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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/28073755/advanced-boolean-modeling-of-biological-networks-applied-to-systems-pharmacology
#1
Itziar Irurzun-Arana, José Martín Pastor, Iñaki F Trocóniz, José David Gómez-Mantilla
MOTIVATION: Literature on complex diseases is abundant but not always quantitative. Many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. Tools for analysis of discrete networks are useful to capture the available information in the literature but have not been efficiently integrated by the pharmaceutical industry. We propose an expansion of the usual analysis of discrete networks that facilitates the identification/validation of therapeutic targets...
January 10, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28068846/impact-of-tamsulosin-and-nifedipine-on-contractility-of-pregnant-rat-ureters-in-vitro
#2
Lisette Haddad, Stéphanie Corriveau, Eric Rousseau, Simon Blouin, Jean-Charles Pasquier, Yves Ponsot, Marie-Ève Roy-Lacroix
OBJECTIVES: To evaluate the in vitro effect of tamsulosin and nifedipine on the contractility of pregnant rat ureters and to perform quantitative analysis of the pharmacological effects. Medical expulsive therapy (MET) is commonly used to treat urolithiasis. However, this treatment is seldom used in pregnant women since no studies support this practice. METHODS: This was an in vitro study on animal tissue derived from pregnant Sprague-Dawley rats. A total of 124 ureteral segments were mounted in an organ bath system and contractile response to methacholine (MCh) was assessed...
January 9, 2017: Journal of Maternal-fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/28067284/oleanolic-acid-ameliorates-high-glucose-induced-endothelial-dysfunction-via-ppar%C3%AE-activation
#3
Zihui Zhang, Manli Jiang, Xinya Xie, Haixia Yang, Xinfeng Wang, Lei Xiao, Nanping Wang
Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a pentacyclic triterpenes widely distributed in food, medicinal plants and nutritional supplements. OA exhibits various pharmacological properties, such as hepatoprotective and anti-tumor effects. In this study, we analyzed the effect of OA on endothelial dysfunction induced by high glucose in human vascular endothelial cells (ECs). Western blotting showed that OA attenuated high glucose-reduced nitric production oxide (NO) as well as Akt-Ser(473) and eNOS-Ser(1177) phosphorylation in cultured human umbilical vein ECs (HUVECs)...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28062203/semi-mechanistic-computer-simulation-of-psychotic-symptoms-in-schizophrenia-with-a-model-of-a-humanized-cortico-striatal-thalamocortical-loop
#4
Athan Spiros, Patrick Roberts, Hugo Geerts
Despite new insights into the pathophysiology of schizophrenia and clinical trials with highly selective drugs, no new therapeutic breakthroughs have been identified. We present a semi-mechanistic Quantitative Systems Pharmacology (QSP) computer model of a biophysically realistic cortical-striatal-thalamo-cortical loop. The model incorporates the direct, indirect and hyperdirect pathway of the basal ganglia and CNS drug targets that modulate neuronal firing, based on preclinical data about their localization and coupling to voltage-gated ion channels...
January 3, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28056959/morphological-densitometric-and-mechanical-properties-of-mandible-in-5-month-old-polish-merino-sheep
#5
Anna Szabelska, Marcin R Tatara, Witold Krupski
BACKGROUND: Among bones building the axial and appendicular skeleton, the mandible is characterized by unique morphological and functional traits. The aim of the study was to evaluate morphological, densitometric and mechanical properties of mandible in 5-month-old Polish Merino sheep. Using quantitative computed tomography, volumetric bone mineral density (vBMD) and calcium hydroxyapatite density of the cortical bone (CbCa-HA), mean vBMD (MvBMD) and total bone volume were determined...
January 5, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28056947/triptolide-induces-hepatotoxicity-via-inhibition-of-cyp450s-in-rat-liver-microsomes
#6
Yan Lu, Tong Xie, Yajie Zhang, Fuqiong Zhou, Jie Ruan, Weina Zhu, Huaxu Zhu, Zhe Feng, Xueping Zhou
BACKGROUND: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored. METHODS: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28003814/the-selective-estrogen-receptor-modulator-raloxifene-inhibits-neutrophil-extracellular-trap-formation
#7
Roxana Flores, Simon Döhrmann, Christina Schaal, Abdul Hakkim, Victor Nizet, Ross Corriden
Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effects on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs)...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27978989/quantitative-systems-pharmacology-a-promising-approach-for-translational-pharmacology
#8
REVIEW
K Gadkar, D Kirouac, N Parrott, S Ramanujan
Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27965088/lanthionine-ketimine-ester-promotes-locomotor-recovery-after-spinal-cord-injury-by-reducing-neuroinflammation-and-promoting-axon-growth
#9
Ken Kotaka, Jun Nagai, Kenneth Hensley, Toshio Ohshima
The mammalian central nervous system (CNS) has limited regenerative ability after injury, largely due to scar formation and axonal growth inhibitors. Experimental suppression of neuroinflammation encourages recovery from spinal cord injury (SCI), yet practical means for pharmacologically treating SCI have remained elusive. Lanthionine ketimine (LK) is a natural brain sulfur amino acid metabolite with demonstrated anti-neuroinflammatory and neurotrophic activities. LK and its synthetic brain-penetrating ethyl ester (LKE) promote growth factor-dependent neurite extension in cultured cell and suppress microglial activation in animal models of neurodegeneration...
