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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/28767254/variability-in-mass-spectrometry-based-quantification-of-clinically-relevant-drug-transporters-and-drug-metabolizing-enzymes
#1
Christine Wegler, Fabienne Z Gaugaz, Tommy B Andersson, Jacek R Wiśniewski, Diana Busch, Christian Gröer, Stefan Oswald, Agneta Norén, Frederik Weiss, Helen S Hammer, Thomas O Joos, Oliver Poetz, Brahim Achour, Amin Rostami-Hodjegan, Evita van de Steeg, Heleen Wortelboer, Per Artursson
Many different methods are used for mass-spectrometry based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various methods are comparable. Here, we compared six different mass spectrometry-based proteomics methods by measuring the expression of clinically relevant drug transporters and metabolizing enzymes in human liver. Mean protein concentrations were in general quantified to similar levels by methods using whole tissue lysates...
August 2, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28762127/microdialysis-as-an-important-technique-in-systems-pharmacology-a-historical-and-methodological-review
#2
Margareta Hammarlund-Udenaes
Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions...
July 31, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28758947/adiponectin-leptin-and-leptin-receptor-in-obese-patients-with-type-2-diabetes-treated-with-insulin-detemir
#3
Paweł Olczyk, Robert Koprowski, Katarzyna Komosinska-Vassev, Agnieszka Jura-Półtorak, Katarzyna Winsz-Szczotka, Kornelia Kuźnik-Trocha, Łukasz Mencner, Alicja Telega, Diana Ivanova, Krystyna Olczyk
The aim of the present study is to quantitatively assess the expression of selected regulatory molecules, such as leptin, leptin receptor, and adiponectin in the blood of obese patients with type 2 diabetes both before treatment and after six months of pharmacological therapy with the long-lasting insulin analogue, insulin detemir. A significant decrease in the analysed regulatory molecules, i.e., leptin receptor and adiponectin, was found in blood plasma of the patients with untreated type 2 diabetes. These changes were accompanied by an increase in plasma leptin concentrations...
July 30, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28754373/cannabidiol-disrupts-the-consolidation-of-specific-and-generalized-fear-memories-via-dorsal-hippocampus-cb1-and-cb2-receptors
#4
Cristina A J Stern, Thiago R da Silva, Ana M Raymundi, Camila P de Souza, Vinicius A Hiroaki-Sato, Luiza Kato, Francisco S Guimarães, Roberto Andreatini, Reinaldo N Takahashi, Leandro J Bertoglio
Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3...
July 25, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28747660/4-dimensional-functional-profiling-in-the-convulsant-treated-larval-zebrafish-brain
#5
Matthew J Winter, Dylan Windell, Jeremy Metz, Peter Matthews, Joe Pinion, Jonathan T Brown, Malcolm J Hetheridge, Jonathan S Ball, Stewart F Owen, Will S Redfern, Julian Moger, Andrew D Randall, Charles R Tyler
Functional neuroimaging, using genetically-encoded Ca(2+) sensors in larval zebrafish, offers a powerful combination of high spatiotemporal resolution and higher vertebrate relevance for quantitative neuropharmacological profiling. Here we use zebrafish larvae with pan-neuronal expression of GCaMP6s, combined with light sheet microscopy and a novel image processing pipeline, for the 4D profiling of chemoconvulsant action in multiple brain regions. In untreated larvae, regions associated with autonomic functionality, sensory processing and stress-responsiveness, consistently exhibited elevated spontaneous activity...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28740605/synthesis-of-a-fluorescently-labeled-68-ga-dota-toc-analog-for-somatostatin-receptor-targeting
#6
Sukhen C Ghosh, Servando Hernandez Vargas, Melissa Rodriguez, Susanne Kossatz, Julie Voss, Kendra S Carmon, Thomas Reiner, Agnes Schonbrunn, Ali Azhdarinia
Fluorescently labeled imaging agents can identify surgical margins in real-time to help achieve complete resections and minimize the likelihood of local recurrence. However, photon attenuation limits fluorescence-based imaging to superficial lesions or lesions that are a few millimeters beneath the tissue surface. Contrast agents that are dual-labeled with a radionuclide and fluorescent dye can overcome this limitation and combine quantitative, whole-body nuclear imaging with intraoperative fluorescence imaging...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28735000/application-of-pharmacometrics-and-quantitative-systems-pharmacology-to-cancer-therapy-the-example-of-luminal-a-breast-cancer
#7
REVIEW
Brett Fleisher, Ashley N Brown, Sihem Ait-Oudhia
Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs' efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC...
