Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor.

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Effects of Nesting Material on the Toxicologic Assessment of Cyclophosphamide in Crl:CD1(ICR) Mice.

The provision of nesting material benefits mice by reducing cold stress, improving feed conversion, increasing litter size, and improving adaptive immunity. The effects of toxins are sensitive to environmental changes, and the introduction of novel items can alter results in some toxicologic studies. We hypothesized that nesting material would reduce stress and positively alter immunologic parameters in Crl:CD1(ICR) mice, thus changing typical results from a well-studied immunomodulating drug, cyclophosphamide. A 13-wk study assessed the following treatments in a factorial design (n = 4; 32 cages total): nesting (0 or 10 g) and drug (50 mg/kg cyclophosphamide or 10 mL/kg saline; IP weekly). Detailed examinations and body weights were recorded weekly, and nests were scored twice weekly. Fecal pellets were collected at 0, 4, 6, and 12 wk for analysis of corticosterone metabolites. At study termination, clinical pathology and immune parameters were collected, a necropsy performed, and lymphoid organs and adrenal glands were submitted for histopathology. All expected results due to cyclophosphamide were observed. Nesting reduced the proportion of mice with piloerection, and body weights were highest in saline-nested male mice. No differences in hematology, clinical chemistry, or absolute lymphocyte counts were observed. Corticosterone metabolites in all nested groups were not different from baseline levels but all nonnested groups had higher levels than baseline. Nested cyclophosphamide-treated groups had significantly lower corticosterone levels than nonnested cyclophosphamide-treated groups. This study illustrates that nesting material does not alter the results of a standard toxicology study of cyclophosphamide but alleviates study-related stress and improves mouse welfare.

Proportional mortality: A study of 152 goats submitted for necropsy from 13 goat herds in Quebec, with a special focus on caseous lymphadenitis.

The objectives of this study were to determine the main causes of mortality, with a special focus on caseous lymphadenits as a cause of death or wasting in caprine herds from Quebec. Goats (n = 152) from 13 herds were submitted for necropsy; the cause of mortality, and the presence, location, and cause of abscesses (if present) were recorded. Proportional mortalities were distributed as: Clostridium perfringens type D enterotoxemia (17.1%), pneumonia (13.8%), paratuberculosis (10.5%), listeriosis (6.6%), pregnancy toxemia (5.3%), caprine arthritis-encephalitis (4.6%), and caseous lymphadenitis (3.9%). Caseous lymphadenitis was diagnosed in 24.3% of the submitted goats, but was not a major cause of wasting or mortality. Abscesses were localized internally in 54.1% of the cases. Paratuberculosis was diagnosed in 29 goats (16 as cause of death) and was considered a major cause of wasting and/or mortality.

Mortalité proportionnelle: Une étude de 152 chèvres soumises pour nécropsie provenant de 13 élevages caprins du Québec, avec une attention particulière à la lymphadénite caséeuse. Les objectifs de cette étude furent de déterminer les principales causes de mortalité avec une attention particulière à la lymphadénite caséeuse comme cause de mortalité ou de dépérissement chez les chèvres du Québec. Cent-cinquante-deux chèvres provenant de 13 élevages différents ont été soumises pour nécropsie; la cause de mortalité, la présence d'abcès, leur localisation et leur cause (s'il y a lieu) furent compilées. Les mortalités proportionnelles furent distribuées ainsi : entérotoxémie de type D (17,1 %), pneumonie (13,8 %), paratuberculose (10,5 %), listériose (6,6 %), toxémie de gestation (5,3 %), arthrite-encéphalite caprine (4,6 %) et lymphadénite caséeuse (3,9 %). La lymphadénite caséeuse a été diagnostiquée chez 24,3 % des chèvres soumises, mais sans être une cause majeure de dépérissement et de mortalité. Les abcès étaient localisés de façon interne dans 54,1 % des cas. Au total, la paratuberculose a été diagnostiquée chez 29 chèvres (16 en étant décédées) et fut considérée comme une cause majeure de dépérissement et/ou de mortalité.(Traduit par les auteurs).