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Regulatory Toxicology and Pharmacology: RTP

Gláucio Barros Saldanha, Glaucia Barros Saldanha, Marina Rebeca Soares Carneiro de Sousa, George Laylson da Silva Oliveira, Ana Paula Dos Santos C L da Silva, Jorge M David, Juceni Pereira David
Neoflavonoids, which are classified as 4-arylcoumarin (neoflavone), 3,4-dihydro-4-arylcoumarin and neoflavene, have been the subject of a number of studies with respect to their therapeutic potential and, despite promising in vitro, ex vivo and in vivo pharmacological activities, there is a lack of studies demonstrating their toxicological properties. Therefore, this study aims to evaluate the acute (14 days) and repeated-dose (28 days) toxicity of synthetic neoflavonoid 7-acetoxy-4-aryl-3,4-dihydrocoumarin in Swiss mice through parameters related to changes in body weight, food and water intake, hematological and biochemical parameters...
January 12, 2018: Regulatory Toxicology and Pharmacology: RTP
Lois Haighton, Ashley Roberts, Brandon Walters, Barry Lynch
The current review assessed cancer studies of aspartame based on a quality appraisal using the Klimisch grading system. Nine studies having complete histopathology were included: three 2-year studies by Searle; three transgenic mice studies by the NTP; three lifetime studies by the Ramazzini Institute. A tenth study limited to brain tumors was not rated. None were determined as Klimisch Code 1 (reliable without restrictions). The Searle studies predated GLP standards but their methodology was comparable; transgenic mouse models are not validated, but are accepted as supporting data...
January 12, 2018: Regulatory Toxicology and Pharmacology: RTP
Davy Guan, Kevin Fan, Ian Spence, Slade Matthews
In vitro genotoxicity bioassays are cost-efficient methods of assessing potential carcinogens. However, many genotoxicity bioassays are inappropriate for detecting chemicals eliciting non-genotoxic mechanisms, such as tumour promotion, this necessitates the use of in vivo rodent carcinogenicity (IVRC) assays. In silico IVRC modelling could potentially address the low throughput and high cost of this assay. We aimed to develop and combine computational QSAR models of novel bioassays for the prediction of IVRC results and compare with existing software...
January 11, 2018: Regulatory Toxicology and Pharmacology: RTP
Hille Suojalehto, Jean-Luc Malo, Paul Cullinan
No abstract text is available yet for this article.
January 11, 2018: Regulatory Toxicology and Pharmacology: RTP
I-Chen Sun, Churn-Shiouh Gau
Generic drugs are accounted for majority of medicinal products. To reduce the unnecessary review for incomplete dossiers of generic drugs, Taiwanese government launched a refuse-to-file (RTF) procedure since 2017. The present study aimed to examine the outcome of RTF procedure by analyzing application characteristic, RTF rate and deficiencies found in the submitted dossiers. Descriptions of administrative information, chemistry, manufacturing and controls, bioequivalence study, and comparative dissolution testing were presented during the first 6 months after the implementation of RTF policy...
January 9, 2018: Regulatory Toxicology and Pharmacology: RTP
Sabitha Papineni, Julie K Passage, Ricardo D Ekmay, Johnson Thomas
Event DAS-444Ø6-6 soybean is genetically modified (GM) to provide tolerance to 2,4-diclorophenoxyacetic acid (2,4-D), glyphosate, and glufosinate herbicides through expression of the AAD-12, 2mEPSPS, and PAT proteins, respectively. DAS-444Ø6-6 soybeans were evaluated for safety in subchronic rat feeding studies. The results from two previous subchronic rat feeding studies evaluating diets formulated with 20% inclusion of DAS-444Ø6-6 soybean meal (the latter also containing DAS-444Ø6-6 derived hulls and oil) did not show any treatment-related adverse effects...
January 6, 2018: Regulatory Toxicology and Pharmacology: RTP
Fiona Sewell, Ian Ragan, Ian Indans, Tim Marczylo, Nigel Stallard, David Griffiths, Thomas Holmes, Paul Smith, Graham Horgan
Acute inhalation studies are conducted in animals as part of chemical hazard identification and for classification and labelling. Current methods employ death as an endpoint (OECD TG403 and TG436) while the recently approved fixed concentration procedure (FCP) (OECD TG433) uses fewer animals and replaces lethality as an endpoint with evident toxicity. Evident toxicity is the presence of clinical signs that predict that exposure to the next highest concentration will cause severe toxicity or death in most animals...
