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Predictive toxicology

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https://www.readbyqxmd.com/read/28534261/the-role-of-drug-metabolites-in-the-inhibition-of-cytochrome-p450-enzymes
#1
Momir Mikov, Maja Đanić, Nebojša Pavlović, Bojan Stanimirov, Svetlana Goločorbin-Kon, Karmen Stankov, Hani Al-Salami
Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug-drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects...
May 22, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28533176/the-mouse-thermoregulatory-system-its-impact-on-translating-biomedical-data-to-humans
#2
REVIEW
Christopher J Gordon
The laboratory mouse has become the predominant test species in biomedical research. The number of papers that translate or extrapolate data from mouse to human has grown exponentially since the year 2000. There are many physiological and anatomical factors to consider in the process of extrapolating data from one species to another. Body temperature is, of course, a critical determinant in extrapolation because it has a direct impact on metabolism, cardiovascular function, drug efficacy, pharmacokinetics of toxins and drugs, and many other effects...
May 19, 2017: Physiology & Behavior
https://www.readbyqxmd.com/read/28533120/evaluation-of-new-chemical-entities-as-substrates-of-liver-transporters-in-the-pharmaceutical-industry-response-to-regulatory-requirements-and-future-steps
#3
Noriko Okudaira
This article discusses the evaluation of drug candidates as hepatic transporter substrates. Recently, research on the applications of hepatic transporters in the pharmaceutical industry has improved to meet the requirements of the regulatory guidelines for the evaluation of drug interactions. To identify the risk of transporter-mediated drug-drug interactions (DDIs) at an early stage of drug development, we employed a strategy of reviewing the in vivo animal pharmacokinetics and tissue distribution data obtained in the discovery stage together with the in vitro data obtained for regulatory submission...
May 19, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28526768/direct-comparison-of-the-enzymatic-characteristics-and-superoxide-production-of-the-four-aldehyde-oxidase-enzymes-present-in-mouse
#4
Gokhan Kucukgoze, Mineko Terao, Enrico Garattini, Silke Leimkuhler
Aldehyde oxidases (AOXs) are molybdoflavoenzymes with an important role in the metabolism and detoxification of heterocyclic compounds and aliphatic as well as aromatic aldehydes. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. Four different enzymes, mAOX1, mAOX3, mAOX4 and mAOX2, which are the products of distinct genes, are present in the mouse. A direct and simultaneous comparison of the enzymatic properties and characteristics of the four enzymes has never been performed...
May 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28525814/risk-assessment-of-triclosan-in-the-global-environment-using-a-probabilistic-approach
#5
Jiahua Guo, Hisato Iwata
The occurrence of antimicrobial agent triclosan (TCS) in the global aquatic and terrestrial environment is an emerging concern. While risk assessment for TCS is available in certain countries, no studies have attempted to assess the risk of TCS worldwide. This could be due to lack of method to characterize the global exposure. The present study therefore proposed a probabilistic-based approach to approximate the percent-ranked measured environmental concentrations (MECs) by estimating exposure concentration distribution (ECD) for different environmental compartments on a global scale, incorporating approximate 1200 single MECs...
May 16, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28523455/-heat-induced-contaminants-in-foodstuffs-acrylamide-furan-and-fatty-acid-esters-of-monochloropropanediols-and-glycidol
#6
REVIEW
Susanne Andres, Katharina Schultrich, Bernhard Monien, Thorsten Buhrke, Nadiya Bakhiya, Falko Frenzel, Klaus Abraham, Bernd Schäfer, Alfonso Lampen
The production and preparation of foodstuffs may entail at high temperatures the generation of undesirable, potentially harmful compounds. Among the best investigated heat-induced contaminants are acrylamide, furan, and the fatty acid esters of glycidol and the monochloropropanediols. This article presents the main insights into the formation, toxicology, and exposure of these compounds. Acrylamide and glycidol were characterized as carcinogens with a genotoxic mechanism in animal experiments. Their content in foods should be minimized...
May 18, 2017: Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz
https://www.readbyqxmd.com/read/28511080/cadmium-and-alzheimer-s-disease-mortality-in-u-s-adults-updated-evidence-with-a-urinary-biomarker-and-extended-follow-up-time
#7
Qing Peng, Kelly M Bakulski, Bin Nan, Sung Kyun Park
Cadmium has been linked to impaired cognitive function in adults and may cause behavioral, physiological and molecular abnormalities characteristic of Alzheimer's disease (AD) in animals. Evidence linking cadmium and AD in humans is limited, but supportive. In the most recent epidemiologic study, blood cadmium in U.S. adults was positively associated with elevated AD mortality 7-13 years later. The association between urinary cadmium - an arguably more appropriate biomarker for studying chronic diseases - and AD mortality has not yet been explored...
