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Quantitative systems pharmacology

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...
October 17, 2016: Photochemical & Photobiological Sciences
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
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
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
Cynthia J Musante, Saroja Ramanujan, Brian J Schmidt, Oliver G Ghobrial, James Lu, Astra Zeneca, Anne C Heatherington
No abstract text is available yet for this article.
October 6, 2016: Clinical Pharmacology and Therapeutics
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
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
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
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
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
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
C J Musante, D R Abernethy, S R Allerheiligen, D A Lauffenburger, M G Zager
Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics. As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal.
September 2016: CPT: Pharmacometrics & Systems Pharmacology
Jingcheng Xiao, Huimin Chen, Dian Kang, Yuhao Shao, Boyu Shen, Xinuo Li, Xiaoxi Yin, Zhangpei Zhu, Haofeng Li, Tai Rao, Lin Xie, Guangji Wang, Yan Liang
ETHNOPHARMACOLOGICAL RELEVANCE: Intestinal microflora plays crucial roles in modulating pharmacokinetic characteristics and pharmacological actions of active ingredients in traditional Chinese medicines (TCMs). However, the exact impact of altered intestinal microflora affecting the biotransformation of TCMs remains poorly understood. AIMS OF THE STUDY: This study aimed to reveal the specific enterobacteria which dominate the metabolism of panax notoginseng saponins (PNSs) via exploring the relationship between bacterial community structures and the metabolic profiles of PNSs...
September 13, 2016: Journal of Ethnopharmacology
Cesar Pichardo-Almarza, Vanessa Diaz-Zuccarini
Current computational and mathematical tools are demonstrating the high value of using systems modeling approaches (e.g. Quantitative Systems Pharmacology) to understand the effect of a given compound on the biological and physiological mechanisms related to a specific disease. This review provides a short survey of the evolution of the mathematical approaches used to understand the effect of particular cholesterol-lowering drugs, from pharmaco-kinetic (PK) / pharmaco-dynamic (PD) models, through physiologically base pharmacokinetic models (PBPK) to QSP...
September 4, 2016: Current Pharmaceutical Design
Rayene Ouelbani, Souheir Bensari, Toma Nardjes Mouas, Douadi Khelifi
ETHNO-PHARMACOLOGICAL RELEVANCE: Constantine and Mila regions have been investigated in an ethnobotanical study for the first time. A total of 102 medicinal plants have been cited to treat human ailments. Twenty-eight new species of 31 common plants with 151 new therapeutic applications and 12 new cited species including one endemic specie Zygophyllum cornutum Coss were found as compared to other Algerian regions. In addition, to the best of our knowledge, 369 new medicinal uses of 75 known plants, were reported for the first time in the Mediterranean basin...
August 31, 2016: Journal of Ethnopharmacology
Feixiong Cheng, Chuang Liu, Bairong Shen, Zhongming Zhao
BACKGROUND: Cancer is increasingly recognized as a cellular system phenomenon that is attributed to the accumulation of genetic or epigenetic alterations leading to the perturbation of the molecular network architecture. Elucidation of network properties that can characterize tumor initiation and progression, or pinpoint the molecular targets related to the drug sensitivity or resistance, is therefore of critical importance for providing systems-level insights into tumorigenesis and clinical outcome in the molecularly targeted cancer therapy...
2016: BMC Systems Biology
Seiichi Sakamoto, Nao Kikkawa, Toshitaka Kohno, Kuniyoshi Shimizu, Hiroyuki Tanaka, Satoshi Morimoto
Ganoderic acid A (GAA) is one of the major Ganoderma triterpenes produced by medicinal mushroom belonging to the genus Ganoderma (Ganodermataceae). Due to its interesting pharmacological activities, Ganoderma species have been traditionally used in China for the treatment of various diseases. Herein, we developed a colloidal gold-based immunochromatographic strip assay (ICA) for the rapid detection of GAA using highly specific monoclonal antibody against GAA (MAb 12A) conjugated with gold nanoparticles. Using the developed ICA, the detection of GAA can be completed within 15min after dipping the test strip into an analyte solution with the limit of detection (LOD) for GAA of ~500ng/mL...
October 2016: Fitoterapia
Ioannis P Androulakis
Quantitative Systems Pharmacology (QSP) is receiving increased attention. As the momentum builds and the expectations grow it is important to (re)assess and formalize the basic concepts and approaches. In this short review, I argue that QSP, in addition to enabling the rational integration of data and development of complex models, maybe more importantly, provides the foundations for developing an integrated framework for the assessment of drugs and their impact on disease within a broader context expanding the envelope to account in great detail for physiology, environment and prior history...
June 2016: Current Pharmacology Reports
Songhee Han, Ae Jin Jeong, Heejung Yang, Kyo Bin Kang, Haeri Lee, Eun Hee Yi, Byung Hak Kim, Chung-Hyun Cho, Jin Woong Chung, Sang Hyun Sung, Sang-Kyu Ye
ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng is one of the most well-known medicinal herbs in Korea and China, which has been used for treatment and prevention of cancer, obesity, diabetes, and cardiovascular diseases. Ginsenosides are the major components of P. ginseng, having a wide range of pharmacological activities. Among the ginsenosides, protopanaxadiol (PPD)-types reportedly have potent anti-cancer effects. Rh2 is PPD-type ginsenoside, and two stereoisomeric forms of Rh2 as 20(S)- and 20(R)-Rh2 were selectively isolated recently...
August 23, 2016: Journal of Ethnopharmacology
Yanyan Niu, Sensen Li, Zongtao Lin, Meixian Liu, Daidong Wang, Hong Wang, Shizhong Chen
Fufang Banbianlian Injection (FBI) has been widely used as an anti-inflammatory and anti-tumor prescription. To understand the relationships between its bioactive ingredients and pharmacological efficacies, our previous study has been successfully identified some DNA-binding compounds in FBI using an established on-line screening system, in which 4',6-diamidino-2-phenylindole (DAPI) was developed as a probe. However, DAPI can be only used to screen ATT-specific DNA minor groove binders, leaving the potential active intercalators unknown in FBI...
September 9, 2016: Journal of Chromatography. A
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