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Regulatory Toxicology and Pharmacology: RTP

Elizabeth Oesterling Owens, Molini M Patel, Ellen Kirrane, Thomas C Long, James Brown, Ila Cote, Mary A Ross, Steven J Dutton
To inform regulatory decisions on the risk due to exposure to ambient air pollution, consistent and transparent communication of the scientific evidence is essential. The United States Environmental Protection Agency (U.S. EPA) develops the Integrated Science Assessment (ISA), which contains evaluations of the policy-relevant science on the effects of criteria air pollutants and conveys critical science judgments to inform decisions on the National Ambient Air Quality Standards. This article discusses the approach and causal framework used in the ISAs to evaluate and integrate various lines of scientific evidence and draw conclusions about the causal nature of air pollution-induced health effects...
May 16, 2017: Regulatory Toxicology and Pharmacology: RTP
Richard A Byrd, Rebecca A Owens, Jamie L Blackbourne, David E Coutant, Mark W Farmen, M Dodson Michael, Julie S Moyers, A Eric Schultze, Michael K Sievert, Niraj K Tripathi, John L Vahle
Basaglar(®)/Abasaglar(®) (Lilly insulin glargine [LY IGlar]) is a long-acting human insulin analogue drug product granted marketing authorisation as a biosimilar to Lantus(®) (Sanofi insulin glargine [SA IGlar]) by the European Medicines Agency. We assessed the similarity of LY IGlar to the reference drug product, European Union-sourced SA IGlar (EU-SA IGlar), using nonclinical in vitro and in vivo studies. No biologically relevant differences were observed for receptor binding affinity at either the insulin or insulin-like growth factor-1 (IGF-1) receptors, or in assays of functional or de novo lipogenic activity...
May 16, 2017: Regulatory Toxicology and Pharmacology: RTP
Sonia Goineau, Vincent Castagné
Drug-induced QT prolongation is a major safety issue in the drug discovery process. This study was conducted to assess the electrophysiological responses of four substances using established preclinical assays usually used in regulatory studies (hERG channel or Purkinje fiber action potential) and a new assay (human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)-field potential). After acute exposure, moxifloxacin and dofetilide concentration-dependently decreased IKr amplitude (IC50 values: 102 μM and 40 nM, respectively) and lengthened action potential (100 μM moxifloxacin: +23% and 10 nM dofetilide: +18%) and field potential (300 μM moxifloxacin: +76% and 10 nM dofetilide: +38%) durations...
May 12, 2017: Regulatory Toxicology and Pharmacology: RTP
Amy K Madl, Kathryn D Devlin, Angela L Perez, Dana M Hollins, Dallas M Cowan, Paul K Scott, Katherine White, Thales J Cheng, John L Henshaw
No abstract text is available yet for this article.
May 12, 2017: Regulatory Toxicology and Pharmacology: RTP
V Lee Grotz, Xavier Pi-Sunyer, Daniel Porte, Ashley Roberts, J Richard Trout
The discovery of gut sweet taste receptors has led to speculations that non-nutritive sweeteners, including sucralose, may affect glucose control. A double-blind, parallel, randomized clinical trial, reported here and previously submitted to regulatory agencies, helps to clarify the role of sucralose in this regard. This was primarily an out-patient study, with 4-week screening, 12-week test, and 4-week follow-up phases. Normoglycemic male volunteers (47) consumed ∼333.3 mg encapsulated sucralose or placebo 3x/day at mealtimes...
May 11, 2017: Regulatory Toxicology and Pharmacology: RTP
Shahrzad Tafazoli, Trung D Vo, Anne Petersen, Anne Constable, Myriam Coulet, Phoukham Phothirath, Johanna Lang, Nigel Baldwin
The potential toxicity of two savory food ingredients produced by fermentation of enzymatically hydrolyzed corn starch (Savory Base 100 and Savory Base 200) was evaluated individually in a bacterial reverse mutation assay, an in vitro mammalian cell gene mutation assay, an acute oral study and as a mixture in a 90-day dietary study. In the bacterial reverse mutation and in vitro mammalian cell gene mutation assays, neither ingredient was mutagenic at concentrations up to 5000 μg/plate and 5000 μg/mL, respectively in the presence and absence of metabolic activation...
