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https://www.readbyqxmd.com/read/29783016/systematic-investigation-of-the-erigeron-breviscapus-mechanism-for-treating-cerebrovascular-disease
#1
Jiangmei Wang, Yangyang Chen, Baoshi Liu, Qian Wang, Lulu Zhang, Zhenzhong Wang, Jun Zhou, Wei Xiao, Chunli Zheng, Yonghua Wang
ETHNOPHARMACOLOGICAL RELEVANCE: Cerebrovascular diseases (CBVDs), characterized by striking morbidity and mortality, have become the most common life-threatening diseases. The existing drugs of CBVDs target one or a few of pathogenic factors, the efficacy of which is limited because of the complexity of CBVDs. Traditional Chinese medicine (TCM), featured by multi-component and multi-target endows the great effectiveness in CBVDs treatment. For instance, Erigeron breviscapus (vant.) Hand...
May 18, 2018: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29782889/development-of-robust-genotype-1a-hepatitis-c-replicons-harboring-adaptive-mutations-for-facilitating-the-antiviral-drug-discovery-and-study-of-virus-replication
#2
Hui-Mei Lin, Pei-Shan Wu, Han-Shu Hu, Wan-Chun Chang, Ren-Huang Wu, Jia-Ni Tian, Jyh-Haur Chern, Andrew Yueh
The hepatitis C virus (HCV) subgenomic replicon is a valuable tool for studying virus replication and HCV drug development. Despite the fact that HCV genotype 1a (HCV1a) is the most prevalent genotype in the United States, few HCV1a reporter replicon constructs have been reported, and their replication capacities are not as efficient as those of HCV1b or 2a, especially in transient expression. In this study, we selected efficient HCV1a replicons and characterized the novel adaptive mutations derived from stable HCV1a (strain H77) replicon cells after G418 selection...
May 18, 2018: Journal of Virological Methods
https://www.readbyqxmd.com/read/29782330/a-transgenic-mouse-model-for-hla-b-57-01-linked-abacavir-drug-tolerance-and-reactivity
#3
Marco Cardone, Karla Garcia, Mulualem E Tilahun, Lisa F Boyd, Sintayehu Gebreyohannes, Masahide Yano, Gregory Roderiquez, Adovi D Akue, Leslie Juengst, Elliot Mattson, Suryatheja Ananthula, Kannan Natarajan, Montserrat Puig, David H Margulies, Michael A Norcross
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo...
May 21, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29781145/core-outcome-set-for-gene-therapy-in-haemophilia-results-of-the-corehem-multistakeholder-project
#4
A Iorio, M W Skinner, E Clearfield, D Messner, G F Pierce, M Witkop, S Tunis
BACKGROUND: Gene therapy trial results show potential to cure haemophilia A and haemophilia B. Securing broad access to a cure for a lifelong chronic disease is anticipated to face barriers at the individual and healthcare system levels, which can be partly mitigated by harmonized planning of clinical research studies. The aim of the coreHEM project was to determine the set of outcome measures required to evaluate efficacy, safety, comparative effectiveness and value of gene therapy for haemophilia...
May 20, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/29781013/design-and-synthesis-of-aza-indolyl-maleimide-based-covalent-inhibitors-of-glycogen-synthase-kinase-3%C3%AE
#5
Zhimin Yang, Hui Liu, Botao Pan, Fengli He, Zhengying Pan
As an important kinase in multiple signal transduction pathways, GSK-3β has been an attractive target for chemical probe discovery and drug development. Compared to numerous reversible inhibitors that have been developed, covalent inhibitors of GSK-3β are noticeably lacking. Here, we report the discovery of a series of covalent GSK-3β inhibitors by optimizing both non-covalent interactions and reactive groups. Among these covalent inhibitors, compound 38b with a mild α-fluoromethyl amide reactive group emerges as a selective and covalent inhibitor against GSK-3β, effectively inhibits the phosphorylation of glycogen synthase and tau protein, and increases β-catenin's levels in living cells...
May 21, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29779664/pks-nrps-enzymology-and-structural-biology-considerations-in-protein-production
#6
Meredith A Skiba, Finn P Maloney, Qingyun Dan, Amy E Fraley, Courtney C Aldrich, Janet L Smith, W Clay Brown
The structural diversity and complexity of marine natural products have made them a rich and productive source of new bioactive molecules for drug development. The identification of these new compounds has led to extensive study of the protein constituents of the biosynthetic pathways from the producing microbes. Essential processes in the dissection of biosynthesis have been the elucidation of catalytic functions and the determination of 3D structures for enzymes of the polyketide synthases and nonribosomal peptide synthetases that carry out individual reactions...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29779382/specific-stereoisomeric-conformations-determine-the-drug-potency-of-cladosporin-scaffold-against-malarial-parasite
#7
Pronay Das, Palak Babbar, Nipun Malhotra, Manmohan Sharma, Gorakhnath R Jachak, Rajesh G Gonnade, Dhanasekaran Shanmugam, Karl Harlos, Manickam Yogavel, Amit Sharma, D Srinivasa Reddy
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332...
