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https://www.readbyqxmd.com/read/29456800/discovery-and-in-vitro-optimization-of-3-sulfamoylbenzamides-as-romk-inhibitors
#1
Matthew F Sammons, Sujay V Kharade, Kevin J Filipski, Markus Boehm, Aaron C Smith, Andre Shavnya, Dilinie P Fernando, Matthew S Dowling, Philip A Carpino, Neil A Castle, Shannon G Zellmer, Brett M Antonio, James R Gosset, Anthony Carlo, Jerod S Denton
Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4 , this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29456707/resveratrol-induces-autophagic-apoptosis-via-the-lysosomal-cathepsin-d-pathway-in-human-drug-resistant-k562-adm-leukemia-cells
#2
Zhewen Zhang, Zhuan Liu, Jing Chen, Juan Yi, Juan Cheng, Wangqing Dun, Hulai Wei
The aim of the present study was to investigate the crosstalk between resveratrol (Res)-induced autophagy and apoptosis, and the molecular pathway by which autophagy leads to apoptotic death in drug-resistant K562/ADM leukemia cells. The viability of K562/ADM cells was determined using the MTT assay. The formation of autophagic vacuoles was detected using transmission electron microscopy and monodansylcadaverine (MDC) staining. Cell apoptosis was evaluated using flow cytometry. The expression of apoptosis- or autophagy-associated proteins was measured using western blotting...
March 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29456650/application-of-an-acellular-dermal-matrix-to-a-rabbit-model-of-oral-mucosal-defects
#3
Xiangliang Xu, Nianhui Cui, Enbo Wang
Acellular dermal matrices (ADMs) are increasingly used for the restoration of soft-tissue defects of the oral cavity due to their ability to facilitate faster healing and reduce scar formation without rejection. However, few studies have focused on the histopathology and biological mechanisms involved in their use. The aim of the present study was to observe tissue growth, histopathologic changes and altered biomolecular signatures that occur during the repair of oral defects in rabbit models over time, either with or without the employment of ADM...
March 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29454190/potholing-of-the-hydrophobic-heme-oxygenase-1-western-region-for-the-search-of-potent-and-selective-imidazole-based-inhibitors
#4
Loredana Salerno, Emanuele Amata, Giuseppe Romeo, Agostino Marrazzo, Orazio Prezzavento, Giuseppe Floresta, Valeria Sorrenti, Ignazio Barbagallo, Antonio Rescifina, Valeria Pittalà
Here we report the design, synthesis, and molecular modeling of new potent and selective imidazole-based HO-1 inhibitors in which the imidazole nucleus and the hydrophobic groups are linked by a phenylethanolic spacer. Most of the tested compounds showed a good inhibitor activity with IC 50 values in the low micromolar range, with two of them (1b and 1j) exhibiting also high selectivity toward HO-2. These results were obtained by the idea of potholing the entire volume of the principal hydrophobic western region with an appropriate ligand volume...
February 9, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29453199/simultaneous-assessment-of-clearance-metabolism-induction-and-drug-drug-interaction-potential-using-a-long-term-in-vitro-liver-model-for-a-novel-hepatitis-b-virus-inhibitor
#5
Nicole A Kratochwil, Miriam Triyatni, Martina B Mueller, Florian Klammers, Brian Leonard, Dan Turley, Josephine Schmaler, Aynur Ekiciler, Birgit Molitor, Isabelle Walter, Pierre-Alexis Gonsard, Charles A Tournillac, Alexandre Durrwell, Michaela Marschmann, Russell Jones, Mohammed Ullah, Franziska Boess, Giorgio Ottaviani, Yuyan Yin, Neil J Parrott, Stephen Fowler
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism, comparison of low clearance drugs as well as induction studies. Here, we present studies using a long-term liver model which show how metabolism and active transport, drug-drug interactions and enzyme induction in healthy and diseased states, e.g. hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for PBPK modeling...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29451392/evaluation-of-cams-for-14-c-microtracer-adme-studies-opportunities-to-change-the-current-drug-development-paradigm
#6
Frédéric Lozac'h, Simon Fahrni, Daniele De Maria, Caroline Welte, Joël Bourquin, Hans-Arno Synal, David Pearson, Markus Walles, Gian Camenisch
AIM: Although regulatory guidances require human metabolism information of drug candidates early in the development process, the human mass balance study (or hADME study), is performed relatively late. hADME studies typically involve the administration of a 14 C-radiolabelled drug where biological samples are measured by conventional scintillation counting analysis. Another approach is the administration of therapeutic doses containing a 14 C-microtracer followed by accelerator mass spectrometry (AMS) analysis, enabling hADME studies completion much earlier...