May 6, 2017: Regulatory Toxicology and Pharmacology: RTP
Jun-Won Yun, Seung-Hyun Kim, Yun-Soon Kim, Ji-Ran You, Eun-Young Cho, Jung-Hee Yoon, Euna Kwon, Jae Hun Ahn, Ja-June Jang, Jeong-Hwan Che, Byeong-Cheol Kang
Artemisia capillaris (AC) has been used as an alternative therapy in obesity, atopic dermatitis, and liver diseases through several biological activity including anti-steatotic, antioxidant, and anti-inflammatory activities. Despite its ethnomedicinal benefits, no sufficient background information is available about the long-term safety and genotoxicity of the AC extract. Therefore, the present study was carried out to investigate the 13-week subchronic toxicity and genotoxicity of the AC extract according to the test guidelines published by the Organization for Economic Cooperation and Development...
May 6, 2017: Regulatory Toxicology and Pharmacology: RTP
(no author information available yet)
No abstract text is available yet for this article.
May 6, 2017: Regulatory Toxicology and Pharmacology: RTP
Yin-Ju Lin, Jian-Yu Lin, Di-Sheng Wang, Chien-Hao Chen, Ming-Hsi Chiou
Astaxanthin is a natural carotenoid with strong antioxidant activity that has been used for decades as a nutrient/color additive and it has recently been marketed as a health supplement. Astaxanthin can be synthesized in a wide range of microalgae, yeast, and bacteria. As genes directing astaxanthin biosynthesis in various organisms have been cloned, this study assessed the safety of astaxanthin crystal produced by Escherichia coli K-12 harboring plasmids carrying astaxanthin biosynthetic genes. The astaxanthin crystal contains a total carotenoid content of 950 mg/g and an astaxanthin content of 795 mg/g...
May 5, 2017: Regulatory Toxicology and Pharmacology: RTP
A Steiner, K Kugarajan, M Wullimann, B Ruty, G Kunze
The safety assessment of pentylene glycol (PG) has been based on a bioavailability extrapolated from those of other 1,2-glycols or an assumed 100% absorption. To make a better safety assessment and an accurate calculation of the margin of safety (MoS), the skin penetration of PG present in a commercially available sunscreen was measured in pig skin at different exposure durations. The mass balance of PG decreased with increasing exposure durations, from 98% (1 h) to 29% (24 h) and the amount of PG detected in the skin wash decreased over time from 93% to 3%...
May 5, 2017: Regulatory Toxicology and Pharmacology: RTP
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No abstract text is available yet for this article.
May 5, 2017: Regulatory Toxicology and Pharmacology: RTP
Lynne D Butler, Peggy Guzzie-Peck, James Hartke, Matthew S Bogdanffy, Yvonne Will, Dolores Diaz, Elisabeth Mortimer-Cassen, Mazin Derzi, Nigel Greene, Joseph J DeGeorge
The transition from nonclinical to First-in-Human (FIH) testing is one of the most challenging steps in drug development. In response to serious outcomes in a recent Phase 1 trial (sponsored by Bial), IQ Consortium/DruSafe member companies reviewed their nonclinical approach to progress small molecules safely to FIH trials. As a common practice, safety evaluation begins with target selection and continues through iterative in silico and in vitro screening to identify molecules with increased probability of acceptable in vivo safety profiles...
May 5, 2017: Regulatory Toxicology and Pharmacology: RTP
Seblework Mekonen, Argaw Ambelu, Belay Negassa, Pieter Spanoghe
Khat (Catha edulis) is one of the most consumed plant in the horn of African countries. However, it is a stimulant plant that has several side effects on the health of consumers. On top of that, the khat leaves used for human consumption are often contain contaminants such as pesticide residues. The present study aims to investigate the level of DDT residue and its metabolites (p'p-DDE, p'p-DDD, o'p-DDT and p'p-DDT) in khat samples and to undertake exposure assessment to consumers. The khat samples were collected from local markets in southwestern Ethiopia...
May 5, 2017: Regulatory Toxicology and Pharmacology: RTP
Dai Yuki, Chikako Sakaguchi, Akira Kikuchi, Yasuyuki Futamura
The objective of this clinical study was to investigate the pharmacokinetics of nicotine following the use of a prototype novel tobacco vapor (PNTV) product in comparison to a conventional cigarette (CC1). The study was conducted in Japanese healthy adult male smokers, using an open-label, randomized, two-period crossover design, to assess the pharmacokinetics of nicotine after controlled use of a PNTV product or CC1. During the study period, blood samples were drawn from subjects for the measurement of plasma nicotine concentrations and nicotine intake was estimated from the mouth level exposure (MLE)...
