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Predictive toxicology

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https://www.readbyqxmd.com/read/28817277/discovery-and-characterization-of-r-6-neopentyl-2-pyridin-2-ylmethoxy-6-7-dihydropyrimido-2-1-c-1-4-oxazin-4-9h-one-pf-06462894-an-alkyne-lacking-metabotropic-glutamate-receptor-5-negative-allosteric-modulator-profiled-in-both-rat-and-non-human-primates
#1
Antonia F Stepan, Michelle M Claffey, Matthew R Reese, Gayatri Balan, Gabriela Barreiro, Jason Barricklow, Michael J Bohanon, Brian P Boscoe, Gregg D Cappon, Lois K Chenard, Julie Cianfrogna, Laigao Chen, Karen J Coffman, Susan E Drozda, Joshua R Dunetz, Somraj Ghosh, Xinjun Hou, Christopher Houle, Kapil Karki, John T Lazzaro, Jessica Y Mancuso, John M Marcek, Emily L Miller, Mark A Moen, Steven V O'Neil, Isao Sakurada, Marc Skaddan, Vinod Parikh, Deborah L Smith, Patrick E Trapa, Jamison B Tuttle, Patrick R Verhoest, Daniel P Walker, Annie C Won, Ann S Wright, Jessica Whritenour, Kenneth Zasadny, Margaret M Zaleska, Lei Zhang, Christopher L Shaffer
We previously observed a cutaneous type IV immune response in non-human primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp(3) character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily)...
August 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28815392/strategy-for-cyp3a-induction-risk-assessment-from-preclinical-signal-to-human-a-case-example-of-a-late-stage-discovery-compound
#2
Jialin Mao, Peter Fan, Susan Wong, Jianshuang Wang, Moulay Hicham Alaoui Ismaili, Brian Dean, Cornelis E C A Hop, Matthew Wright, Yuan Chen
PURPOSE: The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose. METHODS: Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied...
August 16, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28810191/structure-function-studies-of-bpp-brachynh2-and-synthetic-analogues-thereof-with-angiotensin-i-converting-enzyme
#3
Daniel D R Arcanjo, Andreanne G Vasconcelos, Lucas A Nascimento, Ana Carolina Mafud, Alexandra Plácido, Michel M M Alves, Cristina Delerue-Matos, Marcelo P Bemquerer, Nuno Vale, Paula Gomes, Eduardo B Oliveira, Francisco C A Lima, Yvonne P Mascarenhas, Fernando Aécio A Carvalho, Ulf Simonsen, Ricardo M Ramos, José Roberto S A Leite
The vasoactive proline-rich oligopeptide termed BPP-BrachyNH2 (H-WPPPKVSP-NH2) induces in vitro inhibitory activity of angiotensin I-converting enzyme (ACE) in rat blood serum. In the present study, the removal of N-terminal tryptophan or C-terminal proline from BPP-BrachyNH2 was investigated in order to predict which structural components are important or required for interaction with ACE. Furthermore, the toxicological profile was assessed by in silico prediction and in vitro MTT assay. Two BPP-BrachyNH2 analogues (des-Trp(1)-BPP-BrachyNH2 and des-Pro(8)-BPP-BrachyNH2) were synthesized, and in vitro and in silico ACE inhibitory activity and toxicological profile were assessed...
August 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28809622/suicide-in-pretoria-a-retrospective-review-2007-2010
#4
Cornelia Engelbrecht, Ryan Blumenthal, Neil K Morris, Gert Saayman
BACKGROUND: The World Health Organization has declared suicide a global ealth crisis, predicting that ~1.53 million people will commit suicide annually by 2020. OBJECTIVE: A study from South Africa reviewed 1 018 suicide cases in Pretoria over 4 years (1997 - 2000). Our study was undertaken to establish whether there have been substantial changes in the profile of suicide victims who died in Pretoria a decade later. METHODS: Case records at the Pretoria Medico-Legal Laboratory were reviewed retrospectively from 2007 to 2010...