February 16, 2018: Bioanalysis
https://www.readbyqxmd.com/read/29451361/development-of-a-focused-library-of-triazole-linked-privileged-structure-based-conjugates-leading-to-the-discovery-of-novel-phenotypic-hits-against-protozoan-parasitic-infections
#7
Elisa Uliassi, Lorna Piazzi, Federica Belluti, Andrea Mazzanti, Marcel Kaiser, Reto Brun, Carolina B Moraes, Lucio H Freitas-Junior, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Chiara Borsari, Maria Paola Costi, Maria Laura Bolognesi
Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling...
February 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29449587/the-mechanisms-of-bushen-yizhi-formula-as-a-therapeutic-agent-against-alzheimer-s-disease
#8
Haobin Cai, Yunxia Luo, Xin Yan, Peng Ding, Yujie Huang, Shuhuan Fang, Rong Zhang, Yunbo Chen, Zhouke Guo, Jiansong Fang, Qi Wang, Jun Xu
Bushen-Yizhi prescription (BSYZ) has been an effective traditional Chinese medicine (TCM) prescription in treating Alzheimer's disease (AD) for hundreds of years. However, the underlying mechanisms have not been fully elucidated yet. In this work, a systems pharmacology approach was developed to reveal the underlying molecular mechanisms of BSYZ in treating AD. First, we obtained 329 candidate compounds of BSYZ by in silico ADME/T filter analysis and 138 AD-related targets were predicted by our in-house WEGA algorithm via mapping predicted targets into AD-related proteins...
February 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29436997/pyrazole-schiff-base-hybrid-as-an-anti-malarial-agent-synthesis-in-vitro-screening-and-molecular-docking-study
#9
Shilpy Aggarwal, Deepika Paliwal, Dhirender Kaushik, Girish Kumar Gupta, Ajay Kumar
BACKGROUND: Malaria, one of the most vital infectious diseases caused by protozoan parasites of the Plasmodium genus. As P. falciparum, the cause of most of the severe cases of malaria, is increasingly resistant to available drugs such as amodioquine, chloroquine, artemisinin, and antifolates, there is an urgent need of identify new targets for chemotherapy Objective: This study screened novel pyrazole derivatives carrying iminium & benzothiazole group for antimalarial potential against P...
February 12, 2018: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/29436678/trib2-knockdown-as-a-regulator-of-chemotherapy-resistance-and-proliferation-via-the-erk-stat3-signaling-pathway-in-human-chronic-myelogenous-leukemia-k562-adm-cells
#10
Xiancheng Ma, Xue Zhou, Haiyan Qu, Ying Ma, Zhen Yue, Wenjing Shang, Pingyu Wang, Shuyang Xie, Youjie Li, Yunxiao Sun
Acquired resistance to chemotherapy plays a critical role in human drug treatment failure in many tumor types. Multidrug resistance (MDR) to Adriamycin (ADM) also limits the efficacy of therapy in human chronic myelogenous leukemia (CML). The overexpression of drug efflux transporters is one mechanism uderlying MDR. In particular, the consistent activation of MDR1 and MDR‑associated protein 1 (MRP1) is involved in drug resistance. In the present study, ADM‑resistant human CML K562/ADM cells were stably transfected with a Tribbles homolog 2 (TRIB2)‑targeted vector...
