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Metabolism , propranolol

Nikolaos Tsamandouras, Tomasz Kostrzewski, Cynthia L Stokes, Linda G Griffith, David J Hughes, Murat Cirit
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from 5 different donors cultured in a perfused 3D human liver microphysiological system and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of 6 compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability (LDH release, albumin and urea production)...
October 19, 2016: Journal of Pharmacology and Experimental Therapeutics
Victor Hugo DA Silva Braga, Vinicius Araújo Armelin, Mariana Teodoro Teixeira, Augusto Shinya Abe, Francisco Tadeu Rantin, Luiz Henrique Florindo
The metabolic increment that occurs after feeding demands cardiovascular adjustments to be maintained, as increased heart rate (fH ) and cardiac output. In mammals, postprandial tachycardia seems to be triggered by an increase in adrenergic activity and by nonadrenergic noncholinergic (NANC) factors, while in ectothermic vertebrates, this adjustment seems to be linked to a withdrawal of vagal drive as well as to NANC factors. Because the factors behind postprandial tachycardia have not yet been investigated in crocodilians, the present study sought to evaluate the postprandial tachycardia mediators in the broad-nosed caiman...
September 21, 2016: Journal of Experimental Zoology. Part A, Ecological Genetics and Physiology
Nicole D Wagner, André J Simpson, Myrna J Simpson
The use of consumer products and pharmaceuticals that act as contaminants entering waterways through runoff and wastewater effluents alters aquatic ecosystem health. Traditional toxicological endpoints may underestimate the toxicity of contaminants, as lethal concentrations are often orders of magnitude higher than those found within freshwater ecosystems. While newer techniques examine the metabolic responses of sublethal contaminant exposure, there has been no direct comparison with ontogeny in Daphnia. It was hypothesized that Daphnia magna would have distinct metabolic changes after 3 different sublethal contaminant exposures, because of differences in the toxic mode of action and ontogeny...
October 5, 2016: Environmental Toxicology and Chemistry
Yoshiyuki Igawa, Seiya Fujiwara, Kayoko Ohura, Takatsugu Hirokawa, You Nishizawa, Shotaro Uehara, Yasuhiro Uno, Teruko Imai
Cynomolgus monkeys, used as an animal model to predict human pharmacokinetics, occasionally show different oral absorption patterns to humans due to differences in their intestinal metabolism. In this study, we investigated the differences between intestinal hydrolytic activities in cynomolgus monkeys and humans, in particular the catalyzing activities of their carboxylesterase 2 (CES2) isozymes. For this purpose we used both human and monkey microsomes and recombinant enzymes derived from a cell culture system...
September 6, 2016: Molecular Pharmaceutics
Taliha Harika Aydin, Özgür Devrim Can, Ümide Demir Özkay, Nazlı Turan
In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin-induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored by using metabolic cages. Potential effect of agomelatine on diabetes-induced mechanical and thermal allodynia was evaluated by using dynamic plantar aesthesiometer and warm plate (38°C) tests, respectively...
July 16, 2016: Fundamental & Clinical Pharmacology
Imene Nakib, Marie-France Martin-Eauclaire, Fatima Laraba-Djebari
Bot III neurotoxin is the most lethal α neurotoxin purified from Buthus occitanus tunetanus scorpion venom. This toxin binds to the voltage-gated sodium channel of excitable cells and blocks its inactivation, inducing an increased release of neurotransmitters (acetylcholine and catecholamines). This study aims to elucidate the involvement of cholinergic and adrenergic receptors in pathogenesis and inflammatory response triggered by this toxin. Injection of Bot III to animals induces an increase of peroxidase activities, an imbalance of oxidative status, tissue damages in lung parenchyma, and myocardium correlated with metabolic disorders...
