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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/27895618/cyclooxygenase-1-as-a-potential-therapeutic-target-for-seizure-suppression-evidences-from-zebrafish-pentylenetetrazole-seizure-model
#1
Patrícia Gonçalves Barbalho, Benilton de Sá Carvalho, Iscia Lopes-Cendes, Claudia Vianna Maurer-Morelli
Cyclooxygenases (COX)-1 and -2 are isoenzymes that catalyze the conversion of arachidonic acid into prostaglandins (PGs). COX-2 and PGs are rapidly increased following seizures and are known to play important roles in the neuroinflammatory process. COX-2 isoform has been predominantly explored as the most suitable target for pharmacological intervention in epilepsy studies, while COX-1 remains poorly investigated. In the present study, we evaluated the effects of selective COX-1 inhibitor or selective COX-2 inhibitor on seizure suppression in the zebrafish pentylenetetrazole (PTZ)-seizure model...
2016: Frontiers in Neurology
https://www.readbyqxmd.com/read/27886604/a-low-cost-and-palm-size-analyzer-for-rapid-and-sensitive-protein-detection-by-ac-electrokinetics-capacitive-sensing
#2
Xiaozhu Liu, Cheng Cheng, Jayne Wu, Shigetoshi Eda, Yongcai Guo
Specific detection of protein biomarkers has a wide range of applications in areas such as medical science, diagnostics, and pharmacology. Quantitative detection of protein biomarkers in biological media, such as serum, is critically important in detecting disease or physiological malfunction, or tracking disease progression. Among various detection methods, electrical detection is particularly well suited for point-of-care (POC) specific protein detection, being of low cost, light weight and small form factor...
November 11, 2016: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/27864221/cyclin-d-mediates-tolerance-of-genome-doubling-in-cancers-with-functional-p53
#3
A Crockford, L P Zalmas, E Grönroos, S M Dewhurst, N McGranahan, M E Cuomo, V Encheva, A P Snijders, J Begum, S Purewal, J Cerveira, H Patel, M J Renshaw, C Swanton
BACKGROUND: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidisation, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53 We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. METHODS: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently-derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor...
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27863172/building-confidence-in-quantitative-systems-pharmacology-models-an-engineer-s-guide-to-exploring-the-rationale-in-model-design-and-development
#4
J Timmis, K Alden, P Andrews, E Clark, A Nellis, B Naylor, M Coles, P Kaye
This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigour and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviours, are constructed to determine the confidence that a model is fit for the purpose for which it will be applied...
November 11, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27860547/the-discovery-of-suvorexant-the-first-orexin-receptor-drug-for-insomnia
#5
Paul J Coleman, Anthony L Gotter, W Joseph Herring, Christopher J Winrow, John J Renger
Historically, pharmacological therapies have used mechanisms such as γ- aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal...
November 17, 2016: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/27842772/evolution-of-experimental-models-of-the-liver-to-predict-human-drug-hepatotoxicity-and-efficacy
#6
REVIEW
Lawrence A Vernetti, Andreas Vogt, Albert Gough, D Lansing Taylor
In this article, we review the past applications of in vitro models in identifying human hepatotoxins and then focus on the use of multiscale experimental models in drug development, including the use of zebrafish and human cell-based, 3-dimensional, microfluidic systems of liver functions as key components in applying Quantitative Systems Pharmacology (QSP). We have implemented QSP as a platform to improve the rate of success in the process of drug discovery and development of therapeutics.
February 2017: Clinics in Liver Disease
https://www.readbyqxmd.com/read/27810625/computationally-efficient-analysis-of-particle-transport-and-deposition-in-a-human-whole-lung-airway-model-part-i-theory-and-model-validation
#7
Arun V Kolanjiyil, Clement Kleinstreuer
Computational predictions of aerosol transport and deposition in the human respiratory tract can assist in evaluating detrimental or therapeutic health effects when inhaling toxic particles or administering drugs. However, the sheer complexity of the human lung, featuring a total of 16 million tubular airways, prohibits detailed computer simulations of the fluid-particle dynamics for the entire respiratory system. Thus, in order to obtain useful and efficient particle deposition results, an alternative modeling approach is necessary where the whole-lung geometry is approximated and physiological boundary conditions are implemented to simulate breathing...
