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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/28549678/use-of-mathematics-to-guide-target-selection-in-systems-pharmacology-application-to-receptor-tyrosine-kinase-rtk-pathways
#1
Neil Benson, Piet H van der Graaf, Lambertus A Peletier
A key element of the drug discovery process is target selection. Although the topic is subject to much discussion and experimental effort, there are no defined quantitative rules around optimal selection. Often 'rules of thumb', that have not been subject to rigorous exploration, are used. In this paper we explore the 'rule of thumb' notion that the molecule that initiates a pathway signal is the optimal target. Given the multi-factorial and complex nature of this question, we have simplified an example pathway to its logical minimum of two steps and used a mathematical model of this to explore the different options in the context of typical small and large molecule drugs...
May 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28548387/a-quantitative-systems-physiology-model-of-renal-function-and-blood-pressure-regulation-model-description
#2
K M Hallow, Y Gebremichael
Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses...
May 26, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28542505/alzhcpi-a-knowledge-base-for-predicting-chemical-protein-interactions-towards-alzheimer-s-disease
#3
Jiansong Fang, Ling Wang, Yecheng Li, Wenwen Lian, Xiaocong Pang, Hong Wang, Dongsheng Yuan, Qi Wang, Ai-Lin Liu, Guan-Hua Du
Alzheimer's disease (AD) is a complicated progressive neurodegeneration disorder. To confront AD, scientists are searching for multi-target-directed ligands (MTDLs) to delay disease progression. The in silico prediction of chemical-protein interactions (CPI) can accelerate target identification and drug discovery. Previously, we developed 100 binary classifiers to predict the CPI for 25 key targets against AD using the multi-target quantitative structure-activity relationship (mt-QSAR) method. In this investigation, we aimed to apply the mt-QSAR method to enlarge the model library to predict CPI towards AD...
2017: PloS One
https://www.readbyqxmd.com/read/28540623/qsp-toolbox-computational-implementation-of-integrated-workflow-components-for-deploying-multi-scale-mechanistic-models
#4
Yougan Cheng, Craig J Thalhauser, Shepard Smithline, Jyotsna Pagidala, Marko Miladinov, Heather E Vezina, Manish Gupta, Tarek A Leil, Brian J Schmidt
Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, and is a powerful tool to gain mechanistic insights into the complex dynamics of biological systems in response to drug treatment. However, even once a suitable mathematical framework to describe the pathophysiology and mechanisms of interest is established, final model calibration and the exploration of variability can be challenging and time consuming. QSP models are often formulated as multi-scale, multi-compartment nonlinear systems of ordinary differential equations...
May 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28539709/multipathway-integrated-adjustment-mechanism-of-glycyrrhiza-triterpenes-curing-gastric-ulcer-in-rats
#5
Ying Wang, Shuai Wang, Yongrui Bao, Tianjiao Li, Xin Chang, Guanlin Yang, Xiansheng Meng
BACKGROUND: Gastric ulcer is a common chronic disease in human digestive system, which is difficult to cure, easy to relapse, and endangers human health seriously. Compared with western medicine, traditional Chinese medicine has a unique advantage in improving the general situation, stablizing medical condition, and with little side effects. Glycyrrhiza known as "king of all the medicine", has a range of pharmacological activities and is commonly used in a variety of proprietary Chinese medicines and formulations...
April 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28528284/biomarkers-in-epilepsy-a-modelling-perspective
#6
Sven C van Dijkman, Rob A Voskuyl, Elizabeth C de Lange
Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking...