October 2016: Inflammation
Ali Sayqal, Yun Xu, Drupad K Trivedi, Najla AlMasoud, David I Ellis, Nicholas J W Rattray, Royston Goodacre
Efflux pumps are critically important membrane components that play a crucial role in strain tolerance in Pseudomonas putida to antibiotics and aromatic hydrocarbons that result in these toxicants being expelled from the bacteria. Here, the effect of propranolol on P. putida was examined by sudden addition of 0.2, 0.4 and 0.6 mg mL-1 of this β-blocker to several strains of P. putida, including the wild type DOT-T1E and the efflux pump knockout mutants DOT-T1E-PS28 and DOT-T1E-18. Bacterial viability measurements reveal that the efflux pump TtgABC plays a more important role than the TtgGHI pump in strain tolerance to propranolol...
2016: PloS One
Mette M Berger, Olivier Pantet
PURPOSE OF REVIEW: After major progress in the 1980s of burn resuscitation resulting, the last years' research has focused on modulation of metabolic response and optimization of substrate utilization. The persisting variability of clinical practice is confirmed and results in difficult comparisons between burn centers. RECENT FINDINGS: Recent research explores intracellular mechanisms of the massive metabolic turmoil observed after burns: very early alterations at the mitochondrial level largely explain the hypermetabolic response, with a diminished coupling of oxygen consumption and ATP production...
August 2016: Current Opinion in Critical Care
Mile Stanojcic, Celeste C Finnerty, Marc G Jeschke
PURPOSE OF REVIEW: A complex network of hormones and other effectors characterize the hypermetabolic response in critical illness; these mediators work together to induce numerous pathophysiologic alterations. Increased incidence of infection, multiorgan failure, long-term debilitation, delays in rehabilitation, and death result from an inability to meet the prohibitively elevated protein and energy requirements, which occur during illness and can persist for several years. Pharmacologic interventions have been successfully utilized to attenuate particular aspects of the hypermetabolic response; these modalities are a component of managing critically ill patients - including those patients with severe burns...
August 2016: Current Opinion in Critical Care
P I Jewo, I O Fadeyibi
Severe burns trigger a wide range of responses in the victim. Initial vascular changes are followed by hypermetabolic, inflammatory and immunologic changes. The prolonged hypermetabolic response is associated with an elevated resting rate of energy consumption, tissue wasting and altered substrate kinetics. There is increased blood glucose though insulin levels are above normal. The cortisol level is raised and, together with catecholamine, drives the metabolic response. The immune system is typically weakened...
June 30, 2015: Annals of Burns and Fire Disasters
Rowena Cayabyab, Rangasamy Ramanathan
Retinopathy of prematurity (ROP) continues to be a major preventable cause of blindness and visual handicaps globally. With improved perinatal care, improved survival of moderately preterm infants, and limited resources for oxygen delivery and monitoring, more mature preterm infants are developing severe ROP in developing countries. The pathophysiology of ROP is characterized by two phases. Phase I ROP is due to vaso-obliteration beginning immediately after birth secondary to a marked decrease in vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1)...
2016: Neonatology
Gerald A Dienel, Nancy F Cruz
Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist...
July 2016: Journal of Neurochemistry
Cristian Gómez-Canela, Thomas H Miller, Nicolas R Bury, Romà Tauler, Leon P Barron
The effects of pharmaceuticals and personal care products (PPCPs) on aquatic organisms represent a significant current concern. Herein, a targeted metabolomics approach using liquid chromatography-high resolution mass spectrometry (LC-HRMS) is presented to characterise concentration changes in 29 selected metabolites following exposures of aquatic invertebrates, Gammarus pulex, to pharmaceuticals. Method performance revealed excellent linearity (R(2)>0.99), precision (0.1-19%) and lower instrumental limits of detection (0...