October 27, 2016: Computers in Biology and Medicine
https://www.readbyqxmd.com/read/27790730/development-and-validation-of-an-uplc-q-tof-ms-assay-for-the-quantitation-of-neopanaxadiol-in-beagle-dog-plasma-application-to-a-pharmacokinetic-study
#8
Cong Geng, Chun-Hong Wang, Hong Hu, Xiao-Ping Gao, Ai-Hua Gong, Ying-Wei Lin, Xiu-Shuang Fan, Heng Li, Jian-Yuan Yin
Neopanaxadiol (NPD), the main panaxadiol constituents of Panax ginseng C. A. Meyer (Araliaceae), has been regarded as the active component for the treatment of Alzheimer's disease. However, few references are available about pharmacokinetic evaluation for NPD. Accordingly, a rapid and sensitive method for quantitative analysis of NPD in beagle dog plasma based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry was developed and validated. Analytes were extracted from plasma by liquid-liquid extraction and chromatographic separation was achieved on an Agilent Zorbax Stable Bond C18 column...
October 27, 2016: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/27761201/the-promises-of-quantitative-systems-pharmacology-modelling-for-drug%C3%A2-development
#9
V R Knight-Schrijver, V Chelliah, L Cucurull-Sanchez, N Le Novère
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response...
2016: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/27748490/integrating-targeted-gene-expression-and-a-skin-model-system-to-identify-functional-inhibitors-of-the-uv-activated-p38-map-kinase
#10
Amaal Abrahams, Nicolas Mouchet, Nicolas Gouault, Françoise Lohézic Le Dévéhat, Myriam Le Roch, Isabelle Rouaud, David Gilot, Marie-Dominique Galibert
The stress-activated p38α MAP Kinase is an integral and critical component of the UV-induced inflammatory response. Despite the advances in recent years in the development of p38 kinase inhibitors, validation of these compounds in the diseased models remains limited. Based on the pharmacological profile of p38α inhibitor lead compound, SB203580, we synthesized a series of pyrrole-derivatives. Using UV-irradiated human skin punch-biopsies and cell cultures, we identified and validated the inhibitory activity of the derivatives by quantitatively measuring their effect on the expression of p38α target genes using real-time PCR...
November 30, 2016: Photochemical & Photobiological Sciences
https://www.readbyqxmd.com/read/27743502/modeling-and-experimental-studies-of-obeticholic-acid-exposure-and-the-impact-of-cirrhosis-stage
#11
J E Edwards, C LaCerte, T Peyret, N H Gosselin, J F Marier, A F Hofmann, D Shapiro
Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment...
October 15, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27729618/antibody-based-pet-of-upa-upar-signaling-with-broad-applicability-for-cancer-imaging
#12
Dongzhi Yang, Gregory W Severin, Casey A Dougherty, Rachel Lombardi, Daiqin Chen, Marcian E Van Dort, Todd E Barnhart, Brian D Ross, Andrew P Mazar, Hao Hong
Mounting evidence suggests that the urokinase plasminogen activator (uPA) and its receptor (uPAR) play a central role in tumor progression. The goal of this study was to develop an 89Zr-labeled, antibody-based positron emission tomography (PET) tracer for quantitative imaging of the uPA/uPAR system. An anti-uPA monoclonal antibody (ATN-291) was conjugated with a deferoxamine (Df) derivative and subsequently labeled with 89Zr. Flow cytometry, microscopy studies, and competitive binding assays were conducted to validate the binding specificity of Df-ATN-291 against uPA...
October 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27725802/preclinical-in-vivo-imaging-for-fat-tissue-identification-quantification-and-functional-characterization
#13
Pasquina Marzola, Federico Boschi, Francesco Moneta, Andrea Sbarbati, Carlo Zancanaro
Localization, differentiation, and quantitative assessment of fat tissues have always collected the interest of researchers. Nowadays, these topics are even more relevant as obesity (the excess of fat tissue) is considered a real pathology requiring in some cases pharmacological and surgical approaches. Several weight loss medications, acting either on the metabolism or on the central nervous system, are currently under preclinical or clinical investigation. Animal models of obesity have been developed and are widely used in pharmaceutical research...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27709613/quantitative-systems-pharmacology-a-case-for-disease-models
#14
C J Musante, S Ramanujan, B J Schmidt, O G Ghobrial, J Lu, A C Heatherington
Quantitative systems pharmacology (QSP) has emerged as an innovative approach in model-informed drug discovery and development, supporting program decisions from exploratory research through late-stage clinical trials. In this commentary, we discuss the unique value of disease-scale "platform" QSP models that are amenable to reuse and repurposing to support diverse clinical decisions in ways distinct from other pharmacometrics strategies.