May 17, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28514967/at1-receptor-response-to-non-saturating-ang-ii-concentrations-is-amplified-by-calcium-channel-blockers
#7
Kristoffer Bernhem, Kalaiselvan Krishnan, Alexander Bondar, Hjalmar Brismar, Anita Aperia, Lena Scott
BACKGROUND: Blockers of angiotensin II type 1 receptor (AT1R) and the voltage gated calcium channel 1.2 (CaV1.2) are commonly used for treatment of hypertension. Yet there is little information about the effect of physiological concentrations of angiotensin II (AngII) on AT1R signaling and whether there is a reciprocal regulation of AT1R signaling by CaV1.2. METHODS: To elucidate these questions, we have studied the Ca(2+) signaling response to physiological and pharmacological AngII doses in HEK293a cells, vascular smooth muscle cells and cardiomyocytes using a Ca(2+) sensitive dye as the principal sensor...
May 17, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28506868/drug-disease-modeling-in-the-pharmaceutical-industry-where-mechanistic-systems-pharmacology-and-statistical-pharmacometrics-meet
#8
Gabriel Helmlinger, Nidal Al-Huniti, Sergey Aksenov, Kirill Peskov, Melissa Hallow, Lulu Chu, David Boulton, Ulf Eriksson, Bengt Hamrén, Craig Lambert, Eric Masson, Helen Tomkinson, Donald Stanski
Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP)...
May 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28506867/towards-personalized-treatment-of-pain-using-a-quantitative-systems-pharmacology-approach
#9
REVIEW
Sebastiaan C Goulooze, Elke H J Krekels, Monique van Dijk, Dick Tibboel, Piet H van der Graaf, Thomas Hankemeier, Catherijne A J Knibbe, J G Coen van Hasselt
Pain is a complex biopsychosocial phenomenon of which the intensity, location and duration depends on various underlying components. Treatment of pain is associated with considerable inter-individual variability, and as such, requires a personalized approach. However, a priori prediction of optimal analgesic treatment for individual patients is still challenging. Another challenge is the assessment and treatment of pain in patients unable to self-report pain. In this mini-review, we first provide a brief overview of the various components underlying pain, and their associated biomarkers...
May 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28501692/trans-chalcone-added-in-topical-formulation-inhibits-skin-inflammation-and-oxidative-stress-in-a-model-of-ultraviolet-b-radiation-skin-damage-in-hairless-mice
#10
Renata M Martinez, Felipe A Pinho-Ribeiro, David L Vale, Vinicius S Steffen, Fabiana T M C Vicentini, Josiane A Vignoli, Marcela M Baracat, Sandra R Georgetti, Waldiceu A Verri, Rubia Casagrande
Trans-chalcone (TC) is a common precursor of flavonoids. However, the pharmacological properties of TC remain to be fully understood. The present study investigated whether topical formulation containing TC (TFcTC) presents therapeutic effect in UVB radiation-induced skin damage using disease, enzyme activity, antioxidant activity, protein and mRNA parameters. Control topical formulation (CTF) and TFcTC were applied in hairless mice before and after exposure to UVB radiation. Dorsal skin samples were collected after UVB exposure to evaluate: i) skin edema (weight) was measured by punch biopsy; ii) spectrophotometric assays were used to measure myeloperoxidase (MPO) and catalase activities, ferric (FRAP) and ABTS cation reducing antioxidant power, superoxide anion production and levels of reduced glutathione (GSH); iii) enzymography was used to measure matrix metalloproteinase-9 (MMP-9) activity; iv) chemiluminescence was used to measure the lipid peroxidation (LPO); v) enzyme-linked immunosorbent assay (ELISA) was used to measure tumor necrosis factor alpha (TNF-α) levels; vi) reverse transcription quantitative PCR (RT-qPCR) was used to measure cyclooxygenase-2 (COX-2), gp91(phox) (NADPH oxidase sub-unity), glutathione peroxidase-1 (Gpx1), glutathione reductase (Gr), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) mRNA expression...
