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Quantitative systems pharmacology

Collin D Edington, Wen Li Kelly Chen, Emily Geishecker, Timothy Kassis, Luis R Soenksen, Brij M Bhushan, Duncan Freake, Jared Kirschner, Christian Maass, Nikolaos Tsamandouras, Jorge Valdez, Christi D Cook, Tom Parent, Stephen Snyder, Jiajie Yu, Emily Suter, Michael Shockley, Jason Velazquez, Jeremy J Velazquez, Linda Stockdale, Julia P Papps, Iris Lee, Nicholas Vann, Mario Gamboa, Matthew E LaBarge, Zhe Zhong, Xin Wang, Laurie A Boyer, Douglas A Lauffenburger, Rebecca L Carrier, Catherine Communal, Steven R Tannenbaum, Cynthia L Stokes, David J Hughes, Gaurav Rohatgi, David L Trumper, Murat Cirit, Linda G Griffith
Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs...
March 14, 2018: Scientific Reports
Teemu T Turunen, Ari Koskelainen
Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6...
March 5, 2018: Toxicology and Applied Pharmacology
Violeta Balbas-Martinez, Leire Ruiz-Cerdá, Itziar Irurzun-Arana, Ignacio González-García, An Vermeulen, José David Gómez-Mantilla, Iñaki F Trocóniz
MOTIVATION: The literature on complex diseases is abundant but not always quantitative. This is particularly so for Inflammatory Bowel Disease (IBD), where many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. We propose the elaboration and validation of a logic network for IBD able to capture the information available in the literature that will facilitate the identification/validation of therapeutic targets...
2018: PloS One
Carlisle S Bascom, Lawrence J Winship, Magdalena Bezanilla
Tip-growing cells elongate in a highly polarized manner via focused secretion of flexible cell-wall material. Calcium has been implicated as a vital factor in regulating the deposition of cell-wall material. However, deciphering the molecular and mechanistic calcium targets in vivo has remained challenging. Here, we investigated intracellular calcium dynamics in the moss Physcomitrella patens , which provides a system with an abundant source of genetically identical tip-growing cells, excellent cytology, and a large molecular genetic tool kit...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hyoungkyu Kim, Anthony G Hudetz, Joseph Lee, George A Mashour, UnCheol Lee
The integrated information theory (IIT) proposes a quantitative measure, denoted as Φ, of the amount of integrated information in a physical system, which is postulated to have an identity relationship with consciousness. IIT predicts that the value of Φ estimated from brain activities represents the level of consciousness across phylogeny and functional states. Practical limitations, such as the explosive computational demands required to estimate Φ for real systems, have hindered its application to the brain and raised questions about the utility of IIT in general...
2018: Frontiers in Human Neuroscience
Elisabeth Eppard, Ana de la Fuente, Nicole Mohr, Mareli Allmeroth, Rudolf Zentel, Matthias Miederer, Stefanie Pektor, Frank Rösch
BACKGROUND: In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177. RESULTS: Short linkers and as low as 1...
February 27, 2018: EJNMMI Research
Yuri Kosinsky, Simon J Dovedi, Kirill Peskov, Veronika Voronova, Lulu Chu, Helen Tomkinson, Nidal Al-Huniti, Donald R Stanski, Gabriel Helmlinger
BACKGROUND: Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radiation (RT) and anti PD-(L)1 therapies...
February 27, 2018: Journal for Immunotherapy of Cancer
Edward C Stites, Andrey S Shaw
KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles...
February 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
Mohammad O Faruque, Shaikh B Uddin, James W Barlow, Sheng Hu, Shuang Dong, Qian Cai, Xiaohua Li, Xuebo Hu
This study documents information on significant ethnomedicinal plants, which was collected from the traditional healers of three indigenous communities of Bangladesh. The documented data were quantitatively analyzed for the first time in this area. The information was obtained through open-ended, semi-structured questionnaires. The benefits, importance and coverage of ethnomedicine were expressed through several quantitative indices including Informant Consensus Factor (ICF), Use Value (UV), Frequency of Citation (FC), Relative Frequency of Citation (RFC) and Relative Importance Index (RI)...
2018: Frontiers in Pharmacology
Tamara Tomin, Katarina Fritz, Juergen Gindlhuber, Linda Waldherr, Bettina Pucher, Gerhard G Thallinger, Daniel K Nomura, Matthias Schittmayer, Ruth Birner-Gruenberger
Adipose triglyceride lipase (ATGL) catalyzes the rate limiting step in triacylglycerol breakdown in adipocytes but is expressed in most tissues. The enzyme was shown to be lost in many human tumors, and its loss may play a role in early stages of cancer development. Here we report that loss of ATGL supports a more aggressive cancer phenotype in a model system where ATGL was deleted in A549 lung cancer cells by CRISPR/Cas9. We observed that loss of ATGL led to triacylglycerol accumulation in lipid droplets, and higher levels of cellular phospholipid and bioactive lipid species (lyso- and ether-phospholipids)...