October 6, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27703031/quantitative-phosphoproteomic-analysis-identifies-the-critical-role-of-jnk1-in-neuroinflammation-induced-by-japanese-encephalitis-virus
#15
Jing Ye, Hao Zhang, Wen He, Bibo Zhu, Dengyuan Zhou, Zheng Chen, Usama Ashraf, Yanming Wei, Ziduo Liu, Zhen F Fu, Huanchun Chen, Shengbo Cao
Japanese encephalitis virus (JEV) is the leading cause of epidemic encephalitis worldwide. The pathogenesis of JEV is linked to a robust inflammatory response in the central nervous system (CNS). Glial cells are the resident immune cells in the CNS and represent critical effectors of CNS inflammation. To obtain a global overview of signaling events in glial cells during JEV infection, we conducted phosphoproteomics profiling of a JEV-infected glial cell line. We identified 1816 phosphopeptides, corresponding to 1264 proteins, that exhibited a change in phosphorylation status upon JEV infection...
October 4, 2016: Science Signaling
https://www.readbyqxmd.com/read/27698205/a-reverse-genetics-cell-based-evaluation-of-genes-linked-to-healthy-human-tissue-age
#16
Hannah Crossland, Philip J Atherton, Anna Strömberg, Thomas Gustafsson, James A Timmons
We recently developed a binary (i.e., young vs. old) classifier using human muscle RNA profiles that accurately distinguished the age of multiple tissue types. Pathway analysis did not reveal regulators of these 150 genes, so we used reverse genetics and pharmacologic methods to explore regulation of gene expression. Using small interfering RNA, well-studied age-related factors (i.e., rapamycin, resveratrol, TNF-α, and staurosporine), quantitative real-time PCR and clustering analysis, we studied gene-gene interactions in human skeletal muscle and renal epithelial cells...
October 3, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27678262/genetic-and-pharmacologic-inhibition-of-the-chemokine-receptor-cxcr2-prevents-experimental-hypertension-and-vascular-dysfunction
#17
Lei Wang, Xue-Chen Zhao, Wei Cui, Yong-Qiang Ma, Hua-Liang Ren, Xin Zhou, John Fassett, Yan-Zong Yang, Yingjie Chen, Yun-Long Xia, Jie Du, Huihua Li
BACKGROUND: -The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases, however, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown. METHODS: -Angiotensin II (490 ng·kg(-1)·min(-1)) or DOCA-salt-induced mouse hypertensive models in genetic ablation, pharmacological inhibition of CXCR2 and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time PCR analysis), vascular remodeling (studied by haematoxylin and eosin (H&E) and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by NADPH oxidase activity, DHE staining and quantitative real-time PCR analysis)...
September 27, 2016: Circulation
https://www.readbyqxmd.com/read/27666750/a-quantitative-systems-pharmacology-model-of-blood-coagulation-network-describes-in-vivo-biomarker-changes-in-non-bleeding-subjects
#18
D Lee, S Nayak, S W Martin, A C Heatherington, P Vicini, F Hua
BACKGROUND: Prothrombin fragment 1.2 (PF12), thrombin-anti-thrombin III complex (TAT) and D-dimer can be detected in plasma from non-bleeding hemostatic normal or hemophilia subjects. They are often used as safety or pharmacodynamic biomarkers for hemostatic modulating therapies in clinic and provide insights into in vivo coagulation activity. OBJECTIVES: To develop a Quantitative Systems Pharmacology (QSP) model of blood coagulation network to describe in vivo biomarkers including PF12, TAT and D-dimer under non-bleeding condition...
September 26, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27647667/quantitative-systems-pharmacology-model-to-predict-the-effects-of-commonly-used-anticoagulants-on-the-human-coagulation-network
#19
S Hartmann, K Biliouris, L J Lesko, U Nowak-Göttl, M N Trame
Warfarin is the anticoagulant of choice for venous thromboembolism (VTE) treatment, although its suppression of the endogenous clot-dissolution complex APC:PS may ultimately lead to longer time-to-clot dissolution profiles, resulting in increased risk of re-thrombosis. This detrimental effect might not occur during VTE treatment using other anticoagulants, such as rivaroxaban or enoxaparin, given their different mechanisms of action within the coagulation network. A quantitative systems pharmacology model was developed describing the coagulation network to monitor clotting factor levels under warfarin, enoxaparin, and rivaroxaban treatment...
September 20, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27640752/virtual-clinical-trial-toward-polytherapy-safety-assessment-combination-of-physiologically-based-pharmacokinetic-pharmacodynamic-based-modeling-and-simulation-approach-with-drug-drug-interactions-involving-terfenadine-as-an-example
#20
Barbara Wiśniowska, Sebastian Polak
A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration...
November 2016: Journal of Pharmaceutical Sciences
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