditional experimental testings for chemical toxicity profile are costly and time-consuming. Therefore, it is attractive to develop the effective and accurate alternatives, such as in silico prediction models. In this review, we discuss the practical use of some prediction models on three toxicity end points, including acute toxicity, carcinogenicity, and inhibition of the human ether-a-go-go-related gene ion channel (hERG)...
2018: Methods in Molecular Biology
Hari R Desu, Laura A Thoma, George C Wood
PURPOSE: Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo...
March 13, 2018: Pharmaceutical Research
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