December 11, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27959401/midazolam-anesthesia-protects-neuronal-cells-from-oxidative-stress-induced-death-via-activation-of-the-jnk-erk-pathway
#10
Jing-Yu Liu, Feng Guo, Hong-Ling Wu, Ying Wang, Jin-Shan Liu
Midazolam is an anesthetic agent commonly used during clinical and surgical procedures, which has been shown to exert ROS‑suppressing and apoptosis‑modulating pharmacological activities in various cellular systems. However, the effects of midazolam on oxidative stress in neuronal cells require elucidation. The present study investigated the effects of midazolam on buthionine sulfoximine (BSO)‑ and hydrogen peroxide (H2O2)‑induced oxidative stress in primary cortical neuronal cells. In addition, the effects of midazolam on middle cerebral artery occlusion (MCAO) in mice and on ethanol‑induced neuroapoptosis in the brains of neonatal mice were determined...
January 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27934627/characterization-and-prediction-of-cardiovascular-effects-of-fingolimod-and-siponimod-using-a-systems-pharmacology-modelling-approach
#11
Nelleke Snelder, Bart A Ploeger, Olivier Luttringer, Dean F Rigel, Randy L Webb, David Feldman, Fumin Fu, Michael Beil, Liang Jin, Donald R Stanski, Meindert Danhof
Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once daily fingolimod (0, 0.1, 0.3, 1, 3 and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats...
December 1, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27933293/differences-in-the-mechanical-properties-of-the-developing-cerebral-cortical-proliferative-zone-between-mice-and-ferrets-at-both-the-tissue-and-single-cell-levels
#12
Arata Nagasaka, Tomoyasu Shinoda, Takumi Kawaue, Makoto Suzuki, Kazuaki Nagayama, Takeo Matsumoto, Naoto Ueno, Ayano Kawaguchi, Takaki Miyata
Cell-producing events in developing tissues are mechanically dynamic throughout the cell cycle. In many epithelial systems, cells are apicobasally tall, with nuclei and somata that adopt different apicobasal positions because nuclei and somata move in a cell cycle-dependent manner. This movement is apical during G2 phase and basal during G1 phase, whereas mitosis occurs at the apical surface. These movements are collectively referred to as interkinetic nuclear migration, and such epithelia are called "pseudostratified...
2016: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/27932946/increased-brain-neurotensin-and-ntsr2-lead-to-weak-nociception-in-ntsr3-sortilin-knockout-mice
#13
Christelle Devader, Sébastien Moreno, Morgane Roulot, Emmanuel Deval, Thomas Dix, Carlos R Morales, Jean Mazella
The neuropeptide neurotensin (NT) elicits numerous pharmacological effects through three different receptors (NTSR1, NTSR2, and NTSR3 also called sortilin). Pharmacological approaches and generation of NTSR1 and NTSR2-deficient mice allowed to determine the NT-induced antipsychotic like behavior, the inhibitory of weak fear memory and the nociceptive signaling in a rat formalin tonic pain model to NTSR1. Conversely, the effects of NT on thermal and tonic nociceptions were mediated by NTSR2. However, the role of NTSR3/sortilin on the neurotensinergic system was not investigated...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27927703/pharmacokinetics-and-pharmacodynamics-of-oral-mecamylamine-development-of-a-nicotinic-acetylcholine-receptor-antagonist-cognitive-challenge-test-using-modelling-and-simulation
#14
Ricardo Alvarez-Jimenez, Anne Catrien Baakman, Jasper Stevens, Sebastiaan C Goulooze, Ellen P Hart, Robert Rissmann, Joop Ma van Gerven, Geert Jan Groeneveld
A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects...
December 7, 2016: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/27919211/development-of-mlr-and-svm-aided-qsar-models-to-identify-common-sar-of-gaba-uptake-herbal-inhibitors-used-in-the-treatment-of-schizophrenia
#15
Sahila Mohammed Marunnan, Babitha Pallikkara Pulikka, Anitha Jabamalairaj, Srinivas Bandaru, Mukesh Yadav, Anuraj Nayarisseri, Victor Arokia Doss
Deficits in GABAnergic system is implicated in the pathophysiology of schizophrenia. Available antipsychotics that target GABA receptor form a desirable therapeutic strategy in the treatment regimen of schizophrenia but, unfortunately, suffers serious setback due to their prolonged side effects. The present investigation focuses on developing QSAR models from the biological activity of herbal compounds and their derivatives that promise to be alternative candidates to GABA uptake inhibitors. Three sets of compounds were undertaken in the study to develop the QSAR models...
5, 2016: Current Neuropharmacology
https://www.readbyqxmd.com/read/27913166/dose-dependent-effect-of-donepezil-administration-on-long-term-enhancement-of-visually-evoked-potentials-and-cholinergic-receptor-overexpression-in-rat-visual-cortex
#16
Mira Chamoun, Marianne Groleau, Menakshi Bhat, Elvire Vaucher
Stimulation of the cholinergic system tightly coupled with periods of visual stimulation boosts the processing of specific visual stimuli via muscarinic and nicotinic receptors in terms of intensity, priority and long-term effect. However, it is not known whether more diffuse pharmacological stimulation with donepezil, a cholinesterase inhibitor, is an efficient tool for enhancing visual processing and perception. The goal of the present study was to potentiate cholinergic transmission with donepezil treatment (0...
September 2016: Journal of Physiology, Paris
https://www.readbyqxmd.com/read/27895618/cyclooxygenase-1-as-a-potential-therapeutic-target-for-seizure-suppression-evidences-from-zebrafish-pentylenetetrazole-seizure-model
#17
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
#18
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...
April 15, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/27864221/cyclin-d-mediates-tolerance-of-genome-doubling-in-cancers-with-functional-p53
#19
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
#20
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
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