SNBL United States Ltd.

Walla Walla, WA, United States

SNBL United States Ltd.

Walla Walla, WA, United States
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Ema M.,Japan National Institute of Health Sciences | Ise R.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Kato H.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Oneda S.,SNBL United States Ltd. | And 5 more authors.
Reproductive Toxicology | Year: 2010

The present study was performed to determine experimental conditions for thalidomide induction of fetal malformations and to understand the molecular mechanisms underlying thalidomide teratogenicity in cynomolgus monkeys. Cynomolgus monkeys were orally administered thalidomide at 15 or 20 mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses. Cynomolgus monkeys were orally administered thalidomide at 20 mg/kg on day 26 of gestation, and whole embryos were removed from the dams 6 h after administration. Three embryos each were obtained from the thalidomide-treated and control groups. Total RNA was isolated from individual embryos, amplified to biotinylated cRNA and hybridized to a custom Non-Human Primate (NHP) GeneChip® Array. Altered genes were clustered into genes that were up-regulated (1281 genes) and down-regulated (1081 genes) in thalidomide-exposed embryos. Functional annotation by Gene Ontology (GO) categories revealed up-regulation of actin cytoskeletal remodeling and insulin signaling, and down-regulation of pathways for vasculature development and the inflammatory response. These findings show that thalidomide exposure perturbs a general program of morphoregulatory processes in the monkey embryo. Bioinformatics analysis of the embryonic transcriptome following maternal thalidomide exposure has now identified many key pathways implicated in thalidomide embryopathy, and has also revealed some novel processes that can help unravel the mechanism of this important developmental phenotype. © 2009 Elsevier Inc.

Makori N.,SNBL United States Ltd. | Watson R.E.,SNBL United States Ltd. | Hogrefe C.E.,University of California at Davis | Lalayeva N.,SNBL United States Ltd. | Oneda S.,SNBL United States Ltd.
Journal of Medical Primatology | Year: 2013

Background: Biopharmaceutical development necessitates use of non-human primates in toxicology, leading to adoption of non-traditional methods including cognitive function assessment. Methods: A two-object discrimination and reversal test in cynomolgus monkeys (Macaca fascicularis) was performed using a Wisconsin General Testing Apparatus (WGTA). Non-clinical study design and regulatory considerations dictate that infants are raised by their biological mothers until weaning at 6 months. Thirty-four animals (6-21 months of age) were trained to discriminate between two randomly selected stimulus objects to retrieve a reward. Following training, days to first reversal after interchanging the reward were measured. Results: Both sexes acquired visual discrimination skills at similar rates. Trends in learning and reversals completed were uniform across age groups. Completing training early in some subjects had no impact on subsequent testing phases. Conclusions: Weaned cynomolgus monkey infants can be successfully tested for cognitive abilities using the WGTA in a non-clinical laboratory setting. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Johnson J.-I.,Michigan State University | Fenske B.A.,Michigan State University | Jaswa A.S.,Michigan State University | Morris J.A.,SNBL United States Ltd
Frontiers in Systems Neuroscience | Year: 2014

Since its first identification as a thin strip of gray matter enclosed between stretches of neighboring fiber bundles, the claustrum has been considered impossible to study by many modern techniques that need a certain roominess of tissue for their application. Known as the front wall, vormauren in German from 1822, and still called avant-mur in French, we here propose a means for breaking into and through this wall, by utilizing the instances where the claustral tissue itself has broken free into more spacious dimensions. This has occurred several times in the evolution of modern mammals, and all that needs be done is to exploit these natural expansions in order to take advantage of a great panoply of technological advances now at our disposal. So here we review the kinds of breakout "puddles" that await productive exploitation, to bring our knowledge of structure and function up to the level enjoyed for other more accessible regions of the brain. © 2014 Johnson, Fenske, Jaswa and Morris.

PubMed | Shin Nippon Biomedical Laboratories Ltd., Astellas Pharma Inc., SNBL United States Ltd. and University of Tokyo
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2016

A male cynomolgus monkey (Macaca fascicularis) of 5 years and 11 months of age from the vehicle control group of a 4-week repeated oral dose toxicity study had a spontaneously occurring mass lesion directly attached to the proximal part of the left trigeminal nerve. Histologically, the mass was characterized by a multifocal nodular appearance. Nodular zones showed low to moderate cellularity and were composed of small round cells exhibiting nuclear uniformity. On the other hand, inter-nodular zones were composed of nerve fiber containing septa and closely aggregated highly pleomorphic cells. Immunohistochemically, the small round cells were strongly immunopositive for synaptophysin, neuN, and class III beta-tubulin, while the highly pleomorphic cells were weakly immunopositive for neuN and occasionally immunopositive for class III beta-tubulin and doublecortin, suggesting that the tumor had originated from a neuronal lineage cell. Based on these findings, the mass was diagnosed as a neuroblastoma at the trigeminal nerve.

Thrall K.D.,SNBL United States Ltd | Love R.,SNBL United States Ltd | O'Donnell K.C.,University of Maryland, Baltimore | Farese A.M.,University of Maryland, Baltimore | And 2 more authors.
Health Physics | Year: 2015

The Medical Countermeasures against Radiological Threats (MCART) consortiumhas established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animalmodel is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min-1. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures. Copyright © 2015 Health Physics Society.