May 2, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28476677/ethnobotanical-study-of-medicinal-plants-used-by-ribeirinhos-in-the-north-araguaia-microregion-mato-grosso-brazil
#11
Reginaldo Vicente Ribeiro, Isanete Geraldini Costa Bieski, Sikiru Olaitan Balogun, Domingos Tabajara de Oliveira Martins
ETHNOPHARMACOLOGICAL IMPORTANCE: Currently, in many traditional communities, such as the riverine community in the North Araguaia microregion (Mato Grosso, Brazil), plant knowledge and use represent the main, if not the only, therapeutic resource for the maintenance of health and/or treatment of diseases. This study aimed to identify and document species of medicinal plants used by local experts from riverine communities in the North Araguaia microregion in Mato Grosso State, and to further chemical and pharmacological studies on species selected based on searches in the relevant literature...
May 2, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28470301/notch-signaling-in-regulating-angiogenesis-in-a-3d-biomimetic-environment
#12
Yi Zheng, Shue Wang, Xufeng Xue, Alan Xu, Wei Liao, Alice Deng, Guohao Dai, Allen P Liu, Jianping Fu
Angiogenesis is a complex cellular process involving highly orchestrated invasion and organization of endothelial cells (ECs) in a three-dimensional (3D) environment. Recent evidence indicates that Notch signaling is critically involved in regulating specialized functions and distinct fates of ECs in newly formed vasculatures during angiogenesis. Here, we demonstrated, for the first time, the application of a microengineered biomimetic system to quantitatively investigate the role of Notch signaling in regulating early angiogenic sprouting and vasculature formation of ECs in a 3D extracellular matrix...
May 4, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/28467408/modelling-of-the-cancer-cell-cycle-as-a-tool-for-rational-drug-development-a-systems-pharmacology-approach-to-cyclotherapy
#13
Robert C Jackson, Giovanni Y Di Veroli, Siang-Boon Koh, Ian Goldlust, Frances M Richards, Duncan I Jodrell
The dynamic of cancer is intimately linked to a dysregulation of the cell cycle and signalling pathways. It has been argued that selectivity of treatments could exploit loss of checkpoint function in cancer cells, a concept termed "cyclotherapy". Quantitative approaches that describe these dysregulations can provide guidance in the design of novel or existing cancer therapies. We describe and illustrate this strategy via a mathematical model of the cell cycle that includes descriptions of the G1-S checkpoint and the spindle assembly checkpoint (SAC), the EGF signalling pathway and apoptosis...
May 3, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28460635/transcriptomic-profiling-and-quantitative-high-throughput-qhts-drug-screening-of-cdh1-deficient-hereditary-diffuse-gastric-cancer-hdgc-cells-identify-treatment-leads-for-familial-gastric-cancer
#14
Ina Chen, Lesley Mathews-Greiner, Dandan Li, Abisola Abisoye-Ogunniyan, Satyajit Ray, Yansong Bian, Vivek Shukla, Xiaohu Zhang, Raj Guha, Craig Thomas, Berkley Gryder, Athina Zacharia, Joal D Beane, Sarangan Ravichandran, Marc Ferrer, Udo Rudloff
BACKGROUND: Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease...
May 1, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28454554/impaired-lysosomal-activity-mediated-autophagic-flux-disruption-by-graphite-carbon-nanofibers-induce-apoptosis-in-human-lung-epithelial-cells-through-oxidative-stress-and-energetic-impairment
#15
Sandeep Mittal, Pradeep Kumar Sharma, Ratnakar Tiwari, Raja Gopal Rayavarapu, Jai Shankar, Lalit Kumar Singh Chauhan, Alok Kumar Pandey
BACKGROUND: Graphite carbon nanofibers (GCNF) have emerged as a potential alternative of carbon nanotubes (CNT) for various biomedical applications due to their superior physico-chemical properties. Therefore in-depth understanding of the GCNF induced toxic effects and underlying mechanisms in biological systems is of great interest. Currently, autophagy activation by nanomaterials is recognized as an emerging toxicity mechanism. However, the association of GCNF induced toxicity with this form of cell death is largely unknown...