January 5, 2018: Regulatory Toxicology and Pharmacology: RTP
Hyung Soo Kim, Eun Chul Pack, Ye Ji Koo, Ye Jin Lee, Dae Kwan Sung, Seung Ha Lee, Young Soon Kim, Kyeng Hee Kwon, Kyung Min Lim, Dae Yong Jang, Dal Woong Choi
Currently, capsule cigarettes have been introduced by tobacco industries and their sales have increased exponentially. However, the capsule flavoring ingredients and their safety are still unknown. Although the contents of menthol and other ingredients directly added to cigarettes have been determined extensively, no analogous study exists for menthol-containing cigarette capsules. Basic physical properties of capsules in all 31 different capsule cigarettes commercially available in Korea were investigated, and their menthol contents were determined in this study...
January 5, 2018: Regulatory Toxicology and Pharmacology: RTP
Cathy Lester, Allison Reis, Michael Laufersweiler, Shengde Wu, Karen Blackburn
Structure activity relationships (SAR) and read-across are widely used animal alternative approaches for filling toxicological data gaps. A framework describing the use of expert judgment in evaluating analogs for SAR has been published and widely cited, however, reliance on expert judgment can introduce inconsistent results across experts and hinder transparency. Here we explore the use of a quantitative similarity score between an analog and a Structure of Interest (SOI) to see if these scores correlate with the expert judgement-based suitability rankings...
January 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Andrew Van Cott, Charles E Hastings, Robert Landsiedel, Susanne Kolle, Stefan Stinchcombe
In vivo acute systemic testing is a regulatory requirement for agrochemical formulations. GHS specifies an alternative computational approach (GHS additivity formula) for calculating the acute toxicity of mixtures. We collected acute systemic toxicity data from formulations that contained one of several acutely-toxic active ingredients. The resulting acute data set includes 210 formulations tested for oral toxicity, 128 formulations tested for inhalation toxicity and 31 formulations tested for dermal toxicity...
January 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Pingzhe Jiang, Qiqi Liu, Zaizhong Ni, Qian Wei, Xiaodan Li, Shuguang Xing, Deling Kong, Minggang Li
It has been shown that vanadyl trehalose could lower blood glucose but show mild toxicity to the stomach and intestine in diabetic Kunming mice. We analysed antioxidant levels, pro-inflammatory cytokine expression, apoptosis factors and intestinal microflora alteration to explore the mechanism of vanadyl trehalose toxicity in Kunming mice. The results revealed that oral administration of vanadyl trehalose at tested dose caused significant changes in oxidative stress factor (MDA levels elevated but SOD and T-AOC decreased), expression of inflammatory factor (IL-1β, COX-2, TNF-α and iNOS increased), and apoptosis factor (Bcl-2/Bax decreased and caspase-3 increased), and intestinal microflora dysbiosis (the number of Enterobacteriaceae and Enterococcus increased and Lactobacillus and Bifidobacterium decreased) relative to the control of Kunming mice...
January 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Alper Baran, Mine Köktürk, Muhammed Atamanalp, Saltuk Buğrahan Ceyhun
Propyl gallate (PG) is an antioxidant substance widely used in cosmetics, pharmaceutical and food industries. The aim of this study was to evaluate the potential toxic effect of PG injected to zebrafish embryos. To this end, zebrafish embryos were exposed to PG with 0, 1, 10 and 50 ppm concentrations which are lower than ADI and were monitored at 24, 48, 72 and 96 hpf. Survival rate, hatching rate and malformations were evaluated during this period. Moreover, it has been detected the accumulation of fluorescence signal of ROS and apoptotic cell in whole body at the end of 96 hpf...
January 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Tuğba Adak, Afshin Samadi, Ayşe Zeynep Ünal, Suna Sabuncuoğlu
This review investigates the different biological effect of Metformin (MET) in different conditions. MET is an oral antidiabetic drug used for the treatment of type 2 diabetes mellitus (T2DM) particularly in overweight people. The main mechanism of action of the MET is inhibition of hepatic glucose production and reduction of insulin resistance. In addition to its antidiabetic effects, MET is also found to be related with the risk for development of several human solid cancers types such as colorectal, breast and pancreas cancer in the diabetic patients...