July 19, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28732770/pharmacologic-modeling-of-primary-mitochondrial-respiratory-chain-dysfunction-in-zebrafish
#8
James Byrnes, Rebecca Ganetzky, Richard Lightfoot, Michael Tzeng, Eiko Nakamaru-Ogiso, Christoph Seiler, Marni J Falk
Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects on function as well as mitochondrial biochemistry and physiology...
July 18, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28732200/systematic-metrics-depicting-cell-death-kinetics
#9
Ying Li, Junying Yuan
In a recent issue of Cell Systems, Forcina et al. (2017) developed a scalable time-lapse analysis of cell death kinetics (STACK) method and combined it with a "lag exponential death" model to quantitatively characterize the onset and rate of cell death. STACK provides a useful quantitative tool to determine how cell death kinetics may be modulated pharmacologically in cell culture systems.
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28722322/advanced-methods-for-dose-and-regimen-finding-during-drug-development-summary-of-the-ema-efpia-workshop-on-dose-finding-london-4-5-december-2014
#10
F T Musuamba, E Manolis, N Holford, Sya Cheung, L E Friberg, K Ogungbenro, M Posch, Jwt Yates, S Berry, N Thomas, S Corriol-Rohou, B Bornkamp, F Bretz, A C Hooker, P H Van der Graaf, J F Standing, J Hay, S Cole, V Gigante, K Karlsson, T Dumortier, N Benda, F Serone, S Das, A Brochot, F Ehmann, R Hemmings, I Skottheim Rusten
Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014)...
July 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28719615/a-human-tissue-based-functional-assay-platform-to-evaluate-the-immune-function-impact-of-small-molecule-inhibitors-that-target-the-immune-system
#11
Cristina St Pierre, Jane Guo, John D Shin, Laura W Engstrom, Hyun-Hee Lee, Alan Herbert, Laura Surdi, James Baker, Michael Salmon, Sanjiv Shah, J Michael Ellis, Hani Houshyar, Michael A Crackower, Melanie A Kleinschek, Dallas C Jones, Alexandra Hicks, Dennis M Zaller, Stephen E Alves, Ravisankar A Ramadas
While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer...
2017: PloS One
https://www.readbyqxmd.com/read/28705120/qsar-docking-admet-system-pharmacology-studies-on-tormentic-acid-derivatives-for-anticancer-activity
#12
Sarfaraz Alam, Feroz Khan
To explore the anticancer compounds from tormentic acid derivatives, a quantitative structure-activity relationship (QSAR) model was developed by the multiple linear regression methods. The developed QSAR model yielded a high activity-descriptors relationship accuracy of 94% referred by regression coefficient (r(2)= 0.94) and a high activity prediction accuracy of 91%. The QSAR study indicates that chemical descriptors, chiV5, T_T_Cl_7, T_2_T_4, SsCH3count, and Epsilon3 are significantly correlated with anticancer activity...
July 14, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28701209/alantolactone-a-natural-sesquiterpene-lactone-has-potent-antitumor-activity-against-glioblastoma-by-targeting-ikk%C3%AE-kinase-activity-and-interrupting-nf-%C3%AE%C2%BAb-cox-2-mediated-signaling-cascades
#13
Xun Wang, Zhenlong Yu, Chao Wang, Wei Cheng, Xiangge Tian, Xiaokui Huo, Yan Wang, Chengpeng Sun, Lei Feng, Jinshan Xing, Yulong Lan, Dongdong Sun, Qingjuan Hou, Baojing Zhang, Xiaochi Ma, Bo Zhang
BACKGROUND: Glioblastoma multiforme (GBM) is one of the most refractory and palindromic central nervous system (CNS) neoplasms, and current treatments have poor effects in GBM patients. Hence, the identification of novel therapeutic targets and the development of effective treatment strategies are essential. Alantolactone (ATL) has a wide range of pharmacological activities, and its anti-tumor effect is receiving increasing attention. However, the molecular mechanism underlying the anti-GBM activity of ATL remains poorly understood...