April 28, 2017: Particle and Fibre Toxicology
https://www.readbyqxmd.com/read/28438697/predicting-drug-loading-in-pla-peg-nanoparticles
#16
M Meunier, A Goupil, P Lienard
Polymer nanoparticles present advantageous physical and biopharmaceutical properties as drug delivery systems compared to conventional liquid formulations. Active pharmaceutical ingredients (APIs) are often hydrophobic, thus not soluble in conventional liquid delivery. Encapsulating the drugs in polymer nanoparticles can improve their pharmacological and bio-distribution properties, preventing rapid clearance from the bloodstream. Such nanoparticles are commonly made of non-toxic amphiphilic self-assembling block copolymers where the core (poly-[d,l-lactic acid] or PLA) serves as a reservoir for the API and the external part (Poly-(Ethylene-Glycol) or PEG) serves as a stealth corona to avoid capture by macrophage...
April 21, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28435379/shifts-of-subgingival-bacterial-population-after-nonsurgical-and-pharmacological-therapy-of-localized-aggressive-periodontitis-followed-for-1-year-by-ion-torrent-pgm-platform
#17
Giuseppina Campisciano, Annamaria Toschetti, Manola Comar, Rosanna Di Taranto, Federico Berton, Claudio Stacchi
The possibility of targeting the hypervariable region V3 of the 16S rRNA gene using Ion Torrent Personal Genome Machine (PGM) could provide a complete analysis of subgingival plaque samples, potentially able to identify microbiological species missed by culture-based methods. A 16-year-old female smoker patient, affected by localized aggressive periodontitis, underwent a full-mouth disinfection protocol and was inserted in a 3-month recall program. Microbiological samples were collected at baseline and at 30, 100, 365 days follow-up and analyzed by Ion Torrent PGM...
January 2017: European Journal of Dentistry
https://www.readbyqxmd.com/read/28428749/deep-brain-stimulation-improves-the-symptoms-and-sensory-signs-of-persistent-central-neuropathic-pain-from-spinal-cord-injury-a-case-report
#18
Walter J Jermakowicz, Ian D Hentall, Jonathan R Jagid, Corneliu C Luca, James Adcock, Alberto Martinez-Arizala, Eva Widerström-Noga
Central neuropathic pain (CNP) is a significant problem after spinal cord injury (SCI). Pharmacological and non-pharmacological approaches may reduce the severity, but relief is rarely substantial. While deep brain stimulation (DBS) has been used to treat various chronic pain types, the technique has rarely been used to attenuate CNP after SCI. Here we present the case of a 54-year-old female with incomplete paraplegia who had severe CNP in the lower limbs and buttock areas since her injury 30 years prior. She was treated with bilateral DBS of the midbrain periaqueductal gray (PAG)...
2017: Frontiers in Human Neuroscience
https://www.readbyqxmd.com/read/28420580/comparative-pharmacodynamic-analysis-of-imidazoline-compounds-using-rat-model-of-ocular-mydriasis-with-a-test-of-quantitative-structure-activity-relationships
#19
Joanna Raczak-Gutknecht, Antoni Nasal, Teresa Frąckowiak, Anita Kornicka, Franciszek Sączewski, Renata Wawrzyniak, Łukasz Kubik, Roman Kaliszan
Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain...
April 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28418603/towards-quantitative-systems-pharmacology-models-of-chemotherapy-induced-neutropenia
#20
REVIEW
M Craig
Neutropenia is a serious toxic complication of chemotherapeutic treatment. For years, mathematical models have been developed to better predict hematological outcomes during chemotherapy in both the traditional pharmaceutical sciences and mathematical biology disciplines. An increasing number of quantitative systems pharmacology (QSP) models that combine systems approaches, physiology, and pharmacokinetics/pharmacodynamics have been successfully developed. Here, I detail the shift towards QSP efforts, emphasizing the importance of incorporating systems-level physiological considerations in pharmacometrics...
April 18, 2017: CPT: Pharmacometrics & Systems Pharmacology
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