July 28, 2017: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
https://www.readbyqxmd.com/read/28809115/an-intuitive-approach-for-predicting-potential-human-health-risk-with-the-tox21-10k-library
#5
Nisha S Sipes, John F Wambaugh, Robert Pearce, Scott S Auerbach, Barbara Anne Wetmore, Jui-Hua Hsieh, Andrew J Shapiro, Daniel Svoboda, Michael J DeVito, Stephen S Ferguson
In vitro-in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This study represents the first report applying IVIVE approaches and exposure comparisons using the entirety of the Tox21 federal collaboration chemical screening data, incorporating assay response efficacy and quality of concentration-response fits, and providing quantitative anchoring to first address the likelihood of human in vivo interactions with Tox21 compounds. This likelihood was assessed using a maximum blood concentration to in vitro response ratio approach (Cmax/AC50), analogous to decision-making methods for clinical drug-drug interactions...
August 15, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28802948/modelling-the-toxicity-of-a-large-set-of-metal-and-metal-oxide-nanoparticles-using-the-ochem-platform
#6
Vasyl Kovalishyn, Natalia Abramenko, Iryna Kopernyk, Larysa Charochkina, Larysa Metelytsia, Igor V Tetko, Willie Peijnenburg, Leonid Kustov
Inorganic nanomaterials have become one of the new areas of modern knowledge and technology and have already found an increasing number of applications. However, some nanoparticles show toxicity to living organisms, and can potentially have a negative influence on environmental ecosystems. While toxicity can be determined experimentally, such studies are time consuming and costly. Computational toxicology can provide an alternative approach and there is a need to develop methods to reliably assess Quantitative Structure-Property Relationships for nanomaterials (nano-QSPRs)...
August 9, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28801182/prediction-of-regioselectivity-and-preferred-order-of-metabolisms-on-cyp1a2-mediated-reactions-part-2-solving-substrate-interactions-of-cyp1a2-with-non-pah-substrates-on-the-template-system
#7
Yasushi Yamazoe, Kouichi Yoshinari
In our previous paper (Drug Metabolism Parmacokinet31: 363, 2016), a simulation system for ligand interactions of human CYP1A2 was developed using "Template" composed of hexagonal grids focusing on polyaromatic hydrocarbons (PAHs). The system has been expanded for the application of non-PAH chemicals including medical drugs, industrial chemicals and natural products in the present study. Additions of two Templates C and D around Ring C/E and Ring B, respectively, perpendicular each to Template A, offered the accommodation of non-PAH substrates...
May 29, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28800684/sediment-zn-release-during-post-drought-re-flooding-assessing-environmental-risk-to-hyalella-azteca-and-daphnia-magna
#8
Sara M Nedrich, G Allen Burton
Hydrologic variability exacerbated by climate change affects biogeochemical cycling in sediments through changes in pH, redox, and microbial activity. These alterations affect the lability and speciation of metals, such that toxicity may be observed in otherwise non-toxic sediments. In this study, we investigate the effects of drought and reflooding on metal bioavailability in sediments with low to moderate concentrations of Zn (18-270 mg kg(-1)). Sediments were collected from coastal wetlands in Michigan, dried (36-days) and re-inundated in lab microcosms...
August 7, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28798938/evidence-for-tissue-toxicity-in-balb-c-exposed-to-a-long-term-treatment-with-oxiranes-compared-to-meglumine-antimoniate
#9
Luiz Filipe Gonçalves Oliveira, Franklin Souza-Silva, Léa Cysne-Finkelstein, Kíssila Rabelo, Juliana Fernandes Amorim, Adriana de Souza Azevedo, Saulo Cabral Bourguignon, Vitor Francisco Ferreira, Marciano Viana Paes, Carlos Roberto Alves
Leishmaniasis remains a serious public health problem in developing countries without effective control, whether by vaccination or chemotherapy. Part of the failure of leishmaniasis control is due to the lack of new less toxic and more effective drugs able to eliminate both the lesions and the parasite. Oxiranes derived from naphthoquinones now being assayed are promising drugs for the treatment of this group of diseases. The predicted pharmacokinetic properties and toxicological profiles of epoxy-α-lapachone and epoxymethoxy-lawsone have now been compared to those of meglumine antimoniate, and histological changes induced by these drugs in noninfected BALB/c mice tissues are described...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28777439/combining-cytotoxicity-assessment-and-xenopus-laevis-phenotypic-abnormality-assay-as-a-predictor-of-nanomaterial-safety
#10
Karamallah Al-Yousuf, Carl A Webster, Grant N Wheeler, Francesca Baldelli Bombelli, Victoria Sherwood
The African clawed frog, Xenopus laevis, has been used as an efficient pre-clinical screening tool to predict drug safety during the early stages of the drug discovery process. X. laevis is a relatively inexpensive model that can be used in whole organism high-throughput assays whilst maintaining a high degree of homology to the higher vertebrate models often used in scientific research. Despite an ever-increasing volume of biomedical nanoparticles (NPs) in development, their unique physico-chemical properties challenge the use of standard toxicology assays...
