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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.


Enoru J.O.,Ricerca Biosciences LLC | Yang B.,Texas Tech University Health Sciences Center | Krishnamachari S.,Texas Tech University Health Sciences Center | Villanueva E.,Texas Tech University Health Sciences Center | And 5 more authors.
PLoS ONE | Year: 2016

Parkinson's disease (PD) is a neurodegenerative aging disorder in which postmortemPD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatoryoral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya1). We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively. Herein, we describe the metabolic stability and metabolic profiling of FTY720-C2 and FTY720-Mitoxy in liver microsomes and hepatocytes. Using mouse, rat, dog, monkey, and human liver microsomes the intrinsic clearance of FTY720-C2 was 22.5, 79.5, 6.0, 20.2 and 18.3 μL/min/mg; and for FTY720-Mitoxy was 1.8, 7.8, 1.4, 135.0 and 17.5 μL/min/mg, respectively. In hepatocytes, both FTY720-C2 and FTY720-Mitoxy were metabolized from the octyl side chain, generating a series of carboxylic acids similar to the parent FTY720, but without phosphorylated metabolites. To assess absorption and distribution, we gave equivalent single intravenous (IV) or oral doses of FTY720-C2 or FTY720-Mitoxy to C57BL/6 mice, with two mice per time point evaluated. After IV delivery, both FTY720-C2 and FTY720-Mitoxy were rapidly detected in plasma and brain; and reached peak concentrations at the first sampling time points. After oral dosing, FTY720-C2 was present in plasma and brain, although FTY720-Mitoxy was not orally bioavailable. Brain-to-plasma ratio of both compounds increased time-dependently, suggesting a preferential partitioningto the brain. PP2A activity in mouse adrenal gland increased ∼2-fold after FTY720-C2 or FTY720-Mitoxy, as compared to untreated controls. In summary, FTY720-C2 and FTY720-Mitoxy both (i) crossed the blood-brain-barrier; (ii) produced metabolites similar to FTY720, except without phosphorylatedspecies that cause S1P1-mediated-immunosuppression; and (iii) stimulated in vivo PP2A activity, all of which encourage additional preclinical assessment. © 2016 Enoru et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Savides M.C.,Ricerca Biosciences LLC | Pohland R.C.,Elanco Animal Health | Wilkie D.A.,Ohio State University | Abbott J.A.,Virginia Polytechnic Institute and State University | And 3 more authors.
Journal of Veterinary Pharmacology and Therapeutics | Year: 2012

Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6mg/kg (50μL/kg) to the ventral abdominal skin and observed for 14days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal. © 2012 Blackwell Publishing 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.


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.


PubMed | BioSTAT Consultants Inc., Ricerca Biosciences LLC and Aratana Therapeutics
Type: Journal Article | Journal: Journal of veterinary pharmacology and therapeutics | Year: 2016

A new anti-inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9-month) daily oral dose of 6 or 50mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50mg/kg grapiprant as both suspension and table formulations within a cross-over design with a 15-day washout. Clinical observations were vomiting in one high-dose suspension dog and loose stools in two dogs, one in each 6mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUC


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.


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.


PubMed | Ricerca Biosciences LLC
Type: | Journal: Journal of veterinary pharmacology and therapeutics | Year: 2012

Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1, 3, or 5 multiple of the dose of 2.6 mg/kg (50 L/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1 group were transient and included a low prevalence ( 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3 and 5 groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1 dose and describe the outcome of an overdose of up to 5 dose in the absence of opioid reversal.

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