December 29, 2017: Regulatory Toxicology and Pharmacology: RTP
Mei Fen Shih, Kuang-Hung Pan, Chia-Chyuan Liu, Chia-Rui Shen, Jong Yuh Cherng
The initiation of atherosclerosis involves up-regulation of molecules such as E-selectin, VCAM-1, and ICAM-1. The progression of atherosclerosis is linked to proliferation and migration of vascular smooth muscle cell via MMP-2 and MMP-9 activities. However, the etiology of atherosclerosis concerning plasticizers is unknown. We evaluated β-thujaplicin in preventing the development of atherosclerosis in a model induced by pro-inflammatory cytokines. Moreover, we established a new atherosclerosis model in vascular smooth muscle cells (VSMC) exposed to a common contact plasticizer, di(2-ethylhexyl)phthalate (DEHP)...
December 27, 2017: Regulatory Toxicology and Pharmacology: RTP
Camille Jandard, Helena Hemming, Maarten Prause, Claudia Sehner, Markus Schwind, Marc Abromovitz, Ester Lovsin Barle
Within the context of Occupational Hygiene (OH), surface sampling has been employed as a method to assess surface levels of Active Pharmaceutical Ingredients (APIs). There are potentially a number of reasons surface samples are collected including assessing potential health risks, housekeeping and cleaning effectiveness. There are no internationally accepted standards relating to collecting or interpreting surface samples for OH purposes. In the past, surface sampling results have been applied not only for estimating risks due to dermal contact, but also for other routes of exposure (e...
December 27, 2017: Regulatory Toxicology and Pharmacology: RTP
N Suganthy, S Muniasamy, G Archunan
Terminalia chebula and Terminalia arjuna were widely used in traditional medicine for the treatment of memory impairment, inflammatory disorders and as an anti-aging agent. However, reports regarding their safety aspects are lacking. Hence, the present study was carried out to investigate the toxicity of methanolic extracts of Terminalia chebula fruit (TCF), Terminalia arjuna bark (TAB) and its bioactive constituent 7- Methyl gallic acid (7MG) under in vitro and in vivo conditions. In vitro toxicity profile of TCF, TAB and 7MG (250-2000 μg/ml) were assessed through cytotoxicity, hemolytic activity, mutagenicity and genotoxicity assays...
December 27, 2017: Regulatory Toxicology and Pharmacology: RTP
Quanlong Zhang, Zhujun Mao, Qiaoyan Zhang, Jianguo Qiu, Zhengping Jia, Luping Qin
Lamiophlomis rotata(Benth.) Kudo is widely used in traditional Chinese medicine and its iridoid glycosides extract (IGLR) was the main active ingredient with hemostatic, antinociceptive and anti-inflammatory effects. This study was aimed to evaluate the safety of IGLR using acute and sub-chronic toxicity study methods on Sprague-Dawley rats. In acute toxicity test, IGLR caused slight diarrhea in three dose groups and a decreased of RBC and increased of MCH and Ret (P < .05) were observed in 16 g/kg group...
December 26, 2017: Regulatory Toxicology and Pharmacology: RTP
S N Chen, C S Chang, S Chen, Madhu Soni
Antrodia cinnamomea is one of the most highly valued mushrooms utilized in traditional Taiwanese therapeutic practices. Its neutral monosaccharides (mannose, glucose and xylose) linked by a β-D-glucan chain have been claimed to be responsible for its health benefits. The objective of the present study was to investigate adverse effects, if any, of β-glucan (∼65% pure) from A. cinnamomea in subchronic toxicity and mutagenicity studies. In the subchronic toxicity study, Sprague Dawley rats (12/sex/group) were followed Organization for Economic Cooperation and Development (OECD) test guideline with Good Laboratory Practice (GLP) application, and were administered (gavage) Antrodia mushroom β-glucan preparation at dose levels of 0, 500, 1000 and 2000 mg/kg body weight (bw)/day for 90 days...
December 26, 2017: Regulatory Toxicology and Pharmacology: RTP
Jinze Li, Eric Morinello, Thomas Larsen, Denzil Frost, Ivor Caro, Stephen Gould, Lisa Wong, Angela Hendricks, Noel Dybdal, Donna Dambach, Melissa Schutten
Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0...
December 23, 2017: Regulatory Toxicology and Pharmacology: RTP
Simona Bussi, Laure Penard, Roberta Bonafè, Catherine Botteron, Roberto Celeste, Alessandra Coppo, Roberta Queliti, Miles A Kirchin, Fabio Tedoldi, Federico Maisano
To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology...
December 23, 2017: Regulatory Toxicology and Pharmacology: RTP
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