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https://www.readbyqxmd.com/read/29149772/natural-history-of-infantile-onset-spinal-muscular-atrophy
#1
Stephen J Kolb, Christopher S Coffey, Jon W Yankey, Kristin Krosschell, W David Arnold, Seward B Rutkove, Kathryn J Swoboda, Sandra P Reyna, Ai Sakonju, Basil T Darras, Richard Shell, Nancy Kuntz, Diana Castro, Julie Parsons, Anne M Connolly, Claudia A Chiriboga, Craig McDonald, W Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B Shieh, Erika Finanger, Merit E Cudkowicz, Michelle M McGovern, D Elizabeth McNeil, Richard Finkel, Susan T Iannaccone, Edward Kaye, Allison Kingsley, Samantha R Renusch, Vicki L McGovern, Xueqian Wang, Phillip G Zaworski, Thomas W Prior, Arthur H M Burghes, Amy Bartlett, John T Kissel
OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age...
November 17, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/29149495/a-redox-activated-g-quadruplex-dna-binder-based-on-a-platinum-iv-salphen-complex
#2
Ramon Vilar, Stephane Bandeira, Jorge Gonzalez Garcia, Evangelina Pensa, Tim Albrecht
There has been increasing interest in the development of small molecules that can selectively bind to G-quadruplex DNA structures. The latter have been associated to a number of key biological processes and therefore are proposed to be potential targets for drug development. In this paper we report the first example of a reduction-activated G-quadruplex DNA binder. We show that a new octahedral platinum(IV)-salphen complex does not interact with DNA in aqueous media at pH 7.4; however, upon addition of bio-reductants such as ascorbic acid or glutathione, the compound readily reduces to the corresponding square planar platinum(II) complex...
November 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29148875/repurposing-of-kinase-inhibitors-as-broad-spectrum-antiviral-drugs
#3
Stanford Schor, Shirit Einav
The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies.
November 17, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/29146919/nucleosome-acidic-patch-targeting-binuclear-ruthenium-compounds-induce-aberrant-chromatin-condensation
#4
Gabriela E Davey, Zenita Adhireksan, Zhujun Ma, Tina Riedel, Deepti Sharma, Sivaraman Padavattan, Daniela Rhodes, Alexander Ludwig, Sara Sandin, Benjamin S Murray, Paul J Dyson, Curt A Davey
The 'acidic patch' is a highly electronegative cleft on the histone H2A-H2B dimer in the nucleosome. It is a fundamental motif for protein binding and chromatin dynamics, but the cellular impact of targeting this potentially therapeutic site with exogenous molecules remains unclear. Here, we characterize a family of binuclear ruthenium compounds that selectively target the nucleosome acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter-nucleosomal cross-links. In contrast to cisplatin or the progenitor RAPTA-C anticancer drugs, the binuclear agents neither arrest specific cell cycle phases nor elicit DNA damage response, but rather induce an irreversible, anomalous state of condensed chromatin that ultimately results in apoptosis...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29146518/fixed-dose-combinations-a-potential-means-to-boost-drug-development-for-selected-drugs
#5
EDITORIAL
Charles Oo, Sherwin K B Sy
No abstract text is available yet for this article.
November 13, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/29146472/discovery-of-the-first-low-shift-positive-allosteric-modulators-for-the-muscarinic-m1-receptor
#6
Alexander Flohr, Roman Hutter, Barbara Mueller, Claudia Bohnert, Mélanie Pellisson, Hervé Schaffhauser
Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer's disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM's) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor...
November 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29146188/old-drug-new-tricks-chlorhexidine-acts-as-a-potential-allosteric-inhibitor-toward-pak1
#7
Han-Wei Huang, Xiang-Yu Zhang, Pei-Lu Song, Hai-Lun Jiang, Wei Li, Peng-Liang Wang, Jian Wang, Fu-Nan Liu
This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor...
November 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29146135/multivalent-oleanolic-acid-human-serum-albumin-conjugate-as-nonglycosylated-neomucin-for-influenza-virus-capture-and-entry-inhibition
#8
Yang Yang, Hao-Jie He, Hao Chang, Yao Yu, Mei-Bing Yang, Yun He, Zhen-Chuan Fan, Suri S Iyer, Peng Yu
We report the synthesis of multivalent oleanolic acid (OA) protein conjugates as nonglycosylated neomucin mimic for the capture and entry inhibition of influenza viruses. Oleanolic acid derivatives bearing an amine-terminated linker were synthesized by esterification of carboxylic acid and further grafted onto the human serum albumin (HSA) via diethyl squarate method. The binding of hemagglutinin (HA) on the virion surface to the synthetic neomucin was evaluated by hemagglutination inhibition assay. The influenza virus capture ability of the PEGylated OA-HSA conjugate was further investigated by Dynamic Light Scattering (DLS), virus capture assay and Isothermal Titration Calorimeter (ITC) techniques...
