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Quantitative systems pharmacology

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https://www.readbyqxmd.com/read/28182247/translation-and-clinical-development-of-bispecific-t-cell-engaging-antibodies-for-cancer-treatment
#1
Theresa Yuraszeck, Sree Kasichayanula, Jonathan E Benjamin
Bispecific T Cell Engagers (BiTE®) antibody constructs enable a polyclonal T cell response to cell-surface tumor-associated antigens, bypassing the narrow specificities of T cell receptors and the need for antigen presentation through the Major Histocompatibility Complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs...
February 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28181140/real-architecture-for-3d-tissue-raft%C3%A2-culture-system-improves-viability-and-maintains-insulin-and-glucagon-production-of-mouse-pancreatic-islet-cells
#2
Gabor J Szebeni, Zsuzsanna Tancos, Liliana Z Feher, Robert Alfoldi, Julianna Kobolak, Andras Dinnyes, Laszlo G Puskas
There is an unmet medical need for the improvement of pancreatic islet maintenance in culture. Due to restricted donor availability it is essential to ameliorate islet viability and graft engraftment. The aim of this study was to compare the standard tissue culture techniques with the advanced Real Architecture For 3D Tissue (RAFT™) culture system in terms of viability and hormone production. Here, we first report that islets embedded in RAFT™ collagen type I advanced tissue culture system maintain their tissue integrity better than in monolayer and suspension cultures...
February 8, 2017: Cytotechnology
https://www.readbyqxmd.com/read/28174517/a-practical-guide-to-approaching-biased-agonism-at-g-protein-coupled-receptors
#3
Jaimee Gundry, Rachel Glenn, Priya Alagesan, Sudarshan Rajagopal
Biased agonism, the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a "biased" agonist compared to a "balanced" agonist, is a well-established paradigm for G protein-coupled receptor (GPCR) signaling. Biased agonists have the promise to act as smarter drugs by specifically targeting pathogenic or therapeutic signaling pathways while avoiding others that could lead to side effects. A number of biased agonists targeting a wide array of GPCRs have been described, primarily based on their signaling in pharmacological assays...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28166432/quantitative-histochemistry-for-macrophage-biodistribution-on-mice-liver-and-spleen-after-the-administration-of-a-pharmacological-relevant-dose-of-polyacrylic-acid-coated-iron-oxide-nanoparticles
#4
Daniela Rodrigues, Marisa Freitas, Vera Marisa Costa, M Arturo Lopez-Quintela, José Rivas, Paulo Freitas, Félix Carvalho, Eduarda Fernandes, Paula Silva
Understanding in vivo biodistribution of iron oxide nanoparticles (IONs), and the involvement of the phagocyte system in this process, is crucial for the assessment of their potential health risk. In the present study, the histochemical expression of iron in spleen and liver sections of CD-1 mice (aged 8 weeks) was quantified, 24 hours after intravenous administration of polyacrylic acid-coated IONs (PAA-coated IONs) (8, 20, 50 mg/kg). Organ sections were stained with Perls' Prussian blue for iron detection, followed by the quantification of iron deposition with ImageJ software...
February 6, 2017: Nanotoxicology
https://www.readbyqxmd.com/read/28157267/myocardial-fibrosis-biomedical-research-from-bench-to-bedside
#5
REVIEW
Mariann Gyöngyösi, Johannes Winkler, Isbaal Ramos, Quoc-Tuan Do, Hüseyin Firat, Kenneth McDonald, Arantxa González, Thomas Thum, Javier Díez, Frédéric Jaisser, Anne Pizard, Faiez Zannad
Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways...