February 7, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29436331/impact-of-adherence-to-antidepressants-on-long-term-prescription-opioid-use-cessation
#11
Jeffrey F Scherrer, Joanne Salas, Mark D Sullivan, Brian K Ahmedani, Laurel A Copeland, Kathleen K Bucholz, Thomas Burroughs, F David Schneider, Patrick J Lustman
BACKGROUND: Depression contributes to persistent opioid analgesic use (OAU). Treating depression may increase opioid cessation. Aims To determine if adherence to antidepressant medications (ADMs) v. non-adherence was associated with opioid cessation in patients with a new depression episode after >90 days of OAU. METHOD: Patients with non-cancer, non-HIV pain (n = 2821), with a new episode of depression following >90 days of OAU, were eligible if they received ≥1 ADM prescription from 2002 to 2012...
February 2018: British Journal of Psychiatry: the Journal of Mental Science
https://www.readbyqxmd.com/read/29434662/novel-devices-for-implant-based-breast-reconstruction-is-the-use-of-meshes-to-support-the-lower-pole-justified-in-terms-of-benefits-a-review-of-the-evidence
#12
REVIEW
Lorna Jane Cook, Tibor Kovacs
The use of novel devices such as acellular dermal matrices (ADMs) to support the lower pole in implant-based breast reconstructions (IBBRs) has been described as one of the most important advances in breast reconstructive surgery following mastectomy. However, the majority of outcomes studies focus primarily on providing evidence for the rates of short-term complications associated with their use, as opposed to their reported benefits. Given the high costs associated with using ADMs, together with an increasing number of alternative, cheaper synthetic products entering the market, it is important to clarify whether their use is actually justified and whether the alternative products offer equivalent or superior outcomes...
2018: Ecancermedicalscience
https://www.readbyqxmd.com/read/29433928/pharmacology-and-in-vivo-efficacy-of-pyridine-pyrimidine-amides-that-inhibit-microtubule-polymerization
#13
Adam Siddiqui-Jain, Jacob P Hoj, David W Cescon, Marc D Hansen
Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors. Pharmacokinetic experiments show oral bioavailability through gastric absorption. In vitro assays designed to predict absorption, distribution, metabolism, and excretion (ADME) and safety reveal a scaffold that is metabolically stable, evades P-glycoprotein, does not inhibit CYP enzymes, occurs as a significant free fraction in serum, and has exceptionally high cellular permeability...
February 9, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29430796/effect-of-denosumab-on-fasting-glucose-in-women-with-diabetes-or-prediabetes-from-the-freedom-trial
#14
Nicola Napoli, Nicola Pannacciulli, Eric Vittinghoff, Daria Crittenden, Jang Yun, Andrea Wang, Rachel Wagman, Ann V Schwartz
BACKGROUND: RANKL is a key regulator of bone resorption that may also modulate glucose metabolism. Denosumab (DMAb) is a fully human monoclonal antibody that binds RANKL and was associated with fracture risk reduction in the FREEDOM trial. We hypothesized that DMAb treatment decreased fasting serum glucose (FSG) relative to placebo in women with diabetes or prediabetes enrolled in FREEDOM. METHODS: Post-hoc analysis of FREEDOM, in which 7,808 postmenopausal osteoporotic women were randomized to receive DMAb or placebo every 6 months for 36 months...
February 11, 2018: Diabetes/metabolism Research and Reviews
https://www.readbyqxmd.com/read/29429576/in-silico-studies-synthesis-and-pharmacological-evaluation-to-explore-multi-targeted-approach-for-imidazole-analogues-as-potential-cholinesterase-inhibitors-with-neuroprotective-role-for-alzheimer-s-disease
#15
Archana S Gurjar, Mrunali N Darekar, Keng Yoon Yeong, Luyi Ooi
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters...