May 21, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29778696/renal-pre-competitive-consortium-rpc-2-discovering-therapeutic-targets-together
#8
Mark Tomilo, Heather Ascani, Barbara Mirel, Maria Chiara Magnone, Carol Moreno Quinn, Anil Karihaloo, Kevin Duffin, Uptal D Patel, Matthias Kretzler
Despite significant effort, patients with kidney disease have not seen their outcomes improved significantly over the past two decades. This has motivated clinicians and researchers to consider alternative methods to identifying risk factors, disease progression markers, and effective therapies. Genome-scale data sets from patients with renal disease can be used to establish a platform to improve understanding of the molecular basis of disease; however, such studies require expertise and resources. To overcome these challenges, we formed an academic-industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry...
May 17, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29777724/novel-mirna-biomarkers-for-genotoxicity-screening-in-mouse
#9
Hiroyuki Oka, Koichi Masuno, Takeki Uehara, Toru Okamoto, Yoshiharu Matsuura, Toru Nakano, Shinpei Yamaguchi
The genotoxic potential of drugs is a serious problem, and its evaluation is one of the most critical processes of drug development. Although the comet assay of compound-exposed tissue is a frequently used genotoxicity test, its high false-positive rate is a major complication, and we consistently obtained false-positive results using the comet assay of mouse liver for nine hepatotoxic non-genotoxins (NGTXs). To identify novel genotoxin (GTX)-specific biomarkers, we screened the expression of 750 microRNAs (miRNAs) in the livers of mice treated with GTXs or NGTXs...
May 16, 2018: Toxicology
https://www.readbyqxmd.com/read/29777528/state-of-the-art-review-on-physiologically-based-pharmacokinetic-modeling-in-pediatric-drug-development
#10
REVIEW
Venkata Yellepeddi, Joseph Rower, Xiaoxi Liu, Shaun Kumar, Jahidur Rashid, Catherine M T Sherwin
Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets...
May 18, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29776965/developmentally-inspired-human-organs-on-chips
#11
Donald E Ingber
Although initially developed to replace animal testing in drug development, human 'organ on a chip' (organ chip) microfluidic culture technology offers a new tool for studying tissue development and pathophysiology, which has brought us one step closer to carrying out human experimentation in vitro In this Spotlight article, I discuss the central role that developmental biology played in the early stages of organ-chip technology, and how these models have led to new insights into human physiology and disease mechanisms...
May 18, 2018: Development
https://www.readbyqxmd.com/read/29776602/blurring-boundaries-receptor-tyrosine-kinases-as-functional-g-protein-coupled-receptors
#12
Caitrin Crudden, Takashi Shibano, Dawei Song, Naida Suleymanova, Ada Girnita, Leonard Girnita
Receptor tyrosine kinases (RTKs) such as the insulin-like growth factor type 1 receptor (IGF-1R) control important biological activities as well as being involved in pathological processes. Due to their supportive nature in many human cancers they have long been considered attractive therapeutic targets. However, lessons learnt from early targeting trials highlight that a simple "active versus inactive" state model with classical kinase-only signaling is overly simplistic and does not describe reality...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29775322/prediction-of-human-cytochrome-p450-inhibition-using-a-multi-task-deep-autoencoder-neural-network
#13
Xiang Li, Youjun Xu, Luhua Lai, Jianfeng Pei
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multi-task model for concurrent inhibition prediction of five major CYP450 isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training multi-task autoencoder deep neural network (DNN) on a large dataset containing more than 13000 compounds, extracted from PubChem BioAssay Database...
May 18, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29775220/cystatin-c-is-a-more-reliable-biomarker-for-determining-egfr-to-support-drug-development-studies
#14
REVIEW
Sumit Kar, Sabina Paglialunga, Rafiqul Islam
Glomerular filtration rate (GFR) is routinely used as a surrogate endpoint for the development of investigational drugs in clinical trials. GFR and staging of chronic kidney disease are typically assessed by measuring the concentration of endogenous serum biomarkers such as albumin and creatinine. However, creatinine is subject to high biological variability, and levels of creatinine do not rise until nearly 50% of kidney function is damaged, leading to inaccurate chronic kidney disease staging and false negatives...
May 18, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29774062/-in-vivo-imaging-biomarkers-of-neuroinflammation-in-the-development-and-assessment-of-stroke-therapies-towards-clinical-translation
#15
REVIEW
Bastian Zinnhardt, Maximilian Wiesmann, Lisa Honold, Cristina Barca, Michael Schäfers, Amanda J Kiliaan, Andreas H Jacobs
Modulation of the inflammatory microenvironment after stroke opens a new avenue for the development of novel neurorestorative therapies in stroke. Understanding the spatio-temporal profile of (neuro-)inflammatory imaging biomarkers in detail thereby represents a crucial factor in the development and application of immunomodulatory therapies. The early integration of quantitative molecular imaging biomarkers in stroke drug development may provide key information about (i) early diagnosis and follow-up, (ii) spatio-temporal drug-target engagement (pharmacodynamic biomarker), (iii) differentiation of responders and non-responders in the patient cohort (inclusion/exclusion criteria; predictive biomarkers), and (iv) the mechanism of action...