February 2017: European Journal of Heart Failure
https://www.readbyqxmd.com/read/28147303/characterization-of-the-therapeutic-properties-of-chinese-herbal-materials-by-measuring-delayed-luminescence-and-dendritic-cell-based-immunomodulatory-response
#6
Mengmeng Sun, Wen-Te Chang, Eduard Van Wijk, Min He, Slavik Koval, Ming-Kuem Lin, Roel Van Wijk, Thomas Hankemeier, Jan van der Greef, Mei Wang
Based on the traditional Chinese medicine theory, the Chinese pharmacopeia assigns a therapeutic description of "taste" to all herbs; thus, an herb's "taste" is valued in traditional Chinese medicine as a major ethnopharmacological category and reflects the herb's therapeutic properties. These properties guide the practitioner with respect to preparing a specific herbal formula in order to provide each patient with a personalized intervention. The key challenge in evidence-based medicine is to characterize herbal therapeutic properties from a multi-target, multi-dimensional systems pharmacology perspective...
January 22, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28129975/the-role-of-quantitative-systems-pharmacology-modeling-in-the-prediction-and-explanation-of-idiosyncratic-drug-induced-liver-injury
#7
REVIEW
Jeffrey L Woodhead, Paul B Watkins, Brett A Howell, Scott Q Siler, Lisl K M Shoda
Idiosyncratic drug-induced liver injury (iDILI) is a serious concern in drug development. The rarity and multifactorial nature of iDILI makes it difficult to predict and explain. Recently, human leukocyte antigen (HLA) allele associations have provided strong support for a role of an adaptive immune response in the pathogenesis of many iDILI cases; however, it is likely that an adaptive immune attack requires several preceding events. Quantitative systems pharmacology (QSP), an in silico modeling technique that leverages known physiology and the results of in vitro experiments in order to make predictions about how drugs affect biological processes, is proposed as a potentially useful tool for predicting and explaining critical events that likely precede immune-mediated iDILI, as well as the immune attack itself...
November 21, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28125843/pituitary-adenylate-cyclase-activating-peptide-pacap-a-novel-secretagogue-regulates-secreted-morphogens-in-newborn-rat-retina
#8
Monika Lakk, Viktoria Denes, Karmen Kovacs, Orsolya Hideg, Bence F Szabo, Robert Gabriel
Purpose: Pituitary adenylate cyclase-activating peptide (PACAP)1-38 has been reported to be responsible for regulation of a disparate array of developmental processes in the central nervous system, and its antiapoptotic effect has been revealed in numerous models, pointing to its relevance in the etiology of neurodegenerative disorders. However, its function in retinal development remains unclear. Here, we aimed to point out that versatility can be achieved through interaction with other regulators, in which PACAP can act indirectly on the retinal microenvironment...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28120706/advanced-in-silico-approaches-for-drug-discovery-mining-information-from-multiple-biological-and-chemical-data-through-mtk-qsber-and-pt-qspr-strategies
#9
Alejandro Speck-Planche, Maria Natália Dias Soeiro Cordeiro
The last decade has been seeing an increase of public-private partnerships in drug discovery, mostly driven by factors such as the decline in productivity, the high costs, time, and resources needed, along with the requirements of regulatory agencies. In this context, traditional computer-aided drug discovery techniques have been playing an important role, enabling the identification of new molecular entities at early stages. However, recent advances in chemoinformatics and systems pharmacology, alongside with a growing body of high quality, publicly accessible medicinal chemistry data, have led to the emergence of novel in silico approaches...
January 24, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28097810/physicochemical-and-biological-evaluation-of-a-cinnamamide-derivative-r-s-2e-1-3-hydroxypiperidin-1-yl-3-phenylprop-2-en-1-one-km-608-for-nervous-system-disorders
#10
Agnieszka Gunia-Krzyżak, Ewa Żesławska, Florence Bareyre, Wojciech Nitek, Anna M Waszkielewicz, Henryk Marona
A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, additionally thermal analysis showed that it exists in one crystalline form...
January 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28073755/advanced-boolean-modeling-of-biological-networks-applied-to-systems-pharmacology
#11
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
#12
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 31, 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
#13
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
#14
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...
February 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
#15
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
#16
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
#17
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
#18
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
#19
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...
January 29, 2017: 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
#20
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
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