August 4, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28763202/paleo-ecotoxicology-what-can-lake-sediments-tell-us-about-ecosystem-responses-to-environmental-pollutants
#11
Jennifer Korosi, Joshua R Thienpont, John P Smol, Jules M Blais
The development of effective risk reduction strategies for aquatic pollutants requires a comprehensive understanding of toxic impacts on ecosystems. Classical toxicological studies are effective for characterizing pollutant impacts on biota in a controlled, simplified environment. Nonetheless, it is well-acknowledged that predictions based on the results of these studies must be tested over the long-term in a natural ecosystem setting, to account for increased complexity and multiple stressors. Paleolimnology (the study of lake sediment cores to reconstruct environmental change) can address many key knowledge gaps...
August 1, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28760446/in-vitro-to-in-vivo-extrapolation-of-effective-dosimetry-in-developmental-toxicity-testing-application-of-a-generic-pbk-modelling-approach
#12
Styliani Fragki, Aldert H Piersma, Emiel Rorije, Marco J Zeilmaker
Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization...
July 28, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28755860/dynamic-and-accurate-assessment-of-acetaminophen-induced-hepatotoxicity-by-integrated-photoacoustic-imaging-and-mechanistic-biomarkers-in-vivo
#13
Nathalie Brillant, Mohamed Elmasry, Neal C Burton, Josep Monne Rodriguez, Jack W Sharkey, Stephen Fenwick, Harish Poptani, Neil R Kitteringham, Christopher E Goldring, Anja Kipar, B Kevin Park, Daniel J Antoine
The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention...
July 26, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28749029/ecotype-variation-of-methyl-eugenol-content-in-tea-tree-melaleuca-alternifolia-and-m-linariifolia
#14
Mervyn Shepherd, Dale Savins, Ashley Dowell, Samantha Morrow, Gareth Allen, Ian Southwell
Methyl eugenol is a natural phenylpropanoid compound found in a wide range of plants used for food, flavouring, cosmetics and health-care. As a suspected rodent carcinogen, methyl eugenol may also be harmful to humans when present in significant concentrations. Consequently, its level has been restricted in some foodstuffs and cosmetics for some markets. In order to assess the potential to breed uniformly low methyl eugenol cultivars for an essential oil crop, tea tree, the source of "Oil of Melaleuca, terpinene-4-ol type", we examine levels in individual trees (n= 30) from two geographic regions and six terpene chemotypes...
July 27, 2017: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/28745361/in-silico-genotoxicity-of-coumarins-application-of-the-phenol-explorer-food-database-to-functional-food-science
#15
E Guardado Yordi, M J Matos, A Pérez Martínez, A C Tornes, L Santana, E Molina, E Uriarte
Coumarins are a group of phytochemicals that may be beneficial or harmful to health depending on their type and dosage and the matrix that contains them. Some of these compounds have been proven to display pro-oxidant and clastogenic activities. Therefore, in the current work, we have studied the coumarins that are present in food sources extracted from the Phenol-Explorer database in order to predict their clastogenic activity and identify the structure-activity relationships and genotoxic structural alerts using alternative methods in the field of computational toxicology...
