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Carter C.M.,MPI Research | Cregar L.C.,MPI Research | Aulbach A.D.,MPI Research
Toxicologic Pathology | Year: 2017

Cytological bone marrow evaluation is utilized in nonclinical toxicology studies to characterize hematopoietic effects when the combined interpretation of histologic and complete blood count data does not yield sufficient information. Results from cytological bone marrow examination should be interpreted in the context of variability observed in concurrent control animals with consideration of cytologist experience and historical/published data. Cytological bone marrow differential counts and cellular morphologic findings from 130 (66 male, 64 female) healthy control cynomolgus monkeys from nonclinical toxicology studies were retrospectively analyzed. Myeloid to erythroid (M:E) ratios and the percentage of total cells for each cell type were determined from differential cell count data. M:E ratios ranged from 0.6:1 to 2.3:1. Percentages of total granulocytic cells, total erythroid cells, and lymphocytes ranged from 26.6% to 60.6%, 25.7% to 52.2%, and 5.5% to 40.4%, respectively. Monocytes, plasma cells, mast cells, and mitotic figures were typically <1% of total cells. Notable morphologic findings included occasional giant neutrophilic metamyelocytes and band neutrophils, ring-shaped band neutrophil nuclei, metarubricyte nuclear blebbing and binucleation, multiple or nonfused megakaryocyte nuclei, and emperipolesis. These results represent cytological bone marrow findings from healthy control cynomolgus monkeys utilized in nonclinical toxicology studies and provide insight into expected background variability. © Society of Toxicologic Pathology.

Aulbach A.,MPI Research | Provencher A.,Charles River Laboratories | Tripathi N.,Covance
Toxicologic Pathology | Year: 2017

A number of factors related to study design have the potential to impact clinical pathology test results during the conduct of nonclinical safety studies. A thorough understanding of these factors is paramount in drawing accurate conclusions from clinical pathology data generated during such studies, particularly when attempting to make the distinction between test article and nontest article-related effects. Study design and conduct variables with potential to impact clinical pathology data discussed in this overview include those related to species and test system, animal age, animal care and husbandry practices, fasting, acclimatization periods, effects of transportation and stressors, route of administration, effects of in-life and surgical procedures, influence of study length, timing of blood collections, impact of vehicle/formulation composition, and some general concepts related to drug class. The material presented here is a summary based on information presented at the 35th Annual Symposium of the Society of Toxicologic Pathology (June 2016), during Symposium Session 2 titled "Deciphering Sources of Variability in Clinical Pathology - It's Not Just about the Numbers." © Society of Toxicologic Pathology.

Ekanayaka E.A.P.,Michigan State University | Ekanayaka E.A.P.,MPI Research | Celiz M.D.,Michigan State University | Jones A.D.,Michigan State University
Plant Physiology | Year: 2015

The rapid identification of novel plant metabolites and assignments of newly discovered substances to natural product classes present the main bottlenecks to defining plant specialized phenotypes. Although mass spectrometry provides powerful support for metabolite discovery by measuring molecular masses, ambiguities in elemental formulas often fail to reveal the biosynthetic origins of specialized metabolites detected using liquid chromatography-mass spectrometry. A promising approach for mining liquid chromatography-mass spectrometry metabolite profiling data for specific metabolite classes is achieved by calculating relative mass defects (RMDs) from molecular and fragment ions. This strategy enabled the rapid recognition of an extensive range of terpenoid metabolites in complex plant tissue extracts and is independent of retention time, abundance, and elemental formula. Using RMD filtering and tandem mass spectrometry data analysis, 24 novel elemental formulas corresponding to glycosylated sesquiterpenoid metabolites were identified in extracts of the wild tomato Solanum habrochaites LA1777 trichomes. Extensive isomerism was revealed by ultra-high-performance liquid chromatography, leading to evidence of more than 200 distinct sesquiterpenoid metabolites. RMD filtering led to the recognition of the presence of glycosides of two unusual sesquiterpenoid cores that bear limited similarity to known sesquiterpenes in the genus Solanum. In addition, RMD filtering is readily applied to existing metabolomics databases and correctly classified the annotated terpenoid metabolites in the public metabolome database for Catharanthus roseus. © 2014 American Society of Plant Biologists. All Rights Reserved.

Henry S.P.,Isis Pharmaceuticals | Johnson M.,MPI Research | Zanardi T.A.,Isis Pharmaceuticals | Fey R.,Isis Pharmaceuticals | And 3 more authors.
Toxicology | Year: 2012

The primary target organ for uptake of systemically administered phosphorothioate oligonucleotides is the kidney cortex and the proximal tubular epithelium in particular. To determine the effect of oligonucleotide uptake on renal function, a detailed renal physiology study was performed in cynomolgus monkeys treated with 10-40mg/kg/week ISIS 113715 for 4 weeks. The concentrations of oligonucleotide in the kidney cortex ranged from 1400 to 2600μg/g. These concentrations were associated with histologic changes in proximal tubular epithelial cells that ranged from the appearance of cytoplasmic basophilic granules to atrophic and degenerative changes at higher concentrations. However, there were no renal functional abnormalities as determined by the typical measurements of blood urea nitrogen, serum creatinine, creatinine clearance, or urine specific gravity. Nor were there changes in glomerular filtration rate, or renal blood flow. Specific urinary markers of tubular epithelial cell damage, such as N-acetyl-glucosaminidase, and α-glutathione-s-transferase were not affected. Tubular function was further evaluated by monitoring the urinary excretion of amino acids, β 2-microglobulin, or glucose. Renal function was challenged by administering a glucose load and by examining concentrating ability after a 4-h water deprivation. Neither challenge produced any evidence of change in renal function. The only change observed was a low incidence of increased urine protein/creatinine ratio in monkeys treated with ≥40mg/kg/week which was rapidly reversible. Collectively, these data indicate that ISIS 113715-uptake by the proximal tubular epithelium has little or no effect on renal function at concentrations of 2600μg/g. © 2012 Elsevier Ireland Ltd.