PubMed | National Institute of Environmental Research, National Institute of Ecology, SNBL United States Ltd. and Seoul National University
Type: Journal Article | Journal: The Korean journal of parasitology | Year: 2014

This study reports the first case of Capillaria hepatica infection in a nutria in Korea. Ten nutrias, captured near the Nakdong River, were submitted to our laboratory for necropsy. White-yellowish nodules were found in the liver of 1 of the nutrias at necropsy. Histologically, the lesions were granulomatous, and infiltrations of lipid-laden macrophages, eosinophils, and several multinucleated giant cells were observed. The lesions consisted of numerous eggs and necrotic hepatocytes. The eggs were lemon-shaped and had polar plugs at the ends of both long sides. The eggs were morphologically identified as those of C. hepatica. Worldwide, C. hepatica infection in nutrias is very rare. Nutrias are a kind of livestock, as well as wildlife; therefore, an epidemiological study for parasitic infections needs to be conducted.

PubMed | Pfizer, Tox Path Specialists and SNBL United States Ltd.
Type: | Journal: Reproductive toxicology (Elmsford, N.Y.) | Year: 2015

Two intravenous studies with tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. Study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (GD) 20 through parturition. Study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20-21 per group) from GD 20 through 48. In the absence of maternal toxicity, tanezumab increased stillbirth and post-birth infant mortality/morbidity, decreased infant growth and resulted in microscopic changes in the peripheral sympathetic and sensory nervous system of the infants at all doses. Decreased primary antibody responses and increased incidences in skin changes in infants were also observed. The no-observed-adverse-effect-level for maternal toxicity was 30 mg/kg and <0.5 mg/kg for developmental toxicity.

Woodburn K.W.,Affymax Inc. | Schatz R.J.,Affymax Inc. | Fong K.-L.,Pennsylvania Biolab Inc. | Beaumier P.,SNBL United States Ltd.
International Journal of Immunopathology and Pharmacology | Year: 2010

Hematide™ is a synthetic PEGylated peptidic erythropoiesis stimulating agent (ESA) that is presently being developed for the correction of anemia in patients with chronic renal failure. Unlike currently marketed ESAs, Hematide does not possess any sequence homology to erythropoietin (EPO) and has not elicited moribund immune responses in animal safety studies thereby allowing the generation of a robust safety package. Animals administered marketed ESAs develop anti-EPO antibodies that null the effect of the administered ESA and neutralize endogenous EPO, resulting in severe anemia that precludes the interpretation of chronic safety studies. The primary objective of this study is to determine whether Hematide-specific antibodies are generated when male monkeys are exposed to high Hematide doses (10 mg/kg, intravenous [IV] and subcutaneous [SC]) administered at frequent dosing intervals (every two weeks) for a total of 9 doses; secondary objectives are to evaluate whether developed antibodies impact pharmacokinetics (PK) and pharmacology. In this study, no Hematide-specific antibodies were detected. Hematide exhibits a prolonged plasma half-life and slow clearance by either IV or SC administration. Hematide induced significant erythropoiesis with reticulocytosis and subsequent increases in red blood cells, hematocrit and hemoglobin (Hgb) levels. No erythropoietic differences were noted between the IV and the SC dosed groups with mean ± SD Hgb levels of 20.9 ± 2.5 and 20.3 ± 2.1 g/dL, respectively, occurring on Day 48, corresponding to Hgb increases of 6.5 and 6.7 g/dL, respectively, over pre-dose levels. In conclusion, Hematide is a potent erythropoiesis stimulating agent that exhibits plasma persistence in monkeys. Similar erythropoietic responses were produced following IV and SC administration. The absence of antibody development suggests that Hematide, at the doses and regimen described, has a low immunogenic potential in cynomolgus monkeys. © by Biolife, s.a.s.

Butt M.,Tox Path Specialists LLC | Evans M.,Pfizer | Bowman C.J.,Pfizer | Cummings T.,Pfizer | And 3 more authors.
Toxicological Sciences | Year: 2014

Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (~GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to tanezumab 4 mg/kg (n1/49) and 30 mg/kg (n1/41). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology.

Radi Z.A.,Pfizer | Sato K.,SNBL United States Ltd.
Toxicologic Pathology | Year: 2010

The authors describe a case in which well-circumscribed, expansile, and nonencapsulated nodular masses with missing digits were detected on the right and left feet in a 6-year-old female cynomolgus macaque from a routine toxicology study. Grossly, these masses were composed of variably sized and firm nodules containing white, chalklike material in the subcutaneous tissue on cross section. Microscopically, the nodules were composed of irregular lobules containing amorphous to granular, light to dark basophilic material that was surrounded by macrophages and multinucleated giant cells and separated by fibrous connective tissue. The nodules contents were von Kossa and Alizarin red S positive. Serum calcium and phosphorus levels of this monkey were within normal ranges. Based on the gross pathology, histopathology, serum chemistry, and histochemistry, a diagnosis of dystrophic calcinosis circumscripta was made. Dystrophic calcinosis circumscripta is an uncommon syndrome of mineralization that occurs following tissue damage, without abnormalities in calcium and phosphorus homeostasis, and it is characterized by deposition of calcium salts in soft tissues. To the best of the authors knowledge, this is the first report of dystrophic calcinosis circumscripta in a cynomolgus macaque. Copyright © 2010 by The Author(s).

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