May 13, 2017: Environmental Research
https://www.readbyqxmd.com/read/28506817/in-vitro-cyp-mediated-drug-metabolism-in-the-zebrafish-embryo-using-human-reference-compounds
#8
Moayad Saad, An Matheeussen, Sebastiaan Bijttebier, Evy Verbueken, Casper Pype, Christophe Casteleyn, Chris Van Ginneken, Sandra Apers, Louis Maes, Paul Cos, Steven Van Cruchten
The increasing use of zebrafish embryos as an alternative model for toxicological and pharmacological studies necessitates a better understanding of xenobiotic biotransformation in this species. As cytochrome P450 enzymes (CYPs) play an essential role in this process, in vitro drug metabolism of four human CYP-specific substrates, i.e. dextromethorphan (DXM), diclofenac (DIC), testosterone (TST) and midazolam (MDZ) was investigated in adult male and female zebrafish, and in zebrafish embryos and larvae up to 120hours post-fertilization...
May 12, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28503093/alarms-about-structural-alerts
#9
Vinicius Alves, Eugene Muratov, Stephen Capuzzi, Regina Politi, Yen Low, Rodolpho Braga, Alexey V Zakharov, Alexander Sedykh, Elena Mokshyna, Sherif Farag, Carolina Andrade, Victor Kuz'min, Denis Fourches, Alexander Tropsha
Structural alerts are widely accepted in chemical toxicology and regulatory decision support as a simple and transparent means to flag potential chemical hazards or group compounds into categories for read-across. However, there has been a growing concern that alerts disproportionally flag too many chemicals as toxic, which questions their reliability as toxicity markers. Conversely, the rigorously developed and properly validated statistical QSAR models can accurately and reliably predict the toxicity of a chemical; however, their use in regulatory toxicology has been hampered by the lack of transparency and interpretability...
August 21, 2016: Green Chemistry: An International Journal and Green Chemistry Resource: GC
https://www.readbyqxmd.com/read/28501712/3d-bioprinting-for-drug-discovery-and-development-in-pharmaceutics
#10
REVIEW
Weijie Peng, Pallab Datta, Bugra Ayan, Veli Ozbolat, Donna Sosnoski, Ibrahim T Ozbolat
Successful launch of a commercial drug requires significant investment of time and financial resources wherein late-stage failures become a reason for catastrophic failures in drug discovery. This calls for infusing constant innovations in technologies, which can give reliable prediction of efficacy, and more importantly, toxicology of the compound early in the drug discovery process before clinical trials. Though computational advances have resulted in more rationale in silico designing, in vitro experimental studies still require gaining industry confidence and improving in vitro-in vivo correlations...
May 10, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28492309/competitive-inhibition-mechanism-of-acetylcholinesterase-without-catalytic-active-site-interaction-study-on-functionalized-c60-nanoparticles-via-in-vitro-and-in-silico-assays
#11
Yanyan Liu, Bing Yan, David A Winkler, Jianjie Fu, Aiqian Zhang
Acetylcholinesterase (AChE) activity regulation by chemical agents or, potentially, nanomaterials is important for both toxicology and pharmacology. Competitive inhibition via direct catalytic active sites (CAS) binding or noncompetitive inhibition through interference with substrate/product entering/exiting has been recognized previously as an AChE inhibition mechanism for bespoke nanomaterials. The competitive inhibition by peripheral anionic site (PAS) interaction without CAS binding remains unexplored. Here we proposed and verified the occurrence of a presumed competitive inhibition of AChE without CAS binding for hydrophobically functionalized C60 nanoparticles (NPs) by employing both experimental and computational methods...
May 11, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28486152/benzotriazole-ultraviolet-stabilizers-alter-the-expression-of-the-thyroid-hormone-pathway-in-zebrafish-danio-rerio-embryos
#12
Xuefang Liang, Jiajia Li, Christopher J Martyniuk, Juan Wang, Yufeng Mao, Huan Lu, Jinmiao Zha
Benzotriazole ultraviolet stabilizers (BUVSs) are widely used in industrial products as well as personal-hygiene products to protect the material or skin from harmful UV-radiation. Due to their persistence and bioaccumulation, BUVSs have been ubiquitously detected in aquatic environments. Although the toxicological effects of BUVSs in aquatic organisms have been previously examined, the effects of BUVSs on the thyroid system have not been adequately addressed. In this study, we assessed putative thyroid disrupting effects of BUVSs (UV-234, UV-326, UV-329 and UV-P) in zebrafish embryos at 1, 10 and 100 μg/L for 96 h...
May 3, 2017: Chemosphere
https://www.readbyqxmd.com/read/28482314/maternal-transfer-of-dioxin-like-compounds-in-artificially-matured-european-eels
#13
Marko Freese, Roxana Sühring, Lasse Marohn, Jan-Dag Pohlmann, Hendrik Wolschke, Jonathan D Byer, Mehran Alaee, Ralf Ebinghaus, Reinhold Hanel
Several eel species of the genus Anguilla are considered endangered due to a severe decline in recruitment. Up to now, the reasons for this threatening development are not fully understood. The eel's highly specialized biology can lead to explicitly high accumulation of globally distributed organic lipophilic contaminants during its continental life. Because of this and due the particular toxicological sensitivity of early life stages of oviparous organisms towards dioxin-like compounds, it is crucial to improve our understanding concerning toxicokinetics and maternal transfer of organic contaminants in eels...