2018: Theranostics
https://www.readbyqxmd.com/read/29773906/spectrofluorimetric-quantification-of-antibiotic-drug-concentration-in-bacterial-cells-for-the-characterization-of-translocation-across-bacterial-membranes
#16
Julia Vergalli, Estelle Dumont, Jelena Pajović, Bertrand Cinquin, Laure Maigre, Muriel Masi, Matthieu Réfrégiers, Jean-Marie Pagés
The efficacy of antibacterial molecules depends on their capacity to reach inhibitory concentrations in the vicinity of their target. This is particularly challenging for drugs directed against Gram-negative bacteria, which have a complex envelope comprising two membranes and efflux pumps. Precise determination of the bacterial drug content is an essential prerequisite for drug development. Here we describe three approaches that have been developed in our laboratories to quantify drugs accumulated in intact cells by spectrofluorimetry, microspectrofluorimetry, and kinetics microspectrofluorimetry (KMSF)...
June 2018: Nature Protocols
https://www.readbyqxmd.com/read/29773606/optimising-experimental-research-in-respiratory-diseases-an-ers-statement
#17
Philippe Bonniaud, Aurélie Fabre, Nelly Frossard, Christophe Guignabert, Mark Inman, Wolfgang M Kuebler, Tania Maes, Wei Shi, Martin Stampfli, Stefan Uhlig, Eric White, Martin Witzenrath, Pierre-Simon Bellaye, Bruno Crestani, Oliver Eickelberg, Heinz Fehrenbach, Andreas Guenther, Gisli Jenkins, Guy Joos, Antoine Magnan, Bernard Maitre, Ulrich A Maus, Petra Reinhold, Juanita H J Vernooy, Luca Richeldi, Martin Kolb
Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models...
May 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/29773016/is-cannabidiol-a-promising-substance-for-new-drug-development-a-review-of-its-potential-therapeutic-applications
#18
Nida Noreen, Faqir Muhammad, Bushra Akhtar, Farooq Azam, Muhammad Irfan Anwar
The pharmacological importance of cannabidiol (CBD) has been in study for several years. CBD is the major nonpsychoactive constituent of plant Cannabis sativa and its administration is associated with reduced side effects. Currently, CBD is undergoing a lot of research which suggests that it has no addictive effects, good safety profile and has exhibited powerful therapeutic potential in several vital areas. It has wide spectrum of action because it acts through endocannabinoid receptors; CB1 and CB2 and it also acts on other receptors, such as GPR18, GPR55, GPR 119, 5HT1A, and TRPV2...
2018: Critical Reviews in Eukaryotic Gene Expression
https://www.readbyqxmd.com/read/29772998/partially-purified-aqueous-fraction-of-desmodium-gyrans-dc-improves-reverse-cholesterol-transport-and-lipoprotein-metabolism-in-wistar-rats-fed-with-high-fat-diet
#19
M S Indu, Jose Padikkala, Achuthan C Raghavamenon
Apart from the conventional hypolipidemic therapy, plaque regression through enhanced reverse cholesterol transport (RCT) has emerged as novel approach in atherosclerotic drug development. High-density lipoprotein (HDL) mimetics as well as agents that augment the functional HDL and RCT pathways are under intense exploration. Desmodium gyrans (Fabacea) has been shown to have hypolipidemic efficacy, with an HDL-enhancing property. In this study, a chromatographically purified active fraction of D. gyrans (DGMAF) significantly decreased the serum and lipid profiles as well as lipotoxicity in liver in Wistar rats fed with high-fat diet (HFD)...
2018: Journal of Environmental Pathology, Toxicology and Oncology
https://www.readbyqxmd.com/read/29772753/dietary-polysaccharide-from-enteromorpha-clathrata-modulates-gut-microbiota-and-promotes-the-growth-of-akkermansia-muciniphila-bifidobacterium-spp-and-lactobacillus-spp
#20
Qingsen Shang, Ya Wang, Lin Pan, Qingfeng Niu, Chao Li, Hao Jiang, Chao Cai, Jiejie Hao, Guoyun Li, Guangli Yu
Recently, accumulating evidence has suggested that Enteromorpha clathrata polysaccharide (ECP) could contribute to the treatment of diseases. However, as a promising candidate for marine drug development, although ECP has been extensively studied, less consideration has been given to exploring its effect on gut microbiota. In this light, given the critical role of gut microbiota in health and disease, we investigated here the effect of ECP on gut microbiota using 16S rRNA high-throughput sequencing. As revealed by bioinformatic analyses, ECP considerably changed the structure of the gut microbiota and significantly promoted the growth of probiotic bacteria in C57BL/6J mice...
May 17, 2018: Marine Drugs
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