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Mahadevan B.,Abbott Laboratories | Thorsrud B.A.,MPI Research Inc. | Brorby G.P.,ToxStrategies Inc. | Ferguson H.E.,Abbott Laboratories
Food and Chemical Toxicology | Year: 2014

Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2. days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20. g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with Amioca™ Powder to balance the nutritional profiles of all formulations. There were no test article-related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20. g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. © 2014 Elsevier Ltd.

Pugsley M.K.,Janssen Research and Development LLC | Dalton J.A.,MPI Research Inc. | Authier S.,INC Research | Curtis M.J.,Rayne Institute
Journal of Pharmacological and Toxicological Methods | Year: 2014

What do you know about Safety Pharmacology? This is the question that was asked in 2000 with the inception of the Safety Pharmacology Society (SPS). There is now a widespread awareness of the role of safety pharmacology in drug discovery and increasing awareness among the wider community of methods and models used in the assessment of the core battery required set of safety studies. However, safety pharmacology does not stop with core battery studies. New methods are intensively sought in order to achieve a swifter and more reliable assessment of adverse effect liability. The dynamics of the discipline and method expansion are reflected in the content of this issue of the Journal of Pharmacological and Toxicological Methods (JPTM). We are into the second decade of publishing on safety pharmacology methods and models, reflected by the annual themed issue in JPTM, and on willingness of investigators to embrace new technologies and methodologies. This years' themed issue is derived from the annual Safety Pharmacology Society (SPS) meeting, held in Rotterdam, The Netherlands, in 2013. © 2014 Elsevier Inc.

Faqi A.S.,MPI Research Inc. | Prohaska D.,Furiex Pharmaceuticals | Lopez R.,Furiex Pharmaceuticals | Mcintyre G.,Furiex Pharmaceuticals
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2012

PPD10558 is an orally active, lipid-lowering 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin-associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320mg/kg/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50mg/kg/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50mg/kg/day), abortions (2 at 25mg/kg/day and 6 at 50mg/kg/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50mg/kg/day in comparison with the controls. Mean peak exposure (Cmax) and total exposure (AUC(0-24)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be ≥320mg/kg/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5mg/kg/day and 25mg/kg/day, respectively. © 2011 Wiley-Liss, Inc.

Xie H.,Texas Southern University | Wang Z.J.,University of Texas Health Science Center at San Antonio | Wang Z.J.,MPI Research Inc. | Bao A.,University of Texas Health Science Center at San Antonio | And 2 more authors.
International Journal of Pharmaceutics | Year: 2010

Here we report the radiolabeling of gold nanoshells (NSs) for PET imaging in rat tumor model. A conjugation method was developed to attach NSs with the radionuclide, 64Cu. The resulting conjugates showed good labeling efficiency and stability in PBS and serum. The pharmacokinetics of 64Cu-NS and the controls (64Cu-DOTA and 64Cu-DOTA-PEG2K) were determined in nude rats with a head and neck squamous cell carcinoma xenograft by radioactive counting. Using PET/CT imaging, we monitored the in vivo distribution of 64Cu-NS and the controls in the tumor-bearing rats at various time points after their intravenous injection. PET images of the rats showed accumulation of 64Cu-NSs in the tumors and other organs with significant difference from the controls. The organ biodistribution of rats at 46h post-injection was analyzed by radioactive counting and compared between the 64Cu-NS and the controls. Different clearance kinetics was indicated. Neutron activation analysis (NAA) of gold concentration was performed to quantify the amount of NSs in major tissues of the dosed rats and the results showed similar distribution. Overall, PET images with 64Cu had good resolution and therefore can be further applied to guide photothermal treatment of cancer. © 2010.

This perspective article discusses key points to address in the establishment of sound partnerships between sponsors and bioanalytical CROs to assure the timeliness, quality and consistency of bioanalysis throughout biological therapeutic development. The performance of ligand-binding assays can be greatly impacted by low-grade reagents, lot-to-lot variability and lack of stability of the analyte in matrix, impacting both timelines and cost. Thorough characterization of the biologic of interest and its assay-enabling critical reagents will lend itself well to conservation of materials and continuity of assay performance. When unplanned events occur, such as performance declines or premature depletion of material, structured procedures are paramount to supplement the current loosely defined regulatory guidance on critical reagent characterization and method bridging. © 2015 Future Science Ltd.

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