May 4, 2017: Regulatory Toxicology and Pharmacology: RTP
Yonghui Zhang, Chong Zhang, Fulu Dong, Miaomiao Chen, Jingchen Cao, Haiyan Wang, Ming Jiang
4-Nitrophenol (PNP), a well-established human carcinogen, has been proven to have detrimental effects on reproductive system of male rats in previous studies. The molecular mechanisms involved PNP-induced damage remain to be established. Autophagy can exert protective effects on various cytotoxic factors that induce injury. In the present study, we aim to investigate whether autophagy is induced by PNP and the function of autophagy in PNP-induced injury in NHPrE1, a normal human prostate epithelial progenitor cell line...
May 3, 2017: Regulatory Toxicology and Pharmacology: RTP
Carl D D'Ruiz, Grant O'Connell, Donald W Graff, X Sherwin Yan
Acute changes in select physiological parameters associated with cardiovascular physiology (systolic and diastolic blood pressure (BP) and heart rate (HR)), pulmonary function (FVC, FEV1, and exhaled CO and NO) and adverse events were measured in 105 clinically confined subjects who were randomized into groups that either completely or partially switched from conventional cigarettes to e-cigarettes or completely discontinued using tobacco and nicotine products altogether. Use of the e-cigarettes for five days under the various study conditions did not lead to higher BP or HR values, negative respiratory health outcomes or serious adverse health events...
May 3, 2017: Regulatory Toxicology and Pharmacology: RTP
William M Snellings, Kenneth E McMartin, Marcy I Banton, Fred Reitman, Joanna Klapacz
Diethylene glycol (DEG) is an organic chemical that is used mostly as a chemical intermediate and has minor uses as a solvent or antifreeze in consumer products; these minor uses could result in potential human exposure. Potential short and long-term human exposures also occur from misuses. The considerable reporting of DEG misuses as a substitute for other solvents in drug manufacturing and summaries of important events in the history of DEG poisonings are reviewed. Given the potential for human exposure, the disposition and toxicity of DEG were examined, and a health assessment was performed...
April 29, 2017: Regulatory Toxicology and Pharmacology: RTP
Patricia Parris, J Neil Duncan, Andrew Fleetwood, William P Beierschmitt
In response to increasing concerns around the potential environmental impact of industrial chemicals, the pharmaceutical industry is seeking alternatives for traditional solvents used during the manufacturing process. Taking into consideration the principles of green chemistry, 2-methyltetrahydrofuran (2-MeTHF) is proposed as a suitable replacement for the structurally similar solvent tetrahydrofuran (THF). 2-MeTHF is derived from renewable sources and is more easily recovered thereby facilitating its reuse...
April 29, 2017: Regulatory Toxicology and Pharmacology: RTP
Richard D Costlow, Hans Nasshan, Peter Frenkel
Based on previous studies, dioctyltin dichloride [DOTC] was a putative toxophore for dioctyltin thioesters. Our results, generated with the use of (119)Sn-NMR spectroscopy demonstrated that dioctyltin bis(2-ethylhexyl thioglycolate) [DOTE] hydrolyzed to form dioctyltin chloro-(2-ethylhexyl thioglycolate) [DOTCE] under simulated gastric conditions, but no DOTC was formed. DOTE was administered orally at 4, 20, and 80 mg/kg/day [GD6-GD28; rabbits] or at 15, 30, and 60 mg/kg/day [GD5-GD17; mice]. There were no maternal deaths, treatment-related statistically significant reductions in maternal body weight or weight gain, or adverse gestational outcomes in either species...
April 26, 2017: Regulatory Toxicology and Pharmacology: RTP
Qianying Liu, Zhixin Lei, Luqing Cui, Jianwu Zhang, Ihsan Awais, Menghong Dai, Xu Wang, Zonghui Yuan
To investigate the potential carcinogenicity of cyadox, an antimicrobial agent, four groups of Sprague-Dawley rats (50 rats/sex/group) were fed diets containing cyadox (0, 200, 600 or 2000 mg/kg) for up to two years. There were significant decreases in body weight, feed intake and feed efficiency in both genders during most of the period in the 2000 mg/kg group. Significant decreases in serum ALT were observed in the 2000 mg/kg group at weeks 52, 78 and 104. For the control, 200, 600, and 2000 mg/kg groups, the tumor incidence in females was 33...
April 25, 2017: Regulatory Toxicology and Pharmacology: RTP
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