May 5, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28477266/combination-of-multiple-neural-crest-migration-assays-to-identify-environmental-toxicants-from-a-proof-of-concept-chemical-library
#14
Johanna Nyffeler, Xenia Dolde, Alice Krebs, Kevin Pinto-Gil, Manuel Pastor, Mamta Behl, Tanja Waldmann, Marcel Leist
Many in vitro tests have been developed to screen for potential neurotoxicity. However, only few cell function-based tests have been used for comparative screening, and thus experience is scarce on how to confirm and evaluate screening hits. We addressed these questions for the neural crest cell migration test (cMINC). After an initial screen, a hit follow-up strategy was devised. A library of 75 compounds plus internal controls (NTP80-list), assembled by the National Toxicology Program of the USA (NTP) was used...
May 5, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28476634/use-of-bioassays-to-assess-hazard-of-food-contact-material-extracts-state-of-the-art
#15
REVIEW
Isabelle Severin, Emilie Souton, Laurence Dahbi, Marie Christine Chagnon
This review focuses on the use of in vitro bioassays for the hazard assessment of food contact materials (FCM) as a relevant strategy, in complement to analytical methods. FCM may transfer constituents to foods, not always detected by analytical chemistry, resulting in low but measurable human exposures. Testing FCM extracts with bioassays represents the biological response of a combination of substances, able to be released from the finished materials. Furthermore, this approach is particularly useful regarding the current risk assessment challenges with unpredicted/unidentified non-intentionally added substances (NIAS) that can be leached from the FCM in the food...
May 3, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28475417/challenges-and-opportunities-for-the-future-of-monoclonal-antibody-development-improving-safety-assessment-and-reducing-animal-use
#16
Fiona Sewell, Kathryn Chapman, Jessica Couch, Maggie Dempster, Shawn Heidel, Lise Loberg, Curtis Maier, Tim K McLachlan, Marque Todd, Jan Willem van der Laan
The market for biotherapeutic monoclonal antibodies (mAbs) is large and is growing rapidly. However, attrition poses a significant challenge for the development of mAbs, and for biopharmaceuticals in general, with large associated costs in resource and animal use. Termination of candidate mAbs may occur due to poor translation from preclinical models to human safety. It is critical that the industry addresses this problem in order to maintain productivity. Though attrition poses a significant challenge for pharmaceuticals in general, there are specific challenges related to the development of antibody-based products...
May 5, 2017: MAbs
https://www.readbyqxmd.com/read/28472358/metabolic-profile-determination-of-nbome-compounds-using-human-liver-microsomes-and-comparison-with-findings-in-authentic-human-blood-and-urine
#17
Keith-Dane H Temporal, Karen S Scott, Amanda L A Mohr, Barry K Logan
The emergence of novel psychoactive substances (NPS) such as hallucinogenic NBOMes (N-methoxybenzyl derivatives of 2C phenethylamines) in the past few years into the recreational drug market has introduced various challenges in forensic analytical toxicology in regard to adequate and timely detection of these compounds. This is especially true in samples from individuals who have experienced severe and fatal intoxications. The aim of this research was to identify the major Phase I metabolites of selected NBOMe compounds to generate a predicted human metabolic pathway of these substances...
May 3, 2017: Journal of Analytical Toxicology
https://www.readbyqxmd.com/read/28466670/points-to-consider-in-designing-and-conducting-juvenile-toxicology-studies
#18
Norman N Kim, Robert M Parker, Gerhard F Weinbauer, Amera K Remick, Thomas Steinbach
In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28461781/zebrafish-as-an-in-vivo-model-for-sustainable-chemical-design
#19
Pamela D Noyes, Gloria R Garcia, Robert L Tanguay
Heightened public awareness about the many thousands of chemicals in use and present as persistent contaminants in the environment has increased the demand for safer chemicals and more rigorous toxicity testing. There is a growing recognition that the use of traditional test models and empirical approaches is impractical for screening for toxicity the many thousands of chemicals in the environment and the hundreds of new chemistries introduced each year. These realities coupled with the green chemistry movement have prompted efforts to implement more predictive-based approaches to evaluate chemical toxicity early in product development...
December 21, 2016: Green Chemistry: An International Journal and Green Chemistry Resource: GC
https://www.readbyqxmd.com/read/28450578/integrated-assessment-of-diclofenac-biotransformation-pharmacokinetics-and-omics-based-toxicity-in-a-3d-human-liver-immunocompetent-co-culture-system
#20
Ujjal Sarkar, Kodihalli C Ravindra, Emma Large, Carissa L Young, Dinelia Rivera-Burgos, Jiajie Yu, Murat Cirit, David J Hughes, John S Wishnok, Douglas A Lauffenburger, Linda G Griffith, Steven R Tannenbaum
In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immuno-competent co-culture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography tandem mass spectrometry. DCF biotransformation was assessed after 48 h of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans...
April 27, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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