February 19, 2018: Journal of Proteome Research
Tanaya Vaidya, Jeff Kamta, Maher Chaar, Anusha Ande, Sihem Ait-Oudhia
Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking...
February 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Cornelis Smit, Sjoerd De Hoogd, Roger J M Brüggemann, Catherijne A J Knibbe
The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies...
February 12, 2018: Expert Opinion on Drug Metabolism & Toxicology
Jianghui Meng, Masaki Moriyama, Micha Feld, Joerg Buddenkotte, Timo Buhl, Attila Szöllösi, Jingming Zhang, Paul Miller, Andre Ghetti, Michael Fischer, Peter W Reeh, Chunxu Shan, Jiafu Wang, Martin Steinhoff
BACKGROUND: T helper type 2 cell-released interleukin 31 (IL-31) is a critical mediator in atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuro-immune axis of the skin is unknown. OBJECTIVE: To investigate the function of BNP in the peripheral sensory system and skin in IL-31-induced itch and neuro-epidermal communication in AD...
February 7, 2018: Journal of Allergy and Clinical Immunology
Jianping Zhao, Mei Wang, Bharathi Avula, Ikhlas A Khan
Phenethylamines (PEAs) are popular substances found in weight-loss and sports nutrition supplements. They are generally pharmacologically active and primarily affect the sympathetic nervous system. Many PEAs are synthetic chemicals and are on the prohibited list of the World Anti-Doping Agency. In this study, nuclear magnetic resonance (NMR) spectroscopy was applied to detect and identify the presence of PEAs in sports dietary supplements without the need for chromatographic separation or pre-knowledge on formulation...
January 26, 2018: Journal of Pharmaceutical and Biomedical Analysis
Enhua Shao, Seth D Scheetz, Wenting Xie, Edward A Burton
Optokinetic reflex (OKR) responses provide a convenient means to evaluate visual, integrative and oculomotor function in larval zebrafish. We measured multiple aspects of the OKR response in zebrafish exposed systemically to compounds altering signaling at GABAA receptors in order to derive quantitative concentration-response relationships. The GABAA antagonist picrotoxin caused concentration-dependent decreases in reflex gain, saccade velocity, saccade amplitude, interocular concordance and interocular gain...
February 2, 2018: Neuroscience Letters
Hugo Geerts, Athan Spiros, Patrick Roberts, Larry Alphs
Long-acting injectable (LAI) antipsychotic formulations are increasingly used for improving patient compliance and long-term outcomes. Transitioning to LAIs raises questions regarding how optimum efficacy can be rapidly achieved while minimizing potential efficacy and safety concerns related to overlapping plasma levels of prior treatments and the new LAI. Ideally, randomized clinical trials would provide guidance regarding transition algorithms, but the number of studies and sample size required to address relevant questions makes this approach unachievable...
January 25, 2018: Schizophrenia Research
Hugo Geerts, Athan Spiros, Patrick Roberts
BACKGROUND: Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. METHODS: We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission...
February 2, 2018: Alzheimer's Research & Therapy
John Owoicho Orgah, Miao Wang, Xiaohu Yang, Zhilong Wang, Dandan Wang, Qi Zhang, Guanwei Fan, Jihong Han, Gangjian Qin, Xiumei Gao, Yan Zhu
BACKGROUND/AIMS: High blood pressure is a major risk factor for chronic kidney disease. Currently, single-target anti-hypertensive drugs are not designed for high blood pressure-related organ damages. Danhong injection (DHI), made from the aqueous extracts of Radix Salviae miltiorrhizae and Flos Carthamus tinctorius, has various pharmacological effects, including BP lowering in SHR, mediated by the reduction of vascular remodeling and the up-regulation of Kallikrein-kinin system published recently by our team, yet if it renders renal protection remains unknown...
January 23, 2018: Kidney & Blood Pressure Research
Mireia Pagerols, Vanesa Richarte, Cristina Sánchez-Mora, Paula Rovira, María Soler Artigas, Iris Garcia-Martínez, Eva Calvo-Sánchez, Montse Corrales, Bruna Santos da Silva, Nina Roth Mota, Marcelo Moraes Victor, Luis Augusto Rohde, Eugenio Horacio Grevet, Claiton Henrique Dotto Bau, Bru Cormand, Miguel Casas, Josep Antoni Ramos-Quiroga, Marta Ribasés
Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome...
January 30, 2018: Scientific Reports
Zhipeng Wang, Davit A Potoyan, Peter G Wolynes
BACKGROUND: Transfection of NF κB synthetic decoy Oligodeoxynucleotides (ODNs) has been proposed as a promising therapeutic strategy for a variety of diseases arising from constitutive activation of the eukaryotic transcription factor NF κB. The decoy approach faces some limitations under physiological conditions notably nuclease-induced degradation. RESULTS: In this work, we show how a systems pharmacology model of NF κB regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF κB synthetic decoy ODNs on dose, unbinding kinetic rates and nuclease-induced degradation rates...
January 30, 2018: BMC Systems Biology
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