August 15, 2016: Science of the Total Environment
Marlen I Vasquez, Maria Tarapoulouzi, Nancy Lambrianides, Evroula Hapeshi, Kyriakos Felekkis, Maria Saile, Carsten Sticht, Norbert Gretz, Despo Fatta-Kassinos
The selection and prioritization of pharmaceuticals and of their transformation products for evaluating effects on the environment and human health is a challenging task. Both compound- (e.g. mixture composition, concentrations) and biological- (e.g. relevant endpoint, biological organizational level) oriented approaches applied for tackling these issues often resemble a Lernaean hydra by creating more questions than answers. The present study embraces this complexity, providing an integrated approach to assess the potential effects of transformation products of pharmaceuticals by means of mutagenicity, estrogenicity and differences in the gene expression profiles...
April 4, 2016: Environmental Toxicology and Chemistry
Emma L Thompson, Clare J Ray, Andrew P Holmes, Richard L Pye, Christopher N Wyatt, Andrew M Coney, Prem Kumar
KEY POINTS: Hypoglycaemia is counteracted by release of hormones and an increase in ventilation and CO2 sensitivity to restore blood glucose levels and prevent a fall in blood pH. The full counter-regulatory response and an appropriate increase in ventilation is dependent on carotid body stimulation. We show that the hypoglycaemia-induced increase in ventilation and CO2 sensitivity is abolished by preventing adrenaline release or blocking its receptors. Physiological levels of adrenaline mimicked the effect of hypoglycaemia on ventilation and CO2 sensitivity...
August 1, 2016: Journal of Physiology
Jan M Schilling, Yousuke T Horikawa, Alice E Zemljic-Harpf, Kevin P Vincent, Leonid Tyan, Judith K Yu, Andrew D McCulloch, Ravi C Balijepalli, Hemal H Patel, David M Roth
Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac-specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury, suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism...
May 2016: Basic Research in Cardiology
Brittney P Ciszek, Sandra C O'Buckley, Andrea G Nackley
BACKGROUND: Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via β-adrenergic receptor (βAR) activation. The contribution of distinct βAR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation...
May 2016: Anesthesiology
Felicity Currie, David I Broadhurst, Warwick B Dunn, Christopher A Sellick, Royston Goodacre
Human pharmaceuticals have been detected in wastewater treatment plants, rivers, and estuaries throughout Europe and the United States. It is widely acknowledged that there is insufficient information available to determine whether prolonged exposure to low levels of these substances is having an impact on the microbial ecology in such environments. In this study we attempt to measure the effects of exposing cultures of Pseudomonas putida KT2440 (UWC1) to six pharmaceuticals by looking at differences in metabolite levels...
April 2016: Molecular BioSystems
Yeong Ju Yun, Yun Hee Gyon, Sohyoung Yang, Youn Kyung Lee, Joohyun Park, Meerim Park
PURPOSE: To determine the efficacy and safety of oral propranolol as a first-line treatment for superficially located infantile hemangioma (IH) and propose an assessment tool to measure treatment response. METHODS: Patients with superficial IH under 1 year of age were prospectively recruited between May 2012 and December 2013 at the Department of Pediatrics of Chungbuk National University Hospital. Propranolol was administered to 12 infants (median age, 3.8 months) while monitoring cardiovascular and adverse metabolic effects...
December 2015: Korean Journal of Pediatrics
Yoshiyuki Yamaura, Brian D Chapron, Zhican Wang, Jonathan Himmelfarb, Kenneth E Thummel
To further the development of a model for simultaneously assessing intestinal absorption and first-pass metabolism in vitro, Caco-2, LS180, T84, and fetal human small intestinal epithelial cells (fSIECs) were cultured on permeable inserts, and the integrity of cell monolayers, CYP3A4 activity, and the inducibility of enzymes and transporters involved in intestinal drug disposition were measured. Caco-2, T84, and fSIECs all formed tight junctions, as assessed by immunofluorescence microscopy for zonula occludens-1, which was well organized into circumscribing strands in T84, Caco-2, and fSIECs but was diffuse in LS180 cells...
March 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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