July 12, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28698304/prediction-of-clinically-relevant-herb-drug-clearance-interactions-using-a-whole-cell-approach-schisandra-sphenanthera-case-study
#14
Jonathan P Jackson, Kimberly M Freeman, Weslyn W Friley, Ashley G Herman, Christopher B Black, Kenneth R Brouwer, Amy L Roe
The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans including schizandrins and deoxyschizandrins. In China, Schisandra sphenanthera extract (SSE) is often co-administered with immunosuppressant treatment of transplant recipients. In cases of co-administration, the potential for herb-drug interactions (HDI) increases. Clinical studies have been employed to assess HDI of extracts including SSE...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28681552/logic-modeling-in-quantitative-systems-pharmacology
#15
Pauline Traynard, Luis Tobalina, Federica Eduati, Laurence Calzone, Julio Saez-Rodriguez
No abstract text is available yet for this article.
July 6, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28677899/validated-lc-ms-ms-method-for-quantitation-of-demethylbellidifolin-in-rat-plasma-and-its-application-to-pharmacokinetic-and-bioavailability-studies
#16
Jie Zhang, Huiyu Yan, Xiaoyu Qu, Wei Zhou
Demethylbellidifolin, a major xanthone compound of Swertia davidi Franch, showed many beneficial pharmacological effects including antioxidation, anti-inflammation, anti-fibrosis, and cardiovascular protection effects. In this research, a rapid and sensitive LC-MS/MS method for the quantitative analysis of demethylbellidifolin in rat plasma was developed. The demethylbellidifolin and internal standard of aurantio-obtusin were extracted from 50 μL of rat plasma samples with ethyl acetate, then the dried residue was reconstituted and injected in an HPLC system with ZORBAX SB-C18 analytical column (2...
July 5, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28654043/light-mediated-reversible-modulation-of-the-mitogen-activated-protein-kinase-pathway-during-cell-differentiation-and-xenopus-embryonic-development
#17
Vishnu V Krishnamurthy, Aurora J Turgeon, John S Khamo, Payel Mondal, Savanna R Sharum, Wenyan Mei, Jing Yang, Kai Zhang
Kinase activity is crucial for a plethora of cellular functions, including cell proliferation, differentiation, migration, and apoptosis. During early embryonic development, kinase activity is highly dynamic and widespread across the embryo. Pharmacological and genetic approaches are commonly used to probe kinase activities. Unfortunately, it is challenging to achieve superior spatial and temporal resolution using these strategies. Furthermore, it is not feasible to control the kinase activity in a reversible fashion in live cells and multicellular organisms...
June 15, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28651603/a-systems-pharmacology-based-approach-to-identify-novel-kv1-3-channel-dependent-mechanisms-in-microglial-activation
#18
Srikant Rangaraju, Syed Ali Raza, Andrea Pennati, Qiudong Deng, Eric B Dammer, Duc Duong, Michael W Pennington, Malu G Tansey, James J Lah, Ranjita Betarbet, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Kv1.3 potassium channels regulate microglial functions and are overexpressed in neuroinflammatory diseases. Kv1.3 blockade may selectively inhibit pro-inflammatory microglia in neurological diseases but the molecular and cellular mechanisms regulated by Kv1.3 channels are poorly defined. METHODS: We performed immunoblotting and flow cytometry to confirm Kv1.3 channel upregulation in lipopolysaccharide (LPS)-activated BV2 microglia and in brain mononuclear phagocytes freshly isolated from LPS-treated mice...
June 26, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28633807/differential-induction-of-atf3-and-ho-1-in-myeloid-cells-and-keratinocytes-via-dimethylfumarate-or-cyclosporine-a
#19
Stefanie Müller, Nikola Smatlik, Marc Burian, Kamran Ghoreschi, Martin Röcken, Amir S Yazdi
BACKGROUND: Chronic inflammatory skin diseases are characterized by controlled proliferation of keratinocytes. Here, activating transcription factor 3 (ATF3) might play a fundamental role. In these inflammatory diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53...
June 12, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28628860/in-silico-modeling-on-adme-properties-of-natural-products-classification-models-for-blood-brain-barrier-permeability-its-application-to-traditional-chinese-medicine-and-in-vitro-experimental-validation
#20
Xiuqing Zhang, Ting Liu, Xiaohui Fan, Ni Ai
In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high-throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP...
June 7, 2017: Journal of Molecular Graphics & Modelling
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