February 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29428994/occipitalis-muscle-using-for-repetitive-facial-nerve-stimulation-in-myasthenia-gravis
#16
Ahmet Yildirim, Turgut Adatepe, Aysegul Gunduz, Orhan Yagiz, Nurten Uzun
Repetitive nerve stimulation (RNS) is a highly sensitive electrophysiological test used for diagnosing myasthenia gravis (MG). Here, we evaluated electrodiagnostic value of RNS using facial nerve and occipitalis muscle. Patients with generalized MG were included. Clinical findings were assessed. RNS test was performed on occipitalis, nasalis, trapezius, abductor policis brevis (APB) and abductor digiti minimi (ADM) muscles. Twenty-five (78%) patients had relevant decrement during RNS test of at least one muscle...
February 10, 2018: Acta Neurologica Belgica
https://www.readbyqxmd.com/read/29428422/yeasts-from-skin-colonization-are-able-to-cross-the-acellular-dermal-matrix
#17
Isabele Carrilho Jarros, Érika Okuno, Maiara Ignacio Costa, Flávia Franco Veiga, Patricia de Souza Bonfim-Mendonça, Melyssa Fernanda Norman Negri, Terezinha Inez Estivalet Svidzinski
In recent decades, the prognosis for burn patients has improved considerably with the development of specialized care. The acellular dermal matrix (ADM) is a totally artificial acellular device that functions to control water loss, prevent penetration by bacteria and allow migration of endothelial cells and fibroblasts from patient tissues. However, little is known about its effectiveness against yeasts. The present study evaluated the capacity of colonization and migration of some human commensal yeasts. Three clinical isolates from skin scales, identified as Candida parapsilosis, Candida glabrata and Rhodotorula mucilaginosa, were used...
February 8, 2018: Microbial Pathogenesis
https://www.readbyqxmd.com/read/29427740/nk-18-a-promising-antimicrobial-peptide-anti-multidrug-resistant-leukemia-cells-and-lps-neutralizing-properties
#18
Jiexi Yan, Xiaolei Liang, Caijuan Bai, Lanxia Zhou, Juan Li, Kairong Wang, Yan Tang, Li Zhao
With the increase of multidrug resistance, novel anti-leukemia agents with diverse mechanisms of action are required to address this challenge. NK-18, the core region of mammalian derived protein NK-lysin, effectively inhibited the viability of both multidrug resistant and sensitive leukemia cell lines. Meanwhile, this proliferation inhibition effect was not distinct between sensitive and multidrug resistant leukemia cell line. NK-18 showed selectivity between non-tumorigenic and tumorigenic cells. It preferentially bound to tumor cells whose outer leaflet with high phosphatidylserine content...
February 7, 2018: Biochimie
https://www.readbyqxmd.com/read/29427125/survival-complications-and-functional-outcomes-of-cemented-megaprostheses-for-high-grade-osteosarcoma-around-the-knee
#19
Chunlin Zhang, Jianping Hu, Kunpeng Zhu, Tao Cai, Xiaolong Ma
PURPOSE: We initiated a retrospective study on the long-term survival of cemented endoprostheses for bone tumours around the knee to answer the following questions: (1) What was the survival of these patients? (2) What was the overall survival of cemented prostheses around the knee? (3) What types of failures were observed in these reconstructions? (4) Did the survival and complications vary according to the site of the implant? (5) What was the functional result after cemented prosthesis replacement around the knee? METHODS: From January 2006 to December 2013, 108 consecutive patients with an average age of 25 years, who had mature bone development as evidenced by imaging examinations, underwent 108 cemented endoprosthetic knee replacements for osteosarcoma resection...
February 9, 2018: International Orthopaedics
https://www.readbyqxmd.com/read/29426770/diastereoselective-synthesis-of-fused-cyclopropyl-3-amino-2-4-oxazine-%C3%AE-amyloid-cleaving-enzyme-bace-inhibitors-and-their-biological-evaluation
#20
Jonathan D Low, Michael D Bartberger, Yuan Cheng, Doug Whittington, Quifen Xue, Stephen Wood, Jennifer R Allen, Ana E Minatti
The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aβ40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease...
February 1, 2018: Bioorganic & Medicinal Chemistry Letters
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