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Bouvier G.,Galderma RandD | Learn D.B.,Charles River Laboratories Preclinical Services | Nonne C.,Galderma RandD | Feraille G.,Galderma RandD | And 2 more authors.
Photochemistry and Photobiology | Year: 2015

Brimonidine at 0.18%, 1% and 2% concentrations applied topically in hairless mice significantly decreased tumor burden and incidences of erythema, flaking, wrinkling and skin thickening induced by UVR. The unbiased median week to tumor ≥1 mm was increased by the 1% and 2% concentrations. The tumor yield was reduced by all concentrations at week 40 for all tumor sizes but the ≥4 mm tumors with the 0.18% concentration. At week 52, the tumor yield was reduced for all tumor sizes and all brimonidine concentrations. The tumor incidence was reduced by all concentrations at week 40 for all tumor sizes, but the ≥4 mm tumor with the 0.18% concentration and at week 52 for all tumor sizes with the 1% and 2% concentrations and with the 0.18% concentration only for the ≥4 mm tumors. Reductions in ≥4 mm tumor incidences compared to the vehicle control group were 54%, 91% and 86% by week 52 for the 0.18%, 1% and 2% concentrations, respectively. Brimonidine at 2% applied 1 h before or just after UVB irradiation on hairless mice decreased epidermal hyperplasia by 23% and 32% and epithelial cell proliferation by 59% and 64%, respectively, similar to an epidermal growth factor receptor (EGFR) inhibitor. © 2015 The American Society of Photobiology.

Brannen K.C.,Charles River Laboratories Preclinical Services | Fenton S.E.,National Health Research Institute | Hansen D.K.,U.S. Food and Drug Administration | Harrouk W.,U.S. Food and Drug Administration | And 2 more authors.
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2011

In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a "signal" or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration. © 2011 Wiley Periodicals, Inc.

Harper M.S.,DuPont Pioneer | Amanda Shen Z.,DuPont Company | Barnett J.F.,Charles River Laboratories Preclinical Services | Krsmanovic L.,BioReliance | And 2 more authors.
Food and Chemical Toxicology | Year: 2010

N-acetylglycine (NAGly) has been identified as a minor constituent of numerous foods. The current paper reports the outcome of in vitro and in vivo genotoxicity, acute oral and repeated dose dietary toxicology studies conducted with NAGly. No evidence of genotoxicity was observed with NAGly in vitro bacterial tester strains or in vivo bone marrow micronucleus studies conducted in mice. No mortalities or evidence of adverse effects were observed in Sprague-Dawley rats following acute oral gavage with NAGly at a dose of 2000. mg/kg of body weight or following repeated dose dietary exposure to NAGly at targeted doses of 100, 500, or 1000. mg/kg of body weight/day for 28. days. No biologically significant or test substance related differences were observed in body weights, feed consumption, or clinical pathology response variables in any of the treatment groups. Based on these results it was concluded that NAGly is not genotoxic or acutely toxic. Further, the no-observed adverse-effect-level (NOAEL) for systemic toxicity from repeated dose dietary exposure to NAGly was 898.9. mg/kg of body weight/day for male rats and 989.9. mg/kg of body weight/day for female rats. © 2010 Elsevier Ltd.

Wang L.,Millennium Pharmaceuticals Inc. | Wang L.,Millennium: The Takeda Oncology Company | Wang L.,Glaxosmithkline | Jenkins T.J.,Millennium Pharmaceuticals Inc. | And 12 more authors.
Thorax | Year: 2013

Background: Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data. Objective: To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma. Methods: ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine. Results: ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086. Conclusions: These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.

Plomley J.B.,Charles River Laboratories Preclinical Services | Jackson R.L.,Ausio Pharmaceuticals LLC | Schwen R.J.,Ausio Pharmaceuticals LLC | Greiwe J.S.,Ausio Pharmaceuticals LLC
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for the determination of unconjugated and total (conjugated plus unconjugated) S-equol in human plasma and urine were developed and validated. The separation of R and S enantiomers was achieved with a Chiracel OJ-H column operated in a normal phase mode using ethanol/hexane mobile phase components. Ionization of S-equol by negative ion electrospray generated the [M-H] - ion whose response was augmented by post-column addition of ammonium hydroxide. A triple stage quadrupole mass spectrometer was used to measure the ion current generated from the dissociative transitions m/z 241→m/z 121 (S-equol) and m/z 245→m/z 123 (equol-d 4). The determination of total S-equol included an additional deconjugation step involving incubation of the sample with sulfatase and glucuronidase. Average recovery for both unconjugated and total S-equol was 85% with no observable matrix effects. Linearity was established for unconjugated S-equol from 0.025ng/mL to 10ng/mL (plasma) and 0.20ng/mL to 200ng/mL (urine). The average coefficient of variation and accuracy per occasion was within ±15% of the theoretical concentration of S-equol. The method was used to measure the pharmacokinetics of S-equol in human plasma after an oral administration of a single 20mg dose of S-equol to three normal healthy volunteers. © 2011 Elsevier B.V.

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