October 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29146133/synthesis-and-bio-evaluation-of-indole-chalcone-based-benzopyrans-as-promising-antiligase-and-antiproliferative-agents
#9
Sampa Gupta, Pooja Maurya, Akanksha Upadhyay, Pragati Kushwaha, Shagun Krishna, Mohammad Imran Siddiqi, Koneni V Sashidhara, Dibyendu Banerjee
DNA replication and repair are complex processes accomplished by the concerted action of a network of enzymes and proteins. DNA ligases play a crucial role in these processes by catalyzing the nick joining between DNA strands. As compared to normal cells, elevated levels of human DNA ligase I (hLigI) is reported in some cancers. We studied the inhibition of hLigI mediated DNA nick sealing activity followed by the antiproliferative activity of novel indole-chalcone based benzopyran compounds on cancer cells...
November 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29145933/quantitative-structure-pharmacokinetics-relationships-for-plasma-protein-binding-of-basic-drugs
#10
Zvetanka Dobreva Zhivkova
PURPOSE: Binding of drugs to plasma proteins is a common physiological occurrence which may have a profound effect on both pharmacokinetics and pharmacodynamics. The early prediction of plasma protein binding (PPB) of new drug candidates is an important step in drug development process. The present study is focused on the development of quantitative structure - pharmacokinetics relationship (QSPkR) for the negative logarithm of the free fraction of the drug in plasma (pfu) of basic drugs...
2017: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29143192/middle-east-respiratory-syndrome-and-severe-acute-respiratory-syndrome-current-therapeutic-options-and-potential-targets-for-novel-therapies
#11
REVIEW
Julie Dyall, Robin Gross, Jason Kindrachuk, Reed F Johnson, Gene G Olinger, Lisa E Hensley, Matthew B Frieman, Peter B Jahrling
No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search was performed covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed...
November 15, 2017: Drugs
https://www.readbyqxmd.com/read/29142972/a-drug-development-tool-for-trial-enrichment-in-patients-with-autosomal-dominant-polycystic-kidney-disease
#12
Ronald D Perrone, Mohamad-Samer Mouksassi, Klaus Romero, Frank S Czerwiec, Arlene B Chapman, Berenice Y Gitomer, Vicente E Torres, Dana C Miskulin, Steve Broadbent, Jean F Marier
Introduction: Total kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease. Methods: A drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively...
May 2017: KI Reports
https://www.readbyqxmd.com/read/29142299/the-immunomodulatory-drug-glatiramer-acetate-is-also-an-effective-antimicrobial-agent-that-kills-gram-negative-bacteria
#13
Stig Hill Christiansen, Ronan A Murphy, Kristian Juul-Madsen, Marlene Fredborg, Michael Lykke Hvam, Esben Axelgaard, Sandra M Skovdal, Rikke Louise Meyer, Uffe B Skov Sørensen, Arne Möller, Jens Randel Nyengaard, Niels Nørskov-Lauritsen, Mikala Wang, Mihaela Gadjeva, Kenneth A Howard, Jane C Davies, Eskild Petersen, Thomas Vorup-Jensen
Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141549/a-high-throughput-quantitative-expression-analysis-of-cancer-related-genes-in-human-hepg2-cells-in-response-to-limonene-a-potential-anticancer-agent
#14
Rand R Hafidh, Saba Z Hussein, Mohammed Q MalAllah, Ahmed S Abdulamir, Fatimah Abu Bakar
BACKGROUND: Citrus bioactive compounds, as active anticancer agent, have been under focus by several studies worldwide. However, the underlying genes responsible for the anticancer potential have not been sufficiently highlighted. OBJECTIVES: The current study investigated the gene expression profile of hepatocellular carcinoma, HepG2, cells after treatment with Limonene. METHODS: The concentration that killed 50% of HepG2 cells was used to elucidate the genetic mechanisms of limonene anticancer activity...