August 1, 2017: Food & Function
https://www.readbyqxmd.com/read/28743512/inferring-transcription-factor-activity-from-microarray-data-reveals-novel-targets-for-toxicological-investigations
#16
T M Souza, T van den Beucken, J C S Kleinjans, D G J Jennen
Transcription factors (TFs) are important modulators of the inducible portion of the transcriptome, and therefore relevant in the context of exposure to exogenous compounds. Current approaches to predict the activity of TFs in biological systems are usually restricted to a few entities at a time due to low-throughput techniques targeting a limited fraction of annotated human TFs. Therefore, high-throughput alternatives may help to identify new targets of mechanistic and predictive value in toxicological investigations...
July 22, 2017: Toxicology
https://www.readbyqxmd.com/read/28741972/the-effect-of-zirconium-doping-of-cerium-dioxide-nanoparticles-on-pulmonary-and-cardiovascular-toxicity-and-biodistribution-in-mice-after-inhalation
#17
Susan Dekkers, Mark R Miller, Roel P F Schins, Isabella Römer, Mike Russ, Rob J Vandebriel, Iseult Lynch, Marie-France Belinga-Desaunay, Eugenia Valsami-Jones, Shea P Connell, Ian P Smith, Rodger Duffin, John A F Boere, Harm J Heusinkveld, Catrin Albrecht, Wim H de Jong, Flemming R Cassee
Development and manufacture of nanomaterials is growing at an exponential rate, despite an incomplete understanding of how their physicochemical characteristics affect their potential toxicity. Redox activity has been suggested to be an important physicochemical property of nanomaterials to predict their biological activity. This study assessed the influence of redox activity by modification of cerium dioxide nanoparticles (CeO2 NPs) via zirconium (Zr) doping on the biodistribution, pulmonary and cardiovascular effects in mice following inhalation...
August 9, 2017: Nanotoxicology
https://www.readbyqxmd.com/read/28741378/procainamide-induced-autoimmunity-relationship-to-t-helper-2-type-t-cell-activation
#18
Y Huang, Z Lin, Y Huo, X Geng, M Li, Y Yang, B Li
Drug-induced autoimmunity (DIA) refers to a group of adverse drug reactions, and they remain unpredictable largely due to the limited understanding of the mechanisms involved. There is evidence that procainamide can cause autoimmune reactions in humans but the mechanisms involved remain unclear. To examine the cellular and genetic factors involved in the procainamide-induced autoimmune response, we compared rats that are genetically T-helper (Th)2-predisposed (Brown Norway (BN)), Th1-predisposed (Lewis (LEW)) or not genetically predisposed (Sprague Dawley (SD))...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/28732338/toxic-organic-substances-and-marker-compounds-in-size-segregated-urban-particulate-matter-implications-for-involvement-in-the-in%C3%A2-vitro-bioactivity-of-the-extractable-organic-matter
#19
Athanasios Besis, Alexandra Tsolakidou, Dimitra Balla, Constantini Samara, Dimitra Voutsa, Anastasia Pantazaki, Theodora Choli-Papadopoulou, Theodore S Lialiaris
Toxic organic substances and polar organic marker compounds, i.e. polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs) and their nitro-derivatives (N-PAHs), as well as dicarboxylic acids (DCAs) and sugars/sugar anhydrites (S/SAs) were analyzed in size-segregated PM samples (<0.49, 0.49-0.97, 0.97-3 and >3 μm) collected at two urban sites (urban traffic and urban background) during the cold and the warm season...
July 18, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28729132/meclas-an-online-tool-for-hazard-identification-and-classification-of-complex-inorganic-metal-containing-materials
#20
Frederik Verdonck, Hugo Waeterschoot, Patrick Van Sprang, Isabelle Vercaigne, Katrien Delbeke, Chretien Simons, Violaine Verougstraete
MeClas is a web-based tool to generate (eco)toxicity hazard categories and corresponding classification & labelling information of inorganic metal-containing complex materials such as ores, concentrates, intermediates or alloys for which the manual application of the GHS/CLP rules is very complex and requires a high level of consistency. The tool comprises several tiers, aimed at the progressive refinement of classification through recognition of specific mineral content, speciation/mineralogy up to bio-availability corrections...
July 17, 2017: Regulatory Toxicology and Pharmacology: RTP
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