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Ruff K.J.,ESM Technologies LLC | Endres J.R.,AIBMR Life Science Inc. | Clewell A.E.,AIBMR Life Science Inc. | Szabo J.R.,Ricerca Biosciences LLC | Schauss A.G.,AIBMR Life Science Inc.
Food and Chemical Toxicology | Year: 2012

Natural Eggshell Membrane (NEM®) is a novel dietary ingredient that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. NEM® was evaluated for safety via in vitro and in vivo toxicological studies. This included testing for cytotoxicity, genotoxicity, acute oral toxicity, and 90-day repeated-dose oral toxicity. NEM® did not exhibit any cytotoxic effects at a dose of 100 μg in an in vitro human cell viability assay after incubation for up to 20. h. NEM® did not exhibit any genotoxic effects in an in vitro assay of four strains of histidine-dependent Salmonella typhimurium and one strain of tryptophan-dependent Escherichia coli at a dose of up to 5000 μg/plate. NEM® did not exhibit any signs of acute toxicity in rats at a single oral dose of up to 2000. mg/kg body weight, nor signs of toxicity (via urinalysis, hematology, clinical chemistry, or histopathological evaluation) in rats at a repeated oral dose of up to 2000. mg/kg body weight per day for 90. days. The results of these studies suggest that NEM® may be safe for human consumption. © 2012 Elsevier Ltd.

Freise K.J.,Nexcyon Pharmaceuticals Inc. | Savides M.C.,Ricerca Biosciences LLC | Riggs K.L.,Elanco Animal Health | Owens J.G.,Elanco Animal Health | And 2 more authors.
Journal of Veterinary Pharmacology and Therapeutics | Year: 2012

A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2mg/kg (100μL/kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (tlag) of 0.333h in the 1.3mg/kg group and 0 in the other two groups. The mean Cmax increased with dose and were 2.28, 2.67, and 4.71ng/mL in the 1.3, 2.6 and 5.2mg/kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103h in the 1.3, 2.6, and 5.2mg/kg dose groups, respectively. The mean AUC0-LLOQ from lowest to highest dose groups were 157, 268, and 645ng·h/mL and were dose proportional with a R2 value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6mg/kg (50μL/kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2mg/kg group and a more rapid onset of action and longer duration of action compared to the 1.3mg/kg group. © 2012 Blackwell Publishing Ltd.

Cox S.R.,Pfizer | Lesman S.P.,Pfizer | Boucher J.F.,Pfizer | Krautmann M.J.,Pfizer | And 5 more authors.
Journal of Veterinary Pharmacology and Therapeutics | Year: 2010

The pharmacokinetics of mavacoxib were evaluated in an absolute bioavailability study, a dose-proportionality study and a multi-dose study in young healthy adult laboratory Beagle dogs and in a multi-dose safety study in Beagle-sized laboratory Mongrel dogs. When administered as the commercial tablet formulation at 4 mg/kg body weight (bw) to fasted dogs, the absolute bioavailability (F) of mavacoxib was 46.1%; F increased to 87.4% when mavacoxib was administered with food. Following intravenous administration, the total body plasma clearance of mavacoxib was 2.7 mL·h/kg, and the apparent volume of distribution at steady-state was 1.6 L/kg. The plasma protein binding of mavacoxib was approximately 98% in various in vitro and ex vivo studies. The dose-normalized area under the plasma concentration-time curve was similar in Beagle and Beagle-sized Mongrel dogs when mavacoxib was administered with food. Mavacoxib exhibited dose-proportional pharmacokinetics for single oral doses of 2-12 mg/kg in Beagle dogs and for multiple oral doses of 5-25 mg/kg in Beagle-sized Mongrel dogs. Only minor accumulation occurred when mavacoxib was administered at doses of 2-25 mg/kg bw orally to laboratory dogs with a 2-week interval between the 1st two doses but with a monthly interval thereafter. Across all three Beagle studies (n = 63) the median terminal elimination half-life (t) was 16.6 days, with individual values ranging 7.9-38.8 days. The prolonged t for mavacoxib supports the approved regimen in which doses are separated by 2-4 weeks. © 2010 Blackwell Publishing Ltd.

Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11β-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1] heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice. © 2010 American Chemical Society.

Denys G.A.,Indiana University | Davis J.C.,Ricerca Biosciences LLC | O'Hanley P.D.,ExOxEmis Inc. | Stephens Jr. J.T.,ExOxEmis Inc.
Antimicrobial Agents and Chemotherapy | Year: 2011

We evaluated the in vitro and in vivo activity of a novel topical myeloperoxidase-mediated antimicrobial, E-101 solution, against 5 multidrug-resistant Acinetobacter baumannii isolates recovered from wounded American soldiers. Time-kill studies demonstrated rapid bactericidal activity against all A. baumannii strains tested in the presence of 3% blood. The in vitro bactericidal activity of E-101 solution against A. baumannii strains was confirmed in a full-thickness excision rat model. Additional in vivo studies appear warranted. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

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