November 14, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/29141541/ellagic-acid-a-logical-lead-for-drug-development
#15
Abolfazl Shakeri, Mohammad Reza Zirak, Amirhossein Sahebkar
BACKGROUND: Naturally occurring polyphenols are the subject of increasing attention due to their potent antioxidant activity and their marked effects on the prevention of various oxidative stress-associated diseases such as cancer. Ellagic acid (EA) is an herbal polyphenol that is structurally a condensed dimer of gallic acid. METHODS: This review aims to provide a comprehensive and updated overview on the biological activities of EA and potential therapeutic applications...
November 14, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29141224/genetic-and-genomic-characterization-of-462-melanoma-patient-derived-xenografts-tumor-biopsies-and-cell-lines
#16
Bradley Garman, Ioannis N Anastopoulos, Clemens Krepler, Patricia Brafford, Katrin Sproesser, Yuchao Jiang, Bradley Wubbenhorst, Ravi Amaravadi, Joseph Bennett, Marilda Beqiri, David Elder, Keith T Flaherty, Dennie T Frederick, Tara C Gangadhar, Michael Guarino, David Hoon, Giorgos Karakousis, Qin Liu, Nandita Mitra, Nicholas J Petrelli, Lynn Schuchter, Batool Shannan, Carol L Shields, Jennifer Wargo, Brandon Wenz, Melissa A Wilson, Min Xiao, Wei Xu, Xaiowei Xu, Xiangfan Yin, Nancy R Zhang, Michael A Davies, Meenhard Herlyn, Katherine L Nathanson
Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54), or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT) were identified...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29140757/new-insights-into-lymphoma-pathogenesis
#17
Kojo S J Elenitoba-Johnson, Megan S Lim
Lymphomas represent clonal proliferations of lymphocytes that are broadly classified based upon their maturity (peripheral or mature versus precursor) and lineage (B cell, T cell, and natural killer cell). Insights into the pathogenetic mechanisms involved in lymphoma impact the classification of lymphoma and have significant implications for the diagnosis and clinical management of patients. Serial scientific and technologic advances over the last 30 years in immunology, cytogenetics, molecular biology, gene expression profiling, mass spectrometry-based proteomics, and, more recently, next-generation sequencing have contributed to greatly enhance our understanding of the pathogenetic mechanisms in lymphoma...
November 15, 2017: Annual Review of Pathology
https://www.readbyqxmd.com/read/29140657/sunlight-and-other-disinfectants-disclosure-obligations-under-the-federal-securities-and-drug-regulatory-regimes
#18
Joseph G Milner
Drug development requires patience. Beyond the inherent uncertainty of the development process itself, U.S. drug developers must comply with the regulatory approval process overseen by the U.S. Food and Drug Administration (FDA). Because this process takes time, drug development also costs money. Drug companies seeking to raise funds in U.S. capital markets must navigate the securities regime governed by the Securities & Exchange Commission (SEC). Despite their similar roles as protectors of consumers and public markets, SEC and FDA send conflicting signals about the information drug companies need to disclose to the public...
2017: Food and Drug Law Journal
https://www.readbyqxmd.com/read/29140522/ecodrug-a-database-connecting-drugs-and-conservation-of-their-targets-across-species
#19
Bas Verbruggen, Lina Gunnarsson, Erik Kristiansson, Tobias Österlund, Stewart F Owen, Jason R Snape, Charles R Tyler
Pharmaceuticals are designed to interact with specific molecular targets in humans and these targets generally have orthologs in other species. This provides opportunities for the drug discovery community to use alternative model species for drug development. It also means, however, there is potential for mode of action related effects in non-target wildlife species as many pharmaceuticals reach the environment through patient use and manufacturing wastes. Acquiring insight in drug target ortholog predictions across species and taxonomic groups has proven difficult because of the lack of an optimal strategy and because necessary information is spread across multiple and diverse sources and platforms...
November 11, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29140112/a-2017-review-of-pharmacotherapy-for-treating-focal-epilepsy-where-are-we-now-and-how-will-treatment-develop
#20
Andreas Schulze-Bonhage
Focal epilepsy is the most common type of epilepsy with approximately 30 million patients affected worldwide. There is a major challenge to develop new antiepileptic treatments as currently approximately one third of patients remain uncontrolled under our best standards of care. Areas covered: An overview is given on first- and second generation antiepileptic drugs and their mechanisms of action, and on recent new strategies for antiepileptic targets, including drugs aiming at disease modification. Expert opinion: Newer antiepileptic drugs have enabled a better tolerated and individualized treatment for many patients...
November 15, 2017: Expert Opinion on Pharmacotherapy
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