Clark M.R.,Eastern Virginia Medical School | Melissa Peet M.,MPI Research | Davis S.,MPI Research | Doncel G.F.,Eastern Virginia Medical School | Friend D.R.,Eastern Virginia Medical School
Pharmaceutics | Year: 2014

Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups; however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Chow C.P.,Cleveland BioLabs Inc. | Faqi A.S.,MPI Research
Reproductive Toxicology | Year: 2014

CBLB502 is a derivative of a microbial protein that binds to Toll-like receptor 5. It is demonstrated to reduce inflammatory response from acute stresses, such as radiation in animal models. We determined the potential developmental toxicity of CBLB502 in rats. Four groups of 25 time-mated female Wistar rats/group received subcutaneously 0, 30, 100, or 300. μg/kg/day of CBLB502 from Gestation Days (GD) 6 to 17 at a dose volume of 1.0. mL/kg. Toxicokinetic evaluation was performed on GD 6 and 17. On GD 20 C-section was performed for uterine evaluation and blood samples collected from each dam for immunogenicity assay.Significant decrease in gestation body weight, weight changes and food consumption indicative of maternal toxicity were observed in all dose groups. Also adjusted body weight and weight changes were seen at 300. μg/kg/day. No external, visceral and skeletal abnormalities were observed. The NOAEL for developmental toxicity was estimated to be ≥300. μg/kg/day. © 2014.

Faqi A.S.,MPI Research
Systems Biology in Reproductive Medicine | Year: 2012

The nonhuman primates (NHPs) are used in many areas of biomedical research where their similarities to humans make them exclusively valuable animal models. The use of NHPs in pre-clinical testing is expected to increase due to the increase in the development of biological compounds for therapeutic uses. The regulatory agencies around the world including Food and Drug Administration (FDA) generally requires developmental and reproductive toxicity (DART) testing of all new drugs to be used by women of childbearing age or men of reproductive potential. NHPs are most frequently used for DART testing when commonly used rodents and/or rabbits are not pharmacologically relevant species. Animal studies are unique in that assessment of reproduction and development as DART studies are not performed in controlled clinical trials; therefore, pre-clinical safety assessment forms the basis for risk assessment for marketed drug products. This paper provides a critical evaluation of developmental and reproductive toxicity studies in NHPs. The manuscript will focus on species selection, limitation of International Conference for Harmonization stages (A-F) using NHPs as a test system, study designs, logistical/technical challenges, and strength, and limitations. It will also pinpoint confounding factors inherent to the test system that may complicate the interpretation of the NHP DART data. © 2012 Informa Healthcare USA, Inc.

Abernathy M.M.,MPI Research
Handbook of Experimental Pharmacology | Year: 2015

Safety pharmacology satisfies a key requirement in the process of drug development. Safety pharmacology studies are required to assess the impact of a new chemical entity (NCE) or biotechnology-derived product for human use on vital systems, such as those subserving auditory function. Safety pharmacology studies accordingly are defined as those studies that investigate the potential undesirable effects of a substance on auditory functions in relation to exposure in and above the therapeutic range. Auditory safety studies should be designed with the primary objective of determining how administration of a compound influences normal hearing. If an effect on hearing is identified, then it is necessary to determine through histopathology the underlying mechanism for the observed hearing loss. Since the auditory system contains a heterogeneous mixture of structural and cellular components that are organized in a very complex and integrated manner, it is necessary to clearly identify the underlying primary mechanism or target of the new chemical entity that produced the hearing loss. This chapter will highlight major components of auditory function with regard to potential opportunities for drug interaction. Aspects of designing ototoxicity studies will be discussed with an emphasis on standards deemed necessary by the US Food and Drug Administration. Additionally, classes of ototoxic compounds and their proposed mechanisms of action are described in depth. © Springer-Verlag Berlin Heidelberg 2015

Produce and other non-certified foods may be provided to laboratory animals for enrichment, but this practice can generate scientific concerns, particularly if these food items contain nutrients that are pharmacologically active or affect animals' consumption of the basal diet. The author reviews information on potential for a number of nutritional components of food items to affect study data. On the basis of published effect levels, he proposes an upper limit for the consumption of each component in enrichment items relative to the amount present in a standard basal diet. He then assesses the amounts of these nutritional components in a broad range of food enrichment items and proposes a maximum serving size for each item for several common laboratory animals. Total caloric content and sugar content are the limiting components for many enrichment food items, but most items may be used as enrichment for laboratory animals without affecting study results, as long as the amounts of the items provided are managed. © 2015 Nature America, Inc.

One enrichment strategy for laboratory animals is the provision of food variety and foraging opportunities. Fresh agricultural items, including produce or packaged human food items, provide variation in palatability, texture and complexity and can therefore be used as enrichment for lab animals. But concerns are often raised that these food items might sometimes carry contaminants that could affect research subjects and confound experimental results. The author discusses the potential for agriculturally sourced foods used as enrichment for lab animals to be contaminated with mycotoxins, microorganisms and pesticide residues and the effects these contaminants might have on lab animals. He also suggests strategies for reducing the risk of contamination. © 2015 Nature America, Inc. All rights reserved.

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